International Studies in Dementia With Particular Emphasis on Populations of African Origin

PubMed Central

Hendrie, Hugh C.; Murrell, Jill; Gao, Sujuan; Unverzagt, Fredrick W.; Ogunniyi, Adesola; Hall, Kathleen S.

2011-01-01

Epidemiologic studies on dementia generally have 2 major interacting objectives: descriptive, where rates of dementia and Alzheimer Disease (AD) are calculated for communities and selected populations, and analytic, which attempt to explain the observed phenotypic variations in communities and populations by identifying disease risk factors. The public health benefits derived from descriptive studies are exemplified by the recent published review of the global prevalence of dementia under the auspices of Alzheimer Disease International. This review emphasized the enormous and growing burden associated with dementia particularly for countries in the developing world and outlined strategies to influence policy making, planning, and healthcare allocation. One interesting feature of descriptive studies on dementia is that although the few epidemiologic studies conducted in Africa suggest that rates of dementia and AD are relatively low, rates of AD and dementia have been reported to be relatively high for African Americans. The Indianapolis-Ibadan Dementia Project has reported that the incidence rates for AD and dementia in Yoruba are less than half the incidence rates for AD and dementia in African Americans. Analytic studies are now underway to identify risk factors that may account for these rate differences. The risk factor model being applied, attempts to identify not only putative genetic and environmental factors but also their interactions. So far the major findings have included: apolipoprotein E e4, a major risk factor for AD in most populations, is also a risk factor for AD in African Americans but not for Yoruba; African Americans are at higher risk not only for AD, but also for diseases associated with increased cardiovascular risk such as hypertension, diabetes, and metabolic syndrome; African Americans have higher rates of hypercholesterolemia than Yoruba: there is an interaction between apolipoprotein E e4, cholesterol, and AD risk in both Yoruba and African Americans. We eventually hope to create a risk factor model that will not only account for the dementia rate differences between Yoruba and African Americans, but also help explain dementia rates in other developing and developed countries. PMID:16917194

International studies in dementia with particular emphasis on populations of African origin.

PubMed

Hendrie, Hugh C; Murrell, Jill; Gao, Sujuan; Unverzagt, Fredrick W; Ogunniyi, Adesola; Hall, Kathleen S

2006-01-01

Epidemiologic studies on dementia generally have 2 major interacting objectives: descriptive, where rates of dementia and Alzheimer Disease (AD) are calculated for communities and selected populations, and analytic, which attempt to explain the observed phenotypic variations in communities and populations by identifying disease risk factors. The public health benefits derived from descriptive studies are exemplified by the recent published review of the global prevalence of dementia under the auspices of Alzheimer Disease International. This review emphasized the enormous and growing burden associated with dementia particularly for countries in the developing world and outlined strategies to influence policy making, planning, and healthcare allocation. One interesting feature of descriptive studies on dementia is that although the few epidemiologic studies conducted in Africa suggest that rates of dementia and AD are relatively low, rates of AD and dementia have been reported to be relatively high for African Americans. The Indianapolis-Ibadan Dementia Project has reported that the incidence rates for AD and dementia in Yoruba are less than half the incidence rates for AD and dementia in African Americans. Analytic studies are now underway to identify risk factors that may account for these rate differences. The risk factor model being applied, attempts to identify not only putative genetic and environmental factors but also their interactions. So far the major findings have included: apolipoprotein E e4, a major risk factor for AD in most populations, is also a risk factor for AD in African Americans but not for Yoruba; African Americans are at higher risk not only for AD, but also for diseases associated with increased cardiovascular risk such as hypertension, diabetes, and metabolic syndrome; African Americans have higher rates of hypercholesterolemia than Yoruba: there is an interaction between apolipoprotein E e4, cholesterol, and AD risk in both Yoruba and African Americans. We eventually hope to create a risk factor model that will not only account for the dementia rate differences between Yoruba and African Americans, but also help explain dementia rates in other developing and developed countries.

Atopic dermatitis and risk factors in poor children from Great Buenos Aires, Argentina.

PubMed

Dei-Cas, I; Dei-Cas, P; Acuña, K

2009-04-01

In recent decades, the prevalence of atopic dermatitis (AD) has risen steadily, and risk factors for AD are currently being investigated worldwide. In Argentina, there are no available data on risk factors of AD. To determine the prevalence of and any gender predilection for AD, and to identify familial and environmental factors that are associated with increased AD risk. In this case-control cross sectional study, 603 children aged 12-60 months old from a poor urban community in Buenos Aires were recruited. AD was defined following UK Working Party Diagnostic Criteria. We evaluated the relationship between AD and the presence of family history of atopy, > 5 family members, wearing synthetic clothes, having a carpeted room, eating > or = 3 eggs/week, tobacco smoking indoors by family members, and living< 300 m from a main road, polluted stream or industry. The prevalence of AD was 41.1% (95% CI 37.2-45.2%). Logistic regression analysis showed that AD was significantly associated only with a family history of atopy (OR = 5.7; 95% CI 3.7-8.8%; P = 0.0000), wearing synthetic clothes (OR = 2.2; 95% CI 1.4-3.5; P = 0.0009), having a carpeted room OR = 1.9; 95% CI 1.2-3.0%; P = 0.009) and living < 300 m from an industry (OR = 1.93; 95% CI 1.2-3.1%; P = 0.0051). We found a high prevalence of AD in our study population. Not all the investigated risk factors for AD had a significant association with the disease.

Nature Versus Nurture: Does Proteostasis Imbalance Underlie the Genetic, Environmental, and Age-Related Risk Factors for Alzheimer's Disease?

PubMed

Kikis, Elise A

2017-08-22

Aging is a risk factor for a number of "age-related diseases", including Alzheimer's disease (AD). AD affects more than a third of all people over the age of 85, and is the leading cause of dementia worldwide. Symptoms include forgetfulness, memory loss, and cognitive decline, ultimately resulting in the need for full-time care. While there is no cure for AD, pharmacological approaches to alleviate symptoms and target underlying causes of the disease have been developed, albeit with limited success. This review presents the age-related, genetic, and environmental risk factors for AD and proposes a hypothesis for the mechanistic link between genetics and the environment. In short, much is known about the genetics of early-onset familial AD (EO-FAD) and the central role played by the Aβ peptide and protein misfolding, but late-onset AD (LOAD) is not thought to have direct genetic causes. Nonetheless, genetic risk factors such as isoforms of the protein ApoE have been identified. Additional findings suggest that air pollution caused by the combustion of fossil fuels may be an important environmental risk factor for AD. A hypothesis suggesting that poor air quality might act by disrupting protein folding homeostasis (proteostasis) is presented.

Screening of Early and Late Onset Alzheimer's Disease Genetic Risk Factors in a Cohort of Dementia Patients from Liguria, Italy.

PubMed

Ferrari, Raffaele; Ferrara, Michela; Alinani, Anwar; Sutton, Roger Brian; Famà, Francesco; Picco, Agnese; Rodriguez, Guido; Nobili, Flavio; Momeni, Parastoo

2015-01-01

Cohorts from a defined geographical area enable ad hoc genotype-phenotype correlation studies providing novel and unique insight into disease. We analysed genetic risk factors associated with early and late onset Alzheimer's disease (EOAD and LOAD) in a population from Liguria (northern Italy), as part of an ongoing longitudinal study. We screened 37 AD, 8 mild cognitive impairment (MCI), 3 AD and CVD (cerebrovascular disease), 3 MCI and CVD, 8 frontotemporal dementia (FTD) and 2 progressive supranuclear palsy (PSP) patients, and 28 normal controls (NCs).We sequenced PSEN1, PSEN2 and APP (EOAD risk factors), as well as MAPT, GRN and TARDBP for all cases and NCs, and analysed the APOE, CLU, CR1 and PICALM genotypes as well as the MAPT and ACE haplotypes (LOAD risk factors) for the AD (n = 37) and AD + MCI (n = 45) cases and NCs (n = 28).We identified variants in PSEN1, PSEN2 and TARDBP across a range of phenotypes (AD, AD and CVD, FTD and PSP), suggesting that screening of all known candidate genes of Alzheimer's and non-Alzheimer's forms of dementias in all dementia cases might be warranted. The analysis of the LOAD risk factors revealed no association with AD or AD + MCI status after Bonferroni correction. Lack of association with APOE is supported by previous studies in the Italian population. Our data also evidenced: 1) a potentially protective haplotype at the PSEN2 locus; 2) a nominal association with the GWAS-risk allele A for rs3818361 in CR1 and; 3) a threefold prevalence of AD in the female population compared to men.Our results will need to be further assessed and confirmed in larger cohorts from this area. 

Obesity and Sex Interact in the Regulation of Alzheimer’s Disease

PubMed Central

Moser, V. Alexandra; Pike, Christian J.

2015-01-01

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, for which a number of genetic, environmental, and lifestyle risk factors have been identified. A significant modifiable risk factor is obesity in mid-life. Interestingly, both obesity and AD exhibit sex differences and are regulated by sex steroid hormones. Accumulating evidence suggests interactions between obesity and sex in regulation of AD risk, although the pathways underlying this relationship are unclear. Inflammation and the E4 allele of apolipoprotein E have been identified as independent risk factors for AD and both interact with obesity and sex steroid hormones. We review the individual and cooperative effects of obesity and sex on development of AD and examine the potential contributions of apolipoprotein E, inflammation, and their interactions to this relationship. PMID:26708713

Risk factors and preventive interventions for Alzheimer disease: state of the science.

PubMed

Daviglus, Martha L; Plassman, Brenda L; Pirzada, Amber; Bell, Carl C; Bowen, Phyllis E; Burke, James R; Connolly, E Sander; Dunbar-Jacob, Jacqueline M; Granieri, Evelyn C; McGarry, Kathleen; Patel, Dinesh; Trevisan, Maurizio; Williams, John W

2011-09-01

Numerous studies have investigated risk factors for Alzheimer disease (AD). However, at a recent National Institutes of Health State-of-the-Science Conference, an independent panel found insufficient evidence to support the association of any modifiable factor with risk of cognitive decline or AD. To present key findings for selected factors and AD risk that led the panel to their conclusion. An evidence report was commissioned by the Agency for Healthcare Research and Quality. It included English-language publications in MEDLINE and the Cochrane Database of Systematic Reviews from 1984 through October 27, 2009. Expert presentations and public discussions were considered. Study inclusion criteria for the evidence report were participants aged 50 years and older from general populations in developed countries; minimum sample sizes of 300 for cohort studies and 50 for randomized controlled trials; at least 2 years between exposure and outcome assessment; and use of well-accepted diagnostic criteria for AD. Included studies were evaluated for eligibility and data were abstracted. Quality of overall evidence for each factor was summarized as low, moderate, or high. Diabetes mellitus, hyperlipidemia in midlife, and current tobacco use were associated with increased risk of AD, and Mediterranean-type diet, folic acid intake, low or moderate alcohol intake, cognitive activities, and physical activity were associated with decreased risk. The quality of evidence was low for all of these associations. Currently, insufficient evidence exists to draw firm conclusions on the association of any modifiable factors with risk of AD.

Investigation of possible risk factors for depression in Alzheimer's disease: A systematic review of the evidence.

PubMed

Steck, Natassa; Cooper, Claudia; Orgeta, Vasiliki

2018-08-15

Depression is common in people with Alzheimer's disease (AD), and is associated with increased risk of institutionalization and mortality. Understanding risk factors for depression in AD is key to its development and treatment. We searched the MEDLINE, EMBASE, PsycINFO, and CINAL databases for longitudinal prospective cohort studies that evaluated risk factors for depression in people with AD. Two authors independently selected articles for inclusion and assessed quality of studies using predetermined criteria. In seven studies that met the inclusion criteria, 2029 participants were followed up for a median of 5 years. Gender and educational attainment were not predictors of depression risk. History of a past psychiatric disorder and greater cognitive impairment predicted increased risk of depression in more than one study. In single studies, younger age, having a family history of psychiatric disorder, neuroticism, functional decline, presence of sleep disturbance and aggression, and increased cardiovascular risk predicted depression risk. Not being within 6 months of dementia onset and, counterintuitively having two comorbid disorders were protective factors in one study. A small number of studies exist overall and only a few have examined the same risk factors. Most of the studies have measured depression using scales that are not validated in AD. These results inform a preliminary model of depression risk in people with AD. Unlike in the general population, men and women and those with higher and lower educational levels of attainment may be equally at risk of depression. Clinicians should be aware of these possible differences in the risk profile for depression in AD populations, to assist detection and enable early treatment. Interventions to delay cognitive and functional decline may reduce depression risk. Copyright © 2018 Elsevier B.V. All rights reserved.

Menopause, obesity and inflammation: interactive risk factors for Alzheimer’s disease

PubMed Central

Christensen, Amy; Pike, Christian J.

2015-01-01

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder, the development of which is regulated by several environmental and genetic risk factors. Two factors theorized to contribute to the initiation and/or progression of AD pathogenesis are age-related increases in inflammation and obesity. These factors may be particularly problematic in women. The onset of menopause in mid-life elevates the vulnerability of women to AD, an increased risk that is likely associated with the depletion of estrogens. Menopause is also linked with an abundance of additional changes, including increased central adiposity and inflammation. Here, we review the current literature to explore the interactions between obesity, inflammation, menopause and AD. PMID:26217222

Cardiovascular risk factors and dementia.

PubMed

Fillit, Howard; Nash, David T; Rundek, Tatjana; Zuckerman, Andrea

2008-06-01

Dementias, such as Alzheimer's disease (AD) and vascular dementia, are disorders of aging populations and represent a significant economic burden. Evidence is accumulating to suggest that cardiovascular disease (CVD) risk factors may be instrumental in the development of dementia. The goal of this review was to discuss the relationship between specific CVD risk factors and dementia and how current treatment strategies for dementia should focus on reducing CVD risks. We conducted a review of the literature for the simultaneous presence of 2 major topics, cardiovascular risk factors and dementia (eg, AD). Special emphasis was placed on clinical outcome studies examining the effects of treatments of pharmacologically modifiable CVD risk factors on dementia and cognitive impairment. Lifestyle risk factors for CVD, such as obesity, lack of exercise, smoking, and certain psychosocial factors, have been associated with an increased risk of cognitive decline and dementia. Some evidence suggests that effectively managing these factors may prevent cognitive decline/dementia. Randomized, placebo-controlled trials of antihypertensive medications have found that such therapy may reduce the risk of cognitive decline, and limited data suggest a benefit for patients with AD. Some small open-label and randomized clinical trials of statins have observed positive effects on cognitive function; larger studies of statins in patients with AD are ongoing. Although more research is needed, current evidence indicates an association between CVD risk factors--such as hypertension, dyslipidemia, and diabetes mellitus--and cognitive decline/dementia. From a clinical perspective, these data further support the rationale for physicians to provide effective management of CVD risk factors and for patients to be compliant with such recommendations to possibly prevent cognitive decline/dementia.

High blood pressure, Alzheimer disease and antihypertensive treatment.

PubMed

Marfany, Agustí; Sierra, Cristina; Camafort, Miguel; Doménech, Mónica; Coca, Antonio

2018-03-01

Alzheimer's disease (AD), the most common form of dementia, is a complex disease, the mechanisms of which are poorly understood. AD represents 70% of all dementia cases, affecting up to 50% of elderly persons aged 85 or older, with functional dependence, poor quality of life, institutionalization and mortality. Advanced age is the main risk factor of AD, that is why population ageing, due to life expectancy improvements, increases AD incidence and prevalence, as well as the economic, social, and emotional costs associated with this illness. Existing anti-AD drugs present some limitations, as they target specific downstream neurochemical abnormalities while the upstream underlying pathology continues unchecked. Chronic hypertension has been suggested as one of the largest modifiable risk factors for developing AD. At least 25% of all adults and more than 50% of those over 60 years of age have hypertension. Epidemiological studies have shown that hypertension is a risk factor for dementia and AD, but the association is complex. Some studies have demonstrated that antihypertensive drugs can reduce the risk of AD. This review focuses on current knowledge about the relationship between chronic hypertension and AD as well as antihypertensive treatment effect on AD pathogenesis and its clinical outcomes.

Socioeconomic factors, rather than diabetes mellitus per se, contribute to an excessive use of antidepressants among young adults with childhood onset type 1 diabetes mellitus: a register-based study.

PubMed

Lind, T; Waernbaum, I; Berhan, Y; Dahlquist, G

2012-03-01

Mood disorders, including depression, are suggested to be prevalent in persons with type 1 diabetes and may negatively affect self-management and glycaemic control and increase the risk of diabetic complications. The aim of this study was to analyse the prevalence of antidepressant (AD) use in adults with childhood onset type 1 diabetes and to compare risk determinants for AD prescription among diabetic patients and a group of matched controls. Young adults ≥ 18 years on 1 January 2006 with type 1 diabetes (n = 7,411) were retrieved from the population-based Swedish Childhood Diabetes Registry (SCDR) and compared with 30,043 age- and community-matched controls. Individual level data were collected from the Swedish National Drug Register (NDR), the Hospital Discharge Register (HDR) and the Labor Market Research database (LMR). ADs were prescribed to 9.5% and 6.8% of the type 1 diabetes and control subjects, respectively. Female sex, having received economic or other social support, or having a disability pension were the factors with the strongest association with AD prescription in both groups. Type 1 diabetes was associated with a 44% (OR 1.44, 95% CI 1.32, 1.58) higher risk of being prescribed ADs in crude analysis. When adjusting for potential confounders including sex, age and various socioeconomic risk factors, this risk increase was statistically non-significant (OR 1.11, 95% CI 0.99, 1.21). The risk factor patterns for AD use are similar among type 1 diabetic patients and controls, and socioeconomic risk factors, rather than the diabetes per se, contribute to the increased risk of AD use in young adults with type 1 diabetes.

Sex differences in chronic stress responses and Alzheimer's disease.

PubMed

Yan, Yan; Dominguez, Sky; Fisher, Daniel W; Dong, Hongxin

2018-02-01

Clinical studies indicate that Alzheimer's disease (AD) disproportionately affects women in both disease prevalence and severity, but the mechanisms underlying this sex divergence are unknown. Though some have suggested this difference in risk is a reflection of known differences in longevity between men and women, mounting clinical and preclinical evidence supports women also having intrinsic susceptibilities towards the disease. While a number of potential risk factors have been hypothesized to affect these differences in risks, none have been definitively verified. In this review, we discuss a novel hypothesis whereby women's susceptibility to chronic stress also mediates increased risk for AD. As stress is a risk factor for AD, and women are twice as likely to develop mood disorders where stress is a major etiology, it is possible that sex dimorphisms in stress responses contribute to the increase in women with AD. In line with this, sex divergence in biochemical responses to stress have been noted along the hypothalamic-pituitary-adrenal (HPA) axis and among known molecular effectors of AD, with crosstalk between these processes also being likely. In addition, activation of the cortical corticotrophin-releasing factor receptor 1 (CRF1) signaling pathway leads to distinct female-biased increases in molecules associated with AD pathogenesis. Therefore, the different biochemical responses to stress between women and men may represent an intrinsic, sex-dependent risk factor for AD.

Prevalence of Dementia and Main Subtypes in Rural Northern China

PubMed Central

Ji, Yong; Shi, Zhihong; Zhang, Ying; Liu, Shuling; Liu, Shuai; Yue, Wei; Liu, Mengyuan; Huo, Ya Ruth; Wang, Jinhuan; Wisniewski, Thomas

2016-01-01

Background/Aims The aim of this article was to estimate the prevalence of and to determine the sociodemographic risk factors for dementia, Alzheimer’s disease (AD) and vascular dementia (VaD) among individuals residing in rural northern China. Methods Between 2011 and 2012, residents aged ≥ 60 years and residing in rural areas of northern China were clinically assessed for symptoms of dementia, AD and VaD. Diagnoses were made using established criteria and standard procedures. Results Among 5,578 enrolled study participants aged ≥ 60 years, the prevalence rates of dementia, AD and VaD were 7.7, 5.4 and 1.7%, respectively. Older age (OR = 1.17; 95% CI: 1.14–1.19) and female gender (OR = 2.13; 95% CI: 1.51–3.00) were identified as independent risk factors for AD. In turn, a higher educational level (OR = 0.36; 95% CI: 0.21–0.60) and engagement in social activities (OR = 0.219; 95% CI: 0.163–0.295) were protective factors. Risk factors associated with VaD were older age (OR = 1.11; 95% CI: 1.1– 1.12) and hypertension (OR = 1.83; 95% CI: 1.18–2.86), while a higher educational level (OR = 0.53, 95% CI: 0.44–0.65) and engagement in social activities (OR = 0.34; 95% CI: 0.29–0.41) were protective factors. Conclusion High rates of dementia (7.7%) and AD (5.4%) were found in the rural areas of northern China. Older age and female gender were identified as risk factors for AD, while older age and hypertension were risk factors for VaD. A higher educational level and engagement in social activities were identified as protective factors against both AD and VaD. PMID:25792116

Risk profiles for aortic dissection and ruptured or surgically treated aneurysms: a prospective cohort study.

PubMed

Landenhed, Maya; Engström, Gunnar; Gottsäter, Anders; Caulfield, Michael P; Hedblad, Bo; Newton-Cheh, Christopher; Melander, Olle; Smith, J Gustav

2015-01-21

Community screening to guide preventive interventions for acute aortic disease has been recommended in high-risk individuals. We sought to prospectively assess risk factors in the general population for aortic dissection (AD) and severe aneurysmal disease in the thoracic and abdominal aorta. We studied the incidence of AD and ruptured or surgically treated aneurysms in the abdominal (AAA) or thoracic aorta (TAA) in 30 412 individuals without diagnosis of aortic disease at baseline from a contemporary, prospective cohort of middle-aged individuals, the Malmö Diet and Cancer study. During up to 20 years of follow-up (median 16 years), the incidence rate per 100 000 patient-years at risk was 15 (95% CI 11.7 to 18.9) for AD, 27 (95% CI 22.5 to 32.1) for AAA, and 9 (95% CI 6.8 to 12.6) for TAA. The acute and in-hospital mortality was 39% for AD, 34% for ruptured AAA, and 41% for ruptured TAA. Hypertension was present in 86% of individuals who subsequently developed AD, was strongly associated with incident AD (hazard ratio [HR] 2.64, 95% CI 1.33 to 5.25), and conferred a population-attributable risk of 54%. Hypertension was also a risk factor for AAA with a smaller effect. Smoking (HR 5.07, 95% CI 3.52 to 7.29) and high apolipoprotein B/A1 ratio (HR 2.48, 95% CI 1.73 to 3.54) were strongly associated with AAA and conferred a population-attributable risk of 47% and 25%, respectively. Smoking was also a risk factor for AD and TAA with smaller effects. This large prospective study identified distinct risk factor profiles for different aortic diseases in the general population. Hypertension accounted for more than half of the population risk for AD, and smoking for half of the population risk of AAA. © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

The relationship of cardiovascular risk factors to Alzheimer disease in Choctaw Indians.

PubMed

Weiner, Myron F; Hynan, Linda S; Rossetti, Heidi; Womack, Kyle B; Rosenberg, Roger N; Gong, Yun-Hua; Qu, Bao-Xi

2011-05-01

To test the hypothesis that cardiovascular risk factors (CRFs) influence predisposition to and the clinical course of Alzheimer disease (AD), the authors compared Choctaw Indians, a group with known high CRF with white persons with AD. In addition to CRF history, the authors investigated the frequency of apolipoprotein E4 (apoE4) genotype andplasma homocysteine (HC) levels. The authors compared 39 Choctaw Indians with AD and 39 Choctaw Indians without AD to 39 white persons with AD with all groups similar in age. CRF history included diabetes, hypertension, high cholesterol or hypolipidemic agent use, or myocardial infarction. The authors also compared plasma HC concentration and apoE4 allele frequency. Choctaw persons with AD differed significantly from white persons with AD in history of hypertension, diabetes, and in HC values but not from Indians without AD. There was a significantly lower apoE4 allele frequency in Choctaw Indian AD than white persons with AD, and both AD groups had an affected first degree relative significantly more often than Indian controls. There was no relationship between the number of CRF and age at onset among Indians or whites, whereas HC concentration was associated with significantly earlier age of onset for Choctaw Indians but not for whites. This small study suggests that in Choctaw Indians modifiable risk factors may play more of a role in disease pathogenesis than in whites and that nonmodifiable risk factors such as apoE4 may play less of a role.

Association between Diabetes and Risk of Aortic Dissection: A Case-Control Study in a Chinese Population.

PubMed

He, Xingwei; Liu, Xintian; Liu, Wanjun; Wang, Bei; Liu, Yujian; Li, Zhuxi; Wang, Tao; Tan, Rong; Gao, Bo; Zeng, Hesong

2015-01-01

It is well-recognized that diabetes represents a powerful independent risk factor for cardiovascular diseases. However, very few studies have investigated the relationship between diabetes and risk of aortic dissection (AD). The aim of this case-control study was to evaluate the association between diabetes and risk of AD in Chinese population. A hospital-based case-control study, consisting of 2160 AD patients and 4320 controls, was conducted in a Chinese population. Demographic, clinical characteristics and risk factors were collected. Diabetes rate of patients with overall AD, Stanford type A AD and type B AD group was compared with that of corresponding matched control groups. Logistic regression analysis was used to estimate the odds ratios (OR) and 95% confidence intervals (95% CI) for relationship between diabetes and AD risk. The prevalence of diabetes was lower in AD cases than that of control subjects, whether it is the overall AD, type A AD or type B AD group (4.7% vs. 10.0%, 2.9% vs. 8.8%, 5.9% vs. 10.9%, all P<0.001). Furthermore, in multivariate model, diabetes was found to be associated with lower AD risk, which not only applies to the overall AD (OR = 0.2, 95%CI: 0.15-0.26), but also type A AD (OR = 0.12, 95% CI: 0.07-0.20) and type B AD (OR = 0.25, 95%CI: 0.18-0.33). We observed the paradoxical inverse relationship between DM and risk of AD in the Chinese population. These results suggest diabetes may play a protective role in the development of AD. However, further studies are needed to enrich related evidence, especially with regard to underlying mechanisms for these trends.

Neuropsychiatric symptoms as risk factors for progression from CIND to dementia: the Cache County Study.

PubMed

Peters, M E; Rosenberg, P B; Steinberg, M; Norton, M C; Welsh-Bohmer, K A; Hayden, K M; Breitner, J; Tschanz, J T; Lyketsos, C G

2013-11-01

To examine the association of neuropsychiatric symptom (NPS) severity with risk of transition to all-cause dementia, Alzheimer disease (AD), and vascular dementia (VaD). Survival analysis of time to dementia, AD, or VaD onset. Population-based study. 230 participants diagnosed with cognitive impairment, no dementia (CIND) from the Cache County Study of Memory Health and Aging were followed for a mean of 3.3 years. The Neuropsychiatric Inventory (NPI) was used to quantify the presence, frequency, and severity of NPS. Chi-squared statistics, t-tests, and Cox proportional hazard ratios were used to assess associations. The conversion rate from CIND to all-cause dementia was 12% per year, with risk factors including an APOE ε4 allele, lower Mini-Mental State Examination, lower 3MS, and higher CDR sum-of-boxes. The presence of at least one NPS was a risk factor for all-cause dementia, as was the presence of NPS with mild severity. Nighttime behaviors were a risk factor for all-cause dementia and of AD, whereas hallucinations were a risk factor for VaD. These data confirm that NPS are risk factors for conversion from CIND to dementia. Of special interest is that even NPS of mild severity are a risk for all-cause dementia or AD. Copyright © 2013 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.

Neuropsychiatric symptoms as risk factors for progression from CIND to dementia: The Cache County Study

PubMed Central

Peters, ME; Rosenberg, PB; Steinberg, M; Norton, MC; Welsh-Bohmer, KA; Hayden, KM; Breitner, J; Tschanz, JT; CG, Lyketsos

2012-01-01

Objectives To examine the association of neuropsychiatric symptom (NPS) severity with risk of transition to all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VaD). Design Survival analysis of time to dementia, AD, or VaD onset. Setting Population-based study. Participants 230 participants diagnosed with cognitive impairment, no dementia (CIND) from the Cache County Study of Memory Health and Aging were followed for a mean of 3.3 years. Measurements The Neuropsychiatric Inventory (NPI) was used to quantify the presence, frequency, and severity of NPS. Chi-square statistics, t-tests, and Cox proportional hazard ratios were used to assess associations. Results The conversion rate from CIND to all-cause dementia was 12% per year, with risk factors including an APOE ε4 allele, lower MMSE, lower 3MS, and higher CDR sum-of-boxes. The presence of at least one NPS was a risk factor for all-cause dementia, as was the presence of NPS with mild severity. Nighttime behaviors were a risk factor for all-cause dementia and of AD, while hallucinations were a risk factor for VaD. Conclusions These data confirm that NPS are risk factors for conversion from CIND to dementia. Of special interest is that even NPS of mild severity are a risk for all-cause dementia or AD. PMID:23567370

Mechanisms of Risk Reduction in the Clinical Practice of Alzheimer’s Disease Prevention

PubMed Central

Schelke, Matthew W.; Attia, Peter; Palenchar, Daniel J.; Kaplan, Bob; Mureb, Monica; Ganzer, Christine A.; Scheyer, Olivia; Rahman, Aneela; Kachko, Robert; Krikorian, Robert; Mosconi, Lisa; Isaacson, Richard S.

2018-01-01

Alzheimer’s disease (AD) is a neurodegenerative dementia that affects nearly 50 million people worldwide and is a major source of morbidity, mortality, and healthcare expenditure. While there have been many attempts to develop disease-modifying therapies for late-onset AD, none have so far shown efficacy in humans. However, the long latency between the initial neuronal changes and onset of symptoms, the ability to identify patients at risk based on family history and genetic markers, and the emergence of AD biomarkers for preclinical disease suggests that early risk-reducing interventions may be able to decrease the incidence of, delay or prevent AD. In this review, we discuss six mechanisms—dysregulation of glucose metabolism, inflammation, oxidative stress, trophic factor release, amyloid burden, and calcium toxicity—involved in AD pathogenesis that offer promising targets for risk-reducing interventions. In addition, we offer a blueprint for a multi-modality AD risk reduction program that can be clinically implemented with the current state of knowledge. Focused risk reduction aimed at particular pathological factors may transform AD to a preventable disorder in select cases. PMID:29706884

Mechanisms of Risk Reduction in the Clinical Practice of Alzheimer's Disease Prevention.

PubMed

Schelke, Matthew W; Attia, Peter; Palenchar, Daniel J; Kaplan, Bob; Mureb, Monica; Ganzer, Christine A; Scheyer, Olivia; Rahman, Aneela; Kachko, Robert; Krikorian, Robert; Mosconi, Lisa; Isaacson, Richard S

2018-01-01

Alzheimer's disease (AD) is a neurodegenerative dementia that affects nearly 50 million people worldwide and is a major source of morbidity, mortality, and healthcare expenditure. While there have been many attempts to develop disease-modifying therapies for late-onset AD, none have so far shown efficacy in humans. However, the long latency between the initial neuronal changes and onset of symptoms, the ability to identify patients at risk based on family history and genetic markers, and the emergence of AD biomarkers for preclinical disease suggests that early risk-reducing interventions may be able to decrease the incidence of, delay or prevent AD. In this review, we discuss six mechanisms-dysregulation of glucose metabolism, inflammation, oxidative stress, trophic factor release, amyloid burden, and calcium toxicity-involved in AD pathogenesis that offer promising targets for risk-reducing interventions. In addition, we offer a blueprint for a multi-modality AD risk reduction program that can be clinically implemented with the current state of knowledge. Focused risk reduction aimed at particular pathological factors may transform AD to a preventable disorder in select cases.

Is family history of alcohol dependence a risk factor for disturbed sleep in alcohol dependent subjects?

PubMed

Chakravorty, Subhajit; Chaudhary, Ninad S; Morales, Knashawn; Grandner, Michael A; Oslin, David W

2018-07-01

Disturbed sleep and a family history of alcohol dependence (AD) are risk factors for developing AD, yet the underlying relationship between them is unclear among individuals with AD. Understanding these inherited associations will help us not only identify risk for development of these comorbid disorders, but also individualize treatment at this interface. We evaluated whether a first-degree family history of AD (FH+) was a risk factor for sleep continuity disturbance in patients with AD. We also evaluated whether alcohol use or mood disturbance moderated the relationship between FH and sleep. We analyzed cross-sectional baseline data from an alcohol clinical trial in a sample of individuals with AD (N = 280). Their family history of AD among nuclear family members, sleep complaints, alcohol use (over the last 90 days), and mood disturbance were assessed using the Family History Interview for Substance and Mood Disorders, Medical Outcomes Study Sleep Scale, Time Line Follow-Back Interview, and Profile of Mood States-Short Form, respectively. A FH + status (65% of subjects) was significantly associated with lower model estimated mean sleep adequacy (β = - 7.05, p = 0.02) and sleep duration (β = - 0.38, p = 0.04) scale scores. FH was not associated with sleep disturbance scale. No significant moderating effect involving alcohol use or mood disturbance was seen. Family history of AD is a unique risk factor for sleep complaints in AD. Non-restorative sleep and sleep duration may be noteworthy phenotypes to help probe for underlying genotypic polymorphisms in these comorbid disorders. Published by Elsevier B.V.

Alzheimer biomarkers and clinical Alzheimer disease were not associated with increased cerebrovascular disease in a memory clinic population.

PubMed

Spies, Petra E; Verbeek, Marcel M; Sjogren, Magnus J C; de Leeuw, Frank-Erik; Claassen, Jurgen A H R

2014-01-01

Preclinical and post-mortem studies suggest that Alzheimer disease (AD) causes cerebrovascular dysfunction, and therefore may enhance susceptibility to cerebrovascular disease (CVD). The objective of this study was to investigate this association in a memory clinic population. The AD biomarkers CSF amyloid β42, amyloid β40 and APOE-ε4 status have all been linked to increased CVD risk in AD, and therefore the first aim of this study was to analyze the association between these biomarkers and CVD. In 92 memory clinic patients the cross-sectional association between AD biomarkersand the severity of CVD was investigated with linear regression analysis. Additionally, we studied whether AD biomarkers modified the relation between vascular risk factors and CVD. CVD was assessed on MRI through a visual rating scale.Analyses were adjusted for age. The second aim of this study was to investigate the association between clinical AD and CVD, where 'clinical AD' was defined as follows: impairment in episodic memory, hippocampal atrophy and an aberrant concentration of cerebrospinal fluid (CSF) biomarkers. 47 of the 92 patients had AD. No association between CSF amyloid β42, amyloid β40 or APOE-ε4 status and CVD severity was found, nor did these AD biomarkers modify the relation between vascular risk factors and CVD. Clinical AD was not associated with CVD severity (p=0.83). Patients with more vascular risk factors had more CVD, but this relationship was not convincingly modified by AD (p=0.06). In this memory clinic population, CVD in patients with AD was related to vascular risk factors and age, comparable to patients without AD. Therefore, in our study, the preclinical and post-mortem evidence that AD would predispose to CVD could not be translated clinically. Further work, including replication of this work in a different and larger sample, is warranted.

Organic Solvents as Risk Factor for Autoimmune Diseases: A Systematic Review and Meta-Analysis

PubMed Central

Barragán-Martínez, Carolina; Speck-Hernández, Cesar A.; Montoya-Ortiz, Gladis; Mantilla, Rubén D.; Anaya, Juan-Manuel; Rojas-Villarraga, Adriana

2012-01-01

Background Genetic and epigenetic factors interacting with the environment over time are the main causes of complex diseases such as autoimmune diseases (ADs). Among the environmental factors are organic solvents (OSs), which are chemical compounds used routinely in commercial industries. Since controversy exists over whether ADs are caused by OSs, a systematic review and meta-analysis were performed to assess the association between OSs and ADs. Methods and Findings The systematic search was done in the PubMed, SCOPUS, SciELO and LILACS databases up to February 2012. Any type of study that used accepted classification criteria for ADs and had information about exposure to OSs was selected. Out of a total of 103 articles retrieved, 33 were finally included in the meta-analysis. The final odds ratios (ORs) and 95% confidence intervals (CIs) were obtained by the random effect model. A sensitivity analysis confirmed results were not sensitive to restrictions on the data included. Publication bias was trivial. Exposure to OSs was associated to systemic sclerosis, primary systemic vasculitis and multiple sclerosis individually and also to all the ADs evaluated and taken together as a single trait (OR: 1.54; 95% CI: 1.25–1.92; p-value<0.001). Conclusion Exposure to OSs is a risk factor for developing ADs. As a corollary, individuals with non-modifiable risk factors (i.e., familial autoimmunity or carrying genetic factors) should avoid any exposure to OSs in order to avoid increasing their risk of ADs. PMID:23284705

Antenatal Depression in East Asia: A Review of the Literature

PubMed Central

Schatz, David Beck; Liu, Chia-Yih

2012-01-01

This current study's goal is to summarize the literature regarding Antenatal Depression (AD) in the East Asian countries of Taiwan, China (including Hong Kong and Macau), Japan, and Korea. The main search utilized a Pub med Chinese Electronic Periodical Service (CEPS) literature review using keywords 'AD', and 'Prenatal Depression' with searches for 'Japan', 'Korea', 'Taiwan', 'Hong Kong' and Macau'. The rates of AD in East Asia appear to be relatively close to those in the Western literature, although certain studies showed slightly decreased rates. Many of the risk factors for AD were the same in the Eastern and Western literature. These risk factors included demographic factors such as younger age, smoking, low education and income, and unemployment. Other risk factors were physical symptoms such as menstrual pains and nausea. Finally, psychological factors such as a poor response to the pregnancy, poor spousal support, and poor family support were associated with AD. With regard to treatment, there were no studies examining the administration of psychotropic medications for AD. The literature from East Asia both confirmed many Western findings and made unique contributions to the literature on AD. The treatment of AD in East Asia appears to be an entity which, despite its morbidity, has not been adequately studied. PMID:22707960

A multinational study to compare prevalence of atopic dermatitis in the first year of life.

PubMed

Draaisma, Eelco; Garcia-Marcos, Luis; Mallol, Javier; Solé, Dirceu; Pérez-Fernández, Virginia; Brand, Paul L P

2015-06-01

Atopic dermatitis (AD) is common in childhood, with peak prevalence in early childhood. However, international comparisons of prevalence have focused on older children. We analysed differences in prevalence rates of AD and the associations with putative risk and protective factors, among infants in two European and two Central American countries. In 1-yr old infants participating in the International Study of Wheezing in Infants (EISL), prevalence of AD and putative risk and protective factors were assessed by a questionnaire applied to parents. For each risk/protective factor summary, odds ratios with 95% confidence intervals were calculated by means of random effects meta-analysis. Data from 9803 infants were analysed. AD prevalence varied from 10.6% (Valencia, Spain) to 28.2% (San Pedro Sula, Honduras). Average AD prevalences were lower in Europe (14.2%) than in Central America (18.2%, p < 0.01). Consistent with older children, presence of siblings decreased (OR 0.82 [0.72-0.94]), whereas family history of asthma (OR 1.32 [1.10-1.59]), rhinitis (OR 1.33 [1.14-1.54]) and atopic dermatitis (OR 2.40 [1.89-3.05]) increased the risk of infantile AD. However, gender, family size, breastfeeding and socio-economic status were not associated with AD prevalence. This study shows almost threefold differences in the prevalence of AD in infancy between countries. Risk and protective factors involved in the expression of infantile AD differ from those in older children, possibly suggesting a different pathophysiology. There is a need for additional international epidemiological surveys on AD in young children, the peak prevalence age of this condition. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Cholesterol metabolism and transport in the pathogenesis of Alzheimer's disease.

PubMed

Martins, Ian J; Berger, Tamar; Sharman, Matthew J; Verdile, Giuseppe; Fuller, Stephanie J; Martins, Ralph N

2009-12-01

Alzheimer's disease (AD) is the most common neurodegenerative disorder, affecting millions of people worldwide. Apart from age, the major risk factor identified so far for the sporadic form of AD is possession of the epsilon4 allele of apolipoprotein E (APOE), which is also a risk factor for coronary artery disease (CAD). Other apolipoproteins known to play an important role in CAD such as apolipoprotein B are now gaining attention for their role in AD as well. AD and CAD share other risk factors, such as altered cholesterol levels, particularly high levels of low density lipoproteins together with low levels of high density lipoproteins. Statins--drugs that have been used to lower cholesterol levels in CAD, have been shown to protect against AD, although the protective mechanism(s) involved are still under debate. Enzymatic production of the beta amyloid peptide, the peptide thought to play a major role in AD pathogenesis, is affected by membrane cholesterol levels. In addition, polymorphisms in several proteins and enzymes involved in cholesterol and lipoprotein transport and metabolism have been linked to risk of AD. Taken together, these findings provide strong evidence that changes in cholesterol metabolism are intimately involved in AD pathogenic processes. This paper reviews cholesterol metabolism and transport, as well as those aspects of cholesterol metabolism that have been linked with AD.

Role of Pro-Inflammatory Cytokines and Vitamin D in Probable Alzheimer's Disease with Depression

PubMed Central

Banerjee, Anindita; Khemka, Vineet Kumar; Roy, Debashree; Dhar, Aparajita; Sinha Roy, Tapan Kumar; Biswas, Atanu; Mukhopadhyay, Barun; Chakrabarti, Sasanka

2017-01-01

Symptoms of depression are present in a significant proportion of Alzheimer's disease (AD) patients. While epidemiological studies have shown a strong association between depression and AD, it has not been established whether depression is a risk factor or merely a co-morbidity of AD. It is also uncertain if depression affects the pathogenesis of AD. In this paper, we address these questions by measuring the serum levels of two common metabolic risk factors of AD and depression, inflammatory cytokines (IL 6 and TNF alpha) and serum 25-hydroxyvitamin D, in a case-control study. We measured the serum levels of IL 6, TNF α and 25-hydroxyvitamin D in age-matched healthy controls (n= 60) and in AD patients without depression (n=26) or AD patients with depression (n=34), and statistically analyzed the changes in these parameters among different groups under this study. Our results show that in AD there is a significant increase in IL 6 and TNF α and a marked decrease in 25-hydroxyvitamin D in the peripheral circulation compared to age-matched healthy controls. Furthermore, AD patients with depression have even significantly higher levels of IL 6 or TNF α and a lower level of 25-hydroxyvitamin D in circulation than in AD patients without depression. We also found a strong statistical correlation between the disease severity and the serum levels of IL 6, TNF α and 25-hydroxyvitamin D in AD patients with depression. These results suggest that altered circulating levels of common metabolic risk factors lead to the co-existence of depression with AD in many patients, and when they co-exist, the depression presumably affects the severity of AD presentations through more aggravated changes in these risk factors. PMID:28580183

Two Alzheimer’s disease risk genes increase entorhinal cortex volume in young adults

PubMed Central

DiBattista, Amanda Marie; Stevens, Benson W.; Rebeck, G. William; Green, Adam E.

2014-01-01

Alzheimer’s disease (AD) risk genes alter brain structure and function decades before disease onset. Apolipoprotein E (APOE) is the strongest known genetic risk factor for AD, and a related gene, apolipoprotein J (APOJ), also affects disease risk. However, the extent to which these genes affect brain structure in young adults remains unclear. Here, we report that AD risk alleles of these two genes, APOE-ε4 and APOJ-C, cumulatively alter brain volume in young adults. Using voxel-based morphometry (VBM) in 57 individuals, we examined the entorhinal cortex, one of the earliest brain regions affected in AD pathogenesis. Apolipoprotein E-ε4 carriers exhibited higher right entorhinal cortex volume compared to non-carriers. Interestingly, APOJ-C risk genotype was associated with higher bilateral entorhinal cortex volume in non-APOE-ε4 carriers. To determine the combined disease risk of APOE and APOJ status per subject, we used cumulative odds ratios as regressors for volumetric measurements. Higher disease risk corresponded to greater right entorhinal cortex volume. These results suggest that, years before disease onset, two key AD genetic risk factors may exert influence on the structure of a brain region where AD pathogenesis takes root. PMID:25339884

Predicting MCI outcome with clinically available MRI and CSF biomarkers

PubMed Central

Heister, D.; Brewer, J.B.; Magda, S.; Blennow, K.

2011-01-01

Objective: To determine the ability of clinically available volumetric MRI (vMRI) and CSF biomarkers, alone or in combination with a quantitative learning measure, to predict conversion to Alzheimer disease (AD) in patients with mild cognitive impairment (MCI). Methods: We stratified 192 MCI participants into positive and negative risk groups on the basis of 1) degree of learning impairment on the Rey Auditory Verbal Learning Test; 2) medial temporal atrophy, quantified from Food and Drug Administration–approved software for automated vMRI analysis; and 3) CSF biomarker levels. We also stratified participants based on combinations of risk factors. We computed Cox proportional hazards models, controlling for age, to assess 3-year risk of converting to AD as a function of risk group and used Kaplan-Meier analyses to determine median survival times. Results: When risk factors were examined separately, individuals testing positive showed significantly higher risk of converting to AD than individuals testing negative (hazard ratios [HR] 1.8–4.1). The joint presence of any 2 risk factors substantially increased risk, with the combination of greater learning impairment and increased atrophy associated with highest risk (HR 29.0): 85% of patients with both risk factors converted to AD within 3 years, vs 5% of those with neither. The presence of medial temporal atrophy was associated with shortest median dementia-free survival (15 months). Conclusions: Incorporating quantitative assessment of learning ability along with vMRI or CSF biomarkers in the clinical workup of MCI can provide critical information on risk of imminent conversion to AD. PMID:21998317

Family history and APOE4 risk for Alzheimer's disease impact the neural correlates of episodic memory by early midlife.

PubMed

Rajah, M N; Wallace, L M K; Ankudowich, E; Yu, E H; Swierkot, A; Patel, R; Chakravarty, M M; Naumova, D; Pruessner, J; Joober, R; Gauthier, S; Pasvanis, S

2017-01-01

Episodic memory impairment is a consistent, pronounced deficit in pre-clinical stages of late-onset Alzheimer's disease (AD). Individuals with risk factors for AD exhibit altered brain function several decades prior to the onset of AD-related symptoms. In the current event-related fMRI study of spatial context memory we tested the hypothesis that middle-aged adults (MA; 40-58 yrs) with a family history of late onset AD (MA + FH ), or a combined + FH and apolipoprotein E ε4 allele risk factors for AD (MA + FH + APOE4 ), will exhibit differences in encoding and retrieval-related brain activity, compared to - FH - APOE4 MA controls. We also hypothesized that the two at-risk MA groups will exhibit distinct patterns of correlation between brain activity and memory performance, compared to controls. To test these hypotheses we conducted multivariate task, and behavior, partial least squares analysis of fMRI data obtained during successful context encoding and retrieval. Our results indicate that even though there were no significant group differences in context memory performance, there were significant differences in brain activity and brain-behavior correlations involving the hippocampus, inferior parietal cortex, cingulate, and precuneus cortex in MA with AD risk factors, compared to controls. In addition, we observed that brain activity and brain-behavior correlations in anterior-medial PFC and in ventral visual cortex differentiated the two MA risk groups from each other, and from MA controls . Our results indicate that functional differences in episodic memory-related regions are present by early midlife in adults with + FH and + APOE-4 risk factors for late onset AD, compared to middle-aged controls.

Mosaic Loss of Chromosome Y in Blood Is Associated with Alzheimer Disease.

PubMed

Dumanski, Jan P; Lambert, Jean-Charles; Rasi, Chiara; Giedraitis, Vilmantas; Davies, Hanna; Grenier-Boley, Benjamin; Lindgren, Cecilia M; Campion, Dominique; Dufouil, Carole; Pasquier, Florence; Amouyel, Philippe; Lannfelt, Lars; Ingelsson, Martin; Kilander, Lena; Lind, Lars; Forsberg, Lars A

2016-06-02

Men have a shorter life expectancy compared with women but the underlying factor(s) are not clear. Late-onset, sporadic Alzheimer disease (AD) is a common and lethal neurodegenerative disorder and many germline inherited variants have been found to influence the risk of developing AD. Our previous results show that a fundamentally different genetic variant, i.e., lifetime-acquired loss of chromosome Y (LOY) in blood cells, is associated with all-cause mortality and an increased risk of non-hematological tumors and that LOY could be induced by tobacco smoking. We tested here a hypothesis that men with LOY are more susceptible to AD and show that LOY is associated with AD in three independent studies of different types. In a case-control study, males with AD diagnosis had higher degree of LOY mosaicism (adjusted odds ratio = 2.80, p = 0.0184, AD events = 606). Furthermore, in two prospective studies, men with LOY at blood sampling had greater risk for incident AD diagnosis during follow-up time (hazard ratio [HR] = 6.80, 95% confidence interval [95% CI] = 2.16-21.43, AD events = 140, p = 0.0011). Thus, LOY in blood is associated with risks of both AD and cancer, suggesting a role of LOY in blood cells on disease processes in other tissues, possibly via defective immunosurveillance. As a male-specific risk factor, LOY might explain why males on average live shorter lives than females. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Correlation of Alzheimer's disease death rates with historical per capita personal income in the USA.

PubMed

Stępkowski, Dariusz; Woźniak, Grażyna; Studnicki, Marcin

2015-01-01

Alzheimer's disease (AD) is a progressive degenerating disease of complex etiology. A variety of risk factors contribute to the chance of developing AD. Lifestyle factors, such as physical, mental and social activity, education, and diet all affect the susceptibility to developing AD. These factors are in turn related to the level of personal income. Lower income usually coincides with lower level of education, lesser mental, leisure-social and physical activity, and poorer diet. In the present paper, we have analyzed the correlation of historical (1929-2011) per capita personal income (PCPI) for all states of the USA with corresponding age-adjusted AD death rates (AADR) for years 2000, 2005 and 2008. We found negative correlations in all cases, the highest one (R ≈ -0.65) for the PCPIs in the year 1970 correlated against the AADRs in 2005. From 1929 to 2005 the R value varies in an oscillatory manner, with the strongest correlations in 1929, 1970, 1990 and the weakest in 1950, 1980, 1998. Further analysis indicated that this oscillatory behavior of R is not artificially related to the economic factors but rather to delayed biological consequences associated with personal income. We conclude that the influence of the income level on the AD mortality in 2005 was the highest in the early years of life of the AD victims. Overall, the income had a significant, lifelong, albeit constantly decreasing, influence on the risk of developing AD. We postulate that the susceptibility of a population to late-onset AD (LOAD) is determined to a large extent by the history of income-related modifiable lifestyle risk factors. Among these risk factors, inappropriate diet has a significant contribution.

Correlation of Alzheimer’s Disease Death Rates with Historical Per Capita Personal Income in the USA

PubMed Central

Stępkowski, Dariusz; Woźniak, Grażyna; Studnicki, Marcin

2015-01-01

Alzheimer’s disease (AD) is a progressive degenerating disease of complex etiology. A variety of risk factors contribute to the chance of developing AD. Lifestyle factors, such as physical, mental and social activity, education, and diet all affect the susceptibility to developing AD. These factors are in turn related to the level of personal income. Lower income usually coincides with lower level of education, lesser mental, leisure—social and physical activity, and poorer diet. In the present paper, we have analyzed the correlation of historical (1929–2011) per capita personal income (PCPI) for all states of the USA with corresponding age-adjusted AD death rates (AADR) for years 2000, 2005 and 2008. We found negative correlations in all cases, the highest one (R ≈ -0.65) for the PCPIs in the year 1970 correlated against the AADRs in 2005. From 1929 to 2005 the R value varies in an oscillatory manner, with the strongest correlations in 1929, 1970, 1990 and the weakest in 1950, 1980, 1998. Further analysis indicated that this oscillatory behavior of R is not artificially related to the economic factors but rather to delayed biological consequences associated with personal income. We conclude that the influence of the income level on the AD mortality in 2005 was the highest in the early years of life of the AD victims. Overall, the income had a significant, lifelong, albeit constantly decreasing, influence on the risk of developing AD. We postulate that the susceptibility of a population to late-onset AD (LOAD) is determined to a large extent by the history of income-related modifiable lifestyle risk factors. Among these risk factors, inappropriate diet has a significant contribution. PMID:25961738

Possible modification of Alzheimer's disease by statins in midlife: interactions with genetic and non-genetic risk factors.

PubMed

Shinohara, Mitsuru; Sato, Naoyuki; Shimamura, Munehisa; Kurinami, Hitomi; Hamasaki, Toshimitsu; Chatterjee, Amarnath; Rakugi, Hiromi; Morishita, Ryuichi

2014-01-01

The benefits of statins, commonly prescribed for hypercholesterolemia, in treating Alzheimer's disease (AD) have not yet been fully established. A recent randomized clinical trial did not show any therapeutic effects of two statins on cognitive function in AD. Interestingly, however, the results of the Rotterdam study, one of the largest prospective cohort studies, showed reduced risk of AD in statin users. Based on the current understanding of statin actions and AD pathogenesis, it is still worth exploring whether statins can prevent AD when administered decades before the onset of AD or from midlife. This review discusses the possible beneficial effects of statins, drawn from previous clinical observations, pathogenic mechanisms, which include β-amyloid (Aβ) and tau metabolism, genetic and non-genetic risk factors (apolipoprotein E, cholesterol, sex, hypertension, and diabetes), and other clinical features (vascular dysfunction and oxidative and inflammatory stress) of AD. These findings suggest that administration of statins in midlife might prevent AD in late life by modifying genetic and non-genetic risk factors for AD. It should be clarified whether statins inhibit Aβ accumulation, tau pathological features, and brain atrophy in humans. To answer this question, a randomized controlled study using amyloid positron emission tomography (PET), tau-PET, and magnetic resonance imaging would be useful. This clinical evaluation could help us to overcome this devastating disease.

Circulating insulin-like growth factors and Alzheimer disease: A mendelian randomization study.

PubMed

Williams, Dylan M; Karlsson, Ida K; Pedersen, Nancy L; Hägg, Sara

2018-01-23

To examine whether genetically predicted variation in circulating insulin-like growth factor 1 (IGF1) or its binding protein, IGFBP3, are associated with risk of Alzheimer disease (AD), using a mendelian randomization study design. We first examined disease risk by genotypes of 9 insulin-like growth factor (IGF)-related single nucleotide polymorphisms (SNPs) using published summary genome-wide association statistics from the International Genomics of Alzheimer's Project (IGAP; n = 17,008 cases; 37,154 controls). We then assessed whether any SNP-disease results replicated in an independent sample derived from the Swedish Twin Registry (n = 984 cases; 10,304 controls). Meta-analyses of SNP-AD results did not suggest that variation in IGF1, IGFBP3, or the molar ratio of these affect AD risk. Only one SNP appeared to affect AD risk in IGAP data. This variant is located in the gene FOXO3, implicated in human longevity. In a meta-analysis of both IGAP and secondary data, the odds ratio of AD per FOXO3 risk allele was 1.04 (95% confidence interval 1.01-1.08; p = 0.008). These findings suggest that circulating IGF1 and IGFBP3 are not important determinants of AD risk. FOXO3 function may influence AD development via pathways that are independent of IGF signaling (i.e., pleiotropic actions). Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Heart diseases and long-term risk of dementia and Alzheimer's disease: a population-based CAIDE study.

PubMed

Rusanen, Minna; Kivipelto, Miia; Levälahti, Esko; Laatikainen, Tiina; Tuomilehto, Jaakko; Soininen, Hilkka; Ngandu, Tiia

2014-01-01

Many cardiovascular risk factors are shown to increase the risk of dementia and Alzheimer's disease (AD), but the impact of heart disease on later development of dementia is still unclear. The aim of the study was to investigate the long-term risk of dementia and Alzheimer's disease (AD) related to midlife and late-life atrial fibrillation (AF), heart failure (HF), and coronary artery disease (CAD) in a population-based study with a follow-up of over 25 years. Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study includes 2000 participants who were randomly selected from four separate, population-based samples originally studied in midlife (1972, 1977, 1982, or 1987). Re-examinations were carried out in 1998 and 2005-2008. Altogether 1,510 (75.5%) persons participated in at least one re-examination, and 127 (8.4%) persons were diagnosed with dementia (of which 102 had AD). AF in late-life was an independent risk factor for dementia (HR 2.61, 95% CI 1.05-6.47; p = 0.039) and AD (HR 2.54, 95% CI 1.04-6.16; p = 0.040) in the fully adjusted analyses. The association was even stronger among the apolipoprotein E (APOE) ε4 non-carriers. Late-life HF, but not CAD, tended to increase the risks as well. Heart diseases diagnosed at midlife did not increase the risk of later dementia and AD. Late-life heart diseases increase the subsequent risk of dementia and AD. Prevention and effective treatment of heart diseases may be important also from the perspective of brain health and cognitive functioning.

The genetics of Alzheimer's disease.

PubMed

Bertram, Lars; Tanzi, Rudolph E

2012-01-01

Genetic factors play a major role in determining a person's risk to develop Alzheimer's disease (AD). Rare mutations transmitted in a Mendelian fashion within affected families, for example, APP, PSEN1, and PSEN2, cause AD. In the absence of mutations in these genes, disease risk is largely determined by common polymorphisms that, in concert with each other and nongenetic risk factors, modestly impact risk for AD (e.g., the ε4-allele in APOE). Recent genome-wide screening approaches have revealed several additional AD susceptibility loci and more are likely to be discovered over the coming years. In this chapter, we review the current state of AD genetics research with a particular focus on loci that now can be considered established disease genes. In addition to reviewing the potential pathogenic relevance of these genes, we provide an outlook into the future of AD genetics research based on recent advances in high-throughput sequencing technologies. Copyright © 2012 Elsevier Inc. All rights reserved.

Memory Resilience to Alzheimer's Genetic Risk: Sex Effects in Predictor Profiles.

PubMed

McDermott, Kirstie L; McFall, G Peggy; Andrews, Shea J; Anstey, Kaarin J; Dixon, Roger A

2017-10-01

Apolipoprotein E (APOE) ɛ4 and Clusterin (CLU) C alleles are risk factors for Alzheimer's disease (AD) and episodic memory (EM) decline. Memory resilience occurs when genetically at-risk adults perform at high and sustained levels. We investigated whether (a) memory resilience to AD genetic risk is predicted by biological and other risk markers and (b) the prediction profiles vary by sex and AD risk variant. Using a longitudinal sample of nondemented adults (n = 642, aged 53-95) we focused on memory resilience (over 9 years) to 2 AD risk variants (APOE, CLU). Growth mixture models classified resilience. Random forest analysis, stratified by sex, tested the predictive importance of 22 nongenetic risk factors from 5 domains (n = 24-112). For both sexes, younger age, higher education, stronger grip, and everyday novel cognitive activity predicted memory resilience. For women, 9 factors from functional, health, mobility, and lifestyle domains were also predictive. For men, only fewer depressive symptoms was an additional important predictor. The prediction profiles were similar for APOE and CLU. Although several factors predicted resilience in both sexes, a greater number applied only to women. Sex-specific mechanisms and intervention targets are implied. © The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

New Genes and New Insights from Old Genes: Update on Alzheimer Disease

PubMed Central

Ringman, John M.; Coppola, Giovanni

2013-01-01

Purpose of Review: This article discusses the current status of knowledge regarding the genetic basis of Alzheimer disease (AD) with a focus on clinically relevant aspects. Recent Findings: The genetic architecture of AD is complex, as it includes multiple susceptibility genes and likely nongenetic factors. Rare but highly penetrant autosomal dominant mutations explain a small minority of the cases but have allowed tremendous advances in understanding disease pathogenesis. The identification of a strong genetic risk factor, APOE, reshaped the field and introduced the notion of genetic risk for AD. More recently, large-scale genome-wide association studies are adding to the picture a number of common variants with very small effect sizes. Large-scale resequencing studies are expected to identify additional risk factors, including rare susceptibility variants and structural variation. Summary: Genetic assessment is currently of limited utility in clinical practice because of the low frequency (Mendelian mutations) or small effect size (common risk factors) of the currently known susceptibility genes. However, genetic studies are identifying with confidence a number of novel risk genes, and this will further our understanding of disease biology and possibly the identification of therapeutic targets. PMID:23558482

Clinical epidemiology of Alzheimer's disease: assessing sex and gender differences.

PubMed

Mielke, Michelle M; Vemuri, Prashanthi; Rocca, Walter A

2014-01-01

With the aging of the population, the burden of Alzheimer's disease (AD) is rapidly expanding. More than 5 million people in the US alone are affected with AD and this number is expected to triple by 2050. While men may have a higher risk of mild cognitive impairment (MCI), an intermediate stage between normal aging and dementia, women are disproportionally affected with AD. One explanation is that men may die of competing causes of death earlier in life, so that only the most resilient men may survive to older ages. However, many other factors should also be considered to explain the sex differences. In this review, we discuss the differences observed in men versus women in the incidence and prevalence of MCI and AD, in the structure and function of the brain, and in the sex-specific and gender-specific risk and protective factors for AD. In medical research, sex refers to biological differences such as chromosomal differences (eg, XX versus XY chromosomes), gonadal differences, or hormonal differences. In contrast, gender refers to psychosocial and cultural differences between men and women (eg, access to education and occupation). Both factors play an important role in the development and progression of diseases, including AD. Understanding both sex- and gender-specific risk and protective factors for AD is critical for developing individualized interventions for the prevention and treatment of AD.

Clinical epidemiology of Alzheimer’s disease: assessing sex and gender differences

PubMed Central

Mielke, Michelle M; Vemuri, Prashanthi; Rocca, Walter A

2014-01-01

With the aging of the population, the burden of Alzheimer’s disease (AD) is rapidly expanding. More than 5 million people in the US alone are affected with AD and this number is expected to triple by 2050. While men may have a higher risk of mild cognitive impairment (MCI), an intermediate stage between normal aging and dementia, women are disproportionally affected with AD. One explanation is that men may die of competing causes of death earlier in life, so that only the most resilient men may survive to older ages. However, many other factors should also be considered to explain the sex differences. In this review, we discuss the differences observed in men versus women in the incidence and prevalence of MCI and AD, in the structure and function of the brain, and in the sex-specific and gender-specific risk and protective factors for AD. In medical research, sex refers to biological differences such as chromosomal differences (eg, XX versus XY chromosomes), gonadal differences, or hormonal differences. In contrast, gender refers to psychosocial and cultural differences between men and women (eg, access to education and occupation). Both factors play an important role in the development and progression of diseases, including AD. Understanding both sex- and gender-specific risk and protective factors for AD is critical for developing individualized interventions for the prevention and treatment of AD. PMID:24470773

Insulin resistance as a key link for the increased risk of cognitive impairment in the metabolic syndrome

PubMed Central

Kim, Bhumsoo; Feldman, Eva L

2015-01-01

Metabolic syndrome (MetS) is a cluster of cardiovascular risk factors that includes obesity, diabetes, and dyslipidemia. Accumulating evidence implies that MetS contributes to the development and progression of Alzheimer's disease (AD); however, the factors connecting this association have not been determined. Insulin resistance (IR) is at the core of MetS and likely represent the key link between MetS and AD. In the central nervous system, insulin plays key roles in learning and memory, and AD patients exhibit impaired insulin signaling that is similar to that observed in MetS. As we face an alarming increase in obesity and T2D in all age groups, understanding the relationship between MetS and AD is vital for the identification of potential therapeutic targets. Recently, several diabetes therapies that enhance insulin signaling are being tested for a potential therapeutic benefit in AD and dementia. In this review, we will discuss MetS as a risk factor for AD, focusing on IR and the recent progress and future directions of insulin-based therapies. PMID:25766618

Aging, cortical injury and Alzheimer's disease-like pathology in the guinea pig brain.

PubMed

Bates, Kristyn; Vink, Robert; Martins, Ralph; Harvey, Alan

2014-06-01

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized histopathologically by the abnormal deposition of the proteins amyloid-beta (Aβ) and tau. A major issue for AD research is the lack of an animal model that accurately replicates the human disease, thus making it difficult to investigate potential risk factors for AD such as head injury. Furthermore, as age remains the strongest risk factor for most of the AD cases, transgenic models in which mutant human genes are expressed throughout the life span of the animal provide only limited insight into age-related factors in disease development. Guinea pigs (Cavia porcellus) are of interest in AD research because they have a similar Aβ sequence to humans and thus may present a useful non-transgenic animal model of AD. Brains from guinea pigs aged 3-48 months were examined to determine the presence of age-associated AD-like pathology. In addition, fluid percussion-induced brain injury was performed to characterize mechanisms underlying the association between AD risk and head injury. No statistically significant changes were detected in the overall response to aging, although we did observe some region-specific changes. Diffuse deposits of Aβ were found in the hippocampal region of the oldest animals and alterations in amyloid precursor protein processing and tau immunoreactivity were observed with age. Brain injury resulted in a strong and sustained increase in amyloid precursor protein and tau immunoreactivity without Aβ deposition, over 7 days. Guinea pigs may therefore provide a useful model for investigating the influence of environmental and non-genetic risk factors on the pathogenesis of AD. Copyright © 2014 Elsevier Inc. All rights reserved.

Alzheimer's disease and diet: a systematic review.

PubMed

Yusufov, Miryam; Weyandt, Lisa L; Piryatinsky, Irene

2017-02-01

Purpose/Aim: Approximately 44 million people worldwide have Alzheimer's disease (AD). Numerous claims have been made regarding the influence of diet on AD development. The aims of this systematic review were to summarize the evidence considering diet as a protective or risk factor for AD, identify methodological challenges and limitations, and provide future research directions. Medline, PsycINFO and PsycARTICLES were searched for articles that examined the relationship between diet and AD. On the basis of the inclusion and exclusion criteria, 64 studies were included, generating a total of 141 dietary patterns or "models". All studies were published between 1997 and 2015, with a total of 132 491 participants. Twelve studies examined the relationship between a Mediterranean (MeDi) diet and AD development, 10 of which revealed a significant association. Findings were inconsistent with respect to sample size, AD diagnosis and food measures. Further, the majority of studies (81.3%) included samples with mean baseline ages that were at risk for AD based on age (>65 years), ranging from 52.0 to 85.4 years. The range of follow-up periods was 1.5-32.0 years. The mean age of the samples poses a limitation in determining the influence of diet on AD; given that AD has a long prodromal phase prior to the manifestation of symptoms and decline. Further studies are necessary to determine whether diet is a risk or protective factor for AD, foster translation of research into clinical practice and elucidate dietary recommendations. Despite the methodological limitations, the finding that 50 of the 64 reviewed studies revealed an association between diet and AD incidence offers promising implications for diet as a modifiable risk factor for AD.

Osteoporosis in adult patients with atopic dermatitis: A nationwide population-based study

PubMed Central

Lu, Chun-Ching; Su, Yu-Feng; Tsai, Tai-Hsin; Wu, Chieh-Hsin

2017-01-01

The aim of this study was to investigate osteoporosis risk in atopic dermatitis (AD) patients. This study included patients in the Taiwan National Health Insurance Research dataset. The population-based study included all patients aged 20–49 years who had been diagnosed with AD during 1996–2010. In total, 35,229 age and gender-matched patients without AD in a 1:1 ratio were randomly selected as the non-AD group. Cox proportional-hazards regression and Kaplan–Meier analyses were used to measure the hazard ratios and the cumulative incidences of osteoporosis, respectively. During the follow-up period, 360(1.02%) AD patients and 127(0.36%) non-AD patients developed osteoporosis. The overall incidence of osteoporosis was4.72-fold greater in the AD patients compared to the non-AD patients (1.82 vs. 0.24 per 1,000 person-years, respectively) after adjusting for potential confounding factors. Osteoporosis risk factors included female gender, age, advanced Charlson Comorbidity Index, depression and use of corticosteroids. The dataset analysis showed that AD was significantly associated with subsequent risk of osteoporosis. PMID:28207767

Vascular risk factors and neuropsychiatric symptoms in Alzheimer's disease: the Cache County Study.

PubMed

Steinberg, Martin; Hess, Kyle; Corcoran, Chris; Mielke, Michelle M; Norton, Maria; Breitner, John; Green, Robert; Leoutsakos, Jeannie; Welsh-Bohmer, Kathleen; Lyketsos, Constantine; Tschanz, Joann

2014-02-01

Knowledge of potentially modifiable risk factors for neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) is important. This study longitudinally explores modifiable vascular risk factors for NPS in AD. Participants enrolled in the Cache County Study on Memory in Aging with no dementia at baseline were subsequently assessed over three additional waves, and those with incident (new onset) dementia were invited to join the Dementia Progression Study for longitudinal follow-up. A total of 327 participants with incident AD were identified and assessed for the following vascular factors: atrial fibrillation, hypertension, diabetes mellitus, angina, coronary artery bypass surgery, myocardial infarction, cerebrovascular accident, and use of antihypertensive or diabetes medicines. A vascular index (VI) was also calculated. NPS were assessed over time using the Neuropsychiatric Inventory (NPI). Affective and Psychotic symptom clusters were assessed separately. The association between vascular factors and change in NPI total score was analyzed using linear mixed model and in symptom clusters using a random effects model. No individual vascular risk factors or the VI significantly predicted change in any individual NPS. The use of antihypertensive medications more than four times per week was associated with higher total NPI and Affective cluster scores. Use of antihypertensive medication was associated with higher total NPI and Affective cluster scores. The results of this study do not otherwise support vascular risk factors as modifiers of longitudinal change in NPS in AD. Copyright © 2013 John Wiley & Sons, Ltd.

Alzheimer Disease and Its Growing Epidemic: Risk Factors, Biomarkers, and the Urgent Need for Therapeutics.

PubMed

Hickman, Richard A; Faustin, Arline; Wisniewski, Thomas

2016-11-01

Alzheimer disease (AD) represents one of the greatest medical challenges of this century; the condition is becoming increasingly prevalent worldwide and no effective treatments have been developed for this terminal disease. Because the disease manifests at a late stage after a long period of clinically silent neurodegeneration, knowledge of the modifiable risk factors and the implementation of biomarkers is crucial in the primary prevention of the disease and presymptomatic detection of AD, respectively. This article discusses the growing epidemic of AD and antecedent risk factors in the disease process. Disease biomarkers are discussed, and the implications that this may have for the treatment of this currently incurable disease. Copyright © 2016 Elsevier Inc. All rights reserved.

Thirty years of Alzheimer's disease genetics: the implications of systematic meta-analyses.

PubMed

Bertram, Lars; Tanzi, Rudolph E

2008-10-01

The genetic underpinnings of Alzheimer's disease (AD) remain largely elusive despite early successes in identifying three genes that cause early-onset familial AD (those that encode amyloid precursor protein (APP) and the presenilins (PSEN1 and PSEN2)), and one genetic risk factor for late-onset AD (the gene that encodes apolipoprotein E (APOE)). A large number of studies that aimed to help uncover the remaining disease-related loci have been published in recent decades, collectively proposing or refuting the involvement of over 500 different gene candidates. Systematic meta-analyses of these studies currently highlight more than 20 loci that have modest but significant effects on AD risk. This Review discusses the putative pathogenetic roles and common biochemical pathways of some of the most genetically and biologically compelling of these potential AD risk factors.

Systemic inflammation as a predictor of brain aging: Contributions of physical activity, metabolic risk, and genetic risk.

PubMed

Corlier, Fabian; Hafzalla, George; Faskowitz, Joshua; Kuller, Lewis H; Becker, James T; Lopez, Oscar L; Thompson, Paul M; Braskie, Meredith N

2018-05-15

Inflammatory processes may contribute to risk for Alzheimer's disease (AD) and age-related brain degeneration. Metabolic and genetic risk factors, and physical activity may, in turn, influence these inflammatory processes. Some of these risk factors are modifiable, and interact with each other. Understanding how these processes together relate to brain aging will help to inform future interventions to treat or prevent cognitive decline. We used brain magnetic resonance imaging (MRI) to scan 335 older adult humans (mean age 77.3 ± 3.4 years) who remained non-demented for the duration of the 9-year longitudinal study. We used structural equation modeling (SEM) in a subset of 226 adults to evaluate whether measures of baseline peripheral inflammation (serum C-reactive protein levels; CRP), mediated the baseline contributions of genetic and metabolic risk, and physical activity, to regional cortical thickness in AD-relevant brain regions at study year 9. We found that both baseline metabolic risk and AD risk variant apolipoprotein E ε4 (APOE4), modulated baseline serum CRP. Higher baseline CRP levels, in turn, predicted thinner regional cortex at year 9, and mediated an effect between higher metabolic risk and thinner cortex in those regions. A higher polygenic risk score composed of variants in immune-associated AD risk genes (other than APOE) was associated with thinner regional cortex. However, CRP levels did not mediate this effect, suggesting that other mechanisms may be responsible for the elevated AD risk. We found interactions between genetic and environmental factors and structural brain health. Our findings support the role of metabolic risk and peripheral inflammation in age-related brain decline. Copyright © 2018 Elsevier Inc. All rights reserved.

Associations between Potentially Modifiable Risk Factors and Alzheimer Disease: A Mendelian Randomization Study.

PubMed

Østergaard, Søren D; Mukherjee, Shubhabrata; Sharp, Stephen J; Proitsi, Petroula; Lotta, Luca A; Day, Felix; Perry, John R B; Boehme, Kevin L; Walter, Stefan; Kauwe, John S; Gibbons, Laura E; Larson, Eric B; Powell, John F; Langenberg, Claudia; Crane, Paul K; Wareham, Nicholas J; Scott, Robert A

2015-06-01

Potentially modifiable risk factors including obesity, diabetes, hypertension, and smoking are associated with Alzheimer disease (AD) and represent promising targets for intervention. However, the causality of these associations is unclear. We sought to assess the causal nature of these associations using Mendelian randomization (MR). We used SNPs associated with each risk factor as instrumental variables in MR analyses. We considered type 2 diabetes (T2D, NSNPs = 49), fasting glucose (NSNPs = 36), insulin resistance (NSNPs = 10), body mass index (BMI, NSNPs = 32), total cholesterol (NSNPs = 73), HDL-cholesterol (NSNPs = 71), LDL-cholesterol (NSNPs = 57), triglycerides (NSNPs = 39), systolic blood pressure (SBP, NSNPs = 24), smoking initiation (NSNPs = 1), smoking quantity (NSNPs = 3), university completion (NSNPs = 2), and years of education (NSNPs = 1). We calculated MR estimates of associations between each exposure and AD risk using an inverse-variance weighted approach, with summary statistics of SNP-AD associations from the International Genomics of Alzheimer's Project, comprising a total of 17,008 individuals with AD and 37,154 cognitively normal elderly controls. We found that genetically predicted higher SBP was associated with lower AD risk (odds ratio [OR] per standard deviation [15.4 mm Hg] of SBP [95% CI]: 0.75 [0.62-0.91]; p = 3.4 × 10(-3)). Genetically predicted higher SBP was also associated with a higher probability of taking antihypertensive medication (p = 6.7 × 10(-8)). Genetically predicted smoking quantity was associated with lower AD risk (OR per ten cigarettes per day [95% CI]: 0.67 [0.51-0.89]; p = 6.5 × 10(-3)), although we were unable to stratify by smoking history; genetically predicted smoking initiation was not associated with AD risk (OR = 0.70 [0.37, 1.33]; p = 0.28). We saw no evidence of causal associations between glycemic traits, T2D, BMI, or educational attainment and risk of AD (all p > 0.1). Potential limitations of this study include the small proportion of intermediate trait variance explained by genetic variants and other implicit limitations of MR analyses. Inherited lifetime exposure to higher SBP is associated with lower AD risk. These findings suggest that higher blood pressure--or some environmental exposure associated with higher blood pressure, such as use of antihypertensive medications--may reduce AD risk.

Streptozotocin Intracerebroventricular-Induced Neurotoxicity and Brain Insulin Resistance: a Therapeutic Intervention for Treatment of Sporadic Alzheimer's Disease (sAD)-Like Pathology.

PubMed

Kamat, Pradip K; Kalani, Anuradha; Rai, Shivika; Tota, Santosh Kumar; Kumar, Ashok; Ahmad, Abdullah S

2016-09-01

Alzheimer's disease (AD) is a neurodegenerative disorder that is remarkably characterized by pathological hallmarks which include amyloid plaques, neurofibrillary tangles, neuronal loss, and progressive cognitive loss. Several well-known genetic mutations which are being used for the development of a transgenic model of AD lead to an early onset familial AD (fAD)-like condition. However, these settings are only reasons for a small percentage of the total AD cases. The large majorities of AD cases are considered as a sporadic in origin and are less influenced by a single mutation of a gene. The etiology of sporadic Alzheimer's disease (sAD) remains unclear, but numerous risk factors have been identified that increase the chance of developing AD. Among these risk factors are insulin desensitization/resistance state, oxidative stress, neuroinflammation, synapse dysfunction, tau hyperphosphorylation, and deposition of Aβ in the brain. Subsequently, these risk factors lead to development of sAD. However, the underlying molecular mechanism is not so clear. Streptozotocin (STZ) produces similar characteristic pathology of sAD such as altered glucose metabolism, insulin signaling, synaptic dysfunction, protein kinases such as protein kinase B/C, glycogen synthase-3β (GSK-3β) activation, tau hyperphosphorylation, Aβ deposition, and neuronal apoptosis. Further, STZ also leads to inhibition of Akt/PKB, insulin receptor (IR) signaling molecule, and insulin resistance in brain. These alterations mediated by STZ can be used to explore the underlying molecular and pathophysiological mechanism of AD (especially sAD) and their therapeutic intervention for drug development against AD pathology.

Children of Persons With Alzheimer Disease

PubMed Central

Jarvik, Lissy; LaRue, Asenath; Blacker, Deborah; Gatz, Margaret; Kawas, Claudia; McArdle, John J.; Morris, John C.; Mortimer, James A.; Ringman, John M.; Ercoli, Linda; Freimer, Nelson; Gokhman, Izabella; Manly, Jennifer J.; Plassman, Brenda L.; Rasgon, Natalie; Roberts, Jeffrey Scott; Sunderland, Trey; Swan, Gary E.; Wolf, Phillip A.; Zonderman, Alan B.

2012-01-01

Children of persons with Alzheimer disease (AD), as a group, face an increased risk of developing AD. Many of them, throughout their adult lives, seek input on how to reduce their chances of one day suffering their parent’s fate. We examine the state of knowledge with respect to risk and protective factors for AD and recommend a research agenda with special emphasis on AD offspring. PMID:18317242

Protective effect of the APOE-e3 allele in Alzheimer's disease

PubMed Central

de-Almada, B.V.P.; de-Almeida, L.D.; Camporez, D.; de-Moraes, M.V.D.; Morelato, R.L.; Perrone, A.M.S.; Belcavello, L.; Louro, I.D.; de-Paula, F.

2011-01-01

Although several alleles of susceptibility to Alzheimer's disease (AD) have been studied in the last decades, few polymorphisms have been considered as risk factors for the disease. Among them, the APOE-e4 allele appears to be the major genetic risk factor for the onset of the disease. However, it is important to confirm the potential susceptibility of these genetic variants in different populations in order to establish a genetic profile for the disease in specific communities. This study analyzed the APOE polymorphisms regarding susceptibility to AD in a sample of 264 individuals (primarily Caucasians; 82 cases and 182 controls) in the population from Vitória, ES, Brazil, by PCR restriction fragment length polymorphism (PCR-RFLP) methods. The patients were selected according to clinical criteria for probable AD. Whereas the e4 allele showed statistically significant positive association with susceptibility to AD (OR = 3.01, 95%CI = 1.96-4.61; P < 0.0001), the e2 allele did not. The results of the e4 allele confirm the role of this polymorphism as a risk factor for AD in the sample studied as observed in other populations. Although the e3 allele has been considered neutral in several studies, our results suggest that it acts as a protective factor against AD in the population studied (OR = 0.46, 95%CI = 0.30-0.67; P < 0.0001). This study may provide a new insight into the role of the APOE-e3 allele in the etiology of AD and might help to estabilish a profile of risk for AD in the population from Vitória, ES. PMID:22068907

Late-onset Alzheimer disease genetic variants in posterior cortical atrophy and posterior AD.

PubMed

Carrasquillo, Minerva M; Khan, Qurat ul Ain; Murray, Melissa E; Krishnan, Siddharth; Aakre, Jeremiah; Pankratz, V Shane; Nguyen, Thuy; Ma, Li; Bisceglio, Gina; Petersen, Ronald C; Younkin, Steven G; Dickson, Dennis W; Boeve, Bradley F; Graff-Radford, Neill R; Ertekin-Taner, Nilüfer

2014-04-22

To investigate association of genetic risk factors for late-onset Alzheimer disease (LOAD) with risk of posterior cortical atrophy (PCA), a syndrome of visual impairment with predominant Alzheimer disease (AD) pathology in posterior cortical regions, and with risk of "posterior AD" neuropathology. We assessed 81 participants with PCA diagnosed clinically and 54 with neuropathologic diagnosis of posterior AD vs 2,523 controls for association with 11 significant single nucleotide polymorphisms (SNPs) from published LOAD risk genome-wide association studies. There was highly significant association with APOE ε4 and increased risk of PCA (p = 0.0003, odds ratio [OR] = 3.17) and posterior AD (p = 1.11 × 10(-17), OR = 6.43). No other locus was significant after corrections for multiple testing, although rs11136000 near CLU (p = 0.019, OR = 0.60) and rs744373 near BIN1 (p = 0.025, OR = 1. 63) associated nominally significantly with posterior AD, and rs3851179 at the PICALM locus had significant association with PCA (p = 0.0003, OR = 2.84). ABCA7 locus SNP rs3764650, which was also tested under the recessive model because of Hardy-Weinberg disequilibrium, also had nominally significant association with PCA risk. The direction of association at APOE, CLU, and BIN1 loci was the same for participants with PCA and posterior AD. The effects for all SNPs, except rs3851179, were consistent with those for LOAD risk. We identified a significant effect for APOE and nominate CLU, BIN1, and ABCA7 as additional risk loci for PCA and posterior AD. Our findings suggest that at least some of the genetic risk factors for LOAD are shared with these atypical conditions and provide effect-size estimates for their future genetic studies.

CFH Variants Affect Structural and Functional Brain Changes and Genetic Risk of Alzheimer's Disease.

PubMed

Zhang, Deng-Feng; Li, Jin; Wu, Huan; Cui, Yue; Bi, Rui; Zhou, He-Jiang; Wang, Hui-Zhen; Zhang, Chen; Wang, Dong; Kong, Qing-Peng; Li, Tao; Fang, Yiru; Jiang, Tianzi; Yao, Yong-Gang

2016-03-01

The immune response is highly active in Alzheimer's disease (AD). Identification of genetic risk contributed by immune genes to AD may provide essential insight for the prognosis, diagnosis, and treatment of this neurodegenerative disease. In this study, we performed a genetic screening for AD-related top immune genes identified in Europeans in a Chinese cohort, followed by a multiple-stage study focusing on Complement Factor H (CFH) gene. Effects of the risk SNPs on AD-related neuroimaging endophenotypes were evaluated through magnetic resonance imaging scan, and the effects on AD cerebrospinal fluid biomarkers (CSF) and CFH expression changes were measured in aged and AD brain tissues and AD cellular models. Our results showed that the AD-associated top immune genes reported in Europeans (CR1, CD33, CLU, and TREML2) have weak effects in Chinese, whereas CFH showed strong effects. In particular, rs1061170 (P(meta)=5.0 × 10(-4)) and rs800292 (P(meta)=1.3 × 10(-5)) showed robust associations with AD, which were confirmed in multiple world-wide sample sets (4317 cases and 16 795 controls). Rs1061170 (P=2.5 × 10(-3)) and rs800292 (P=4.7 × 10(-4)) risk-allele carriers have an increased entorhinal thickness in their young age and a higher atrophy rate as the disease progresses. Rs800292 risk-allele carriers have higher CSF tau and Aβ levels and severe cognitive decline. CFH expression level, which was affected by the risk-alleles, was increased in AD brains and cellular models. These comprehensive analyses suggested that CFH is an important immune factor in AD and affects multiple pathological changes in early life and during disease progress.

Implications of Our Developing Understanding of Risk and Protective Factors in the Treatment of Adult Male Sexual Offenders

ERIC Educational Resources Information Center

Thornton, David

2013-01-01

This paper summarizes our developing knowledge of factors that contribute added risk of sexual recidivism (risk factors) and factors that are associated with a reduced risk of sexual recidivism (protective factors). Specific implications for the design of future treatment programs are drawn. This information is contrasted with the common foci of…

A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease.

PubMed

Huang, Kuan-Lin; Marcora, Edoardo; Pimenova, Anna A; Di Narzo, Antonio F; Kapoor, Manav; Jin, Sheng Chih; Harari, Oscar; Bertelsen, Sarah; Fairfax, Benjamin P; Czajkowski, Jake; Chouraki, Vincent; Grenier-Boley, Benjamin; Bellenguez, Céline; Deming, Yuetiva; McKenzie, Andrew; Raj, Towfique; Renton, Alan E; Budde, John; Smith, Albert; Fitzpatrick, Annette; Bis, Joshua C; DeStefano, Anita; Adams, Hieab H H; Ikram, M Arfan; van der Lee, Sven; Del-Aguila, Jorge L; Fernandez, Maria Victoria; Ibañez, Laura; Sims, Rebecca; Escott-Price, Valentina; Mayeux, Richard; Haines, Jonathan L; Farrer, Lindsay A; Pericak-Vance, Margaret A; Lambert, Jean Charles; van Duijn, Cornelia; Launer, Lenore; Seshadri, Sudha; Williams, Julie; Amouyel, Philippe; Schellenberg, Gerard D; Zhang, Bin; Borecki, Ingrid; Kauwe, John S K; Cruchaga, Carlos; Hao, Ke; Goate, Alison M

2017-08-01

A genome-wide survival analysis of 14,406 Alzheimer's disease (AD) cases and 25,849 controls identified eight previously reported AD risk loci and 14 novel loci associated with age at onset. Linkage disequilibrium score regression of 220 cell types implicated the regulation of myeloid gene expression in AD risk. The minor allele of rs1057233 (G), within the previously reported CELF1 AD risk locus, showed association with delayed AD onset and lower expression of SPI1 in monocytes and macrophages. SPI1 encodes PU.1, a transcription factor critical for myeloid cell development and function. AD heritability was enriched within the PU.1 cistrome, implicating a myeloid PU.1 target gene network in AD. Finally, experimentally altered PU.1 levels affected the expression of mouse orthologs of many AD risk genes and the phagocytic activity of mouse microglial cells. Our results suggest that lower SPI1 expression reduces AD risk by regulating myeloid gene expression and cell function.

Increased cardiovascular risk in South African patients with Addison's disease.

PubMed

Ross, I L; Bergthorsdottir, R; Levitt, N S; Schatz, D A; Johannsson, G; Marais, A D

2013-11-01

Patients with Addison's disease (AD) are believed to be at risk for cardiovascular disease (CVD). South Africa, like the rest of the developing world is experiencing an increase in CVD and patients with AD may be at double the risk of their peers. We wished to explore AD patients' CVD risk factors. A cross-sectional nationwide study in South Africa of patients with AD was conducted. A cohort of 147 patients with AD and 147 healthy control subjects were matched by age, gender, ethnicity, and BMI as far as was possible. Lipoproteins and highly-sensitive C-reactive-protein (hs-CRP) were the main outcome measures. AD patients had significantly higher triglycerides; (p=0.001), lower HDLC (p<0.001), higher hs-CRP (p<0.001), and more small dense LDL; (p=0.002) than controls. Nonesterified fatty acids were lower in patients (p<0.001). Approximately 65% [95% confidence interval (CI 55.6-72.4%)] had hypercholesterolaemia, 75% (CI 64.8-81.2%) had low HDLC, and 75% (CI 68.0-84.1%) had a higher LDLC. Thirteen percent of AD patients had diabetes mellitus, but none of the risk factors differed from the nondiabetics. Only HDLC correlated positively with daily hydrocortisone dose (r=0.32; p=0.005). In conclusion dyslipidaemia is common in South African AD patients; CVD risk assessment and intervention are probably warranted in the management of these patients. © Georg Thieme Verlag KG Stuttgart · New York.

Subtle gray matter changes in temporo-parietal cortex associated with cardiovascular risk factors.

PubMed

de Toledo Ferraz Alves, Tânia Corrêa; Scazufca, Márcia; Squarzoni, Paula; de Souza Duran, Fábio Luiz; Tamashiro-Duran, Jaqueline Hatsuko; Vallada, Homero P; Andrei, Anna; Wajngarten, Mauricio; Menezes, Paulo R; Busatto, Geraldo F

2011-01-01

Vascular risk factors may play an important role in the pathophysiology of Alzheimer's disease (AD). While there is consistent evidence of gray matter (GM) abnormalities in earlier stages of AD, the presence of more subtle GM changes associated with vascular risk factors in the absence of clinically significant vascular events has been scarcely investigated. This study aimed to examine GM changes in elderly subjects with cardiovascular risk factors. We predicted that the presence of cardiovascular risk would be associated with GM abnormalities involving the temporal-parietal cortices and limbic structures. We recruited 248 dementia-free subjects, age range 66-75 years, from the population-based "São Paulo Ageing and Health Study", classified in accordance to their Framingham Coronary Heart Disease Risk (FCHDR) score to undergo an MRI scan. We performed an overall analysis of covariance, controlled to total GM and APOE4 status, to investigate the presence of regional GM abnormalities in association with FCHDR subgroups (high-risk, medium-risk, and low-risk), and followed by post hoc t-test. We also applied a co-relational design in order to investigate the presence of linear progression of the GM vulnerability in association with cardiovascular risk factor. Voxel-based morphometry showed that the presence of cardiovascular risk factors were associated with regional GM loss involving the temporal cortices bilaterally. Those results retained statistical significance after including APOE4 as a covariate of interest. We also observed that there was a negative correlation between FCHDR scores and rGM distribution in the parietal cortex. Subclinical cerebrovascular abnormalities involving GM loss may provide an important link between cardiovascular risk factors and AD.

Vascular risk factors promote conversion from mild cognitive impairment to Alzheimer disease.

PubMed

Li, J; Wang, Y J; Zhang, M; Xu, Z Q; Gao, C Y; Fang, C Q; Yan, J C; Zhou, H D

2011-04-26

Growing evidence suggests that vascular risk factors (VRF) contribute to cognitive decline. The aim of this study was to investigate the impact of VRF on the conversion from mild cognitive impairment (MCI) to Alzheimer disease (AD) dementia. A total of 837 subjects with MCI were enrolled at baseline and followed up annually for 5 years. The incidence of AD dementia was investigated. A mixed random effects regression model was used to analyze the association between VRF and the progression of MCI assessed with Mini-Mental State Examination and instrumental Activities of Daily Living. Cox proportional hazard models were used to identify the association between VRF and dementia conversion, and to examine whether treatment of VRF can prevent dementia conversion. At the end of the follow-up, 298 subjects converted to AD dementia, while 352 remained MCI. Subjects with VRF had a faster progression in cognition and function relative to subjects without. VRF including hypertension, diabetes, cerebrovascular diseases, and hypercholesterolemia increased the risk of dementia conversion. Those subjects with MCI in whom all VRF were treated had a lower risk of dementia than those who had some VRF treated. Treatment of individual VRF including hypertension, diabetes, and hypercholesterolemia was associated with the reduced risk of AD conversion. VRF increased the risk of incident AD dementia. Treatment of VRF was associated with a reduced risk of incident AD dementia. Although our findings are observational, they suggest active intervention for VRF might reduce progression in MCI to AD dementia.

Cardiovascular Involvement in Autoimmune Diseases

PubMed Central

Amaya-Amaya, Jenny

2014-01-01

Autoimmune diseases (AD) represent a broad spectrum of chronic conditions that may afflict specific target organs or multiple systems with a significant burden on quality of life. These conditions have common mechanisms including genetic and epigenetics factors, gender disparity, environmental triggers, pathophysiological abnormalities, and certain subphenotypes. Atherosclerosis (AT) was once considered to be a degenerative disease that was an inevitable consequence of aging. However, research in the last three decades has shown that AT is not degenerative or inevitable. It is an autoimmune-inflammatory disease associated with infectious and inflammatory factors characterized by lipoprotein metabolism alteration that leads to immune system activation with the consequent proliferation of smooth muscle cells, narrowing arteries, and atheroma formation. Both humoral and cellular immune mechanisms have been proposed to participate in the onset and progression of AT. Several risk factors, known as classic risk factors, have been described. Interestingly, the excessive cardiovascular events observed in patients with ADs are not fully explained by these factors. Several novel risk factors contribute to the development of premature vascular damage. In this review, we discuss our current understanding of how traditional and nontraditional risk factors contribute to pathogenesis of CVD in AD. PMID:25177690

ARAC--The Montreal Jewish General Hospital Alzheimer Risk Assessment Clinic.

PubMed

Schipper, Hyman M; Liberman, Adrienne; Kelner, Nora; Babins, Lennie; Fried, Lynda; Bilbul, Melanie; Goodman, Rachel

2011-07-01

In parallel with robust efforts world-wide to develop effective neuroprotection for established disease, resources are being mobilized to delineate risk factors and implement preventive measures in a concerted effort to forestall the anticipated Alzheimer disease (AD) epidemic. A review of heritable and 'acquired' dementia risk factors, many operating at midlife, is presented in a companion paper. In 2009, an Alzheimer Risk Assessment Clinic (ARAC) was established at the Jewish General Hospital (Montreal) to address the concerns increasingly being voiced by active middle-aged individuals at risk for AD. A positive family history of AD and/or perceived changes in personal cognitive function (predominantly short-term memory) are main reasons for referral. The primary objectives of ARAC are to (i) ascertain, inform and mitigate the risks of developing AD in cognitively-healthy persons aged 40-65 based on best available medical and epidemiological evidence, (ii) conduct scientific research on midlife dementia risk and prevention in this population and (iii) provide instruction in dementia risk assessment and management to health professionals, clinical/research fellows, medical residents and students. ARAC infrastructure, evaluation protocol, risk profile classification scheme, interventions, knowledge dissemination program, case vignettes, and seminal research projects are described. It is hoped that ARAC and similar initiatives will help prevent or delay dementia by innovating effective interventions based on increasingly nuanced estimation of modifiable AD risk in presymptomatic persons.

Added sugar intake in South Africa: findings from the Adult Prospective Urban and Rural Epidemiology cohort study.

PubMed

Vorster, Hester H; Kruger, Annamarie; Wentzel-Viljoen, Edelweiss; Kruger, H Salome; Margetts, Barrie M

2014-06-01

Obesity and other noncommunicable disease (NCD) risk factors are increasing in low- and middle-income countries. There are few data on the association between increased added sugar intake and NCD risk in these countries. We assessed the relation between added sugar intake and NCD risk factors in an African cohort study. Added sugars were defined as all monosaccharides and disaccharides added to foods and beverages during processing, cooking, and at the table. We conducted a 5-y follow-up of a cohort of 2010 urban and rural men and women aged 30-70 y of age at recruitment in 2005 from the North West Province in South Africa. Added sugar intake, particularly in rural areas, has increased rapidly in the past 5 y. In rural areas, the proportion of adults who consumed sucrose-sweetened beverages approximately doubled (for men, from 25% to 56%; for women, from 33% to 63%) in the past 5 y. After adjustment, subjects who consumed more added sugars (≥10% energy from added sugars) compared with those who consumed less added sugars had a higher waist circumference [mean difference (95% CI): 1.07 cm (0.35, 1.79 cm)] and body mass index (in kg/m²) [0.43 (0.12, 0.74)] and lower HDL cholesterol [-0.08 mmol/L (-0.14, 0.002 mmol/L)]. This cohort showed dramatic increases in added sugars and sucrose-sweetened beverage consumption in both urban and rural areas. Increased consumption was associated with increased NCD risk factors. In addition, the study showed that the nutrition transition has reached a remote rural area in South Africa. Urgent action is needed to address these trends. © 2014 American Society for Nutrition.

Apolipoprotein E-epsilon 4 allele and familial risk in Alzheimer's disease.

PubMed

Li, G; Silverman, J M; Altstiel, L D; Haroutunian, V; Perl, D P; Purohit, D; Birstein, S; Lantz, M; Mohs, R C; Davis, K L

1996-01-01

Recent studies have found an association between presence of apolipoprotein E (APOE) epsilon 4 allele and Alzheimer's disease (AD). The present study compared the cumulative risk of primary progressive dementia (PPD) in relatives of AD probands carrying at least one copy of the epsilon 4 allele with the relatives of AD probands not carrying epsilon 4 and with relatives of non-demented controls. Our aim was to determine whether the familial aggregation of PPD in relatives of AD probands is primarily due to those carrying epsilon 4. Seventy-seven neuropathologically diagnosed AD patients were obtained as probands through our Alzheimer's Disease Research Center Brain Bank. AD probands were genotyped for APOE. As a comparison group, 198 non-demented probands were also included. Through family informants, demographic and diagnostic data were collected on 382 first-degree relatives (age > or = 45 years) of AD probands and 848 relatives of the controls. We found that the cumulative risk of PPD in both relatives of AD probands with and without the epsilon 4 allele was significantly higher than that in the relatives of non-demented controls. However, the increased risk in the relatives of AD probands with the epsilon 4 allele was marginally, but not significantly, lower than the risk in the relatives of probands without epsilon 4. A greater likelihood of death by heart diseases over developing PPD in relatives of AD probands with epsilon 4 (3.1-fold increase) was found compared to relatives of probands without epsilon 4 (1.7-fold increase), especially prior to age 70, although the difference was not statistically significant. The increased familial risk for PPD in the relatives of AD probands with the APOE-epsilon 4 allele relative to controls suggests that familial factors in addition to APOE-epsilon 4 are risk factors for AD. Differential censorship from increased mortality of heart diseases may have prevented a higher incidence of PPD among the relatives of probands with epsilon 4.

Effect of Alzheimer's disease risk and protective factors on cognitive trajectories in subjective memory complainers.

PubMed

Teipel, Stefan J; Cavedo, Enrica; Lista, Simone; Habert, Marie-Odile; Potier, Marie-Claude; Grothe, Michel J; Epelbaum, Stephane; Sambati, Luisa; Gagliardi, Geoffroy; Toschi, Nicola; Greicius, Michael; Dubois, Bruno; Hampel, Harald

2018-05-21

Cognitive change in people at risk of Alzheimer's disease (AD) such as subjective memory complainers is highly variable across individuals. We used latent class growth modeling to identify distinct classes of nonlinear trajectories of cognitive change over 2 years follow-up from 265 subjective memory complainers individuals (age 70 years and older) of the INSIGHT-preAD cohort. We determined the effect of cortical amyloid load, hippocampus and basal forebrain volumes, and education on the cognitive trajectory classes. Latent class growth modeling identified distinct nonlinear cognitive trajectories. Education was associated with higher performing trajectories, whereas global amyloid load and basal forebrain atrophy were associated with lower performing trajectories. Distinct classes of cognitive trajectories were associated with risk and protective factors of AD. These associations support the notion that the identified cognitive trajectories reflect different risk for AD that may be useful for selecting high-risk individuals for intervention trials. Copyright © 2018. Published by Elsevier Inc.

Comparing the prevalence and the risk profile for antenatal depressive symptoms across cultures.

PubMed

Corbani, Irene E; Rucci, Paola; Iapichino, Elena; Quartieri Bollani, Marta; Cauli, Gilla; Ceruti, Mara R; Gala, Costanzo; Bassi, Mariano

2017-11-01

Although several studies have analyzed the risk factors of antenatal and post-partum depression, evidence on the prevalence and the risk profile for antenatal depressive symptoms (ADS) between native-born and different groups of non-native born women living in the same country is scant. The aim of this article is to compare the prevalence and the risk profile for ADS across geographical areas in women recruited from two large hospitals of North-western Italy. The presence of ADS was defined as an Edinburgh Post-natal Depression Scale (EPDS) score ≥12 or a Beck Depression Inventory, Short Form (BDI-SF) score ≥9 or the presence of suicidal ideation/behavior. Crude and adjusted odds ratios (ORs) of ADS were calculated using logistic regression models. The prevalence of ADS was 12.4% among Italian women and ranged from 11.4% in other European to 44.7% in North-African women. Crude ORs of ADS were OR = 3.3 (95% confidence interval (CI), 1.2-8.8) for Asian, 3.3 (95% CI, 1.9-5.6) for South-American and 5.7 (95% CI, 3.4-9.6) for North-African women. Marital problems, at-risk pregnancy, past psychiatric history, pharmacological treatment, psychological treatment, financial problems, change in residence and number of children were significantly associated with ADS in multivariate analyses, regardless of women's origin. After adjusting for these variables, the OR of ADS remained significant for South-American and North-African women. Our results demonstrate that the risk of ADS varies across geographical areas of origin and is highest among North-African women. The risk factors identified should be assessed in routine obstetric care to inform decisions about interventions to prevent post-partum depression and its consequences on the mothers and the newborns.

The Geography of the Alzheimer's Disease Mortality in Spain: Should We Focus on Industrial Pollutants Prevention?

PubMed

2017-11-25

Alzheimer's disease (AD) has a high worldwide prevalence but little is known about its aetiology and risk factors. Recent research suggests environmental factors might increase AD risk. We aim to describe the association between AD mortality and the presence of highly polluting industry in small areas in Spain between 1999 and 2010. We calculated AD age-adjusted Standardized Mortality Ratio (SMR), stratified by sex, grouped by industrial pollution density, compared for each small area of Spain. In the small areas with the highest mortality, the SMR among women was at least 25% greater than the national average (18% in men). The distribution of AD mortality was generally similar to that of high industrial pollution (higher mortality in the north, the Mediterranean coast and in some southern areas). The risk of AD mortality among women was 140% higher (123% among men) in areas with the highest industrial density in comparison to areas without polluting industries. This study has identified a geographical pattern of small areas with higher AD mortality risk and an ecological positive association with the density of highly polluting industry. Further research is needed on the potential impact of this type of industry pollution on AD aetiology and mortality.

Atherosclerosis risk factors in American Indians with Alzheimer disease: preliminary findings.

PubMed

Weiner, Myron F; Rosenberg, Roger N; Womack, Kyle B; Svetlik, Doris A; Fuller, Carey; Fields, Julie; Hynan, Linda S

2008-01-01

Factors predisposing to and associated with atherosclerosis may impact the onset and progression of Alzheimer disease (AD). The high prevalence of atherosclerosis and associated risk factors in American Indians makes them ideal subjects to test this association. We compared frequency of history of hypertension, myocardial infarction, stroke, diabetes, and high cholesterol in 34 American Indians with AD with 34 age-matched American Indian controls, and 34 age-matched whites with probable AD. We also measured waist size, height, and weight, and acquired blood for determination of plasma homocysteine and apolipoprotein E genotype. The 3 groups did not differ significantly in age or sex. History of hypertension and diabetes was significantly more common among American Indian AD patients than Indian controls or whites with AD. The 3 groups did not differ in history of stroke or myocardial infarction. Body mass index was significantly greater in both Indian groups than the white AD group. Plasma homocysteine levels were greater, but not significantly so, in the Indian AD than the Indian control group. Thus, there is preliminary evidence of a modest association between history of hypertension and diabetes and AD in a small sample of American Indians. This suggests that changes in lifestyle factors could influence the expression of AD in American Indians.

Peer Relationship Problems of Children with AD/HD: Risk Factors and New Directions in Interventions

ERIC Educational Resources Information Center

Ozdemir, Selda

2009-01-01

This review integrates and evaluates research conducted on possible contributing factors to peer relationship problems of children with attention deficit/hyperactivity disorder (AD/HD). Substantial evidence suggests that children with AD/HD have serious problems in multiple aspects of their relationships with peers. Difficulties resulting from…

A gene-brain-cognition pathway for the effect of an Alzheimer׳s risk gene on working memory in young adults.

PubMed

Stevens, Benson W; DiBattista, Amanda M; William Rebeck, G; Green, Adam E

2014-08-01

Identifying pathways by which genetic Alzheimer׳s disease (AD) risk factors exert neurocognitive effects in young adults are essential for the effort to develop early interventions to forestall or prevent AD onset. Here, in a brain-imaging cohort of 59 young adults, we investigated effects of a variant within the clusterin (CLU) gene on working memory function and gray matter volume in cortical areas that support working memory. In addition, we investigated the extent to which effects of CLU genotype on working memory were independent of variation in the strongest AD risk factor gene apolipoprotein E (APOE). CLU is among the strongest genetic AD risk factors and, though it appears to share AD pathogenesis-related features with, APOE, it has been far less well studied. CLU genotype was associated with working memory performance in our study cohort. Notably, we found that variation in gray matter volume in a parietal region, previously implicated in maintenance of information for working memory, mediated the effect of CLU on working memory performance. APOE genotype did not affect working memory within our sample, and did not interact with CLU genotype. To our knowledge, this work represents the first evidence of a behavioral effect of CLU genotype in young people. In addition, this work identifies the first gene-brain-cognition mediation effect pathway for the transmission of the effect of an AD risk factor. Relative to conventional pairwise associations in cognitive neurogenetic research, gene-brain-cognition mediation modeling provides a more integrated understanding of how genetic effects transmit from gene to brain to cognitive function. Copyright © 2014 Elsevier Ltd. All rights reserved.

Relation of Plasma Lipids to Alzheimer Disease and Vascular Dementia

PubMed Central

Reitz, Christiane; Tang, Ming-Xin; Luchsinger, Jose; Mayeux, Richard

2009-01-01

Background The relation between plasma lipid levels and Alzheimer disease (AD) and vascular dementia (VaD), and the impact of drugs to lower lipid levels remains unclear. Objective To investigate the relation between plasma lipid levels and the risk of AD and VaD and the impact of drugs to lower lipid levels on this relationship. Design and Setting Cross-sectional and prospective community-based cohort studies. Participants Random sample of 4316 Medicare recipients, 65 years and older, residing in northern Manhattan, NY. Main Outcome Measures Vascular dementia and AD according to standard criteria. Results Elevated levels of non–high-density lipoprotein (HDL-C) and low-density lipoprotein cholesterol (LDL-C) and decreased levels of HDL-C were weak risk factors for VaD in either cross-sectional or prospective analyses. Higher levels of total cholesterol were associated with a decreased risk of incident AD after adjustment for demographics, apolipoprotein E genotype, and cardiovascular risk factors. Treatment with drugs to lower lipid levels did not change the disease risk of either disorder. Conclusions We found a weak relation between non–HDL-C, LDL-C, and HDL-C levels and the risk of VaD. Lipid levels and the use of agents to lower them do not seem to be associated with the risk of AD. PMID:15148148

Risk Factors for Falls in Older Adults With Mild Cognitive Impairment and Mild Alzheimer Disease.

PubMed

Ansai, Juliana Hotta; de Andrade, Larissa Pires; Masse, Fernando Arturo Arriagada; Gonçalves, Jessica; de Medeiros Takahashi, Anielle Cristhine; Vale, Francisco Assis Carvalho; Rebelatto, José Rubens

2017-03-03

Understanding fall risk factors in people with mild cognitive impairment (MCI) and Alzheimer disease (AD) can help to establish specific plans for prevention of falls. The purpose of this study was to identify fall risk factors in older adults with MCI and mild AD. A prospective study was conducted with community-dwelling older adults (40 MCI; 38 mild AD). The assessments consisted of sociodemographic and health variables, caloric expenditure, functional status, functional mobility (10-m walk test, dual-task test, and transition Timed Up and Go phases), cognitive domains, and depressive symptoms. Falls were recorded for 6 months by a falls calendar and monthly telephone calls. Falls were reported in 52.6% and 51.4% of people with MCI and mild AD, respectively. Among people with MCI, lower functional status, higher time spent on walk and dual task tests, and higher depressive symptom scores were associated with falls. Higher time spent on the dual-task test was independently associated with falls. Among people with mild AD, falls were associated with lower time spent on the walk test and turn-to-sit phase, and a higher visuospatial domain score. Lower time spent on the turn-to-sit phase was identified as an independent predictor of falls. Careful attention should be given to dual-task and turn-to-sit activities when detecting risk of falls among older people with MCI and mild AD.

Alzheimer's Disease in the Latino Community: Intersection of Genetics and Social Determinants of Health.

PubMed

Vega, Irving E; Cabrera, Laura Y; Wygant, Cassandra M; Velez-Ortiz, Daniel; Counts, Scott E

2017-01-01

Alzheimer's disease (AD) is the most common type of dementia among individuals 65 or older. There are more than 5 million diagnosed cases in the US alone and this number is expected to triple by 2050. Therefore, AD has reached epidemic proportions with significant socioeconomic implications. While aging in general is the greatest risk factor for AD, several additional demographic factors that have contributed to the rise in AD in the US are under study. One such factor is associated with the relatively fast growth of the Latino population. Several reports indicate that AD is more prevalent among blacks and Latinos. However, the reason for AD disparity among different ethnic groups is still poorly understood and highly controversial. The Latino population is composed of different groups based on nationality, namely South and Central America, Mexico, and Caribbean Hispanics. This diversity among the Latino population represents an additional challenge since there are distinct characteristics associated with AD and comorbidities. In this review, we aim to bring attention to the intersection between social determinants of health and genetic factors associated with AD within the Latino community. We argue that understanding the interplay between identified social determinants of health, co-morbidities, and genetic factors could lead to community empowerment and inclusiveness in research and healthcare services, contributing to improved diagnosis and treatment of AD patients. Lastly, we propose that inserting a neuroethics perspective could help understand key challenges that influence healthcare disparities and contribute to increased risk of AD among Latinos.

The effect of increased genetic risk for Alzheimer’s disease on hippocampal and amygdala volume

PubMed Central

Lupton, Michelle K.; Strike, Lachlan; Hansell, Narelle K.; Wen, Wei; Mather, Karen A.; Armstrong, Nicola J.; Thalamuthu, Anbupalam; McMahon, Katie L.; de Zubicaray, Greig I.; Assareh, Amelia A.; Simmons, Andrew; Proitsi, Petroula; Powell, John F.; Montgomery, Grant W.; Hibar, Derrek P.; Westman, Eric; Tsolaki, Magda; Kloszewska, Iwona; Soininen, Hilkka; Mecocci, Patrizia; Velas, Bruno; Lovestone, Simon; Brodaty, Henry; Ames, David; Trollor, Julian N.; Martin, Nicholas G.; Thompson, Paul M.; Sachdev, Perminder S.; Wright, Margaret J.

2016-01-01

Reduction in hippocampal and amygdala volume measured via structural magnetic resonance imaging is an early marker of Alzheimer’s disease (AD). Whether genetic risk factors for AD exert an effect on these subcortical structures independent of clinical status has not been fully investigated. We examine whether increased genetic risk for AD influences hippocampal and amygdala volumes in case-control and population cohorts at different ages, in 1674 older (aged >53 years; 17% AD, 39% mild cognitive impairment [MCI]) and 467 young (16–30 years) adults. An AD polygenic risk score combining common risk variants excluding apolipoprotein E (APOE), and a single nucleotide polymorphism in TREM2, were both associated with reduced hippocampal volume in healthy older adults and those with MCI. APOE ɛ4 was associated with hippocampal and amygdala volume in those with AD and MCI but was not associated in healthy older adults. No associations were found in young adults. Genetic risk for AD affects the hippocampus before the clinical symptoms of AD, reflecting a neurodegenerative effect before clinical manifestations in older adults. PMID:26973105

Associations between Potentially Modifiable Risk Factors and Alzheimer Disease: A Mendelian Randomization Study

PubMed Central

Østergaard, Søren D.; Mukherjee, Shubhabrata; Sharp, Stephen J.; Proitsi, Petroula; Lotta, Luca A.; Day, Felix; Perry, John R. B.; Boehme, Kevin L.; Walter, Stefan; Kauwe, John S.; Gibbons, Laura E.; Larson, Eric B.; Powell, John F.; Langenberg, Claudia; Crane, Paul K.; Wareham, Nicholas J.; Scott, Robert A.

2015-01-01

Background Potentially modifiable risk factors including obesity, diabetes, hypertension, and smoking are associated with Alzheimer disease (AD) and represent promising targets for intervention. However, the causality of these associations is unclear. We sought to assess the causal nature of these associations using Mendelian randomization (MR). Methods and Findings We used SNPs associated with each risk factor as instrumental variables in MR analyses. We considered type 2 diabetes (T2D, N SNPs = 49), fasting glucose (N SNPs = 36), insulin resistance (N SNPs = 10), body mass index (BMI, N SNPs = 32), total cholesterol (N SNPs = 73), HDL-cholesterol (N SNPs = 71), LDL-cholesterol (N SNPs = 57), triglycerides (N SNPs = 39), systolic blood pressure (SBP, N SNPs = 24), smoking initiation (N SNPs = 1), smoking quantity (N SNPs = 3), university completion (N SNPs = 2), and years of education (N SNPs = 1). We calculated MR estimates of associations between each exposure and AD risk using an inverse-variance weighted approach, with summary statistics of SNP–AD associations from the International Genomics of Alzheimer’s Project, comprising a total of 17,008 individuals with AD and 37,154 cognitively normal elderly controls. We found that genetically predicted higher SBP was associated with lower AD risk (odds ratio [OR] per standard deviation [15.4 mm Hg] of SBP [95% CI]: 0.75 [0.62–0.91]; p = 3.4 × 10−3). Genetically predicted higher SBP was also associated with a higher probability of taking antihypertensive medication (p = 6.7 × 10−8). Genetically predicted smoking quantity was associated with lower AD risk (OR per ten cigarettes per day [95% CI]: 0.67 [0.51–0.89]; p = 6.5 × 10−3), although we were unable to stratify by smoking history; genetically predicted smoking initiation was not associated with AD risk (OR = 0.70 [0.37, 1.33]; p = 0.28). We saw no evidence of causal associations between glycemic traits, T2D, BMI, or educational attainment and risk of AD (all p > 0.1). Potential limitations of this study include the small proportion of intermediate trait variance explained by genetic variants and other implicit limitations of MR analyses. Conclusions Inherited lifetime exposure to higher SBP is associated with lower AD risk. These findings suggest that higher blood pressure—or some environmental exposure associated with higher blood pressure, such as use of antihypertensive medications—may reduce AD risk. PMID:26079503

Dietary inflammation factor rating™ system and risk of Alzheimer’s disease in elders

PubMed Central

Gu, Yian; Nieves, Jeri W; Luchsinger, Jose A; Scarmeas, Nikolaos

2010-01-01

It has been suggested that inflammation is involved in Alzheimer’s disease (AD) pathogenesis. The aim of this study is to evaluate the association between inflammatory aspects of diet and incident AD risk. 2258 non-demented elderly (age ≥ 65) in New York who provided dietary information at baseline were followed-up prospectively for AD development. We examined the composite total Inflammation Factor Rating (tIFR), as a measure of inflammatory impact of foods, in relation with (i) serum level of high-sensitivity C-reactive protein (hsCRP) and (ii) risk of incident AD using Cox proportional hazards model. The tIFR was not associated with serum hsCRP level. After an average of 4.0 years of follow-up, 262 subjects developed incident AD. The tIFR was not associated with AD risk: compared to the lowest tertile of tIFR (most pro-inflammatory), HRs (95% CI) for the highest tertile (most anti-inflammatory) was 0.97(0.69–1.35) (p-for-trend=0.84), in the adjusted model. We conclude that tIFR might not be a biologically relevant measure of the inflammatory impact of the diet. Additionally, although it remains possible that tIFR might be related with some other aspects of inflammation not captured by hsCRP, lack of association with AD risk suggests its limited clinical utility. PMID:21606905

ApoE -491A/T promoter polymorphism is not an independent risk factor, but associated with the epsilon4 allele in Hungarian Alzheimer's dementia population.

PubMed

Juhász, Anna; Palotás, András; Janka, Zoltán; Rimanóczy, Agnes; Palotás, Miklós; Bódi, Nikoletta; Boda, Krisztina; Zana, Marianna; Vincze, Gábor; Kálmán, János

2005-05-01

Apolipoprotein E gene (Apo(epsilon)) has three common alleles (epsilon2, epsilon3, and epsilon4), of which epsilon4 has been shown to be associated with an increased risk for Alzheimer's disease (AD). Possible additional genetic factors, like the -491A variant of ApoE promoter may modify the development of AD, independently of the ApoE allele status. The objective of this study was to investigate whether A/T allelic polymorphism at site-491 of the ApoE promoter is associated with AD in a Hungarian population. The genomic DNA isolated from peripheral blood lymphocytes of 52 late-onset AD and 53 control individuals was used as a template for the two examined polymorphisms and PCR assay was applied. The epsilon4 allele was significantly over-represented in the AD group (28%) as compared with the control population (7%). No significant differences have been found between the control and the AD populations regarding the occurrence of the promoter A allele frequencies (control: 77%, AD: 70%). However, the AA genotype was more frequent in the AD group (48%) than in the control (10%) when the presence of epsilon4 allele was also considered. It is unlikely therefore that the -491A variant of the ApoE promoter gene is an independent risk factor in the Hungarian AD population, but a linkage disequilibrium exists between the two examined mutations.

Mechanism of depression as a risk factor in the development of Alzheimer's disease: the function of AQP4 and the glymphatic system.

PubMed

Xia, Maosheng; Yang, Li; Sun, Guangfeng; Qi, Shuang; Li, Baoman

2017-02-01

Many studies have indicated that a history of depression increases the risk of developing Alzheimer's disease (AD); however, the potential pathogenestic mechanism by which depression functions as a high risk factor for AD remains unknown. Recently, a "cerebral lymphatic system" referred to as "glymphatic system" has been demonstrated to be responsible for neuronal extracellular waste protein clearance via a paravascular pathway. However, the function of glymphatic pathway has not been determined in depressive disorders. The present study used an animal model of chronic unpredictable mild stress (CUMS) to determine the function of glymphatic pathway by using fluorescence tracers. Immunohistochemistry was used to assess the accumulation of endogenous mouse and exogenous human amyloid beta 42 (Aβ42) in CUMS-treated mice with or without treatment with antidepressant fluoxetine. Glymphatic pathway circulation was impaired in mice treated with CUMS; moreover, glymphatic pathway dysfunction suppressed Aβ42 metabolism, because the accumulation of endogenous and exogenous Aβ42 was increased in the brains of the CUMS-treated mice. However, treatment with fluoxetine reversed these destructive effects of CUMS on glymphatic system. In anhedonic mice, the expression of the water channel aquaporin 4 (AQP4), a factor in glymphatic pathway dysfunction, was down-regulated in cortex and hippocampus. The dysfunction of glymphatic system suggested why a history of depression may be a strong risk factor for AD in anhedonic mice. We hope our study will contribute to an understanding of the risk mechanism of depressive disorder in the development of AD and the mechanisms of antidepressant therapies in AD.

HIGHER SERUM TOTAL CHOLESTEROL LEVELS IN LATE MIDDLE AGE ARE ASSOCIATED WITH GLUCOSE HYPOMETABOLISM IN BRAIN REGIONS AFFECTED BY ALZHEIMER’S DISEASE AND NORMAL AGING

PubMed Central

Reiman, Eric M.; Chen, Kewei; Langbaum, Jessica B.S.; Lee, Wendy; Reschke, Cole; Bandy, Daniel; Alexander, Gene E.; Caselli, Richard J.

2010-01-01

Epidemiological studies suggest that higher midlife serum total cholesterol levels are associated with an increased risk of Alzheimer’s disease (AD). Using fluorodeoxyglucose positron emission tomography (PET) in the study of cognitively normal late-middle-aged people, we demonstrated an association between apolipoprotein E (APOE) ε4 gene dose, the major genetic risk factor for late-onset AD, and lower measurements of the cerebral metabolic rate for glucose (CMRgl) in AD-affected brain regions, we proposed using PET as a presymptomatic endophenotype to evaluate other putative AD risk modifiers, and we then used it to support an aggregate cholesterol-related genetic risk score in the risk of AD. In the present study, we used PET to investigate the association between serum total cholesterol levels and cerebral metabolic rate for glucose metabolism (CMRgl) in 117 cognitively normal late middle-aged APOE ε4 homozygotes, heterozygotes and noncarriers. Higher serum total cholesterol levels were associated with lower CMRgl bilaterally in precuneus, parietotemporal and prefrontal regions previously found to be preferentially affected by AD, and in additional frontal regions previously found to be preferentially affected by normal aging. The associations were greater in APOE ε4 carriers than non-carriers in some of the AD-affected brain regions. We postulate the higher midlife serum total cholesterol levels accelerate brain processes associated with normal aging and conspire with other risk factors in the predisposition to AD. We propose using PET in proof-of-concept randomized controlled trials to rapidly evaluate the effects of midlife cholesterol-lowering treatments on the brain changes associated with normal aging and AD. PMID:19631758

Smoking, death, and Alzheimer disease: a case of competing risks.

PubMed

Chang, Chung-Chou H; Zhao, Yongyun; Lee, Ching-Wen; Ganguli, Mary

2012-01-01

If smoking is a risk factor for Alzheimer disease (AD) but a smoker dies of another cause before developing or manifesting AD, smoking-related mortality may mask the relationship between smoking and AD. This phenomenon, referred to as competing risk, complicates efforts to model the effect of smoking on AD. Typical survival regression models assume that censorship from analysis is unrelated to an individual's probability for developing AD (ie, censoring is noninformative). However, if individuals who die before developing AD are younger than those who survive long enough to develop AD, and if they include a higher percentage of smokers than nonsmokers, the incidence of AD will appear to be higher in older individuals and in nonsmokers. Further, age-specific mortality rates are higher in smokers because they die earlier than nonsmokers. Therefore, if we fail to take into account the competing risk of death when we estimate the effect of smoking on AD, we bias the results and are in fact only comparing the incidence of AD in nonsmokers with that in the healthiest smokers. In this study, we demonstrate that the effect of smoking on AD differs in models that are and are not adjusted for competing risks.

Adding Salt to Meals as a Risk Factor of Type 2 Diabetes Mellitus: A Case-Control Study.

PubMed

Radzeviciene, Lina; Ostrauskas, Rytas

2017-01-13

Type 2 diabetes mellitus (T2DM) is thought to arise from the complex interplay between genetic and environmental factors. It is important to identify modifiable risk factors that may help to reduce the risk of diabetes. Data on salt intake and the risk of type 2 diabetes are limited. The aim of this study was to assess the relationship between adding salt to prepared meals and the risk of type 2 diabetes. In a case-control study, we included 234 cases, all of whom were patients aged 35-86 years with a newly confirmed diagnosis of T2DM, and 468 controls that were free of the disease. Cases and controls (ratio 1:2) were matched by gender and age (±5 years). A questionnaire was used to collect information on possible risk factors for diabetes. Adding salt to prepared meals was assessed according to: Never, when there was not enough, or almost every time without tasting. The odds ratios (OR), and 95% confidence intervals (CI) for type 2 diabetes was calculated using a conditional logistic regression. The cases had a higher body mass index and a significantly lower education level compared to the controls. Variables such as waist circumference, body mass index, eating speed, smoking, family history of diabetes, arterial hypertension, plasma triglycerides, educational level, occupational status, morning exercise, marital status, daily urine sodium excretion, and daily energy intake were retained in the models as confounders. After adjusting for possible confounders, an approximately two-fold increased risk of type 2 diabetes was determined in subjects who add salt to prepared meals when "it is not enough" or "almost every time without tasting" (1.82; 95% CI 1.19-2.78; p = 0.006) compared with never adding salt. Presented data suggest the possible relationship between additional adding of salt to prepared meals and an increased risk of type 2 diabetes.

Environmental risk factors and their role in the management of atopic dermatitis

PubMed Central

Kantor, Robert; Silverberg, Jonathan I.

2016-01-01

Introduction The etiology of atopic dermatitis (AD) is multifactorial with interaction between genetics, immune and environmental factors. Areas covered We review the role of prenatal exposures, irritants and pruritogens, pathogens, climate factors, including temperature, humidity, ultraviolet radiation, outdoor and indoor air pollutants, tobacco smoke exposure, water hardness, urban vs. rural living, diet, breastfeeding, probiotics and prebiotics on AD. Expert commentary The increased global prevalence of AD cannot be attributed to genetics alone, suggesting that evolving environmental exposures may trigger and/or flare disease in predisposed individuals. There is a complex interplay between different environmental factors, including individual use of personal care products and exposure to climate, pollution, food and other exogenous factors. Understanding these complex risk factors is crucial to developing targeted interventions to prevent the disease in millions. Moreover, patients require counseling on optimal regimens for minimization of exposure to irritants and pruritogens and other harmful exposures. PMID:27417220

Environmental risk factors and their role in the management of atopic dermatitis.

PubMed

Kantor, Robert; Silverberg, Jonathan I

2017-01-01

The etiology of atopic dermatitis (AD) is multifactorial with interaction between genetics, immune and environmental factors. Areas covered: We review the role of prenatal exposures, irritants and pruritogens, pathogens, climate factors, including temperature, humidity, ultraviolet radiation, outdoor and indoor air pollutants, tobacco smoke exposure, water hardness, urban vs. rural living, diet, breastfeeding, probiotics and prebiotics on AD. Expert commentary: The increased global prevalence of AD cannot be attributed to genetics alone, suggesting that evolving environmental exposures may trigger and/or flare disease in predisposed individuals. There is a complex interplay between different environmental factors, including individual use of personal care products and exposure to climate, pollution, food and other exogenous factors. Understanding these complex risk factors is crucial to developing targeted interventions to prevent the disease in millions. Moreover, patients require counseling on optimal regimens for minimization of exposure to irritants and pruritogens and other harmful exposures.

Role of familial factors in late-onset Alzheimer disease as a function of age.

PubMed

Wu, Z; Kinslow, C; Pettigrew, K D; Rapoport, S I; Schapiro, M B

1998-09-01

Whereas early-onset Alzheimer disease (AD; usually onset at age < 50 years) has been defined with genetic mutation on chromosomes 1, 14, and 21, the degree of familial contribution to late-onset AD is unclear. Further, it is uncertain if subgroups of late-onset AD exist. To examine the influence of familial factors as a function of age in late-onset AD we investigated lifetime risks and age-specific hazard rates of AD-like illness among late-onset AD probands' and controls' first-degree relatives, using questionnaires and medical records. As part of a longitudinal study on aging and AD, we studied 78 AD probands with age of onset > or =50 years (28 "definite" and 50 "probable" AD according to NINCDS/ADRDA criteria) and 101 healthy old controls seen since 1981. Both probands and controls were screened rigorously with medical tests and brain imaging and seen regularly until autopsy. Multiple informants and medical records were used for first-degree relatives. Among first-degree relatives, 49 secondary cases of AD-like illness were found for the AD probands' relatives (391 relatives 40 years old or older) compared with 20 cases among controls' relatives (456 relatives 40 years old or older). Relatives of AD probands had a significantly increased lifetime risk of AD-like illness of 52.8+/-11.4% by age 94 years compared with a lifetime risk in relatives of controls of 22.1+/-5.8% by age 90 years. Age-specific hazard rates in relatives of AD probands increased until the 75-79-year age interval and then decreased; in contrast the age-specific hazard rates increased in relatives of controls after the 80-84-year age interval. To determine if a dividing line exist among late-onset AD, several cutoff ages were used in our study to compare cumulative risk curves of AD-like illness between relatives of late-onset probands and relatives of late-late-onset probands. Differences in the pattern of cumulative incidence of AD in relatives showed that 67-71 years is the range for a dividing line between late- and late-late-onset AD. Age-specific hazard rates of AD in relatives supported a difference between late- and late-late-onset. Whereas these rates increased until the 75-79-year age interval and then decreased in late-onset AD, the rates began increasing after the 65-69-year age interval and through the oldest age interval in both late-late-onset AD and control groups. Our results support the concept that familial factors exist in late-onset AD and that different familial factors may exist in late-onset AD subgroups.

Depression as a risk factor for dementia and mild cognitive impairment: a meta-analysis of longitudinal studies.

PubMed

Gao, Yuan; Huang, Changquan; Zhao, Kexiang; Ma, Louyan; Qiu, Xuan; Zhang, Lei; Xiu, Yun; Chen, Lin; Lu, Wei; Huang, Chunxia; Tang, Yong; Xiao, Qian

2013-05-01

This study examined whether depression was a risk factor for onset of dementia including Alzheimer's disease (AD), vascular dementia (VD) and any dementia, and mild cognitive impairment (MCI) by using a quantitative meta-analysis of longitudinal studies. EMBASE and MEDLINE were searched for articles published up to February 2011. All studies that examined the relationship between depression and the onset of dementia or MCI were included. Pooled relative risk was calculated using fixed-effects models. Twelve studies met our inclusion criteria for this meta-analysis. All subjects were without dementia or MCI at baseline. Four, two, five, and four studies compared the incidence of AD, VD, any dementia, and MCI between subjects with or without depression, respectively. After pooling all the studies, subjects with depression had higher incidence of AD (relative risk (RR):1.66, 95% confidence interval (CI): 1.29-2.14), VD (RR: 1.89, 95% CI: 1.19-3.01), any dementia (RR: 1.55, 95% CI: 1.31-2.83), and MCI (RR: 1.97, 95% CI: 1.53-2.54) than those without depression. The quantitative meta-analysis showed that depression was a major risk factor for incidence of dementia (including AD, VD, and any dementia) and MCI. Copyright © 2012 John Wiley & Sons, Ltd.

Patterns of aeroallergen sensitization predicting risk for asthma in preschool children with atopic dermatitis.

PubMed

Calamelli, Elisabetta; Ricci, Giampaolo; Neri, Iria; Ricci, Lorenza; Rondelli, Roberto; Pession, Andrea; Patrizi, Annalisa

2015-06-01

Atopic dermatitis (AD) is a chronic inflammatory skin disorder mostly affecting young children. Although several studies aimed to identify the risk factors for asthma in AD children, many aspects still need to be clarified. The aim of this study was to investigate the possible risk factors for asthma at school age in 99 children with early-onset and IgE-mediated AD. All children performed clinical evaluation and total and specific IgE assay for a panel of inhalant and food allergens at two different times (t1 and t2) during preschool, and asthma diagnosis was assessed at one follow-up visit (t3) at school age. At t3, 39% of children had developed asthma. Of the variables compared, the sensitization to more than one class of inhalant allergens at t2 (mean age = 30 months) was associated with asthma, with grass (OR = 3.24, p = 0.020) and cat sensitization (OR = 2.74, p = 0.043) as independent risk factors. The sensitization pattern of a child with early-onset AD, also within the first 2-3 years of life, can reflect his risk to develop asthma. Therefore, testing these children for the more common allergens during this time frame should be recommended to predict the evolution of atopic diseases.

Prevalence and risk factors of maladaptive behaviour in young children with Autistic Disorder

PubMed Central

Hartley, S. L.; Sikora, D. M.; McCoy, R.

2010-01-01

Background Children with Autistic Disorder (AD) evidence more co-occurring maladaptive behaviours than their typically developing peers and peers with intellectual disability because of other aetiologies. The present study investigated the prevalence of Clinically Significant maladaptive behaviours during early childhood and identified at-risk subgroups of young children with AD. Method Parents rated their child’s maladaptive behaviours on the Child Behaviour Checklist (CBCL) in 169 children with AD aged 1.5 to 5.8 years. Results One-third of young children with AD had a CBCL Total Problems score in the Clinically Significant range. The highest percentage of Clinically Significant scores were in the Withdrawal, Attention, and Aggression CBCL syndrome scales. There was a high degree of co-morbidity of Clinically Significant maladaptive behaviours. Several subject characteristic risk factors for maladaptive behaviours were identified. Conclusions Findings highlight the need to include behavioural management strategies aimed at increasing social engagement, sustained attention and decreasing aggressive behaviour in comprehensive intervention programmes for young children with AD. PMID:18444989

Risk factors for atopic dermatitis in New Zealand children at 3.5 years of age.

PubMed

Purvis, D J; Thompson, J M D; Clark, P M; Robinson, E; Black, P N; Wild, C J; Mitchell, E A

2005-04-01

The prevalence of atopic dermatitis (AD) is increasing in Western societies. The hygiene hypothesis proposes that this is due to reduced exposure to environmental allergens and infections during early life. To examine factors associated with a diagnosis of AD at 3.5 years of age, especially those factors implicated by the hygiene hypothesis. The Auckland Birthweight Collaborative study is a case-control study of risk factors for small for gestational age babies. Cases were born at term with birthweight < or = 10th centile; controls were appropriate for gestational age, with birthweight > 10th centile. The infants were assessed at birth, 1 year and 3.5 years of age. Data were collected by parental interview and examination of the child. AD was defined as the presence of an itchy rash in the past 12 months with three or more of the following: history of flexural involvement; history of generally dry skin; history of atopic disease in parents or siblings; and visible flexural dermatitis as per photographic protocol. Statistical analyses took into account the disproportionate sampling of the study population. Analysis was restricted to European subjects. Eight hundred and seventy-one children were enrolled at birth, 744 (85.4%) participated at 1 year, and 550 (63.2%) at 3.5 years. AD was diagnosed in 87 (15.8%) children seen at 3.5 years. The prevalence of AD did not differ by birthweight. AD at 3.5 years was associated with raised serum IgE > 200 kU L(-1), and wheezing, asthma, rash or eczema at 1 year. In multivariate analysis, adjusted for parental atopy and breastfeeding, AD at 3.5 years was associated with atopic disease in the parents: maternal atopy only, adjusted odds ratio (OR) 3.83, 95% confidence interval (CI) 1.20-12.23; paternal atopy only, adjusted OR 3.59, 95% CI 1.09-11.75; both parents atopic, adjusted OR 6.12, 95% CI 2.02-18.50. There was a higher risk of AD with longer duration of breastfeeding: < 6 months, adjusted OR 6.13, 95% CI 1.45-25.86; > or = 6 months, adjusted OR 9.70, 95% CI 2.47-38.15 compared with never breastfed. These findings remained significant after adjusting for environmental factors and a personal history of atopy. AD at 3.5 years was associated with owning a cat at 3.5 years (adjusted OR 0.45, 95% CI 0.21-0.97) but not with owning a dog at 3.5 years, pets at 1 year, nor with older siblings. Furthermore, AD at 3.5 years was not associated with gender, socioeconomic status, maternal smoking, parity, damp, mould, immunizations, body mass index or antibiotic use in first year of life. A personal and a parental history of atopic disease are risk factors for AD at 3.5 years. Duration of breastfeeding was associated with an increased risk of AD. No association was found with those factors implicated by the hygiene hypothesis. This study suggests that breastfeeding should not be recommended for the prevention of AD.

[Relationship between multi-slice spiral CT angiography imaging features and in-hospital death of patients with aortic dissection].

PubMed

Xiao, Z Y; Wang, H J; Yao, C L; Gu, G R; Xue, Y; Yin, J; Chen, J; Zhang, C; Tong, C Y; Song, Z J

2017-03-24

Objective: To explore the imaging manifestations of multi-slice spiral CT angiography (CTA) and relationship with in-hospital death in patients with aortic dissection (AD). Methods: The clinical data of 429 patients with AD who underwent CTA in Zhongshan Hospital of Fudan University between January 2009 and January 2016 were retrospectively analyzed. AD patients were divided into 2 groups, including operation group who underwent surgery or interventional therapy (370 cases) and non-operation group who underwent medical conservative treatment(59 cases). The multi-slice spiral CTA imaging features of AD were analyzed, and multivariate logistic regression analysis was used to investigate the relationship between imaging manifestations and in-hospital death in AD patients. Results: There were 12 cases (3.24%) of in-hospital death in operation group, and 28 cases (47.46%) of in-hospital death in non-operation group( P <0.001). AD involved different vascular branches. Multi-slice spiral CTA can clearly show the dissection of true and false lumen, and intimal tear was detected in 363 (84.62%) cases, outer wall calcification was revealed in 63 (14.69%) cases, and thrombus formation was present in 227 (52.91%) cases. The multivariate logistic regression analysis showed that the number of branch vessels involved ( OR =1.374, 95% CI 1.081-1.745, P =0.009) and tearing false lumen range( OR =2.059, 95% CI 1.252-3.385, P =0.004) were independent risk factors of in-hospital death in AD patients, and the number of branch vessels involved ( OR =1.600, 95% CI 1.062-2.411, P =0.025) was independent risk factor of in-hospital death in the operation group, while the tearing false lumen range ( OR =2.315, 95% CI 1.019-5.262, P =0.045) was independent risk factor of in-hospital death of non-operation group. Conclusions: Multi-slice spiral CTA can clearly show the entire AD, true and false lumen, intimal tear, wall calcification and thrombosis of AD patients. The number of branch vessels involved and tearing false lumen range are the independent risk factors of in-hospital death in AD patients.

Risk Factors for Initiation of Potentially Inappropriate Medications in Community-Dwelling Older Adults with and without Alzheimer's Disease.

PubMed

Hyttinen, Virva; Taipale, Heidi; Tanskanen, Antti; Tiihonen, Jari; Tolppanen, Anna-Maija; Hartikainen, Sirpa; Valtonen, Hannu

2017-01-01

Various criteria have been created to define potentially inappropriate medications (PIMs) to help improve the quality and safety of medicine use in older patients. Individuals with Alzheimer's disease (AD) may be at higher risk of adverse drug events associated with PIMs (such as falls). Our objective was to determine the risk factors for PIM initiation in a nationwide cohort of community dwellers aged ≥65 years with and without AD. The Finnish nationwide MEDALZ cohort includes all patients diagnosed with AD in 2005-2011 (n = 70,718) and two comparison individuals without AD (non-AD) matched for age, sex and region of residence for each person with AD. After a 1-year washout period for PIM use and exclusion of those aged <65 years, we included 50,494 patients with AD and 106,306 comparison subjects. PIM use was defined according to Finnish criteria. Subjects without AD initiated PIMs more frequently than those with AD (16.4 vs. 12.2%, respectively; p < 0.001). The most common PIMs were muscle relaxants and urinary antispasmodics. Older individuals (aged ≥75 years) were less likely to initiate PIMs. In the AD group, women were less likely to initiate PIMs than men. More comorbidities were associated with PIM initiation, especially in the non-AD group. The use of opioids or psychotropic medicines was associated with PIM initiation in both cohorts. Regional differences between university hospital districts were observed. PIM initiation was dependent on patient characteristics and possibly also some healthcare system-related factors such as differing regional treatment practices. It is important that medicines prescribed to the older vulnerable population are assessed regularly to avoid adverse effects and ensure safe pharmacotherapy, especially in those with multiple comorbidities.

IGF-I gene variability is associated with an increased risk for AD.

PubMed

Vargas, Teo; Martinez-Garcia, Ana; Antequera, Desiree; Vilella, Elisabet; Clarimon, Jordi; Mateo, Ignacio; Sanchez-Juan, Pascual; Rodriguez-Rodriguez, Eloy; Frank, Ana; Rosich-Estrago, Marcel; Lleo, Alberto; Molina-Porcel, Laura; Blesa, Rafael; Gomez-Isla, Teresa; Combarros, Onofre; Bermejo-Pareja, Felix; Valdivieso, Fernando; Bullido, Maria Jesus; Carro, Eva

2011-03-01

Insulin-like growth factor I (IGF-I), a neuroprotective factor with a wide spectrum of actions in the adult brain, is involved in the pathogenesis of Alzheimer's disease (AD). Circulating levels of IGF-I change in AD patients and are implicated in the clearance of brain amyloid beta (Aβ) complexes. To investigate this hypothesis, we screened the IGF-I gene for various well known single nucleotide polymorphisms (SNPs) covering % of the gene variability in a population of 2352 individuals. Genetic analysis indicated different distribution of genotypes of 1 single nucleotide polymorphism, and 1 extended haplotype in the AD population compared with healthy control subjects. In particular, the frequency of rs972936 GG genotype was significantly greater in AD patients than in control subjects (63% vs. 55%). The rs972936 GG genotype was associated with an increased risk for disease, independently of apolipoprotein E genotype, and with enhanced circulating levels of IGF-I. These findings suggest that polymorphisms within the IGF-I gene could infer greater risk for AD through their effect on IGF-I levels, and confirm the physiological role IGF-I in the pathogenesis of AD. Copyright © 2011 IBRO. Published by Elsevier Inc. All rights reserved.

Visit-to-Visit Variations in Fasting Plasma Glucose and HbA1c Associated With an Increased Risk of Alzheimer Disease: Taiwan Diabetes Study.

PubMed

Li, Tsai-Chung; Yang, Chun-Pai; Tseng, Shih-Ting; Li, Chia-Ing; Liu, Chiu-Shong; Lin, Wen-Yuan; Hwang, Kai-Lin; Yang, Sing-Yu; Chiang, Jen-Huai; Lin, Cheng-Chieh

2017-09-01

The relationship between glycemic variability and the incidence of Alzheimer disease (AD) in patients with type 2 diabetes mellitus (T2DM) is unclear. The aim of this study was to examine visit-to-visit variations in fasting plasma glucose (FPG) and glycated hemoglobin (HbA 1c ) represented by the coefficient of variation (CV) and to determine whether they were independently associated with AD, irrespective of HbA 1c and other traditional risk factors in such patients. Patients with T2DM enrolled in the National Diabetes Care Management Program, age ≥60 years, and without diagnosis of AD ( n = 16,706) were included in the study. Potential risk factors were analyzed using extended Cox proportional hazards regression models for competing risk of mortality on AD incidence. During a median follow-up of 8.88 years, 831 incident cases of AD were identified, with a crude incidence rate of 3.5/1,000 person-years. After adjustment for sociodemographic factors, lifestyle behaviors, diabetes-related variables, FPG and HbA 1c , drug-related variables, and comorbidities, both FPG CV and HbA 1c CV were found to be significant predictors of AD, with corresponding hazard ratios of 1.27 (95% CI 1.06-1.52) for the third tertile in FPG CV and 1.32 (95% CI 1.11-1.58) for the third tertile in HbA 1c CV. FPG CV and HbA 1c CV are independently associated with AD. The associations between glycemic variability and AD demonstrated in this study suggest a linked pathophysiological mechanism, which is worthy of further investigation. Further research is required to confirm our results and to evaluate whether FPG CV and HbA 1c CV can be valuable therapeutic targets for patients with T2DM at risk. © 2017 by the American Diabetes Association.

Observational and ecological studies of dietary advanced glycation end products in national diets and Alzheimer's disease incidence and prevalence.

PubMed

Perrone, Lorena; Grant, William B

2015-01-01

Considerable evidence indicates that diet is an important risk-modifying factor for Alzheimer's disease (AD). Evidence is also mounting that dietary advanced glycation end products (AGEs) are important risk factors for AD. This study strives to determine whether estimated dietary AGEs estimated from national diets and epidemiological studies are associated with increased AD incidence. We estimated values of dietary AGEs using values in a published paper. We estimated intake of dietary AGEs from the Washington Heights-Inwood Community Aging Project (WHICAP) 1992 and 1999 cohort studies, which investigated how the Mediterranean diet (MeDi) affected AD incidence. Further, AD prevalence data came from three ecological studies and included data from 11 countries for 1977-1993, seven developing countries for 1995-2005, and Japan for 1985-2008. The analysis used dietary AGE values from 20 years before the AD prevalence data. Meat was always the food with the largest amount of AGEs. Other foods with significant AGEs included fish, cheese, vegetables, and vegetable oil. High MeDi adherence results in lower meat and dairy intake, which possess high AGE content. By using two different models to extrapolate dietary AGE intake in the WHICAP 1992 and 1999 cohort studies, we showed that reduced dietary AGE significantly correlates with reduced AD incidence. For the ecological studies, estimates of dietary AGEs in the national diets corresponded well with AD prevalence data even though the cooking methods were not well known. Dietary AGEs appear to be important risk factors for AD.

Occupational Attainment as Risk Factor for Progression from Mild Cognitive Impairment to Alzheimer's Disease: A CREDOS Study.

PubMed

Myung, Woojae; Lee, Chunsoo; Park, Jin Hong; Woo, Sook-Young; Kim, Seonwoo; Kim, Sangha; Chung, Jae Won; Kang, Hyo Shin; Lim, Shinn-Won; Choi, Junbae; Na, Duk L; Kim, Seong Yoon; Lee, Jae-Hong; Han, Seol-Heui; Choi, Seong Hye; Kim, Sang Yun; Carroll, Bernard J; Kim, Doh Kwan

2017-01-01

High occupational attainment has been known as a marker of cognitive reserve. Previous studies in the general population have shown that high occupational attainment is associated with reduced risk of Alzheimer's disease (AD). However, few studies have assessed the effect of occupational attainment on the clinical course of mild cognitive impairment (MCI). In this study, we evaluated whether individuals with high occupational attainment show more frequent progression from MCI to AD. Participants (n = 961) with MCI were recruited from a nationwide, hospital-based multi-center cohort, and were followed for up to 60 months (median: 17.64, interquartile range [12.36, 29.28]). We used Cox regression for competing risks to analyze the effect of occupational attainment on development of AD, treating dementia other than AD as a competing risk. Among the 961 individuals with MCI, a total of 280 (29.1%) converted to dementia during the follow-up period. The risk of progression to AD was higher in the individuals with high occupational attainment after controlling for potential confounders (hazard ratio = 1.83, 95% confidence interval = 1.25-2.69, p = 0.002). High occupational attainment in individuals with MCI is an independent risk factor for higher progression rate of MCI to AD. This result suggests that the protective effect of high occupational attainment against cognitive decline disappears in the MCI stage, and that careful assessment of occupational history can yield important clinical information for prognosis in individuals with MCI.

Recall bias in childhood atopic diseases among adults in the Odense Adolescence Cohort Study.

PubMed

Mortz, Charlotte G; Andersen, Klaus E; Bindslev-Jensen, Carsten

2015-11-01

Atopic dermatitis (AD) is a common disease in childhood and an important risk factor for the later development of other atopic diseases. Many publications on childhood AD use questionnaires based on information obtained in adulthood, which introduce the possibility of recall bias. In a prospective cohort study, recall bias was evaluated in 1,501 unselected schoolchildren (mean age 14 years) evaluated for the first time in 1995 with a standardized questionnaire combined with a clinical examination and repeated in 2010. The lifetime prevalence of AD was 34.1% including data obtained both during school age and 15 years later, compared with 23.6% including data only from adulthood. The most important factors for remembering having had AD in childhood were: (i) long duration of dermatitis in childhood; (ii) adult hand eczema; and (iii) concomitant atopic disease. Recall bias for childhood AD affected the results of logistic regression on adult hand eczema and is a significant problem in retrospective epidemiological questionnaire studies evaluating previous AD as a risk factor for development of other diseases.

Development and validation of the Alzheimer's prevention beliefs measure in a multi-ethnic cohort-a behavioral theory approach.

PubMed

Seifan, Alon; Ganzer, Christine A; Vermeylen, Francoise; Parry, Stephen; Zhu, Jifeng; Lyons, Abigail; Isaacson, Richard; Kim, Sarang

2017-12-01

Understanding health beliefs and how they influence willingness will enable the development of targeted curricula that maximize public engagement in Alzheimer's disease (AD) risk reduction behaviors. Literature on behavioral theory and community input was used to develop and validate a health beliefs survey about AD risk reduction among 428 community-dwelling adults. Principal component analysis was performed to assess internal consistency. Linear regression was performed to identify key predictors of Willingness to engage in AD risk reduction behaviors. The measure as well as the individual scales (Benefits, Barriers, Severity, Susceptibility and Social Norm) were found to be internally consistent. Overall, as Benefits and Barriers scores increased, Willingness scores also increased. Those without prior AD experience or family history had lower willingness scores. Finally, we observed an interaction between age and norms, suggesting that social factors related to AD prevention may differentially affect people of different ages. The Alzheimer Prevention Beliefs Measure provides assessment of several health belief factors related to AD prevention. Age, Family History, Logistical Barriers and total Benefits are significant determinants of willingness to engage in AD risk reduction behaviors, such as seeing a doctor or making a lifestyle change. © The Author 2017. Published by Oxford University Press on behalf of Faculty of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Seizures and Epilepsy in Alzheimer’s Disease

PubMed Central

Friedman, Daniel; Honig, Lawrence S.; Scarmeas, Nikolaos

2013-01-01

Introduction Many studies have shown that patients with Alzheimer’s disease (AD) are at increased risk for developing seizures and epilepsy. However, reported prevalence and incidence of seizures and relationship of seizures to disease measures such as severity, outcome and progression vary widely between studies. Methods Literature review of the available clinical and epidemiological data on the topic of seizures in patients with AD. We review seizure rates and types, risk factors for seizures, electroencephalogram (EEG)studies, and treatment responses. Finally, we consider limitations and methodological issues. Results There is considerable variability in the reported prevalence and incidence of seizures in patients with AD - with reported lifetime prevalence rates of 1.5 - 64%. More recent, prospective, and larger studies in general report lower rates. Some, but not all, studies have noted increased seizure risk with increasing dementia severity or with younger age of AD onset. Generalized convulsive seizures are the most commonly reported type, but often historical information is the only basis used to determine seizure type and the manifestation of seizures may be difficult to distinguish from other behaviors common in demented patients. EEG has infrequently been performed and reported. Data on treatment of seizures in AD are extremely limited. Similarly, the relationship between seizures and cognitive impairment in AD is unclear. Conclusions The literature on seizures and epilepsy in AD, including diagnosis, risk factors, and response to treatment suffers from methodological limitations and gaps. PMID:22070283

Effect of prolonged breast-feeding on risk of atopic dermatitis in early childhood.

PubMed

Hong, Soyoung; Choi, Won-Jun; Kwon, Ho-Jang; Cho, Yoon Hee; Yum, Hye Yung; Son, Dong Koog

2014-01-01

The effect of breast-feeding on the risk of developing atopic disease remains controversial. This study is an investigation of the effect of breast-feeding on current atopic dermatitis (AD) among Korean children. This cross-sectional study of children's histories of current AD and environmental factors was completed by the subjects' parents. The subjects included 10,383 children aged 0-13 years in Seoul, Korea, in 2008. The diagnostic criteria of the International Study of Asthma and Allergies in Childhood were applied in this study. Adjustments were performed for age, gender, maternal education, smoking in the household, relocation to a new house within 1 year of birth, and parental history of atopic disease. After adjustment for confounders, age and duration of maternal education were found to be inversely associated with the prevalence of AD. Among subjects aged ≤5 years, the prevalence of AD was positively associated with the duration of breast-feeding (p < 0.001). However, there was no significant association between AD and breast-feeding among children >5 years of age. Regardless of parental history of atopic diseases, breast-feeding >12 months was a significant risk factor for AD. The effect of breast-feeding differed by age group. Prolonged breast-feeding increased the risk of AD in children <5 years of age, regardless of parental history of atopic diseases.

CHOLESTEROL-RELATED GENETIC RISK SCORES ARE ASSOCIATED WITH HYPOMETABOLISM IN ALZHEIMER’S-AFFECTED BRAIN REGIONS

PubMed Central

Reiman, Eric M.; Chen, Kewei; Caselli, Richard J.; Alexander, Gene E.; Bandy, Daniel; Adamson, Jennifer L.; Lee, Wendy; Cannon, Ashley; Stephan, Elizabeth A.; Stephan, Dietrich A.; Papassotiropoulos, Andreas

2008-01-01

We recently implicated a cluster of nine single nucleotide polymorphisms from seven cholesterol-related genes in the risk of Alzheimer’s disease (AD) in a European cohort, and we proposed calculating an aggregate cholesterol-related genetic score (CREGS) to characterize a person’s risk. In a separate study, we found that apolipoprotein E (APOE) ε4 gene dose, an established AD risk factor, was correlated with fluorodeoxyglucose (FDG) positron emission tomography (PET) measurements of hypometabolism in AD-affected brain regions in a cognitively normal American cohort, and we proposed using PET as a presymptomatic endophenotype to help assess putative modifiers of AD risk. Thus, the objective in the present study is to determine whether CREGS is related to PET measurements of hypometabolism in AD-affected brain regions. DNA and PET data from 141 cognitively normal late middle-aged APOE ε4 homozygotes, heterozygotes and non-carriers were analyzed to evaluate the relationship between CREGS and regional PET measurements. Cholesterol-related genetic risk scores were associated with hypometabolism in AD-affected brain regions, even when controlling for the effects of APOE ε4 gene dose. The results support the role of cholesterol-related genes in the predisposition to AD, and support the value of neuroimaging in the presymptomatic assessment of putative modifiers of AD risk. PMID:18280754

Linking vascular disorders and Alzheimer’s disease: Potential involvement of BACE1

PubMed Central

Cole, Sarah L.; Vassar, Robert

2012-01-01

The etiology of Alzheimer’s disease (AD) remains unknown. However, specific risk factors have been identified, and aging is the strongest AD risk factor. The majority of cardiovascular events occur in older people and a close relationship between vascular disorders and AD exists. Amyloid plaques, composed of the beta amyloid peptide (Aβ), are hallmark lesions in AD and evidence indicates that Aβ plays a central role in AD pathophysiology. The BACE1 enzyme is essential for Aβ generation, and BACE1 levels are elevated in AD brain. The cause(s) of this BACE1 elevation remains undetermined. Here we review the potential contribution of vascular disease to AD pathogenesis. We examine the putative vasoactive properties of Aβ and how the cellular changes associated with vascular disease may elevate BACE1 levels. Despite increasing evidence, the exact role(s) vascular disorders play in AD remains to be determined. However, given that vascular diseases can be addressed by lifestyle and pharmacologic interventions, the potential benefits of these therapies in delaying the clinical appearance and progression of AD may warrant investigation. PMID:18289733

Role of Environmental Contaminants in the Etiology of Alzheimer's Disease: A Review

PubMed Central

Manivannan, Yegambaram; Manivannan, Bhagyashree; Beach, Thomas G.; Halden, Rolf U.

2015-01-01

Alzheimer's dis ease (AD) is a leading cause of mortality in the developed world with 70% risk attributable to genetics. The remaining 30% of AD risk is hypothesized to include environmental factors and human lifestyle patterns. Environmental factors possibly include inorganic and organic hazards, exposure to toxic metals (aluminium, copper), pesticides (organochlorine and organophosphate insecticides), industrial chemicals (flame retardants) and air pollutants (particulate matter). Long term exposures to these environmental contaminants together with bioaccumulation over an individual's life-time are speculated to induce neuroinflammation and neuropathology paving the way for developing AD. Epidemiologic associations between environmental contaminant exposures and AD are still limited. However, many in vitro and animal studies have identified toxic effects of environmental contaminants at the cellular level, revealing alterations of pathways and metabolisms associated with AD that warrant further investigations. This review provides an overview of in vitro, animal and epidemiological studies on the etiology of AD, highlighting available data supportive of the long hypothesized link between toxic environmental exposures and development of AD pathology. PMID:25654508

Brain-Derived Neurotrophic Factor in Alzheimer's Disease: Risk, Mechanisms, and Therapy.

PubMed

Song, Jing-Hui; Yu, Jin-Tai; Tan, Lan

2015-12-01

Brain-derived neurotrophic factor (BDNF) has a neurotrophic support on neuron of central nervous system (CNS) and is a key molecule in the maintenance of synaptic plasticity and memory storage in hippocampus. However, changes of BDNF level and expression have been reported in the CNS as well as blood of Alzheimer's disease (AD) patients in the last decade, which indicates a potential role of BDNF in the pathogenesis of AD. Therefore, this review aims to summarize the latest progress in the field of BDNF and its biological roles in AD pathogenesis. We will discuss the interaction between BDNF and amyloid beta (Aβ) peptide, the effect of BDNF on synaptic repair in AD, and the association between BDNF polymorphism and AD risk. The most important is, enlightening the detailed biological ability and complicated mechanisms of action of BDNF in the context of AD would provide a future BDNF-related remedy for AD, such as increment in the production or release of endogenous BDNF by some drugs or BDNF mimics.

9β Polymorphism of the Glucocorticoid Receptor Gene Appears to Have Limited Impact in Patients with Addison’s Disease

PubMed Central

Ross, Ian Louis; Dandara, Collet; Swart, Marelize; Lacerda, Miguel; Schatz, Desmond; Blom, Dirk Jacobus

2014-01-01

Background Addison’s disease (AD) has been associated with an increased risk of cardiovascular disease. Glucocorticoid receptor polymorphisms that alter glucocorticoid sensitivity may influence metabolic and cardiovascular risk factors in patients with AD. The 9β polymorphism of the glucocorticoid receptor gene is associated with relative glucocorticoid resistance and has been reported to increase the risk of myocardial infarction in the elderly. We explored the impact of this polymorphism in patients with AD. Materials and Methods 147 patients with AD and 147 age, gender and ethnicity matched healthy controls were recruited. Blood was taken in a non-fasted state for plasma lipid determination, measurement of cardiovascular risk factors and DNA extraction. Results Genotype data for the 9β polymorphism was available for 139 patients and 146 controls. AD patients had a more atherogenic lipid profile characterized by an increase in the prevalence of small dense LDL (p = 0.003), increased triglycerides (p = 0.002), reduced HDLC (p<0.001) an elevated highly sensitive C-reactive protein (p = 0.01), compared with controls. The 9β polymorphism (at least one G allele) was found in 28% of patients and controls respectively. After adjusting for age, gender, ethnicity, BMI and hydrocortisone dose per metre square of body surface area in patients, there were no significant metabolic associations with this polymorphism and hydrocortisone doses were not higher in patients with the polymorphism. Conclusions This study did not identify any associations between the 9β polymorphism and cardiovascular risk factors or hydrocortisone dose and determination of this polymorphism is therefore unlikely to be of clinical benefit in the management of patients with AD. PMID:24466047

9β Polymorphism of the glucocorticoid receptor gene appears to have limited impact in patients with Addison's disease.

PubMed

Ross, Ian Louis; Dandara, Collet; Swart, Marelize; Lacerda, Miguel; Schatz, Desmond; Blom, Dirk Jacobus

2014-01-01

Addison's disease (AD) has been associated with an increased risk of cardiovascular disease. Glucocorticoid receptor polymorphisms that alter glucocorticoid sensitivity may influence metabolic and cardiovascular risk factors in patients with AD. The 9β polymorphism of the glucocorticoid receptor gene is associated with relative glucocorticoid resistance and has been reported to increase the risk of myocardial infarction in the elderly. We explored the impact of this polymorphism in patients with AD. 147 patients with AD and 147 age, gender and ethnicity matched healthy controls were recruited. Blood was taken in a non-fasted state for plasma lipid determination, measurement of cardiovascular risk factors and DNA extraction. Genotype data for the 9β polymorphism was available for 139 patients and 146 controls. AD patients had a more atherogenic lipid profile characterized by an increase in the prevalence of small dense LDL (p = 0.003), increased triglycerides (p = 0.002), reduced HDLC (p<0.001) an elevated highly sensitive C-reactive protein (p = 0.01), compared with controls. The 9β polymorphism (at least one G allele) was found in 28% of patients and controls respectively. After adjusting for age, gender, ethnicity, BMI and hydrocortisone dose per metre square of body surface area in patients, there were no significant metabolic associations with this polymorphism and hydrocortisone doses were not higher in patients with the polymorphism. This study did not identify any associations between the 9β polymorphism and cardiovascular risk factors or hydrocortisone dose and determination of this polymorphism is therefore unlikely to be of clinical benefit in the management of patients with AD.

Early-versus Late-Onset Alzheimer Disease: Long-Term Functional Outcomes, Nursing Home Placement, and Risk Factors for Rate of Progression.

PubMed

Wattmo, Carina; Wallin, Åsa K

2017-01-01

Whether age at onset influences functional deterioration in Alzheimer disease (AD) is unclear. We, therefore, investigated risk factors for progression in activities of daily living (ADL) and nursing home placement (NHP) in cholinesterase inhibitor (ChEI)-treated patients with early-onset AD (EOAD) versus late-onset AD (LOAD). This 3-year, prospective, observational, multicenter study included 1,017 participants with mild-to-moderate AD; 143 had EOAD (onset <65 years) and 874 LOAD (onset ≥65 years). Possible sociodemographic and clinical factors that could affect functional outcome and NHP were analyzed using mixed-effects models and logistic regression, respectively. Younger individuals exhibited longer illness duration before AD diagnosis, whereas 6-month functional response to ChEI therapy, 3-year changes in ADL capacities, time from diagnosis to NHP, and survival time in nursing homes were similar between the groups. In LOAD, a higher ChEI dose, no antidepressant use, and lower education level were protective factors for slower instrumental ADL (IADL) decline. In EOAD, antihypertensives/cardiac therapy implied faster IADL progression but lower risk of NHP. This study highlights the clinical importance of an earlier diagnosis and treatment initiation and the need for functional evaluations in EOAD. Despite the age differences between EOAD and LOAD, a similar need for nursing homes was observed.

Suicidality among pregnant women in Brazil: prevalence and risk factors.

PubMed

Castro e Couto, Tiago; Brancaglion, Mayra Yara Martins; Cardoso, Mauro Nogueira; Faria, Gustavo Coutinho; Garcia, Frederico Duarte; Nicolato, Rodrigo; Aguiar, Regina Amélia Lopes P; Leite, Henrique Vitor; Corrêa, Humberto

2016-04-01

Suicide is one of the major causes of preventable death. We evaluated suicidality among pregnant women who participated in prenatal care in Brazil. A total of 255 patients were assessed using semi-structured interviews as well as the Edinburgh Postnatal Depression Scale (EPDS), Beck Depression Inventory (BDI), and Mini-International Neuropsychiatric Interview (MINI) Plus. Thereafter, Stata 12 was used to identify the significant predictors of current suicide risk (CSR) among participants using univariate and multivariate analyses (p < 0.05). According to MINI Plus module C, the lifetime suicide attempt rate was 12.55%. The overall CSR was 23.53%, distributed across risk levels of low (12.55%), moderate (1.18%), and high (9.80%). Our rates approximate those found in another Brazilian study (18.4%). Antenatal depression (AD), lifetime bipolar disorder, and any current anxiety disorder (as measured using the MINI) as well as BDI scores ≥15 and EPDS scores ≥11 were identified as positive risk factors in a univariate analysis (p < 0.001). These factors changed after a multivariate analysis was employed, and only years of education [odds ratio (OR) = 0.45; 95% confidence intervals (CIs) = 0.21-0.99], AD (OR = 3.42; 95% CIs = 1.37-8.53), and EPDS scores ≥11 (OR = 4.44; 95% CIs = 1.97-9.97) remained independent risk factors. AD and other psychiatric disorders were the primary risk factors for suicidality, although only the former remained an independent factor after a multivariate analysis. More than 10 years of education and EPDS scores ≥11 were also independent factors; the latter can be used as a screening tool for suicide risk.

Advanced brain aging: relationship with epidemiologic and genetic risk factors, and overlap with Alzheimer disease atrophy patterns.

PubMed

Habes, M; Janowitz, D; Erus, G; Toledo, J B; Resnick, S M; Doshi, J; Van der Auwera, S; Wittfeld, K; Hegenscheid, K; Hosten, N; Biffar, R; Homuth, G; Völzke, H; Grabe, H J; Hoffmann, W; Davatzikos, C

2016-04-05

We systematically compared structural imaging patterns of advanced brain aging (ABA) in the general-population, herein defined as significant deviation from typical BA to those found in Alzheimer disease (AD). The hypothesis that ABA would show different patterns of structural change compared with those found in AD was tested via advanced pattern analysis methods. In particular, magnetic resonance images of 2705 participants from the Study of Health in Pomerania (aged 20-90 years) were analyzed using an index that captures aging atrophy patterns (Spatial Pattern of Atrophy for Recognition of BA (SPARE-BA)), and an index previously shown to capture atrophy patterns found in clinical AD (Spatial Patterns of Abnormality for Recognition of Early Alzheimer's Disease (SPARE-AD)). We studied the association between these indices and risk factors, including an AD polygenic risk score. Finally, we compared the ABA-associated atrophy with typical AD-like patterns. We observed that SPARE-BA had significant association with: smoking (P<0.05), anti-hypertensive (P<0.05), anti-diabetic drug use (men P<0.05, women P=0.06) and waist circumference for the male cohort (P<0.05), after adjusting for age. Subjects with ABA had spatially extensive gray matter loss in the frontal, parietal and temporal lobes (false-discovery-rate-corrected q<0.001). ABA patterns of atrophy were partially overlapping with, but notably deviating from those typically found in AD. Subjects with ABA had higher SPARE-AD values; largely due to the partial spatial overlap of associated patterns in temporal regions. The AD polygenic risk score was significantly associated with SPARE-AD but not with SPARE-BA. Our findings suggest that ABA is likely characterized by pathophysiologic mechanisms that are distinct from, or only partially overlapping with those of AD.

Apolipoprotein E genotypes associated with Alzheimer disease and concomitant stroke.

PubMed

Fekih-Mrissa, Najiba; Klai, Sarra; Mrad, Meriem; Mansour, Malek; Zaouali, Jamel; Gritli, Nasreddine; Mrissa, Ridha

2014-04-01

The ɛ4 allele of the apolipoprotein E (APOE) gene is a well-characterized genetic risk factor for Alzheimer disease (AD). The association between stroke and a higher risk for AD has also been reported. Our study sought to determine the relationship between the APOE gene and AD and the comorbid risk of stroke. The subjects of this study consisted of 48 patients with AD and 48 members of a control group. All subjects were genotyped for APOE. The results clearly show a significant increased risk of AD in carriers of the APOE ε3/ε4 genotype (P = .003, odds ratio [OR] = 4.1) or ε4 allele (P = .001, OR = 4.2). The risk for stroke in AD patients was also increased for carriers of the APOE ε3/ε4 genotype (P = .02, OR = 9.0) and for carriers of the APOE ε4 allele (P = .004, OR = 5.5). The present study is the first to establish a relationship between APOE ε4 and concomitant AD and stroke in the Tunisian population. Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.

CDK5RAP2 gene and tau pathophysiology in late-onset sporadic Alzheimer's disease.

PubMed

Miron, Justin; Picard, Cynthia; Nilsson, Nathalie; Frappier, Josée; Dea, Doris; Théroux, Louise; Poirier, Judes

2018-06-01

Because currently known Alzheimer's disease (AD) single-nucleotide polymorphisms only account for a small fraction of the genetic variance in this disease, there is a need to identify new variants associated with AD. Our team performed a genome-wide association study in the Quebec Founder Population isolate to identify novel protective or risk genetic factors for late-onset sporadic AD and examined the impact of these variants on gene expression and AD pathology. The rs10984186 variant is associated with an increased risk of developing AD and with a higher CDK5RAP2 mRNA prevalence in the hippocampus. On the other hand, the rs4837766 variant, which is among the best cis-expression quantitative trait loci in the CDK5RAP2 gene, is associated with lower mild cognitive impairment/AD risk and conversion rate. The rs10984186 risk and rs4837766 protective polymorphic variants of the CDK5RAP2 gene might act as potent genetic modifiers for AD risk and/or conversion by modulating the expression of this gene. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Differential Risk of Incident Alzheimer's Disease Dementia in Stable Versus Unstable Patterns of Subjective Cognitive Decline.

PubMed

Wolfsgruber, Steffen; Kleineidam, Luca; Wagner, Michael; Mösch, Edelgard; Bickel, Horst; Lϋhmann, Dagmar; Ernst, Annette; Wiese, Birgitt; Steinmann, Susanne; König, Hans-Helmut; Brettschneider, Christian; Luck, Tobias; Stein, Janine; Weyerer, Siegfried; Werle, Jochen; Pentzek, Michael; Fuchs, Angela; Maier, Wolfgang; Scherer, Martin; Riedel-Heller, Steffi G; Jessen, Frank

2016-10-04

It is unknown whether longitudinal stability versus instability in subjective cognitive decline (SCD) is a modifying factor of the association between SCD and risk of incident Alzheimer's disease (AD) dementia. We tested the modifying role of temporal stability of the SCD report on AD dementia risk in cognitively normal elderly individuals. We analyzed data of 1,990 cognitively normal participants from the longitudinal AgeCoDe Study. We assessed SCD with/without associated worries both at baseline and first follow-up 18 months later. Participants were then classified either as (a) Controls (CO, with no SCD at both baseline and follow-up 1, n = 613), (b) inconsistent SCD (with SCD reported only at baseline or at follow-up 1, n = 637), (c) consistent SCD but without/or with inconsistent worries (n = 610) or (d) consistent SCD with worries (n = 130). We estimated incident AD dementia risk over up to 6 years for each group with Cox-Proportional Hazard Regression analyses adjusted for age, gender, education, ApoE4 status, and depression. Compared to CO, inconsistent SCD was not associated with increased risk of incident AD dementia. In contrast, risk was doubled in the group of consistent SCD without/ with inconsistent worries, and almost 4-fold in the group of consistent SCD with worries. These results could be replicated when using follow-up 1 to follow-up 2 response patterns for group definition. These findings suggest that longitudinal stability versus instability is an important modifying factor of the association between SCD and AD dementia risk. Worrisome SCD that is also consistently reported over time is associated with greatly increased risk of AD dementia.

Physical fitness and injury reporting among active duty and National Guard/Reserve women: associations with risk and lifestyle factors.

PubMed

Kazman, Josh B; de la Motte, Sarah; Bramhall, Elizabeth M S; Purvis, Dianna L; Deuster, Patricia A

2015-01-01

As more women enter the military, it is important to understand how different risks and lifestyle factors influence physical fitness and injury among women in both active duty (AD) and National Guard/Reserve (NG/R). Women in military service are less fit and more likely to suffer musculoskeletal injuries during physical training than men. They also use more medical care during deployment than men. Using data from the Comprehensive Soldier and Family Fitness Global Assessment Tool 2.0 (GAT 2.0), self-reported health and lifestyle and behavioral risk factors were analyzed in nondeployed Army personnel, with the goals of examining (1) service-component differences across traditional risk and lifestyle factors, and (2) correlates of physical performance and physical activity-related injury. Self-report GAT 2.0 data included health risk factors (overall perceived health, sleep, diet, tobacco and alcohol use), self-reported health metrics (height, weight, Army Physical Fitness Test (APFT) scores), and history of physical activity-related injury. The GAT 2.0 was completed by 1,322 AD and 1,033 NG/R women, and APFT data were available for a subsample of 605 AD and 582 NG/R women. Initial analyses of GAT 2.0 data indicated that AD had higher rates of fair/poor perceived health, poor sleep, and unhealthy diet compared to NG/R women. However, AD women had a lower APFT fail rate (8%) than NG (27%) and R (28%). Active duty women were more likely to experience a physical injury in the past 6 months (38%) than NG (19%) and R (22%) women, and more likely to seek medical care than NG/R women. Across all service components, predictive factors for APFT failure included high body mass index (BMI), fair/poor health, and unhealthy diet. Predictive factors for physical injury included high BMI, fair/poor health, and binge drinking. Our analyses suggest that AD women Soldiers are more physically fit than NG/R women Soldiers, which is accompanied by a greater prevalence of physical activity-related injuries. As women's roles expand into combat military occupation specialties, a thorough understanding of service component differences will be critical to inform training programs, mitigate physical injury, and enhance force health protection and readiness.

Risk stratification for arrhythmic death in an emergency department cohort: a new method of nonlinear PD2i analysis of the ECG

PubMed Central

Skinner, James E; Meyer, Michael; Dalsey, William C; Nester, Brian A; Ramalanjaona, George; O’Neil, Brian J; Mangione, Antoinette; Terregino, Carol; Moreyra, Abel; Weiss, Daniel N; Anchin, Jerry M; Geary, Una; Taggart, Pamela

2008-01-01

Heart rate variability (HRV) reflects both cardiac autonomic function and risk of sudden arrhythmic death (AD). Indices of HRV based on linear stochastic models are independent risk factors for AD in postmyocardial infarction (MI) cohorts. Indices based on nonlinear deterministic models have a higher sensitivity and specificity for predicting AD in retrospective data. A new nonlinear deterministic model, the automated Point Correlation Dimension (PD2i), was prospectively evaluated for prediction of AD. Patients were enrolled (N = 918) in 6 emergency departments (EDs) upon presentation with chest pain and being determined to be at risk of acute MI (AMI) >7%. Brief digital ECGs (>1000 heartbeats, ∼15 min) were recorded and automated PD2i results obtained. Out-of-hospital AD was determined by modified Hinkle-Thaler criteria. All-cause mortality at 1 year was 6.2%, with 3.5% being ADs. Of the AD fatalities, 34% were without previous history of MI or diagnosis of AMI. The PD2i prediction of AD had sensitivity = 96%, specificity = 85%, negative predictive value = 99%, and relative risk >24.2 (p ≤ 0.001). HRV analysis by the time-dependent nonlinear PD2i algorithm can accurately predict risk of AD in an ED cohort and may have both life-saving and resource-saving implications for individual risk assessment. PMID:19209249

Biomarkers for insulin resistance and inflammation and the risk for all-cause dementia and alzheimer disease: results from the Framingham Heart Study.

PubMed

van Himbergen, Thomas M; Beiser, Alexa S; Ai, Masumi; Seshadri, Sudha; Otokozawa, Seiko; Au, Rhoda; Thongtang, Nuntakorn; Wolf, Philip A; Schaefer, Ernst J

2012-05-01

To investigate the contribution of biomarkers of glucose homeostasis (adiponectin, glucose, glycated albumin, and insulin levels) and inflammation (high-sensitivity C-reactive protein and lipoprotein-associated phospholipase A(2) levels) to the risk of developing Alzheimer disease (AD) and all-cause dementia. Prospective cohort study. Dementia-free Framingham Heart Study participants had sera measured for these biomarkers at the 19th biennial examination (1985-1988) and were followed up prospectively for the development of AD and all-cause dementia. Eight hundred forty (541 women, median age of 76 years) subjects participated in the study. We used sex-pooled and sex-specific multivariable Cox proportional hazards models adjusted for age, education, body mass index, recent change in weight, APOE ε4 allele status, and plasma docosahexaenoic acid levels to determine association of these biomarkers with the development of all-cause dementia and AD. Over a mean follow-up period of 13 years, 159 persons developed dementia (including 125 with AD). After adjustment for other risk factors, only adiponectin in women was associated with an increased risk of all-cause dementia (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.00-1.66; P=.054) and AD (HR, 1.33; 95% CI, 1.00-1.76; P=.050) per 1-SD increase in adiponectin level. Women with baseline adiponectin values more than the median had a higher risk of all-cause dementia (HR, 1.63; 95% CI, 1.03-2.56; P=.04) and AD (HR, 1.87; 95% CI, 1.13-3.10; P=.01) as compared with those with values less than the median. In women, increased plasma adiponectin levels are an independent risk factor for the development of both all-cause dementia and AD.

Averting Dementia of the Alzheimer's Type in Women: Can Counselors Help?

ERIC Educational Resources Information Center

Douthit, Kathryn Z.

2007-01-01

Alzheimer's disease (AD) is the most common cause of dementia in late life, taking its greatest toll on women over age 80. This article provides an overview of AD, including risk factors and counseling strategies targeting risk. Counseling strategies address stress, cardiovascular health, social integration, depression, and holistic wellness.

Inflammation in Alzheimer's Disease and Molecular Genetics: Recent Update.

PubMed

Zhang, Zhi-Gang; Li, Yan; Ng, Cheung Toa; Song, You-Qiang

2015-10-01

Alzheimer's disease (AD) is a complex age-related neurodegenerative disorder of the central nervous system. Since the first description of AD in 1907, many hypotheses have been established to explain its causes. The inflammation theory is one of them. Pathological and biochemical studies of brains from AD individuals have provided solid evidence of the activation of inflammatory pathways. Furthermore, people with long-term medication of anti-inflammatory drugs have shown a reduced risk to develop the disease. After three decades of genetic study in AD, dozens of loci harboring genetic variants influencing inflammatory pathways in AD patients has been identified through genome-wide association studies (GWAS). The most well-known GWAS risk factor that is responsible for immune response and inflammation in AD development should be APOE ε4 allele. However, a growing number of other GWAS risk AD candidate genes in inflammation have recently been discovered. In the present study, we try to review the inflammation in AD and immunity-associated GWAS risk genes like HLA-DRB5/DRB1, INPP5D, MEF2C, CR1, CLU and TREM2.

Genetic risk factors for the posterior cortical atrophy variant of Alzheimer's disease.

PubMed

Schott, Jonathan M; Crutch, Sebastian J; Carrasquillo, Minerva M; Uphill, James; Shakespeare, Tim J; Ryan, Natalie S; Yong, Keir X; Lehmann, Manja; Ertekin-Taner, Nilufer; Graff-Radford, Neill R; Boeve, Bradley F; Murray, Melissa E; Khan, Qurat Ul Ain; Petersen, Ronald C; Dickson, Dennis W; Knopman, David S; Rabinovici, Gil D; Miller, Bruce L; González, Aida Suárez; Gil-Néciga, Eulogio; Snowden, Julie S; Harris, Jenny; Pickering-Brown, Stuart M; Louwersheimer, Eva; van der Flier, Wiesje M; Scheltens, Philip; Pijnenburg, Yolande A; Galasko, Douglas; Sarazin, Marie; Dubois, Bruno; Magnin, Eloi; Galimberti, Daniela; Scarpini, Elio; Cappa, Stefano F; Hodges, John R; Halliday, Glenda M; Bartley, Lauren; Carrillo, Maria C; Bras, Jose T; Hardy, John; Rossor, Martin N; Collinge, John; Fox, Nick C; Mead, Simon

2016-08-01

The genetics underlying posterior cortical atrophy (PCA), typically a rare variant of Alzheimer's disease (AD), remain uncertain. We genotyped 302 PCA patients from 11 centers, calculated risk at 24 loci for AD/DLB and performed an exploratory genome-wide association study. We confirm that variation in/near APOE/TOMM40 (P = 6 × 10(-14)) alters PCA risk, but with smaller effect than for typical AD (PCA: odds ratio [OR] = 2.03, typical AD: OR = 2.83, P = .0007). We found evidence for risk in/near CR1 (P = 7 × 10(-4)), ABCA7 (P = .02) and BIN1 (P = .04). ORs at variants near INPP5D and NME8 did not overlap between PCA and typical AD. Exploratory genome-wide association studies confirmed APOE and identified three novel loci: rs76854344 near CNTNAP5 (P = 8 × 10(-10) OR = 1.9 [1.5-2.3]); rs72907046 near FAM46A (P = 1 × 10(-9) OR = 3.2 [2.1-4.9]); and rs2525776 near SEMA3C (P = 1 × 10(-8), OR = 3.3 [2.1-5.1]). We provide evidence for genetic risk factors specifically related to PCA. We identify three candidate loci that, if replicated, may provide insights into selective vulnerability and phenotypic diversity in AD. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Evaluation of fetal anthropometric measures to predict the risk for shoulder dystocia.

PubMed

Burkhardt, T; Schmidt, M; Kurmanavicius, J; Zimmermann, R; Schäffer, L

2014-01-01

To evaluate the quality of anthropometric measures to improve the prediction of shoulder dystocia by combining different sonographic biometric parameters. This was a retrospective cohort study of 12,794 vaginal deliveries with complete sonographic biometry data obtained within 7 days before delivery. Receiver-operating characteristics (ROC) curves of various combinations of the biometric parameters, namely, biparietal diameter (BPD), occipitofrontal diameter (OFD), head circumference, abdominal diameter (AD), abdominal circumference (AC) and femur length were analyzed. The influences of independent risk factors were calculated and their combination used in a predictive model. The incidence of shoulder dystocia was 1.14%. Different combinations of sonographic parameters showed comparable ROC curves without advantage for a particular combination. The difference between AD and BPD (AD - BPD) (area under the curve (AUC) = 0.704) revealed a significant increase in risk (odds ratio (OR) 7.6 (95% CI 4.2-13.9), sensitivity 8.2%, specificity 98.8%) at a suggested cut-off ≥ 2.6 cm. However, the positive predictive value (PPV) was low (7.5%). The AC as a single parameter (AUC = 0.732) with a cut-off ≥ 35 cm performed worse (OR 4.6 (95% CI 3.3-6.5), PPV 2.6%). BPD/OFD (a surrogate for fetal cranial shape) was not significantly different between those with and those without shoulder dystocia. The combination of estimated fetal weight, maternal diabetes, gender and AD - BPD provided a reasonable estimate of the individual risk. Sonographic fetal anthropometric measures appear not to be a useful tool to screen for the risk of shoulder dystocia due to a low PPV. However, AD - BPD appears to be a relevant risk factor. While risk stratification including different known risk factors may aid in counseling, shoulder dystocia cannot effectively be predicted. Copyright © 2013 ISUOG. Published by John Wiley & Sons Ltd.

Apolipoprotein E4, Gender, Body Mass Index, Inflammation, Insulin Resistance, and Air Pollution Interactions: Recipe for Alzheimer's Disease Development in Mexico City Young Females.

PubMed

Calderón-Garcidueñas, Lilian; de la Monte, Suzanne M

2017-01-01

Given the epidemiological trends of increasing Alzheimer's disease (AD) and growing evidence that exposure and lifestyle factors contribute to AD risk and pathogenesis, attention should be paid to variables such as air pollution, in order to reduce rates of cognitive decline and dementia. Exposure to fine particulate matter (PM2.5) and ozone (O3) above the US EPA standards is associated with AD risk. Mexico City children experienced pre- and postnatal high exposures to PM2.5, O3, combustion-derived iron-rich nanoparticles, metals, polycyclic aromatic hydrocarbons, and endotoxins. Exposures are associated with early brain gene imbalance in oxidative stress, inflammation, innate and adaptive immune responses, along with epigenetic changes, accumulation of misfolded proteins, cognitive deficits, and brain structural and metabolic changes. The Apolipoprotein E (APOE) 4 allele, the most prevalent genetic risk for AD, plays a key role in the response to air pollution in young girls. APOE 4 heterozygous females with >75% to <94% BMI percentiles are at the highest risk of severe cognitive deficits (1.5-2 SD from average IQ). This review focused on the relationships between gender, BMI, systemic and neural inflammation, insulin resistance, hyperleptinemia, dyslipidemia, vascular risk factors, and central nervous system involvement in APOE4 urbanites exposed to PM2.5 and magnetite combustion-derived iron-rich nanoparticles that can reach the brain. APOE4 young female heterozygous carriers constitute a high-risk group for a fatal disease: AD. Multidisciplinary intervention strategies could be critical for prevention or amelioration of cognitive deficits and long-term AD progression in young individuals at high risk.

Seizures and epilepsy in Alzheimer's disease.

PubMed

Friedman, Daniel; Honig, Lawrence S; Scarmeas, Nikolaos

2012-04-01

Many studies have shown that patients with Alzheimer's disease (AD) are at increased risk for developing seizures and epilepsy. However, reported prevalence and incidence of seizures and relationship of seizures to disease measures such as severity, outcome, and progression vary widely between studies. We performed a literature review of the available clinical and epidemiological data on the topic of seizures in patients with AD. We review seizure rates and types, risk factors for seizures, electroencephalogram (EEG) studies, and treatment responses. Finally, we consider limitations and methodological issues. There is considerable variability in the reported prevalence and incidence of seizures in patients with AD-with reported lifetime prevalence rates of 1.5-64%. More recent, prospective, and larger studies in general report lower rates. Some, but not all, studies have noted increased seizure risk with increasing dementia severity or with younger age of AD onset. Generalized convulsive seizures are the most commonly reported type, but often historical information is the only basis used to determine seizure type and the manifestation of seizures may be difficult to distinguish from other behaviors common in demented patients. EEG has infrequently been performed and reported. Data on treatment of seizures in AD are extremely limited. Similarly, the relationship between seizures and cognitive impairment in AD is unclear. We conclude that the literature on seizures and epilepsy in AD, including diagnosis, risk factors, and response to treatment suffers from methodological limitations and gaps. © 2011 Blackwell Publishing Ltd.

Specific BACE1 genotypes provide additional risk for late-onset Alzheimer disease in APOE epsilon 4 carriers.

PubMed

Gold, Gabriel; Blouin, Jean-Louis; Herrmann, François R; Michon, Agnès; Mulligan, Reinhild; Duriaux Saïl, Geneviève; Bouras, Constantin; Giannakopoulos, Panteleimon; Antonarakis, Stylianos E

2003-05-15

Alzheimer disease (AD) is characterized neuropathologically by neurofibrillary tangles and senile plaques. A key component of plaques is A beta, a polypeptide derived from A beta-precursor protein (APP) through proteolytic cleavage catalyzed by beta and gamma-secretase. We hypothesized that sequence variation in genes BACE1 (on chromosome 11q23.3) and BACE2 (on chromosome 21q22.3), which encode two closely related proteases that seem to act as the APP beta-secretase, may represent a genetic risk factor for AD. We analyzed the frequencies of single nucleotide polymorphisms (SNPs) in BACE1 and BACE2 genes in a community-based sample of 96 individuals with late-onset AD and 170 controls selected randomly among residents of the same community. The genotype data in both study groups did not demonstrate any association between AD and BACE1 or BACE2. After stratification for APOE status, however, an association between a BACE1 polymorphism located within codon V262 and AD in APOE epsilon 4 carriers was observed (P = 0.03). We conclude that sequence variation in the BACE1 or BACE 2 gene is not a significant risk factor for AD; however, a combination of a specific BACE1 allele and APOE epsilon 4 may increase the risk for Alzheimer disease over and above that attributed to APOE epsilon 4 alone. Copyright 2003 Wiley-Liss, Inc.

Nutritional approaches in the risk reduction and management of Alzheimer's disease.

PubMed

Mi, Weiqian; van Wijk, Nick; Cansev, Mehmet; Sijben, John W C; Kamphuis, Patrick J G H

2013-09-01

Alzheimer's disease (AD) is a heterogeneous and devastating neurodegenerative disease with increasing socioeconomic burden for society. In the past 30 y, notwithstanding advances in the understanding of the pathogenesis of the disease and consequent development of therapeutic approaches to novel pathogenic targets, no cure has so far emerged. This contribution focuses on recent nutritional approaches in the risk reduction and management of AD with emphasis on factors providing a rationale for nutritional approaches in AD, including compromised nutritional status, altered nutrient uptake and metabolism, and nutrient requirements for synapse formation. Collectively these factors are believed to result in specific nutritional requirement in AD. The chapter also emphasizes investigated nutritional interventions in patients with AD, including studies with single nutrients and with the specific nutrient combination Fortasyn Connect and discusses the current shift of paradigm to intervene in earlier stages of AD, which offers opportunities for investigating nutritional strategies to reduce the risk for disease progression. Fortasyn Connect was designed to enhance synapse formation and function in AD by addressing the putative specific nutritional requirements and contains docosahexaenoic acid, eicosapentaenoic acid, uridine-5'-mono-phosphate, choline, phospholipids, antioxidants, and B vitamins. Two randomized controlled trials (RCTs) with the medical food Souvenaid, containing Fortasyn Connect, showed that this intervention improved memory performance in mild, drug-naïve patients with AD. Electroencephalography outcome in one of these clinical studies suggests that Souvenaid has an effect on brain functional connectivity, which is a derivative of changed synaptic activity. Thus, these studies suggest that nutritional requirements in AD can be successfully addressed and result in improvements in behavioral and neuro-physiological alterations that are characteristic to AD. The recent advance of methodologies and techniques for early diagnosis of AD facilitates the investigation of strategies to reduce the risk for AD progression in the earliest stages of the disease. Nutrition-based approaches deserve further investigation as an integral part of such strategies due to their low risk for side effects and their potential to affect pathological processes of very early AD. Copyright © 2013 Elsevier Inc. All rights reserved.

Risk Factor Analysis in Low-Temperature Geothermal Play Fairway Analysis for the Appalachian Basin (GPFA-AB)

DOE Data Explorer

Teresa E. Jordan

2015-09-30

This submission contains information used to compute the risk factors for the GPFA-AB project (DE-EE0006726). The risk factors are natural reservoir quality, thermal resource quality, potential for induced seismicity, and utilization. The methods used to combine the risk factors included taking the product, sum, and minimum of the four risk factors. The files are divided into images, rasters, shapefiles, and supporting information. The image files show what the raster and shapefiles should look like. The raster files contain the input risk factors, calculation of the scaled risk factors, and calculation of the combined risk factors. The shapefiles include definition of the fairways, definition of the US Census Places, the center of the raster cells, and locations of industries. Supporting information contains details of the calculations or processing used in generating the files. An image of the raster will have the same name except *.png as the file ending instead of *.tif. Images with “fairways” or “industries” added to the name are composed of a raster with the relevant shapefile added. The file About_GPFA-AB_Phase1RiskAnalysisTask5DataUpload.pdf contains information the citation, special use considerations, authorship, etc. More details on each file are given in the spreadsheet “list_of_contents.csv” in the folder “SupportingInfo”. Code used to calculate values is available at https://github.com/calvinwhealton/geothermal_pfa under the folder “combining_metrics”.

The Cache County Study on Memory in Aging: Factors Affecting Risk of Alzheimer's disease and its Progression after Onset

PubMed Central

Tschanz, JoAnn T.; Norton, Maria C.; Zandi, Peter P.; Lyketsos, Constantine G.

2014-01-01

The Cache County Study on Memory in Aging is a longitudinal, population-based study of Alzheimer's disease (AD) and other dementias. Initiated in 1995 and extending to 2013, the study has followed over 5,000 elderly residents of Cache County, Utah (USA) for over twelve years. Achieving a 90% participation rate at enrollment, and spawning two ancillary projects, the study has contributed to the literature on genetic, psychosocial and environmental risk factors for AD, late life cognitive decline, and the clinical progression of dementia after its onset. This paper describes the major study contributions to the literature on AD and dementia. PMID:24423221

The Cache County Study on Memory in Aging: factors affecting risk of Alzheimer's disease and its progression after onset.

PubMed

Tschanz, Joann T; Norton, Maria C; Zandi, Peter P; Lyketsos, Constantine G

2013-12-01

The Cache County Study on Memory in Aging is a longitudinal, population-based study of Alzheimer's disease (AD) and other dementias. Initiated in 1995 and extending to 2013, the study has followed over 5,000 elderly residents of Cache County, Utah (USA) for over twelve years. Achieving a 90% participation rate at enrolment, and spawning two ancillary projects, the study has contributed to the literature on genetic, psychosocial and environmental risk factors for AD, late-life cognitive decline, and the clinical progression of dementia after its onset. This paper describes the major study contributions to the literature on AD and dementia.

Associations of Spatial Disparities of Alzheimer's Disease Mortality Rates with Soil Selenium and Sulfur Concentrations and Four Common Risk Factors in the United States.

PubMed

Sun, Hongbing

2017-01-01

Associations between environmental factors and spatial disparity of mortality rates of Alzheimer's disease (AD) in the US are not well understood. To find associations between 41 trace elements, four common risk factors, and AD mortality rates in the48 contiguous states. Isopleth maps of AD mortality rates of the 48 states and associated factors were examined. Correlations between state average AD mortality rates and concentrations of 41 soil elements, wine consumption, percentage of current smokers, obesity, and diagnosed diabetes of the 48 states between 1999 and 2014 were analyzed. Among 41 elements, soil selenium concentrations have the most significant inverse correlations with AD mortality rates. Rate ratio (RR) of the 6 states with the lowest product of soil selenium and sulfur concentrations is 53% higher than the 6 states with the highest soil selenium sulfur product in the 48 states (RR = 1.53, CI95% 1.51-1.54). Soil tin concentrations have the most significant inverse correlation with AD mortality growth rates between 1999 and 2014, followed by soil sulfur concentrations. Percentages of obesity, diagnosed diabetes, smoking, and wine consumption per capita also correlate significantly with AD mortality growth rates. High soil selenium and sulfur concentrations and wine consumption are associated with low AD mortality rates. Given that average soil selenium and sulfur concentrations are indicators of their intakes from food, water, and air by people in a region, long-term exposure to high soil selenium and sulfur concentrations might be beneficial to AD mortality rate reduction in a region.

Nutritional status of community-dwelling elderly with newly diagnosed Alzheimer's disease: prevalence of malnutrition and the relation of various factors to nutritional status.

PubMed

Droogsma, E; van Asselt, D Z B; Schölzel-Dorenbos, C J M; van Steijn, J H M; van Walderveen, P E; van der Hooft, C S

2013-07-01

To determine the prevalence of malnutrition and its relation to various factors in community-dwelling elderly with newly diagnosed Alzheimer's disease (AD). Retrospective cross-sectional study. Memory clinic in a rural part of the Netherlands. 312 Community-dwelling AD patients, aged 65 years or older, were included. At the time the diagnosis AD was made, socio-demographic characteristics and data on nutritional status (Mini Nutritional Assessment (MNA)), cognitive function (Mini Mental State Examination (MMSE), Cambridge Cognitive Examination (Camcog)), functional status (Interview for Deterioration in Daily Living Activities in Dementia (IDDD), Barthel Index (BI)) and behaviour (Revised Memory and Behaviour Problems Checklist (RMBPC)) were assessed. Characteristics of well-nourished patients (MNA score >23.5) were compared to characteristics of patients at risk of malnutrition (MNA score 17-23.5). Linear regression analysis was performed to assess the effect of various factors on nutritional status. The prevalence of malnutrition was 0% and 14.1% was at risk of malnutrition. AD patients at risk of malnutrition were more impaired in basic and complex daily functioning than well-nourished AD patients (median IDDD score 41.5 [25th -75th percentile 38.8-48.0] versus median IDDD score 40.0 [25th -75th percentile 37.0-43.0], p = 0.028). The degree of impairment in basic and complex daily functioning (IDDD) was independently related to nutritional status (MNA) (p = 0.001, B = -0.062). One in seven community-dwelling elderly with newly diagnosed AD is at risk of malnutrition. The degree of impairment in daily functioning is independently related to nutritional status. Therefore, assessment of the nutritional status should be included in the comprehensive assessment of AD patients. The relation between daily functioning, nutritional status and AD warrants further investigation.

Prevalence of Drug Combinations Increasing Bleeding Risk Among Warfarin Users With and Without Alzheimer's Disease.

PubMed

Taipale, Heidi; Vuorikari, Hanna; Tanskanen, Antti; Koponen, Marjaana; Tiihonen, Jari; Kettunen, Raimo; Hartikainen, Sirpa

2015-11-01

The aim of this study was to analyse the prevalence and predictors of drug combinations increasing bleeding risk among warfarin users with and without Alzheimer's disease (AD). This retrospective observational study utilised data from the Finnish MEDALZ-2005 cohort. The MEDALZ-2005 study included all community-dwelling persons with a clinically verified diagnosis of AD at the end of 2005, and one comparison person without AD for each case. Data on drug use was collected from the Prescription Register. We included persons who were warfarin users during the study period 2006-2009. Drug combinations increasing bleeding risk with warfarin included selective serotonin reuptake inhibitors (SSRIs), non-steroidal anti-inflammatory agents (NSAIDs), other antithrombotic drugs and tramadol. Factors associated with combination use were investigated with logistic regression. During the follow-up, 3385 persons with AD and 4830 persons without AD used warfarin. Drug combinations increasing bleeding risk were more common in warfarin users with AD than without AD [35.9 and 30.5%, respectively (p < 0.0001)]. The most common combination was SSRIs and warfarin, which was more common among persons with AD (23.8%) than among persons without AD (10.9%). NSAIDs and warfarin combination was more common among persons without AD. Combination use was associated with AD, female gender, younger age, diabetes mellitus, rheumatoid arthritis and asthma/chronic obstructive pulmonary disease (COPD). Use of drug combinations increasing bleeding risk was more common among warfarin users with AD. Special attention should be paid to minimise the duration of concomitant use and to find safer alternatives without increased bleeding risk.

Semantic memory activation in individuals at risk for developing Alzheimer disease.

PubMed

Seidenberg, M; Guidotti, L; Nielson, K A; Woodard, J L; Durgerian, S; Antuono, P; Zhang, Q; Rao, S M

2009-08-25

To determine whether whole-brain, event-related fMRI can distinguish healthy older adults with known Alzheimer disease (AD) risk factors (family history, APOE epsilon4) from controls using a semantic memory task involving discrimination of famous from unfamiliar names. Sixty-nine cognitively asymptomatic adults were divided into 3 groups (n = 23 each) based on AD risk: 1) no family history, no epsilon4 allele (control [CON]); 2) family history, no epsilon4 allele (FH); and 3) family history and epsilon4 allele (FH+epsilon4). Separate hemodynamic response functions were extracted for famous and unfamiliar names using deconvolution analysis (correct trials only). Cognitively intact older adults with AD risk factors (FH and FH+epsilon4) exhibited greater activation in recognizing famous relative to unfamiliar names than a group without risk factors (CON), especially in the bilateral posterior cingulate/precuneus, bilateral temporoparietal junction, and bilateral prefrontal cortex. The increased activation was more apparent in the FH+epsilon4 than in the FH group. Unlike the 2 at-risk groups, the control group demonstrated greater activation for unfamiliar than familiar names, predominately in the supplementary motor area, bilateral precentral, left inferior frontal, right insula, precuneus, and angular gyrus. These results could not be attributed to differences in demographic variables, cerebral atrophy, episodic memory performance, global cognitive functioning, activities of daily living, or depression. Results demonstrate that a low-effort, high-accuracy semantic memory activation task is sensitive to Alzheimer disease risk factors in a dose-related manner. This increased activation in at-risk individuals may reflect a compensatory brain response to support task performance in otherwise asymptomatic older adults.

Central insulin dysregulation and energy dyshomeostasis in two mouse models of Alzheimer's disease.

PubMed

Velazquez, Ramon; Tran, An; Ishimwe, Egide; Denner, Larry; Dave, Nikhil; Oddo, Salvatore; Dineley, Kelly T

2017-10-01

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder worldwide. While the causes of AD are not known, several risk factors have been identified. Among these, type two diabetes (T2D), a chronic metabolic disease, is one of the most prevalent risk factors for AD. Insulin resistance, which is associated with T2D, is defined as diminished or absent insulin signaling and is reflected by peripheral blood hyperglycemia and impaired glucose clearance. In this study, we used complementary approaches to probe for peripheral insulin resistance, central nervous system (CNS) insulin sensitivity and energy homeostasis in Tg2576 and 3xTg-AD mice, two widely used animal models of AD. We report that CNS insulin signaling abnormalities are evident months before peripheral insulin resistance. In addition, we find that brain energy metabolism is differentially altered in both mouse models, with 3xTg-AD mice showing more extensive changes. Collectively, our data suggest that early AD may reflect engagement of different signaling networks that influence CNS metabolism, which in turn may alter peripheral insulin signaling. Copyright © 2017 Elsevier Inc. All rights reserved.

Altered Expression of Diabetes-Related Genes in Alzheimer's Disease Brains: The Hisayama Study

PubMed Central

Hokama, Masaaki; Oka, Sugako; Leon, Julio; Ninomiya, Toshiharu; Honda, Hiroyuki; Sasaki, Kensuke; Iwaki, Toru; Ohara, Tomoyuki; Sasaki, Tomio; LaFerla, Frank M.; Kiyohara, Yutaka; Nakabeppu, Yusaku

2014-01-01

Diabetes mellitus (DM) is considered to be a risk factor for dementia including Alzheimer's disease (AD). However, the molecular mechanism underlying this risk is not well understood. We examined gene expression profiles in postmortem human brains donated for the Hisayama study. Three-way analysis of variance of microarray data from frontal cortex, temporal cortex, and hippocampus was performed with the presence/absence of AD and vascular dementia, and sex, as factors. Comparative analyses of expression changes in the brains of AD patients and a mouse model of AD were also performed. Relevant changes in gene expression identified by microarray analysis were validated by quantitative real-time reverse-transcription polymerase chain reaction and western blotting. The hippocampi of AD brains showed the most significant alteration in gene expression profile. Genes involved in noninsulin-dependent DM and obesity were significantly altered in both AD brains and the AD mouse model, as were genes related to psychiatric disorders and AD. The alterations in the expression profiles of DM-related genes in AD brains were independent of peripheral DM-related abnormalities. These results indicate that altered expression of genes related to DM in AD brains is a result of AD pathology, which may thereby be exacerbated by peripheral insulin resistance or DM. PMID:23595620

Progranulin mutations as risk factors for Alzheimer disease.

PubMed

Perry, David C; Lehmann, Manja; Yokoyama, Jennifer S; Karydas, Anna; Lee, Jason Jiyong; Coppola, Giovanni; Grinberg, Lea T; Geschwind, Dan; Seeley, William W; Miller, Bruce L; Rosen, Howard; Rabinovici, Gil

2013-06-01

Mutations in the progranulin gene are known to cause diverse clinical syndromes, all attributed to frontotemporal lobar degeneration. We describe 2 patients with progranulin gene mutations and evidence of Alzheimer disease (AD) pathology. We also conducted a literature review. This study focused on case reports of 2 unrelated patients with progranulin mutations at the University of California, San Francisco, Memory and Aging Center. One patient presented at age 65 years with a clinical syndrome suggestive of AD and showed evidence of amyloid aggregation on positron emission tomography. Another patient presented at age 54 years with logopenic progressive aphasia and, at autopsy, showed both frontotemporal lobar degeneration with TDP-43 inclusions and AD. In addition to autosomal-dominant frontotemporal lobar degeneration, mutations in the progranulin gene may be a risk factor for AD clinical phenotypes and neuropathology.

PRENATAL STRESS AND RISK FOR AUTISM

PubMed Central

Kinney, Dennis K.; Munir, Kerim M.; Crowley, David J.; Miller, Andrea M.

2008-01-01

This paper reviews several converging lines of research that suggest that prenatal exposure to environmental stress may increase risk for Autistic Disorder (AD). We first discuss studies finding that prenatal exposure to stressful life events is associated with significantly increased risk of AD, as well as other disorders, such as schizophrenia and depression. We then review evidence from animal and human studies that prenatal stress can produce both (a) abnormal postnatal behaviors that resemble the defining symptoms of AD, and (b) other abnormalities that have elevated rates in AD, such as learning deficits, seizure disorders, perinatal complications, immunologic and neuroinflammatory anomalies, and low postnatal tolerance for stress. We explain why an etiologic role for prenatal stress is compatible with genetic factors in AD, and describe how stress can disrupt fetal brain development. Finally, we discuss implications for understanding underlying processes in AD, including potential gene-environment interactions, and developing new therapies and early prevention programs. PMID:18598714

Reproductive Risk Factors and Coronary Heart Disease in the Women’s Health Initiative Observational Study

PubMed Central

Parikh, Nisha I.; Jeppson, Rebecca P.; Berger, Jeffrey S.; Eaton, Charles B.; Kroenke, Candyce H.; LeBlanc, Erin S.; Lewis, Cora E.; Loucks, Eric B.; Parker, Donna R.; Rillamas-Sun, Eileen; Ryckman, Kelli K; Waring, Molly E.; Schenken, Robert S.; Johnson, Karen C; Edstedt-Bonamy, Anna-Karin; Allison, Matthew A.; Howard, Barbara V.

2016-01-01

Background Reproductive factors provide an early window into a woman’s coronary heart disease (CHD) risk, however their contribution to CHD risk stratification is uncertain. Methods and Results In the Women’s Health Initiative Observational Study, we constructed Cox proportional hazards models for CHD including age, pregnancy status, number of live births, age at menarche, menstrual irregularity, age at first birth, stillbirths, miscarriages, infertility ≥ 1 year, infertility cause, and breastfeeding. We next added each candidate reproductive factor to an established CHD risk factor model. A final model was then constructed with significant reproductive factors added to established CHD risk factors. Improvement in C-statistic, net reclassification index (or NRI with risk categories of <5%, 5–<10%, and ≥10% 10-year risk of CHD) and integrated discriminatory index (IDI) were assessed. Among 72,982 women [n=4607 CHD events, median follow-up=12.0 (IQR=8.3–13.7) years, mean (SD) age 63.2 (7.2) years], an age-adjusted reproductive risk factor model had a C-statistic of 0.675 for CHD. In a model adjusted for established CHD risk factors, younger age at first birth, number of still births, number of miscarriages and lack of breastfeeding were positively associated with CHD. Reproductive factors modestly improved model discrimination (C-statistic increased from 0.726 to 0.730; IDI=0.0013, p-value < 0.0001). Net reclassification for women with events was not improved (NRI events=0.007, p-value=0.18); and for women without events was marginally improved (NRI non-events=0.002, p-value=0.04) Conclusions Key reproductive factors are associated with CHD independently of established CHD risk factors, very modestly improve model discrimination and do not materially improve net reclassification. PMID:27143682

The KEEPS-Cognitive and Affective Study: baseline associations between vascular risk factors and cognition.

PubMed

Wharton, Whitney; Gleason, Carey E; Dowling, N Maritza; Carlsson, Cynthia M; Brinton, Eliot A; Santoro, M Nanette; Neal-Perry, Genevieve; Taylor, Hugh; Naftolin, Frederick; Lobo, Rogerio A; Merriam, George; Manson, Joann E; Cedars, Marcelle I; Miller, Virginia M; Black, Dennis M; Budoff, Matthew; Hodis, Howard N; Harman, S Mitchell; Asthana, Sanjay

2014-01-01

Midlife vascular risk factors influence later cognitive decline and Alzheimer's disease (AD). The decrease in serum estradiol levels during menopause has been associated with cognitive impairment and increased vascular risk, such as high blood pressure (BP), which independently contributes to cognitive dysfunction and AD. We describe the extent to which vascular risk factors relate to cognition in healthy, middle-aged, recently postmenopausal women enrolled in the Kronos Early Estrogen Prevention Cognitive and Affective Study (KEEPS-Cog) at baseline. KEEPS-Cog is a double-blind, randomized, placebo-controlled, parallel group, clinical trial, investigating the efficacy of low-dose, transdermal 17β-estradiol and oral conjugated equine estrogen on cognition. All results are cross-sectional and represent baseline data only. Analyses confirm that the KEEPS-Cog cohort (n = 571) was middle aged (mean 52.7 years, range 42-59 years), healthy, and free of cognitive dysfunction. Higher systolic BP was weakly related to poorer performance in auditory working memory and attention (p = 0.004; adjusted for multiple comparisons p = 0.10). This relationship was not associated with endogenous hormone levels, and systolic BP was not related to any other cognitive domain. BP levels may be more sensitive than other vascular risk factors in detecting subtle differences in cognitive task performance in healthy, recently menopausal women. Lower BP early in menopause may affect cognitive domains known to be associated with AD.

APOE ε4 and the risk for Alzheimer disease and cognitive decline in African Americans and Yoruba

PubMed Central

Hendrie, Hugh C.; Murrell, Jill; Baiyewu, Olusegun; Lane, Kathleen A.; Purnell, Christianna; Ogunniyi, Adesola; Unverzagt, Frederick W.; Hall, Kathleen; Callahan, Christopher M.; Saykin, Andrew J.; Gureje, Oye; Hake, Ann; Foroud, Tatiana; Gao, Sujuan

2014-01-01

Background There is little information on the association of the APOEe4 allele and AD risk in African populations. In previous analyses from the Indianapolis-Ibadan dementia project, we have reported that APOE ε4 increased the risk for Alzheimer’s disease (AD) in African Americans but not in Yoruba. This study represents a replication of this earlier work using enriched cohorts and extending the analysis to include cognitive decline. Methods In this longitudinal study of two community dwelling cohorts of elderly Yoruba and African Americans, APOE genotyping was conducted from blood samples taken on or before 2001 (1,871 African Americans & 2,200 Yoruba). Mean follow up time was 8.5 years for African Americans and 8.8 years for Yoruba. The effects of heterozygosity or homozygosity of ε4 and of the possession of e4 on time to incident AD and on cognitive decline were determined using Cox’s proportional hazards regression and mixed effects models. Results After adjusting for covariates, one or two copies of the APOE ε4 allele were significant risk factors for incident AD (p < 0.0001) and cognitive decline in the African-American population (p < 0001). In the Yoruba, only homozygosity for APOE ε4 was a significant risk factor for AD (p = 0.0002) but not for cognitive decline (p = 0.2346), however, possession of an e4 allele was significant for both incident AD (p = 0.0489) and cognitive decline (p = 0.0425). Conclusions In this large longitudinal comparative study, APOE ε4 had a significant, but weaker, effect on incident AD and on cognitive decline in Yoruba than in African Americans. The reasons for these differences remain unclear. PMID:24565289

Fibrillar amyloid-β burden in cognitively normal people at 3 levels of genetic risk for Alzheimer's disease

PubMed Central

Reiman, Eric M.; Chen, Kewei; Liu, Xiaofen; Bandy, Daniel; Yu, Meixiang; Lee, Wendy; Ayutyanont, Napatkamon; Keppler, Jennifer; Reeder, Stephanie A.; Langbaum, Jessica B. S.; Alexander, Gene E.; Klunk, William E.; Mathis, Chester A.; Price, Julie C.; Aizenstein, Howard J.; DeKosky, Steven T.; Caselli, Richard J.

2009-01-01

Fibrillar amyloid-beta (Aβ) is found in the brains of many cognitively normal older people. Whether or not this reflects a predisposition to Alzheimer's disease (AD) is unknown. We used Pittsburgh Compound B (PiB) PET to characterize the relationship between fibrillar Aβ burden and this predisposition in cognitively normal older people at 3 mean levels of genetic risk for AD. Dynamic PiB PET scans, the Logan method, statistical parametric mapping, and automatically labeled regions of interest (ROIs) were used to characterize and compare cerebral-to-cerebellar PIB distribution volume ratios, reflecting fibrillar Aβ burden, in 28 cognitively normal persons (mean age, 64 years) with a reported family history of AD and 2 copies, 1 copy, and no copies of the apolipoprotein E (APOE) ε4 allele. The 8 ε4 homozygotes, 8 heterozygotes, and 12 noncarriers did not differ significantly in terms of age, sex, or cognitive scores. Fibrillar Aβ was significantly associated with APOE ε4 carrier status and ε4 gene dose in AD-affected mean cortical, frontal, temporal, posterior cingulate-precuneus, parietal, and basal ganglia ROIs, and was highest in an additional homozygote who had recently developed mild cognitive impairment. These findings suggest that fibrillar Aβ burden in cognitively normal older people is associated with APOE ε4 gene dose, the major genetic risk factor for AD. Additional studies are needed to track fibrillar Aβ accumulation in persons with different kinds and levels of AD risk; to determine the extent to which fibrillar Aβ, alone or in combination with other biomarkers and risk factors, predicts rates of cognitive decline and conversion to clinical AD; and to establish the role of fibrillar Aβ imaging in primary prevention trials. PMID:19346482

GPFA-AB_Phase1RiskAnalysisTask5DataUpload

DOE Data Explorer

Teresa E. Jordan

2015-09-30

This submission contains information used to compute the risk factors for the GPFA-AB project (DE-EE0006726). The risk factors are natural reservoir quality, thermal resource quality, potential for induced seismicity, and utilization. The methods used to combine the risk factors included taking the product, sum, and minimum of the four risk factors. The files are divided into images, rasters, shapefiles, and supporting information. The image files show what the raster and shapefiles should look like. The raster files contain the input risk factors, calculation of the scaled risk factors, and calculation of the combined risk factors. The shapefiles include definition of the fairways, definition of the US Census Places, the center of the raster cells, and locations of industries. Supporting information contains details of the calculations or processing used in generating the files. An image of the raster will have the same name except *.png as the file ending instead of *.tif. Images with “fairways” or “industries” added to the name are composed of a raster with the relevant shapefile added. The file About_GPFA-AB_Phase1RiskAnalysisTask5DataUpload.pdf contains information the citation, special use considerations, authorship, etc. More details on each file are given in the spreadsheet “list_of_contents.csv” in the folder “SupportingInfo”. Code used to calculate values is available at https://github.com/calvinwhealton/geothermal_pfa under the folder “combining_metrics”.

Does fibrinogen add to prediction of cardiovascular disease? Results from the Scottish Heart Health Extended Cohort Study.

PubMed

Woodward, Mark; Tunstall-Pedoe, Hugh; Rumley, Ann; Lowe, Gordon D O

2009-08-01

Plasma fibrinogen is an established risk factor for cardiovascular disease (CVD), but it has not been established whether it adds predictive value to risk scores. In the Scottish Heart Health Extended Cohort Study, we measured plasma fibrinogen in 13 060 men and women, aged 30-74 years, initially free of CVD. After follow-up for a median of 19.2 years, 2626 subjects had at least one CVD event. After adjusting for classical CVD risk factors and socio-economic status, the hazard ratios (95% confidence interval) for a one unit (g/l) increase in plasma fibrinogen were 1.09 (1.02, 1.16) for men and 1.10 (1.02, 1.19) for women. Although fibrinogen added significantly to the discrimination of the Framingham risk score for women, it failed to do so for men. Fibrinogen did not add significantly to the ASSIGN risk score. Fibrinogen added between 1.3% and 3.2% to the classification of CVD status by the existing risk scores. We conclude that the added value of fibrinogen to two currently used risk scores is low; hence population screening with fibrinogen for this purpose is unlikely to be clinically useful or cost-effective.

Low serum insulin-like growth factor-I (IGF-I) level is associated with increased risk of vascular dementia.

PubMed

Quinlan, Patrick; Horvath, Alexandra; Nordlund, Arto; Wallin, Anders; Svensson, Johan

2017-12-01

Insulin-like growth factor-I (IGF-I) is important for the adult brain, but little is known of the role of IGF-I in Alzheimeŕs disease (AD) or vascular dementia (VaD). A prospective study of 342 patients with subjective or objective mild cognitive impairment recruited at a single memory clinic. We determined whether serum IGF-I concentrations at baseline were associated with the risk of all-cause dementia, AD, or VaD. Patients developing mixed forms of AD and VaD were defined as suffering from VaD. The statistical analyses included Cox proportional hazards regression analysis. During the follow-up (mean 3.6 years), 95 (28%) of the patients developed all-cause dementia [AD, n=37 (11%) and VaD, n=42 (12%)]. Low as well as high serum IGF-I (quartile 1 or 4 vs. quartiles 2-3) did not associate with all-cause dementia [crude hazard ratio (HR) 1.30, 95% confidence interval (CI): 0.81-2.08 and crude HR 1.05, 95% CI: 0.63-1.75, respectively] or AD (crude HR 0.79, 95% CI: 0.35-1.79 and crude HR 0.94, 95% CI: 0.43-2.06, respectively]. In contrast, low serum IGF-I concentrations were associated with increased risk of VaD (quartile 1 vs. quartiles 2-3, crude HR 2.22, 95% CI: 1.13-4.36). The latter association remained significant also after adjustment for multiple covariates. In a memory clinic population, low serum IGF-I was a risk marker for subsequent VaD whereas low IGF-I did not associate with the risk of AD. High serum IGF-I was not related to the risk of conversion to dementia. Copyright © 2017 Elsevier Ltd. All rights reserved.

The impact of Alzheimer disease genetics on expert and advanced gerontological nursing practice.

PubMed

Schutte, D L

1998-11-01

Alzheimer disease (AD), a progressive neurodegenerative disorder, is the most common cause of dementia in the United States, affecting as many as 4 million people. Extensive research is under way to identify environmental and genetic risk factors for this complex disease. Currently, four genes are associated with an increased risk for AD: the amyloid precursor protein gene on chromosome 21, the Presenilin I gene on chromosome 14, the Presenilin II gene on chromosome 1, and the apolipoprotein E gene on chromosome 19. Expert and advanced practice gerontological nurses are faced with new challenges as a result of these gene discoveries. Gerontological nurses should assess for relevant environmental and genetic risk factors; obtain comprehensive family health histories recorded as pedigrees; integrate genetic information into diagnosis, intervention, and evaluation strategies; initiate and coordinate referrals to genetic specialists; and provide ongoing emotional and decision-making support for patients and families experiencing AD.

Traumatic Brain Injury as a Risk Factor for Alzheimer's Disease: Is Inflammatory Signaling a Key Player?

PubMed

Djordjevic, Jelena; Sabbir, Mohammad Golam; Albensi, Benedict C

2016-01-01

Traumatic brain injury (TBI) has become a significant medical and social concern within the last 30 years. TBI has acute devastating effects, and in many cases, seems to initiate long-term neurodegeneration. With advances in medical technology, many people are now surviving severe brain injuries and their long term consequences. Post trauma effects include communication problems, sensory deficits, emotional and behavioral problems, physical complications and pain, increased suicide risk, dementia, and an increased risk for chronic CNS diseases, such as Alzheimer's disease (AD). In this review, we provide an introduction to TBI and hypothesize how it may lead to neurodegenerative disease in general and AD in particular. In addition, we discuss the evidence that supports the hypothesis that TBI may lead to AD. In particular, we focus on inflammatory responses as key processes in TBI-induced secondary injury, with emphasis on nuclear factor kappa B (NF-κB) signaling.

Common variation in PHACTR1 is associated with susceptibility to cervical artery dissection.

PubMed

Debette, Stéphanie; Kamatani, Yoichiro; Metso, Tiina M; Kloss, Manja; Chauhan, Ganesh; Engelter, Stefan T; Pezzini, Alessandro; Thijs, Vincent; Markus, Hugh S; Dichgans, Martin; Wolf, Christiane; Dittrich, Ralf; Touzé, Emmanuel; Southerland, Andrew M; Samson, Yves; Abboud, Shérine; Béjot, Yannick; Caso, Valeria; Bersano, Anna; Gschwendtner, Andreas; Sessa, Maria; Cole, John; Lamy, Chantal; Medeiros, Elisabeth; Beretta, Simone; Bonati, Leo H; Grau, Armin J; Michel, Patrik; Majersik, Jennifer J; Sharma, Pankaj; Kalashnikova, Ludmila; Nazarova, Maria; Dobrynina, Larisa; Bartels, Eva; Guillon, Benoit; van den Herik, Evita G; Fernandez-Cadenas, Israel; Jood, Katarina; Nalls, Michael A; De Leeuw, Frank-Erik; Jern, Christina; Cheng, Yu-Ching; Werner, Inge; Metso, Antti J; Lichy, Christoph; Lyrer, Philippe A; Brandt, Tobias; Boncoraglio, Giorgio B; Wichmann, Heinz-Erich; Gieger, Christian; Johnson, Andrew D; Böttcher, Thomas; Castellano, Maurizio; Arveiler, Dominique; Ikram, M Arfan; Breteler, Monique M B; Padovani, Alessandro; Meschia, James F; Kuhlenbäumer, Gregor; Rolfs, Arndt; Worrall, Bradford B; Ringelstein, Erich-Bernd; Zelenika, Diana; Tatlisumak, Turgut; Lathrop, Mark; Leys, Didier; Amouyel, Philippe; Dallongeville, Jean

2015-01-01

Cervical artery dissection (CeAD), a mural hematoma in a carotid or vertebral artery, is a major cause of ischemic stroke in young adults although relatively uncommon in the general population (incidence of 2.6/100,000 per year). Minor cervical traumas, infection, migraine and hypertension are putative risk factors, and inverse associations with obesity and hypercholesterolemia are described. No confirmed genetic susceptibility factors have been identified using candidate gene approaches. We performed genome-wide association studies (GWAS) in 1,393 CeAD cases and 14,416 controls. The rs9349379[G] allele (PHACTR1) was associated with lower CeAD risk (odds ratio (OR) = 0.75, 95% confidence interval (CI) = 0.69-0.82; P = 4.46 × 10(-10)), with confirmation in independent follow-up samples (659 CeAD cases and 2,648 controls; P = 3.91 × 10(-3); combined P = 1.00 × 10(-11)). The rs9349379[G] allele was previously shown to be associated with lower risk of migraine and increased risk of myocardial infarction. Deciphering the mechanisms underlying this pleiotropy might provide important information on the biological underpinnings of these disabling conditions.

Quantitative modelling of amyloidogenic processing and its influence by SORLA in Alzheimer's disease.

PubMed

Schmidt, Vanessa; Baum, Katharina; Lao, Angelyn; Rateitschak, Katja; Schmitz, Yvonne; Teichmann, Anke; Wiesner, Burkhard; Petersen, Claus Munck; Nykjaer, Anders; Wolf, Jana; Wolkenhauer, Olaf; Willnow, Thomas E

2012-01-04

The extent of proteolytic processing of the amyloid precursor protein (APP) into neurotoxic amyloid-β (Aβ) peptides is central to the pathology of Alzheimer's disease (AD). Accordingly, modifiers that increase Aβ production rates are risk factors in the sporadic form of AD. In a novel systems biology approach, we combined quantitative biochemical studies with mathematical modelling to establish a kinetic model of amyloidogenic processing, and to evaluate the influence by SORLA/SORL1, an inhibitor of APP processing and important genetic risk factor. Contrary to previous hypotheses, our studies demonstrate that secretases represent allosteric enzymes that require cooperativity by APP oligomerization for efficient processing. Cooperativity enables swift adaptive changes in secretase activity with even small alterations in APP concentration. We also show that SORLA prevents APP oligomerization both in cultured cells and in the brain in vivo, eliminating the preferred form of the substrate and causing secretases to switch to a less efficient non-allosteric mode of action. These data represent the first mathematical description of the contribution of genetic risk factors to AD substantiating the relevance of subtle changes in SORLA levels for amyloidogenic processing as proposed for patients carrying SORL1 risk alleles.

Quantitative modelling of amyloidogenic processing and its influence by SORLA in Alzheimer's disease

PubMed Central

Schmidt, Vanessa; Baum, Katharina; Lao, Angelyn; Rateitschak, Katja; Schmitz, Yvonne; Teichmann, Anke; Wiesner, Burkhard; Petersen, Claus Munck; Nykjaer, Anders; Wolf, Jana; Wolkenhauer, Olaf; Willnow, Thomas E

2012-01-01

The extent of proteolytic processing of the amyloid precursor protein (APP) into neurotoxic amyloid-β (Aβ) peptides is central to the pathology of Alzheimer's disease (AD). Accordingly, modifiers that increase Aβ production rates are risk factors in the sporadic form of AD. In a novel systems biology approach, we combined quantitative biochemical studies with mathematical modelling to establish a kinetic model of amyloidogenic processing, and to evaluate the influence by SORLA/SORL1, an inhibitor of APP processing and important genetic risk factor. Contrary to previous hypotheses, our studies demonstrate that secretases represent allosteric enzymes that require cooperativity by APP oligomerization for efficient processing. Cooperativity enables swift adaptive changes in secretase activity with even small alterations in APP concentration. We also show that SORLA prevents APP oligomerization both in cultured cells and in the brain in vivo, eliminating the preferred form of the substrate and causing secretases to switch to a less efficient non-allosteric mode of action. These data represent the first mathematical description of the contribution of genetic risk factors to AD substantiating the relevance of subtle changes in SORLA levels for amyloidogenic processing as proposed for patients carrying SORL1 risk alleles. PMID:21989385

Antenatal depression.

PubMed

Bowen, Angela; Muhajarine, Nazeem

2006-11-01

About 20 per cent of pregnant women experience antenatal depression (AD), which not only has deleterious effects on the woman and her baby but also increases the risk of developing postpartum depression. Nurses who understand the prevalence, signs and symptoms, and risk factors associated with AD can help to identify it and prevent the sequelae. The signs and symptoms of depression in pregnancy do not differ from depression at at any other time. However, AD may go undiagnosed because of a focus on maternal and fetal well-being and the attribution of complaints to the physical and hormonal changes associated with pregnancy. Risk factors include history of depression, lack of partner, marital difficulties, lack of social support, poverty, family violence, increased life stress, substance abuse, history of previous abortions, unplanned pregnancy, ambivalence toward the pregnancy and anxiety about the fetus. Most of the standard treatments for depression can be used in pregnant women, with the exception of some antidepressant medications. Supportive therapies--exercise, adequate nutrition, adequate sleep, and support from family and friends--are also indicated. Screening of women with known risk factors is crucial, but the authors suggest that the high overall prevalence of depressive symptoms during pregnancy indicates a need for universal screening.

[Atopic dermatitis - risk factors and treatment].

PubMed

Zaleska, Martyna; Trojacka, Ewelina; Savitskyi, Stepan; Terlikowska-Brzósko, Agnieszka; Galus, Ryszard

2017-08-21

Atopic dermatitis (AD) is a chronic, inflammatory skin disease characterized by severe itching and eczematic skin lesions. In Poland from 1.5 to 2.5 million people suffer from AD. The pathophysiologic complexity and the wide spectrum of clinical phenotypes cause diagnostic and therapeutic problems and this is the basis for the division of the disease into subtypes. Heterogeneity of the disease is also confirmed in the study of the genotype of the disease. In relation with AZS more than 1000 loci in chromosomes were demonstrated. The roles of certain genes and the pathophysiology of lesions caused by their polymorphism were described. Wide spectrums of AD risk factors are: cigarette smoking, alcohol consumption during pregnancy, obesity and high and low birth weight. The quality of life in patients with AD is impaired, the disease disrupts family and professional relationships. Biological medical products are an example of an individual approach to the treatment of AD. It seems, individual approach to disease and treatment can be a successive solution to the problem.

Cystatin C as a risk factor for Alzheimer disease.

PubMed

Cathcart, H M; Huang, R; Lanham, I S; Corder, E H; Poduslo, S E

2005-02-22

Cystatin C, a protease inhibitor with widespread distribution, is upregulated in response to injury. Levels are elevated in the brains of patients with Alzheimer disease (AD). We compared frequencies for the CST 3 exon 1 polymorphism in patients with AD and controls. A proportional odds model indicated that the CST 3 A and APOE4 combination carried a high risk: a 14-fold elevation for men and 16-fold for women. These risks apply to risk at ages older than 64 years and to a shift in onset to ages younger than 65 years.

Teaching primary prevention of Alzheimer's disease: does it make a difference?

PubMed

Clevenger, Carolyn K; Cantey, Shileah; Quinn, Mary Ellen

2010-07-01

Alzheimer's disease (AD) is one of the most feared illnesses among older adults. Although no cure exists, an emerging body of literature has outlined potentially risk-reducing behaviors. As evidence has become available on risk reduction, community organizations and advocacy groups have developed health education courses on the topic. This study examines the impact of one educational program on the audience's efficacy expectations and outcome expectations for behavior change. Participants included 53 older adults residing in a continuing care retirement community. The study used a pretest-posttest design with an experimental group (n = 33) and a control group (n = 20). Topics on weekly classes included the relationship between cardiovascular factors and AD, dietary factors implicated in AD, and mental stimulation to reduce AD risk. Class sessions consisted of lecture, discussion, and demonstration. Between-group differences were found for both efficacy (P = .016) and outcome expectations (P = .000). Within-group differences were only significant for increased outcome expectations related to literature-derived behaviors (P = .000). Future work should focus on action and prevention and on replication of the educational program's evaluation in a more diverse population.

Omega-3 Fatty Acid Docosahexaenoic Acid Increases SorLA/LR11, a Sorting Protein with Reduced Expression in Sporadic Alzheimer’s Disease (AD): Relevance to AD Prevention

PubMed Central

Ma, Qiu-Lan; Teter, Bruce; Ubeda, Oliver J.; Morihara, Takashi; Dhoot, Dilsher; Nyby, Michael D.; Tuck, Michael L.; Frautschy, Sally A.; Cole, Greg M.

2008-01-01

Environmental and genetic factors, notably ApoE4, contribute to the etiology of late-onset Alzheimer’s disease (LOAD). Reduced mRNA and protein for an apolipoprotein E (ApoE) receptor family member, SorLA (LR11) has been found in LOAD but not early-onset AD, suggesting that LR11 loss is not secondary to pathology. LR11 is a neuronal sorting protein that reduces amyloid precursor protein (APP) trafficking to secretases that generate β-amyloid (Aβ). Genetic polymorphisms that reduce LR11 expression are associated with increased AD risk. However these polymorphisms account for only a fraction of cases with LR11 deficits, suggesting involvement of environmental factors. Because lipoprotein receptors are typically lipid-regulated, we postulated that LR11 is regulated by docosahexaenoic acid (DHA), an essential ω-3 fatty acid related to reduced AD risk and reduced Aβ accumulation. In this study, we report that DHA significantly increases LR11 in multiple systems, including primary rat neurons, aged non-Tg mice and an aged DHA-depleted APPsw AD mouse model. DHA also increased LR11 in a human neuronal line. In vivo elevation of LR11 was also observed with dietary fish oil in young rats with insulin resistance, a model for type II diabetes, another AD risk factor. These data argue that DHA induction of LR11 does not require DHA-depleting diets and is not age dependent. Because reduced LR11 is known to increase Aβ production and may be a significant genetic cause of LOAD, our results indicate that DHA increases in SorLA/LR11 levels may play an important role in preventing LOAD. PMID:18160637

Association of Low Serum Concentration of Bilirubin with Increased Risk of Coronary Artery Disease

DTIC Science & Technology

1994-01-01

g AD-A276 272... 08/17/93 Association of Low Serum Concentration of Bilirubin IN-House with Increased Risk of Coronary Artery Disease PE 62202F...as possible risk factors for angiographicaiiy documenLed coronary artery disease (CAD). The studies involved a "training" set of 619 men for whom...complete data on all risk factors considered were available, and a "test" set of 258 men for whom some risk factor data were not available. In both study

Meditation as a Therapeutic Intervention for Adults at Risk for Alzheimer’s Disease – Potential Benefits and Underlying Mechanisms

PubMed Central

Innes, Kim E.; Selfe, Terry Kit

2014-01-01

Alzheimer’s disease (AD) is a chronic, progressive, brain disorder that affects at least 5.3 million Americans at an estimated cost of $148 billion, figures that are expected to rise steeply in coming years. Despite decades of research, there is still no cure for AD, and effective therapies for preventing or slowing progression of cognitive decline in at-risk populations remain elusive. Although the etiology of AD remains uncertain, chronic stress, sleep deficits, and mood disturbance, conditions common in those with cognitive impairment, have been prospectively linked to the development and progression of both chronic illness and memory loss and are significant predictors of AD. Therapies such as meditation that specifically target these risk factors may thus hold promise for slowing and possibly preventing cognitive decline in those at risk. In this study, we briefly review the existing evidence regarding the potential utility of meditation as a therapeutic intervention for those with and at risk for AD, discuss possible mechanisms underlying the observed benefits of meditation, and outline directions for future research. PMID:24795656

Validation of the Italian Version of the Caregiver Abuse Screen among Family Caregivers of Older People with Alzheimer's Disease.

PubMed

Melchiorre, Maria Gabriella; Di Rosa, Mirko; Barbabella, Francesco; Barbini, Norma; Lattanzio, Fabrizia; Chiatti, Carlos

2017-01-01

Introduction . Elder abuse is often a hidden phenomenon and, in many cases, screening practices are difficult to implement among older people with dementia. The Caregiver Abuse Screen (CASE) is a useful tool which is administered to family caregivers for detecting their potential abusive behavior. Objectives . To validate the Italian version of the CASE tool in the context of family caregiving of older people with Alzheimer's disease (AD) and to identify risk factors for elder abuse in Italy. Methods . The CASE test was administered to 438 caregivers, recruited in the Up-Tech study. Validity and reliability were evaluated using Spearman's correlation coefficients, principal-component analysis, and Cronbach's alphas. The association between the CASE and other variables potentially associated with elder abuse was also analyzed. Results . The factor analysis suggested the presence of a single factor, with a strong internal consistency (Cronbach's alpha = 0.86). CASE score was strongly correlated with well-known risk factors of abuse. At multivariate level, main factors associated with CASE total score were caregiver burden and AD-related behavioral disturbances. Conclusions . The Italian version of the CASE is a reliable and consistent screening tool for tackling the risk of being or becoming perpetrators of abuse by family caregivers of people with AD.

Validation of the Italian Version of the Caregiver Abuse Screen among Family Caregivers of Older People with Alzheimer's Disease

PubMed Central

Di Rosa, Mirko; Barbabella, Francesco; Barbini, Norma; Chiatti, Carlos

2017-01-01

Introduction. Elder abuse is often a hidden phenomenon and, in many cases, screening practices are difficult to implement among older people with dementia. The Caregiver Abuse Screen (CASE) is a useful tool which is administered to family caregivers for detecting their potential abusive behavior. Objectives. To validate the Italian version of the CASE tool in the context of family caregiving of older people with Alzheimer's disease (AD) and to identify risk factors for elder abuse in Italy. Methods. The CASE test was administered to 438 caregivers, recruited in the Up-Tech study. Validity and reliability were evaluated using Spearman's correlation coefficients, principal-component analysis, and Cronbach's alphas. The association between the CASE and other variables potentially associated with elder abuse was also analyzed. Results. The factor analysis suggested the presence of a single factor, with a strong internal consistency (Cronbach's alpha = 0.86). CASE score was strongly correlated with well-known risk factors of abuse. At multivariate level, main factors associated with CASE total score were caregiver burden and AD-related behavioral disturbances. Conclusions. The Italian version of the CASE is a reliable and consistent screening tool for tackling the risk of being or becoming perpetrators of abuse by family caregivers of people with AD. PMID:28265571

Association between atopic dermatitis and attention deficit hyperactivity disorder in U.S. children and adults*

PubMed Central

Strom, M.A.; Fishbein, A.B.; Paller, A.S.; Silverberg, J.I.

2016-01-01

Summary Background Atopic dermatitis (AD) is associated with chronic itch, allergic disease and sleep disturbance, all of which might increase the risk of attention deficit (hyperactivity) disorder (ADD/ADHD). Previous analyses have found a consistent association between AD and ADD/ADHD, although the underlying factors contributing to such an association remain underexplored. Additionally, the relationship has been underexplored in adults. Objectives To determine if childhood and adult AD and AD severity are associated with ADD/ADHD and to delineate the factors contributing to such an association. Methods We analysed data on 354 416 children aged 2–17 years and 34 613 adults age 18+ years from 19 U.S. population-based surveys, including the National Health Interview Survey 1997–2013 and the National Survey of Children’s Health 2003/4 and 2007/8. Results In multivariate models adjusting for age, sex, sociodemographics, allergic disease and healthcare utilization, AD was associated with ADD/ADHD in both children [adjusted odds ratio (95% confidence interval), 1·14 (1·03–1·26)] and adults [1·61 (1·25–2·06)]. Children with both severe AD and only 0–3 nights of adequate sleep per week had much higher odds of ADD/ADHD [16·83 (7·02–40·33)] than those with 0–3 nights of adequate sleep per week [1·83 (1·47–2·26)] or mild–moderate AD alone [1·56 (1·22–1·99)]. AD was most strongly associated with severe ADHD. AD unaccompanied by other allergic disease was also associated with increased risk of ADD/ADHD in children. Among children with AD, history of anaemia, headaches and obesity were associated with even higher odds of ADD/ADHD. Asthma, insomnia and headaches increased the odds of ADHD in adults with AD, although underweight body mass index was protective. Conclusions Atopic dermatitis is associated with increased odds of ADD/ADHD in adults and children. Several factors increase the risk of ADHD in adults and children with AD. PMID:27105659

Reducing Ribosomal Protein S6 Kinase 1 Expression Improves Spatial Memory and Synaptic Plasticity in a Mouse Model of Alzheimer's Disease

PubMed Central

Caccamo, Antonella; Branca, Caterina; Talboom, Joshua S.; Shaw, Darren M.; Turner, Dharshaun; Ma, Luyao; Messina, Angela; Huang, Zebing; Wu, Jie

2015-01-01

Aging is the most important risk factor associated with Alzheimer's disease (AD); however, the molecular mechanisms linking aging to AD remain unclear. Suppression of the ribosomal protein S6 kinase 1 (S6K1) increases healthspan and lifespan in several organisms, from nematodes to mammals. Here we show that S6K1 expression is upregulated in the brains of AD patients. Using a mouse model of AD, we found that genetic reduction of S6K1 improved synaptic plasticity and spatial memory deficits, and reduced the accumulation of amyloid-β and tau, the two neuropathological hallmarks of AD. Mechanistically, these changes were linked to reduced translation of tau and the β-site amyloid precursor protein cleaving enzyme 1, a key enzyme in the generation of amyloid-β. Our results implicate S6K1 dysregulation as a previously unidentified molecular mechanism underlying synaptic and memory deficits in AD. These findings further suggest that therapeutic manipulation of S6K1 could be a valid approach to mitigate AD pathology. SIGNIFICANCE STATEMENT Aging is the most important risk factor for Alzheimer's disease (AD). However, little is known about how it contributes to AD pathogenesis. S6 kinase 1 (S6K1) is a protein kinase involved in regulation of protein translation. Reducing S6K1 activity increases lifespan and healthspan. We report the novel finding that reducing S6K1 activity in 3xTg-AD mice ameliorates synaptic and cognitive deficits. These improvement were associated with a reduction in amyloid-β and tau pathology. Mechanistically, lowering S6K1 levels reduced translation of β-site amyloid precursor protein cleaving enzyme 1 and tau, two key proteins involved in AD pathogenesis. These data suggest that S6K1 may represent a molecular link between aging and AD. Given that aging is the most important risk factor for most neurodegenerative diseases, our results may have far-reaching implications into other diseases. PMID:26468204

Risk factors for falls in community-dwelling patients with Alzheimer's disease and dementia with Lewy bodies: walking with visuocognitive impairment may cause a fall.

PubMed

Kudo, Yuri; Imamura, Toru; Sato, Atsushi; Endo, Naoto

2009-01-01

To identify risk factors for falls in community-dwelling patients with Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). 78 consecutive patients (51 AD, 27 DLB) were recruited from the Niigata Rehabilitation Hospital memory clinic. We assessed the number of falls each patient had had in the previous 4 months. The data for DLB patients without motor parkinsonism were analyzed both as part of the whole DLB group and separately to determine the effect of parkinsonism alone on falls. Of 78 patients, 17 (21.8%) reported at least 1 fall during the period. A diagnosis of DLB, visual hallucinations, parkinsonism and cognitive fluctuation were significant predictors, but none of them was significant in the stepwise multivariate analysis. After excluding patients with parkinsonism, the use of hypnotics-anxiolytics and a worse score on the constructional task were significant and independent predictors of falling. Parkinsonism was a major risk factor for falls. When AD or DLB patients walk with incongruent visual information, they may increase their postural sway or instability, because of their executive dysfunction. If elementary and/or higher-order visuocognitive impairment in AD or DLB patients alters visual information sufficiently, they may fall when walking. Copyright 2009 S. Karger AG, Basel.

Shared additive genetic influences on DSM-IV criteria for alcohol dependence in subjects of European ancestry.

PubMed

Palmer, Rohan H C; McGeary, John E; Heath, Andrew C; Keller, Matthew C; Brick, Leslie A; Knopik, Valerie S

2015-12-01

Genetic studies of alcohol dependence (AD) have identified several candidate loci and genes, but most observed effects are small and difficult to reproduce. A plausible explanation for inconsistent findings may be a violation of the assumption that genetic factors contributing to each of the seven DSM-IV criteria point to a single underlying dimension of risk. Given that recent twin studies suggest that the genetic architecture of AD is complex and probably involves multiple discrete genetic factors, the current study employed common single nucleotide polymorphisms in two multivariate genetic models to examine the assumption that the genetic risk underlying DSM-IV AD is unitary. AD symptoms and genome-wide single nucleotide polymorphism (SNP) data from 2596 individuals of European descent from the Study of Addiction: Genetics and Environment were analyzed using genomic-relatedness-matrix restricted maximum likelihood. DSM-IV AD symptom covariance was described using two multivariate genetic factor models. Common SNPs explained 30% (standard error=0.136, P=0.012) of the variance in AD diagnosis. Additive genetic effects varied across AD symptoms. The common pathway model approach suggested that symptoms could be described by a single latent variable that had a SNP heritability of 31% (0.130, P=0.008). Similarly, the exploratory genetic factor model approach suggested that the genetic variance/covariance across symptoms could be represented by a single genetic factor that accounted for at least 60% of the genetic variance in any one symptom. Additive genetic effects on DSM-IV alcohol dependence criteria overlap. The assumption of common genetic effects across alcohol dependence symptoms appears to be a valid assumption. © 2015 Society for the Study of Addiction.

Can stress increase Alzheimer's disease risk in women?

PubMed

Johansson, Lena

2014-02-01

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of β-amyloid peptides and neurofibrilllary tangles in brain, resulting in neuronal death and loss of cognitive abilities. It has been hypothesized that longstanding psychological stress can result in neural degeneration and AD due to pathological alterations in the hypothalamic-pituitary-adrenal axis. In recent years several epidemiological studies been published on stress as a risk factor for AD. As women are more likely to suffer from stress-related psychiatric disorders, such as post-traumatic stress disorder and clinical burnout syndrome, special effort has been made according to the gender differences in risk of AD. However, few studies have stratified for gender, due to small sample sizes and limited statistic power, and no reliable findings have been found. Additional longitudinal studies are therefore needed for studying gender differences and for determining what mediates the stress and AD association, in both genders.

Cholesterol as a Causative Factor in Alzheimer Disease: A Debatable Hypothesis

PubMed Central

Wood, W. Gibson; Li, Ling; Müller, Walter E.; Eckert, Gunter P.

2014-01-01

High serum/plasma cholesterol levels have been suggested as a risk factor for Alzheimer disease (AD). Some reports, mostly retrospective epidemiological studies, have observed a decreased prevalence of AD in patients taking the cholesterol lowering drugs, statins. The strongest evidence causally linking cholesterol to AD is provided by experimental studies showing that adding/reducing cholesterol alters amyloid precursor protein (APP) and amyloid beta-protein (Aβ) levels. However, there are problems with the cholesterol-AD hypothesis. Cholesterol levels in serum/plasma and brain of AD patients do not support cholesterol as a causative factor in AD. Prospective studies on statins and AD have largely failed to show efficacy. Even the experimental data are open to interpretation given that it is well-established that modification of cholesterol levels has effects on multiple proteins, not only APP and Aβ. The purpose of this review, therefore, is to examine the above-mentioned issues and discuss the pros and cons of the cholesterol-AD hypothesis, and the involvement of other lipids in the mevalonate pathway, such as isoprenoids and oxysterols, in AD. PMID:24329875

Psychosis of Alzheimer disease: prevalence, incidence, persistence, risk factors, and mortality.

PubMed

Vilalta-Franch, Joan; López-Pousa, Secundino; Calvó-Perxas, Laia; Garre-Olmo, Josep

2013-11-01

To establish the prevalence, incidence, persistence, risk factors, and mortality risk increase of psychosis of Alzheimer disease (PoAD) in a clinical sample. Cross-sectional, observational study of 491 patients with probable AD who, at baseline visit, were evaluated with the Cambridge Examination for Mental Disorders of the Elderly, the Neuropsychiatric Inventory-10, the Rapid Disability Rating Scale-2, and the Zarit Burden Interview. All participants were reevaluated at 6, 12, 18, and 24 months. PoAD diagnoses were made using specific criteria. PoAD prevalence was 7.3%, and the cumulative incidence at 6, 12, 18, and 24 months was 5.8%, 10.6%, 13.5%, and 15.1%, respectively. After 1 year, psychotic symptoms persisted in 68.7% of the patients with initial PoAD. At baseline, patients with PoAD scored lower in the Cambridge Cognitive Examination and Mini-Mental State Examination and higher in the Rapid Disability Rating Scale-2 and Zarit Burden Interview tests. Both low scores in the Cambridge Cognitive Examination subscale of learning memory (hazard ratio [HR] = 0.874; 95% CI: 0.788-0.969; Wald χ2 = 6.515; df = 1) and perception (HR = 0.743; 95% CI: 0.610-0.904; Wald χ2 = 8.778; df = 1), and high scores in expressive language (HR = 1.179; 95% CI: 1.024-1.358; Wald χ2 = 5.261; df = 1) and calculation skills (HR = 1.763; 95% CI: 1.067-2.913; Wald χ2 = 4.905; df = 1) were found to be associated with PoAD. PoAD leads to a faster functional impairment, and it increases mortality risk (HR = 2.191; 95% CI: 1.136-4.228; Wald χ2 = 5.471; df = 1) after controlling for age, gender, cognitive and functional disability, general health status, and antipsychotic treatment. PoAD seems to define a phenotype of AD of greater severity, with worsened functional progression and increased mortality risk. Copyright © 2013 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.

A blood-based biomarker panel indicates IL-10 and IL-12/23p40 are jointly associated as predictors of β-amyloid load in an AD cohort.

PubMed

Pedrini, Steve; Gupta, Veer B; Hone, Eugene; Doecke, James; O'Bryant, Sid; James, Ian; Bush, Ashley I; Rowe, Christopher C; Villemagne, Victor L; Ames, David; Masters, Colin L; Martins, Ralph N

2017-10-25

Alzheimer's Disease (AD) is the most common form of dementia, characterised by extracellular amyloid deposition as plaques and intracellular neurofibrillary tangles of tau protein. As no current clinical test can diagnose individuals at risk of developing AD, the aim of this project is to evaluate a blood-based biomarker panel to identify individuals who carry this risk. We analysed the levels of 22 biomarkers in clinically classified healthy controls (HC), mild cognitive impairment (MCI) and Alzheimer's participants from the well characterised Australian Imaging, Biomarker and Lifestyle (AIBL) study of aging. High levels of IL-10 and IL-12/23p40 were significantly associated with amyloid deposition in HC, suggesting that these two biomarkers might be used to detect at risk individuals. Additionally, other biomarkers (Eotaxin-3, Leptin, PYY) exhibited altered levels in AD participants possessing the APOE ε4 allele. This suggests that the physiology of some potential biomarkers may be altered in AD due to the APOE ε4 allele, a major risk factor for AD. Taken together, these data highlight several potential biomarkers that can be used in a blood-based panel to allow earlier identification of individuals at risk of developing AD and/or early stage AD for which current therapies may be more beneficial.

Familial occurrence of cervical artery dissection--coincidence or sign of familial predisposition?

PubMed

Grond-Ginsbach, Caspar; de Freitas, Gabriel R; Campos, Cynthia R; Thie, Andreas; Caso, Valeria; Machetanz, Jochen; Kloss, Manja

2012-01-01

BACKGROUNDAND PURPOSE: The etiology of spontaneous cervical artery dissection (CeAD) is poorly understood in most patients. Mild cervical trauma preceding the dissection event is a common finding, but many CeAD occur spontaneously. It is likely that genetic factors may increase the risk for CeAD. However, familial cases are excedingly rare. Familial clustering of CeAD may be accidental or associated with genetic or environmental risk factors shared between affected relatives. In this explorative study, we aim to show that specific risk factors for familial CeAD exist. Age of onset, sex, affected artery and number of recurrent CeAD were documented for familial patients and compared with published findings from patients with sporadic CeAD. Concordance of age, sex and dissected artery within the families was analyzed by correlation analysis and by analysis of variance or Kruskal-Wallis testing. The study sample consisted of 9 new patients with a family history of CeAD enrolled in the Neurology Department of the University of Heidelberg or referred to Heidelberg from other centers. The study sample also included published findings from another 23 patients, in total 32 patients. The mean age of the patients with familial CeAD at their first dissections was 38.4 ± 13.3 years. Twenty (62.5%) patients were female and 12 patients (37.5%) suffered multiple dissections. Four patients (12.5%) presented with recurrent dissections after >1 year. Patients with a familial history of CeAD were younger (p = 0.023) and presented more often with multiple dissections (p = 0.024) and recurrent dissections (p = 0.018). Age at the first event (correlation analysis p = 0.026; analysis of variance p = 0.029) and site of the dissection (correlation analysis p = 0.032; Kruskal-Wallis test p = 0.018) differed between the families, and there was no concordance of gender of affected family members (correlation analysis p = 0.500; Kruskal-Wallis test p = 0.211). The high prevalence of multiple dissection events and of long-term (>1 year) recurrent dissections in patients with a familial history of CeAD indicates that a specific predisposition for familial CeAD exists. Since age of onset and affected vessel differ between families, the risk profile for familial CeAD is heterogeneous. A large-scale (whole exome) sequencing analysis of 14 patients from 7 of the analyzed families is currently being performed in order to identify causative genetic variants. Copyright © 2012 S. Karger AG, Basel.

Cumulative risk effects for the development of behaviour difficulties in children and adolescents with special educational needs and disabilities.

PubMed

Oldfield, Jeremy; Humphrey, Neil; Hebron, Judith

2015-01-01

Research has identified multiple risk factors for the development of behaviour difficulties. What have been less explored are the cumulative effects of exposure to multiple risks on behavioural outcomes, with no study specifically investigating these effects within a population of young people with special educational needs and disabilities (SEND). Furthermore, it is unclear whether a threshold or linear risk model better fits the data for this population. The sample included 2660 children and 1628 adolescents with SEND. Risk factors associated with increases in behaviour difficulties over an 18-month period were summed to create a cumulative risk score, with this explanatory variable being added into a multi-level model. A quadratic term was then added to test the threshold model. There was evidence of a cumulative risk effect, suggesting that exposure to higher numbers of risk factors, regardless of their exact nature, resulted in increased behaviour difficulties. The relationship between risk and behaviour difficulties was non-linear, with exposure to increasing risk having a disproportionate and detrimental impact on behaviour difficulties in child and adolescent models. Interventions aimed at reducing behaviour difficulties need to consider the impact of multiple risk variables. Tailoring interventions towards those exposed to large numbers of risks would be advantageous. Copyright © 2015 Elsevier Ltd. All rights reserved.

Comparison of linear–stochastic and nonlinear–deterministic algorithms in the analysis of 15-minute clinical ECGs to predict risk of arrhythmic death

PubMed Central

Skinner, James E; Meyer, Michael; Nester, Brian A; Geary, Una; Taggart, Pamela; Mangione, Antoinette; Ramalanjaona, George; Terregino, Carol; Dalsey, William C

2009-01-01

Objective: Comparative algorithmic evaluation of heartbeat series in low-to-high risk cardiac patients for the prospective prediction of risk of arrhythmic death (AD). Background: Heartbeat variation reflects cardiac autonomic function and risk of AD. Indices based on linear stochastic models are independent risk factors for AD in post-myocardial infarction (post-MI) cohorts. Indices based on nonlinear deterministic models have superior predictability in retrospective data. Methods: Patients were enrolled (N = 397) in three emergency departments upon presenting with chest pain and were determined to be at low-to-high risk of acute MI (>7%). Brief ECGs were recorded (15 min) and R-R intervals assessed by three nonlinear algorithms (PD2i, DFA, and ApEn) and four conventional linear-stochastic measures (SDNN, MNN, 1/f-Slope, LF/HF). Out-of-hospital AD was determined by modified Hinkle–Thaler criteria. Results: All-cause mortality at one-year follow-up was 10.3%, with 7.7% adjudicated to be AD. The sensitivity and relative risk for predicting AD was highest at all time-points for the nonlinear PD2i algorithm (p ≤0.001). The sensitivity at 30 days was 100%, specificity 58%, and relative risk >100 (p ≤0.001); sensitivity at 360 days was 95%, specificity 58%, and relative risk >11.4 (p ≤0.001). Conclusions: Heartbeat analysis by the time-dependent nonlinear PD2i algorithm is comparatively the superior test. PMID:19707283

Interactions Among Polymorphisms of Susceptibility Loci for Alzheimer’s Disease or Depressive Disorder

PubMed Central

Kitzlerová, Eva; Lelková, Petra; Jirák, Roman; Zvěřová, Martina; Hroudová, Jana; Manukyan, Ada; Martásek, Pavel; Raboch, Jiří

2018-01-01

Background Several genetic susceptibility loci for major depressive disorder (MDD) or Alzheimer’s disease (AD) have been described. Interactions among polymorphisms are thought to explain the differences between low- and high-risk groups. We tested for the contribution of interactions between multiple functional polymorphisms in the risk of MDD or AD. Material/Methods A genetic association case-control study was performed in 68 MDD cases, 84 AD cases (35 of them with comorbid depression), and 90 controls. The contribution of 7 polymorphisms from 5 genes (APOE, HSPA1A, SLC6A4, HTR2A, and BDNF) related to risk of MDD or AD development was analyzed. Results Significant associations were found between MDD and interactions among polymorphisms in HSPA1A, SLC6A4, and BDNF or HSPA1A, BDNF, and APOE genes. For polymorphisms in the APOE gene in AD, significant differences were confirmed on the distributions of alleles and genotype rates compared to the control or MDD. Increased probability of comorbid depression was found in patients with AD who do not carry the ɛ4 allele of APOE. Conclusions Assessment of the interactions among polymorphisms of susceptibility loci in both MDD and AD confirmed a synergistic effect of genetic factors influencing inflammatory, serotonergic, and neurotrophic pathways at these heterogenous complex diseases. The effect of interactions was greater in MDD than in AD. A presence of the ɛ4 allele was confirmed as a genetic susceptibility factor in AD. Our findings indicate a role of APOE genotype in onset of comorbid depression in a subgroup of patients with AD who are not carriers of the APOE ɛ4 allele. PMID:29703883

Prevalence of atherogenic dyslipidemia: association with risk factors and cardiovascular risk in Spanish working population. "ICARIA" study.

PubMed

Cabrera, M; Sánchez-Chaparro, M A; Valdivielso, P; Quevedo-Aguado, L; Catalina-Romero, C; Fernández-Labandera, C; Ruiz-Moraga, M; González-Santos, P; Calvo-Bonacho, E

2014-08-01

The aim of this study was to assess the prevalence of atherogenic dyslipidemia (AD) and the lipid triad (LT) in the working population in Spain, their associated variables and how far they are linked to cardiovascular risk (CVR). Observational cross-sectional study of 70,609 workers (71.5% male (M), 28.5% female (F), mean age 39.2 ± 10), who attended medical checkups and agreed to participate. Plasma samples were analysed in a central laboratory. AD definition used was: triglycerides ≥150 mg/dl and HDL cholesterol <40 mg/dl (M)/<50 mg/dl (F) and LT when LDL cholesterol > 160 mg/dl is further added. Univariate comparisons in the absence and presence of AD and LT and the probability of AD according to different parameters and their possible association with CVR were assessed. CVR was stratified following the European SCORE model for low risk-population. 5.7% (95% CI 4.7-6.9) of the working population have AD and 1.1% (95% CI 1.0-1.2) LT. In univariate analysis, workers with AD and LT had a higher prevalence of obesity, hypertension, smoking and diabetes than those who had not (p < 0.001). In multivariate analysis, BMI, sex, age 40-49, diabetes, tobacco, uric acid, LDL or blood pressure significantly influenced the risk of AD. AD was significantly associated with CVR after adjusting for alcohol and obesity. However, most of the AD subjects (91.8%) were classified as low risk. About 6% of the working population in Spain meets AD criteria. Assuming that these subjects have increased CVR, AD allows to identify additional 5% of subjects with increased CVR to that one the SCORE model detects, helping to improve cardiovascular risk stratification. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Subtle learning and memory impairment in an idiopathic rat model of Alzheimer's disease utilizing cholinergic depletions and β-amyloid.

PubMed

Deibel, S H; Weishaupt, N; Regis, A M; Hong, N S; Keeley, R J; Balog, R J; Bye, C M; Himmler, S M; Whitehead, S N; McDonald, R J

2016-09-01

Alzheimer's disease (AD) is a disease of complex etiology, involving multiple risk factors. When these risk factors are presented concomitantly, cognition and brain pathology are more severely compromised than if those risk factors were presented in isolation. Reduced cholinergic tone and elevated amyloid-beta (Aβ) load are pathological hallmarks of AD. The present study sought to investigate brain pathology and alterations in learning and memory when these two factors were presented together in rats. Rats received either sham surgeries, cholinergic depletions of the medial septum, intracerebroventricular Aβ25-35 injections, or both cholinergic depletion and Aβ25-35 injections (Aβ+ACh group). The Aβ+ACh rats were unimpaired in a striatal dependent visual discrimination task, but had impaired acquisition in the standard version of the Morris water task. However, these rats displayed normal Morris water task retention and no impairment in acquisition of a novel platform location during a single massed training session. Aβ+ACh rats did not have exacerbated brain pathology as indicated by activated astroglia, activated microglia, or accumulation of Aβ. These data suggest that cholinergic depletions and Aβ injections elicit subtle cognitive deficits when behavioural testing is conducted shortly after the presentation of these factors. These factors might have altered hippocampal synaptic plasticity and thus resemble early AD pathology. Copyright © 2016 Elsevier B.V. All rights reserved.

Added sugars and risk factors for obesity, diabetes and heart disease.

PubMed

Rippe, J M; Angelopoulos, T J

2016-03-01

The effects of added sugars on various chronic conditions are highly controversial. Some investigators have argued that added sugars increase the risk of obesity, diabetes and cardiovascular disease. However, few randomized controlled trials are available to support these assertions. The literature is further complicated by animal studies, as well as studies which compare pure fructose to pure glucose (neither of which is consumed to any appreciable degree in the human diet) and studies where large doses of added sugars beyond normal levels of human consumption have been administered. Various scientific and public health organizations have offered disparate recommendations for upper limits of added sugar. In this article, we will review recent randomized controlled trials and prospective cohort studies. We conclude that the normal added sugars in the human diet (for example, sucrose, high-fructose corn syrup and isoglucose) when consumed within the normal range of normal human consumption or substituted isoenergetically for other carbohydrates, do not appear to cause a unique risk of obesity, diabetes or cardiovascular disease.

Direct-to-consumer advertising and its utility in health care decision making: a consumer perspective.

PubMed

Deshpande, Aparna; Menon, Ajit; Perri, Matthew; Zinkhan, George

2004-01-01

The growth in direct-to-consumer advertising(DTCA)over the past two decades has facilitated the communication of prescription drug information directly to consumers. Data from a 1999 national survey are employed to determine the factors influencing consumers' opinions of the utility of DTC ads for health care decision making. We also analyze whether consumers use DTC ad information in health care decision making and who are the key drivers of such information utilization. The study results suggest that consumers have positive opinions of DTCA utility, varying across demographics and perceptions of certain advertisement features. Specifically, consumers value information about both risks and benefits, but the perception of risk information is more important in shaping opinions of ad utility than the perception of benefit information. Consumers still perceive, however that the quality of benefit information in DTC ads is better than that of risk information. Opinions about ad utility significantly influence whether information from DTC ads is used in health care decision making.

Depressive symptoms associated with hereditary Alzheimer's disease: a case description.

PubMed

Contreras, Mónica Yicette Sánchez; Vargas, Paula Alejandra Osorio; Ramos, Lucero Rengifo; Velandia, Rafael Alarcón

The authors describe a family group studied by the Centro de Biología Molecular y Biotecnología, and the Clínica de la Memoria, las Demencias y el Envejecimiento (Universidad Tecnológica de Pereira, Colombia), and evaluate the association of depressive symptoms with Alzheimer's disease (AD). This family presented a hereditary pattern for AD characterized by an early onset of dementia symptoms, a long preclinical depressive course, and, once the first symptoms of dementia appeared, a rapid progression to severe cognitive function impairment. The authors found a high prevalence of depressive symptoms in this family and propose that the symptoms could be an important risk factor for developing AD in the presence of other risk factors such as the APOE E4 allele.

Added Sugars and Cardiovascular Disease Risk in Children: A Scientific Statement From the American Heart Association.

PubMed

Vos, Miriam B; Kaar, Jill L; Welsh, Jean A; Van Horn, Linda V; Feig, Daniel I; Anderson, Cheryl A M; Patel, Mahesh J; Cruz Munos, Jessica; Krebs, Nancy F; Xanthakos, Stavra A; Johnson, Rachel K

2017-05-09

Poor lifestyle behaviors are leading causes of preventable diseases globally. Added sugars contribute to a diet that is energy dense but nutrient poor and increase risk of developing obesity, cardiovascular disease, hypertension, obesity-related cancers, and dental caries. For this American Heart Association scientific statement, the writing group reviewed and graded the current scientific evidence for studies examining the cardiovascular health effects of added sugars on children. The available literature was subdivided into 5 broad subareas: effects on blood pressure, lipids, insulin resistance and diabetes mellitus, nonalcoholic fatty liver disease, and obesity. Associations between added sugars and increased cardiovascular disease risk factors among US children are present at levels far below current consumption levels. Strong evidence supports the association of added sugars with increased cardiovascular disease risk in children through increased energy intake, increased adiposity, and dyslipidemia. The committee found that it is reasonable to recommend that children consume ≤25 g (100 cal or ≈6 teaspoons) of added sugars per day and to avoid added sugars for children <2 years of age. Although added sugars most likely can be safely consumed in low amounts as part of a healthy diet, few children achieve such levels, making this an important public health target. © 2017 American Heart Association, Inc.

Meta-Prediction of the Effect of Methylenetetrahydrofolate Reductase Polymorphisms and Air Pollution on Alzheimer's Disease Risk.

PubMed

Wu, Suh-Mian; Chen, Zhao-Feng; Young, Lufei; Shiao, S Pamela K

2017-01-11

Background : Alzheimer's disease (AD) is a significant public health issue. AD has been linked with methylenetetrahydrofolate reductase ( MTHFR ) C677T polymorphism, but the findings have been inconsistent. The purpose of this meta-predictive analysis is to examine the associations between MTHFR polymorphisms and epigenetic factors, including air pollution, with AD risk using big data analytics approaches. Methods and Results : Forty-three studies (44 groups) were identified by searching various databases. MTHFR C677T TT and CT genotypes had significant associations with AD risk in all racial populations (RR = 1.13, p = 0.0047; and RR = 1.12, p < 0.0001 respectively). Meta-predictive analysis showed significant increases of percentages of MTHFR C677T polymorphism with increased air pollution levels in both AD case group and control group ( p = 0.0021-0.0457); with higher percentages of TT and CT genotypes in the AD case group than that in the control group with increased air pollution levels. Conclusions : The impact of MTHFR C677T polymorphism on susceptibility to AD was modified by level of air pollution. Future studies are needed to further examine the effects of gene-environment interactions including air pollution on AD risk for world populations.

Added Sugars and Cardiovascular Disease Risk in Children

PubMed Central

Vos, Miriam B.; Kaar, Jill L.; Welsh, Jean A.; Van Horn, Linda V.; Feig, Daniel I.; Anderson, Cheryl A.M.; Patel, Mahesh J.; Munos, Jessica Cruz; Krebs, Nancy F.; Xanthakos, Stavra A.; Johnson, Rachel K.

2017-01-01

BACKGROUND Poor lifestyle behaviors are leading causes of preventable diseases globally. Added sugars contribute to a diet that is energy dense but nutrient poor and increase risk of developing obesity, cardiovascular disease, hypertension, obesity-related cancers, and dental caries. METHODS AND RESULTS For this American Heart Association scientific statement, the writing group reviewed and graded the current scientific evidence for studies examining the cardiovascular health effects of added sugars on children. The available literature was subdivided into 5 broad subareas: effects on blood pressure, lipids, insulin resistance and diabetes mellitus, nonalcoholic fatty liver disease, and obesity. CONCLUSIONS Associations between added sugars and increased cardiovascular disease risk factors among US children are present at levels far below current consumption levels. Strong evidence supports the association of added sugars with increased cardiovascular disease risk in children through increased energy intake, increased adiposity, and dyslipidemia. The committee found that it is reasonable to recommend that children consume ≤25 g (100 cal or ≈6 teaspoons) of added sugars per day and to avoid added sugars for children <2 years of age. Although added sugars most likely can be safely consumed in low amounts as part of a healthy diet, few children achieve such levels, making this an important public health target. PMID:27550974

Meta-Prediction of the Effect of Methylenetetrahydrofolate Reductase Polymorphisms and Air Pollution on Alzheimer’s Disease Risk

PubMed Central

Wu, Suh-Mian; Chen, Zhao-Feng; Young, Lufei; Shiao, S. Pamela K.

2017-01-01

Background: Alzheimer’s disease (AD) is a significant public health issue. AD has been linked with methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, but the findings have been inconsistent. The purpose of this meta-predictive analysis is to examine the associations between MTHFR polymorphisms and epigenetic factors, including air pollution, with AD risk using big data analytics approaches. Methods and Results: Forty-three studies (44 groups) were identified by searching various databases. MTHFR C677T TT and CT genotypes had significant associations with AD risk in all racial populations (RR = 1.13, p = 0.0047; and RR = 1.12, p < 0.0001 respectively). Meta-predictive analysis showed significant increases of percentages of MTHFR C677T polymorphism with increased air pollution levels in both AD case group and control group (p = 0.0021–0.0457); with higher percentages of TT and CT genotypes in the AD case group than that in the control group with increased air pollution levels. Conclusions: The impact of MTHFR C677T polymorphism on susceptibility to AD was modified by level of air pollution. Future studies are needed to further examine the effects of gene-environment interactions including air pollution on AD risk for world populations. PMID:28085050

The genetics of Alzheimer disease.

PubMed

Tanzi, Rudolph E

2012-10-01

Family history is the second strongest risk factor for Alzheimer disease (AD) following advanced age. Twin and family studies indicate that genetic factors are estimated to play a role in at least 80% of AD cases. The inheritance of AD exhibits a dichotomous pattern. On one hand, rare mutations in APP, PSEN1, and PSEN2 virtually guarantee early-onset (<60 years) familial AD, which represents ∼5% of AD. On the other hand, common gene polymorphisms, such as the ε4 and ε2 variants of the APOE gene, can influence susceptibility for ∼50% of the common late-onset AD. These four genes account for 30%-50% of the inheritability of AD. Genome-wide association studies have recently led to the identification of 11 additional AD candidate genes. This paper reviews the past, present, and future attempts to elucidate the complex and heterogeneous genetic underpinnings of AD.

The Genetics of Alzheimer Disease

PubMed Central

Tanzi, Rudolph E.

2012-01-01

Family history is the second strongest risk factor for Alzheimer disease (AD) following advanced age. Twin and family studies indicate that genetic factors are estimated to play a role in at least 80% of AD cases. The inheritance of AD exhibits a dichotomous pattern. On one hand, rare mutations in APP, PSEN1, and PSEN2 virtually guarantee early-onset (<60 years) familial AD, which represents ∼5% of AD. On the other hand, common gene polymorphisms, such as the ε4 and ε2 variants of the APOE gene, can influence susceptibility for ∼50% of the common late-onset AD. These four genes account for 30%–50% of the inheritability of AD. Genome-wide association studies have recently led to the identification of 11 additional AD candidate genes. This paper reviews the past, present, and future attempts to elucidate the complex and heterogeneous genetic underpinnings of AD. PMID:23028126

Disordered APP metabolism and neurovasculature in trauma and aging: Combined risks for chronic neurodegenerative disorders.

PubMed

Ikonomovic, Milos D; Mi, Zhiping; Abrahamson, Eric E

2017-03-01

Traumatic brain injury (TBI), advanced age, and cerebral vascular disease are factors conferring increased risk for late onset Alzheimer's disease (AD). These conditions are also related pathologically through multiple interacting mechanisms. The hallmark pathology of AD consists of pathological aggregates of amyloid-β (Aβ) peptides and tau proteins. These molecules are also involved in neuropathology of several other chronic neurodegenerative diseases, and are under intense investigation in the aftermath of TBI as potential contributors to the risk for developing AD and chronic traumatic encephalopathy (CTE). The pathology of TBI is complex and dependent on injury severity, age-at-injury, and length of time between injury and neuropathological evaluation. In addition, the mechanisms influencing pathology and recovery after TBI likely involve genetic/epigenetic factors as well as additional disorders or comorbid states related to age and central and peripheral vascular health. In this regard, dysfunction of the aging neurovascular system could be an important link between TBI and chronic neurodegenerative diseases, either as a precipitating event or related to accumulation of AD-like pathology which is amplified in the context of aging. Thus with advanced age and vascular dysfunction, TBI can trigger self-propagating cycles of neuronal injury, pathological protein aggregation, and synaptic loss resulting in chronic neurodegenerative disease. In this review we discuss evidence supporting TBI and aging as dual, interacting risk factors for AD, and the role of Aβ and cerebral vascular dysfunction in this relationship. Evidence is discussed that Aβ is involved in cyto- and synapto-toxicity after severe TBI, and that its chronic effects are potentiated by aging and impaired cerebral vascular function. From a therapeutic perspective, we emphasize that in the fields of TBI- and aging-related neurodegeneration protective strategies should include preservation of neurovascular function. Published by Elsevier B.V.

Common variation in PHACTR1 is associated with susceptibility to cervical artery dissection

PubMed Central

Debette, Stéphanie; Kamatani, Yoichiro; Metso, Tiina M; Kloss, Manja; Chauhan, Ganesh; Engelter, Stefan T; Pezzini, Alessandro; Thijs, Vincent; Markus, Hugh S; Dichgans, Martin; Wolf, Christiane; Dittrich, Ralf; Touzé, Emmanuel; Southerland, Andrew M; Samson, Yves; Abboud, Shérine; Béjot, Yannick; Caso, Valeria; Bersano, Anna; Gschwendtner, Andreas; Sessa, Maria; Cole, John; Lamy, Chantal; Medeiros, Elisabeth; Beretta, Simone; Bonati, Leo H; Grau, Armin J; Michel, Patrik; Majersik, Jennifer J; Sharma, Pankaj; Kalashnikova, Ludmila; Nazarova, Maria; Dobrynina, Larisa; Bartels, Eva; Guillon, Benoit; van den Herik, Evita G; Fernandez-Cadenas, Israel; Jood, Katarina; Nalls, Michael A; De Leeuw, Frank-Erik; Jern, Christina; Cheng, Yu-Ching; Werner, Inge; Metso, Antti J; Lichy, Christoph; Lyrer, Philippe A; Brandt, Tobias; Boncoraglio, Giorgio B; Wichmann, Heinz-Erich; Gieger, Christian; Johnson, Andrew D; Böttcher, Thomas; Castellano, Maurizio; Arveiler, Dominique; Ikram, M Arfan; Breteler, Monique M B; Padovani, Alessandro; Meschia, James F; Kuhlenbäumer, Gregor; Rolfs, Arndt; Worrall, Bradford B; Ringelstein, Erich-Bernd; Zelenika, Diana; Tatlisumak, Turgut; Lathrop, Mark; Leys, Didier; Amouyel, Philippe; Dallongeville, Jean

2018-01-01

Cervical artery dissection (CeAD), a mural hematoma in a carotid or vertebral artery, is a major cause of ischemic stroke in young adults although relatively uncommon in the general population (incidence of 2.6/100,000 per year)1. Minor cervical traumas, infection, migraine and hypertension are putative risk factors1–3, and inverse associations with obesity and hypercholesterolemia are described3,4. No confirmed genetic susceptibility factors have been identified using candidate gene approaches5. We performed genome-wide association studies (GWAS) in 1,393 CeAD cases and 14,416 controls. The rs9349379[G] allele (PHACTR1) was associated with lower CeAD risk (odds ratio (OR) = 0.75, 95% confidence interval (CI) = 0.69–0.82; P = 4.46 × 10−10), with confirmation in independent follow-up samples (659 CeAD cases and 2,648 controls; P = 3.91 × 10−3; combined P = 1.00 × 10−11). The rs9349379[G] allele was previously shown to be associated with lower risk of migraine and increased risk of myocardial infarction6–9. Deciphering the mechanisms underlying this pleiotropy might provide important information on the biological underpinnings of these disabling conditions. PMID:25420145

Strong evidence for a genetic contribution to late-onset Alzheimer's disease mortality: a population-based study.

PubMed

Kauwe, John S K; Ridge, Perry G; Foster, Norman L; Cannon-Albright, Lisa A

2013-01-01

Alzheimer's disease (AD) is an international health concern that has a devastating effect on patients and families. While several genetic risk factors for AD have been identified much of the genetic variance in AD remains unexplained. There are limited published assessments of the familiality of Alzheimer's disease. Here we present the largest genealogy-based analysis of AD to date. We assessed the familiality of AD in The Utah Population Database (UPDB), a population-based resource linking electronic health data repositories for the state with the computerized genealogy of the Utah settlers and their descendants. We searched UPDB for significant familial clustering of AD to evaluate the genetic contribution to disease. We compared the Genealogical Index of Familiality (GIF) between AD individuals and randomly selected controls and estimated the Relative Risk (RR) for a range of family relationships. Finally, we identified pedigrees with a significant excess of AD deaths. The GIF analysis showed that pairs of individuals dying from AD were significantly more related than expected. This excess of relatedness was observed for both close and distant relationships. RRs for death from AD among relatives of individuals dying from AD were significantly increased for both close and more distant relatives. Multiple pedigrees had a significant excess of AD deaths. These data strongly support a genetic contribution to the observed clustering of individuals dying from AD. This report is the first large population-based assessment of the familiality of AD mortality and provides the only reported estimates of relative risk of AD mortality in extended relatives to date. The high-risk pedigrees identified show a true excess of AD mortality (not just multiple cases) and are greater in depth and width than published AD pedigrees. The presence of these high-risk pedigrees strongly supports the possibility of rare predisposition variants not yet identified.

Vitamin D, Homocysteine, and Folate in Subcortical Vascular Dementia and Alzheimer Dementia.

PubMed

Moretti, Rita; Caruso, Paola; Dal Ben, Matteo; Conti, Corrado; Gazzin, Silvia; Tiribelli, Claudio

2017-01-01

Dementia is a worldwide health problem which affects millions of patients; Alzheimer's disease (AD) and subcortical vascular dementia (sVAD) are the two most frequent forms of its presentation. As no definite therapeutic options have been discovered, different risk factors for cognitive impairment have been searched for potential therapies. This report focuses on the possible evidence that vitamin D deficiency and hyper-homocysteinemia can be considered as two important factors for the development or the progression of neurodegenerative or vascular pathologies. To this end, we assessed: the difference in vascular risk factors and vitamin D-OH25 levels among groups of sVAD, AD, and healthy age-matched controls; the association of folate, B12, homocysteine, and vitamin D with sVAD/AD and whether a deficiency of vitamin D and an increment in homocysteine levels may be related to neurodegenerative or vessel damages. The commonly-considered vascular risk factors were collected in 543 patients and compared with those obtained from a healthy old volunteer population. ANOVA group comparison showed that vitamin D deficiency was present in demented cases, as well as low levels of folate and high levels of homocysteine, more pronounced in sVAD cases. The statistical models we employed, with regression models built, and adjustments for biochemical, demographic and neuropsychiatric scores, confirmed the association between the three measures (folate decrease, hyperhomocysteinemia and vitamin D decrease) and dementia, more pronounced in sVAD than in AD.

White matter hyperintensities and cerebral amyloidosis: necessary and sufficient for clinical expression of Alzheimer disease?

PubMed

Provenzano, Frank A; Muraskin, Jordan; Tosto, Giuseppe; Narkhede, Atul; Wasserman, Ben T; Griffith, Erica Y; Guzman, Vanessa A; Meier, Irene B; Zimmerman, Molly E; Brickman, Adam M

2013-04-01

Current hypothetical models emphasize the importance of β-amyloid in Alzheimer disease (AD) pathogenesis, although amyloid alone is not sufficient to account for the dementia syndrome. The impact of small-vessel cerebrovascular disease, visualized as white matter hyperintensities (WMHs) on magnetic resonance imaging scans, may be a key factor that contributes independently to AD presentation. To determine the impact of WMHs and Pittsburgh Compound B (PIB) positron-emission tomography-derived amyloid positivity on the clinical expression of AD. Baseline PIB-positron-emission tomography values were downloaded from the Alzheimer's Disease Neuroimaging Initiative database. Total WMH volume was derived on accompanying structural magnetic resonance imaging data. We examined whether PIB positivity and total WMHs predicted diagnostic classification of patients with AD (n = 20) and control subjects (n = 21). A second analysis determined whether WMHs discriminated between those with and without the clinical diagnosis of AD among those who were classified as PIB positive (n = 28). A third analysis examined whether WMHs, in addition to PIB status, could be used to predict future risk for AD among subjects with mild cognitive impairment (n = 59). The Alzheimer's Disease Neuroimaging Initiative public database. The study involved data from 21 normal control subjects, 59 subjects with mild cognitive impairment, and 20 participants with clinically defined AD from the Alzheimer Disease's Neuroimaging Initiative database. Clinical AD diagnosis and WMH volume. Pittsburgh Compound B positivity and increased total WMH volume independently predicted AD diagnosis. Among PIB-positive subjects, those diagnosed as having AD had greater WMH volume than normal control subjects. Among subjects with mild cognitive impairment, both WMH and PIB status at baseline conferred risk for future diagnosis of AD. White matter hyperintensities contribute to the presentation of AD and, in the context of significant amyloid deposition, may provide a second hit necessary for the clinical manifestation of the disease. As risk factors for the development of WMHs are modifiable, these findings suggest intervention and prevention strategies for the clinical syndrome of AD.

A longitudinal study of change in falls risk and balance and mobility in healthy older people and people with Alzheimer disease.

PubMed

Suttanon, Plaiwan; Hill, Keith D; Said, Catherine M; Dodd, Karen J

2013-08-01

The aim of this study was to determine the rate of change in falls risk and balance and mobility performance in people with Alzheimer disease (AD) compared with those of healthy older people over a 1-yr period. A 1-yr follow-up study of change in levels of falls risk, balance, and mobility performance in 15 community-dwelling older people with mild to moderate AD and 15 healthy age-matched older people was conducted. Each participant completed a comprehensive assessment of balance and mobility, falls and falls risk, and level of physical activity at baseline and 1 yr later. The rate of increase in the number of falls and risk of falling was greater in people with AD. The rate of deterioration on a number of balance and mobility measures was also significantly greater in people with AD compared with the healthy older people. People with mild to moderate AD have an increased rate of decline in falls risk, balance, and mobility over a 12-mo period compared with age-matched healthy older people. Given this increased rate of decline, intermittent review of falls, balance and mobility, and interventions to address identified contributory risk factors should be considered by health practitioners.

Cutting Corners: Provider Perceptions of Interpretation Services and Factors Related to Use of an Ad Hoc Interpreter.

PubMed

Mayo, Rachel; Parker, Veronica G; Sherrill, Windsor W; Coltman, Kinneil; Hudson, Matthew F; Nichols, Christina M; Yates, Adam M; Pribonic, Anne Paige

2016-06-01

This study assessed health providers' perceptions of factors related to professional interpretation services and the association between these factors and the potential use of ad hoc interpreters. Data were collected from a convenience sample of 150 health services providers at a large, regional health system in South Carolina. Providers rated "ability to communicate effectively during a clinical encounter" as paramount regarding the use of interpretation services. The most important factors related to the likely use of ad hoc interpreters (cutting corners) included locating a qualified interpreter, having to wait for a qualified interpreter, and technical difficulties regarding phone and video technology. Health care organizations may benefit from increasing staff awareness about patient safety and legal and regulatory risks involved with the use of ad hoc interpreters. © The Author(s) 2016.

Prevention of Alzheimer disease

PubMed Central

Scalco, Monica Zavaloni; van Reekum, Robert

2006-01-01

OBJECTIVE To review the evidence regarding prevention of Alzheimer disease (AD) in order to highlight the role of family medicine. QUALITY OF EVIDENCE Most of the evidence relating to prevention of AD is derived from observational (cross-sectional, case-control, or longitudinal) studies. Evidence from randomized controlled trials (RCTs) is available only for blood pressure control and for hormone replacement therapy for menopausal women. MAIN MESSAGE Many preventive approaches to AD have been identified, but no RCTs support their efficacy. Evidence from RCTs supports the effectiveness of blood pressure control in reducing incidence of AD, but demonstrates that postmenopausal women’s use of estrogen is ineffective in reducing it. Observational studies suggest that some preventive approaches, such as healthy lifestyle, ongoing education, regular physical activity, and cholesterol control, play a role in prevention of AD. These approaches can and should be used for every patient because they carry no significant risk. Currently, no effective pharmacologic interventions have been researched enough to support their use in prevention of AD. CONCLUSION Health professionals should educate patients, especially patients at higher risk of AD, about preventive strategies and potentially modifiable risk factors. PMID:16529393

Risk factors associated with atherogenic dyslipidemia in the presence of optimal statin therapy.

PubMed

Zhao, Wang; Zheng, Xi-Long; Jiang, Ze-Nan; Liao, Xiao-Bo; Zhao, Shui-Ping

2017-12-01

This study investigated the prevalence of atherogenic dyslipidemia (AD) in Chinese outpatients whose low-density lipoprotein cholesterol (LDL-C) levels reached the goals with statin monotherapy and evaluated the characteristics of these patients. An analysis of the Dyslipidemia International Survey-China study that was carried out at 122 hospitals in China. Among patients reaching their LDL-C goals, the presence of AD was defined as triglyceride levels ≥1.7mmol/L and/or low levels of high-density lipoprotein cholesterol (men: <1.0mmol/L; women: <1.3mmol/L). 22,039 patients receiving statin monotherapy were analyzed. According to the American National Cholesterol Education Program Adult Treatment Panel III, 13,088 patients reached LDL-C goals, and 7134 patients of them had AD. Age, male gender, BMI, sedentary lifestyle, diabetes mellitus, ischemic cerebrovascular disease, serum uric acid levels, and fasting plasma glucose (all P<0.05) were independently associated with AD. Based on the Chinese guideline for the management of dyslipidemia, 13,551 patients reached LDL-C goals, and 7719 patients of them had AD. Age, male gender, BMI, sedentary lifestyle, coronary heart disease, serum uric acid levels, and fasting plasma glucose (all P<0.05) were independently associated with AD. The intensity of statin therapy did not affect the prevalence of AD. There was a high prevalence of AD in Chinese patients with optimal statin treatment. Some risk factors associated with AD were identified, but these factors were slightly different according to two criteria/guidelines. The intensity of statin therapy did not reduce the prevalence of AD. A combination lipid therapy may be more suitable for Chinese patients. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

The Guinea Pig as a Model for Sporadic Alzheimer’s Disease (AD): The Impact of Cholesterol Intake on Expression of AD-Related Genes

PubMed Central

Ong, Daniel; Wijaya, Linda; Laws, Simon M.; Taddei, Kevin; Newman, Morgan; Lardelli, Michael; Martins, Ralph N.; Verdile, Giuseppe

2013-01-01

We investigated the guinea pig, Cavia porcellus, as a model for Alzheimer’s disease (AD), both in terms of the conservation of genes involved in AD and the regulatory responses of these to a known AD risk factor - high cholesterol intake. Unlike rats and mice, guinea pigs possess an Aβ peptide sequence identical to human Aβ. Consistent with the commonality between cardiovascular and AD risk factors in humans, we saw that a high cholesterol diet leads to up-regulation of BACE1 (β-secretase) transcription and down-regulation of ADAM10 (α-secretase) transcription which should increase release of Aβ from APP. Significantly, guinea pigs possess isoforms of AD-related genes found in humans but not present in mice or rats. For example, we discovered that the truncated PS2V isoform of human PSEN2, that is found at raised levels in AD brains and that increases γ-secretase activity and Aβ synthesis, is not uniquely human or aberrant as previously believed. We show that PS2V formation is up-regulated by hypoxia and a high-cholesterol diet while, consistent with observations in humans, Aβ concentrations are raised in some brain regions but not others. Also like humans, but unlike mice, the guinea pig gene encoding tau, MAPT, encodes isoforms with both three and four microtubule binding domains, and cholesterol alters the ratio of these isoforms. We conclude that AD-related genes are highly conserved and more similar to human than the rat or mouse. Guinea pigs represent a superior rodent model for analysis of the impact of dietary factors such as cholesterol on the regulation of AD-related genes. PMID:23805206

Association of dietary cholesterol and egg intakes with the risk of incident dementia or Alzheimer disease: the Kuopio Ischaemic Heart Disease Risk Factor Study.

PubMed

Ylilauri, Maija Pt; Voutilainen, Sari; Lönnroos, Eija; Mursu, Jaakko; Virtanen, Heli Ek; Koskinen, Timo T; Salonen, Jukka T; Tuomainen, Tomi-Pekka; Virtanen, Jyrki K

2017-02-01

There is little information about the associations of intakes of cholesterol and eggs, a major source of dietary cholesterol, with the risk of cognitive decline in general populations or in carriers of apolipoprotein E ɛ4 (APO-E4), a major risk factor for dementia. We investigated the associations of cholesterol and egg intakes with incident dementia, Alzheimer disease (AD), and cognitive performance in middle-aged and older men from Eastern Finland. A total of 2497 dementia-free men, aged 42-60 y in 1984-1989 at the baseline examinations of the prospective, population-based Kuopio Ischaemic Heart Disease Risk Factor Study, were included in the study. Information on the apolipoprotein E (Apo-E) phenotype was available for 1259 men. Data on cognitive performance tests at the 4-y re-examinations were available for 480 men. Dietary intakes were assessed with the use of 4-d food records at baseline. Dementia and AD diagnoses were based on Finnish health registers. Cox regression and ANCOVA were used for the analyses. During the 21.9-y follow-up, 337 men were diagnosed with dementia, and 266 men were diagnosed with AD. Neither cholesterol nor egg intake was associated with a higher risk of incident dementia or AD. For example, when evaluated continuously, each intake of 100 mg cholesterol/d was associated with a multivariable-adjusted HR of 0.90 (95% CI: 0.79, 1.02) for incident dementia, and each additional 0.5 egg (27 g)/d was associated with an HR of 0.89 (95% CI: 0.78, 1.01). However, egg intake was associated with better performance on neuropsychological tests of the frontal lobe and executive functioning, the Trail Making Test, and the Verbal Fluency Test. The Apo-E4 phenotype did not modify the associations of cholesterol or egg intake (P-interactions > 0.11). Neither cholesterol nor egg intake is associated with an increased risk of incident dementia or AD in Eastern Finnish men. Instead, moderate egg intake may have a beneficial association with certain areas of cognitive performance. © 2017 American Society for Nutrition.

Maternal family history of Alzheimer's disease predisposes to reduced brain glucose metabolism.

PubMed

Mosconi, Lisa; Brys, Miroslaw; Switalski, Remigiusz; Mistur, Rachel; Glodzik, Lidia; Pirraglia, Elizabeth; Tsui, Wai; De Santi, Susan; de Leon, Mony J

2007-11-27

Having a parent affected with late-onset Alzheimer's disease (AD) is a risk factor for developing AD among cognitively normal subjects. We examined whether cognitively normal subjects with a parental family history of AD show cerebral metabolic rate of glucose (CMRglc) reductions consistent with AD as compared with those without a family history and whether there are parent gender effects. Forty-nine 50- to 80-year-old normal subjects were examined who received clinical, neuropsychological, and 2-[(18)F]fluoro-2-deoxy-d-glucose-positron emission tomography examinations, including 16 subjects with a maternal (FHm) and eight with a paternal (FHp) family history of AD and 25 with no family history (FH(-)). FH groups were comparable for demographic and neuropsychological measures. As compared with both FH(-) and FHp groups, FHm subjects showed CMRglc reductions in the same regions as clinically affected AD patients, involving the posterior cingulate cortex/precuneus, parietotemporal and frontal cortices, and medial temporal lobes (P < 0.05, corrected for multiple comparisons). These effects remained significant after accounting for possible risk factors for AD, including age, gender, education, apolipoprotein E genotype, and subjective memory complaints. No CMRglc differences were found between FHp and FH(-) subjects. This study shows a relationship between reduced CMRglc in AD-vulnerable brain regions and a maternal family history of AD in cognitively normal individuals.

Incidence of Depression and Associated Factors in Patients With Type 2 Diabetes in Quebec, Canada: A Population-Based Cohort Study.

PubMed

Lunghi, Carlotta; Moisan, Jocelyne; Grégoire, Jean-Pierre; Guénette, Line

2016-05-01

It has been reported that the risk of depression is higher among people with type 2 diabetes compared with a nondiabetic population. Among diabetic patients, depression has been associated with worse self-care behaviors, poor glycemic control, and an increased risk of diabetes complications. Identifying factors associated with the occurrence of depression may help physicians identify earlier diabetic patients at a high risk of developing depression, improve prevention, and accelerate proper treatment. To our knowledge, very few population-based studies have reported on the incidence of clinically diagnosed depression as a consequence of type 2 diabetes over a long follow-up period. The objective of this study was to estimate the incidence of clinically diagnosed depression among type 2 diabetic patients newly treated with oral antidiabetic drugs (ADs) and to identify factors associated with the occurrence of depression.Administrative claims data from the public health insurance plan were used to identify a cohort of new oral AD users aged ≥18 years between 2000 and 2006. Patients were followed from oral AD treatment initiation until the diagnosis of depression, ineligibility for the public drug plan, death, or the end of the study, whichever came first. Incidence rates were determined using person-time analysis. Factors associated with depression were identified using multivariable Cox regression analysis.We identified 114,366 new oral AD users, of which 4808 had a diagnosis of depression. The overall incidence rate of depression was 9.47/1000 person-years (PYs) (10.72/1000 PYs for women and 8.27/1000 PYs for men). The incidence of depression was higher during the year after oral AD treatment initiation. Independent factors associated with depression included having had mental disorders other than depression, hospitalization, a higher number of different drugs taken and of physicians visited during the year before oral AD initiation. Moreover, we observed a statistically significant age-by-socioeconomic status interaction.The incidence of diagnosed depression is higher during the first year after oral AD treatment initiation. Clinicians could pay particular attention to women, patients starting an AD at a young age, those with a low socioeconomic status, and especially those with a history of anxiety or dementia.

Meta-analyses of four polymorphisms of lipoprotein lipase associated with the risk of Alzheimer's disease.

PubMed

Ren, Liang; Ren, Xingxing

2016-04-21

We evaluated the contributions of four polymorphisms of the lipoprotein lipase (LPL) gene to the risk of Alzheimer's disease (AD). Through a comprehensive literature search for genetic variants of LPL involved in AD association studies, we found four polymorphisms for the current meta-analyses. These polymorphisms were Asn291Ser(rs268), PvuII(rs285), HindIII(rs320) and Ser447Ter(rs328). In total, eight studies with 5064 cases and 5016 controls were retrieved for the meta-analyses of the four genetic variants. The analyses showed that Asn291Ser(rs268) (OR=2.34, 95% CI=1.05-5.25, P=0.04), HindIII(rs320) (OR=1.44, 95% CI=1.17-1.78, P=0.0006), and Ser447Ter(rs328) (OR=0.80, 95% CI=0.66-0.98, P=0.03) were significantly associated with a risk of AD. No association was found between the PvuII(rs285) polymorphism and the risk of AD. Our results showed that Asn291Ser(rs268), HindIII(rs320) and Ser447Ter(rs328) polymorphisms of LPL were associated with a risk of AD. Asn291Ser(rs268) and HindIII(rs320) were predisposing factors of AD, whereas Ser447Ter(rs328) showed a protective effect for AD. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Viral exposures and MS outcome in a prospective cohort of children with acquired demyelination.

PubMed

Makhani, Naila; Banwell, Brenda; Tellier, Raymond; Yea, Carmen; McGovern, Suzanne; O'Mahony, Julia; Ahorro, Jean M; Arnold, Douglas; Sadovnick, A Dessa; Marrie, Ruth A; Bar-Or, Amit

2016-03-01

Epstein-Barr virus (EBV) infection is associated with increased multiple sclerosis (MS) risk. Recently, cytomegalovirus (CMV) infection has been proposed as a protective factor against MS development. We determined EBV, herpes simplex virus, varicella-zoster virus and CMV seroprevalence in 247 prospectively followed children with acquired demyelinating syndromes (ADS). Remote EBV infection was more common in children with MS than those with monophasic ADS while CMV infection was more common in children with monophasic ADS. Children displaying evidence of remote EBV without CMV infection were at highest risk of subsequent MS diagnosis. Viral infection repertoire detected at ADS provides important prognostic information. © The Author(s), 2015.

Epidemiology of Alzheimer disease

PubMed Central

Reitz, Christiane; Brayne, Carol; Mayeux, Richard

2012-01-01

The global prevalence of dementia is estimated to be as high as 24 million, and is predicted to double every 20 years through to 2040, leading to a costly burden of disease. Alzheimer disease (AD) is the leading cause of dementia and is characterized by a progressive decline in cognitive function, which typically begins with deterioration in memory. Before death, individuals with this disorder have usually become dependent on caregivers. The neuropathological hallmarks of the AD brain are diffuse and neuritic extracellular amyloid plaques—which are frequently surrounded by dystrophic neurites—and intracellular neurofibrillary tangles. These hallmark pathologies are often accompanied by the presence of reactive microgliosis and the loss of neurons, white matter and synapses. The etiological mechanisms underlying the neuropathological changes in AD remain unclear, but are probably affected by both environmental and genetic factors. Here, we provide an overview of the criteria used in the diagnosis of AD, highlighting how this disease is related to, but distinct from, normal aging. We also summarize current information relating to AD prevalence, incidence and risk factors, and review the biomarkers that may be used for risk assessment and in diagnosis. PMID:21304480

Metal Dyshomeostasis and Inflammation in Alzheimer's and Parkinson's Diseases: Possible Impact of Environmental Exposures

PubMed Central

Myhre, Oddvar; Utkilen, Hans; Duale, Nur; Brunborg, Gunnar; Hofer, Tim

2013-01-01

A dysregulated metal homeostasis is associated with both Alzheimer's (AD) and Parkinson's (PD) diseases; AD patients have decreased cortex and elevated serum copper levels along with extracellular amyloid-beta plaques containing copper, iron, and zinc. For AD, a putative hepcidin-mediated lowering of cortex copper mechanism is suggested. An age-related mild chronic inflammation and/or elevated intracellular iron can trigger hepcidin production followed by its binding to ferroportin which is the only neuronal iron exporter, thereby subjecting it to lysosomal degradation. Subsequently raised neuronal iron levels can induce translation of the ferroportin assisting and copper binding amyloid precursor protein (APP); constitutive APP transmembrane passage lowers the copper pool which is important for many enzymes. Using in silico gene expression analyses, we here show significantly decreased expression of copper-dependent enzymes in AD brain and metallothioneins were upregulated in both diseases. Although few AD exposure risk factors are known, AD-related tauopathies can result from cyanobacterial microcystin and β-methylamino-L-alanine (BMAA) intake. Several environmental exposures may represent risk factors for PD; for this disease neurodegeneration is likely to involve mitochondrial dysfunction, microglial activation, and neuroinflammation. Administration of metal chelators and anti-inflammatory agents could affect disease outcomes. PMID:23710288

METABOLIC SYNDROME AND THE ROLE OF DIETARY LIFESTYLES IN ALZHEIMER’S DISEASE

PubMed Central

Pasinetti, Giulio Maria; Eberstein, Jacqueline A.

2008-01-01

Since Alzheimer’s disease (AD) has no cure or preventive treatment, an urgent need exists to find a means of preventing, delaying the onset, or reversing the course of the disease. Clinical and epidemiological evidence suggests that lifestyle factors, especially nutrition, may be crucial in controlling AD. Unhealthy lifestyle choices lead to an increasing incidence of obesity, dyslipidemia and hypertension — components of the metabolic syndrome. These disorders can also be linked to AD. Recent research supports the hypothesis that calorie intake, among other nongenetic factors, can influence the risk of clinical dementia. In animal studies, high calorie intake in the form of saturated fat promoted AD-type amyloidosis, while calorie restriction via reduced carbohydrate intake prevented it. Pending further study, it is prudent to recommend to those at risk for AD — e.g., with a family history or features of metabolic syndrome, such as obesity, insulin insensitivity, etc. — to avoid foods and beverages with added sugars; to eat whole, unrefined foods with natural fats, especially fish, nuts and seeds, olives and olive oil; and to minimize foods that disrupt insulin and blood sugar balance. PMID:18466323

Maternal employment and atopic dermatitis in children: a prospective cohort study.

PubMed

Wang, I J; Wen, H J; Chiang, T L; Lin, S J; Chen, P C; Guo, Y L

2013-04-01

Considering the early onset of atopic dermatitis (AD), which most often arises in the first year of life, risk factors occurring very early in life must be considered. Little is known about the effects of maternal occupational exposure on the development of atopic disorders in children. The aim of this study was to evaluate associations between maternal employment and childhood AD. We used multistage stratified systematic sampling to recruit 24,200 mother-newborn pairs from the Taiwan national birth register. Information on maternal occupation categories, work stress, working time, shift work and potential confounders during pregnancy was gathered by questionnaires after birth. At 3 years of age, information on the development of AD was assessed by home interviews. Multiple logistic regression analysis was performed to estimate the association of maternal employment and AD. Overall, 11,962 out of 19,381 mothers (61·7%) worked during pregnancy. The children of mothers who worked during pregnancy had an increased risk of AD compared with those whose mothers did not work [odds ratio (OR) 1·38, 95% confidence interval (CI) 1·25-1·53]. The children of mothers with a professional or technical occupation had a higher risk of AD (OR 1·64, 95% CI 1·44-1·87). The risk of AD was found to increase with maternal work stress during pregnancy in a dose-response manner (P(trend)<0·01). The mothers of children with AD had a longer working time than those without AD (P<0·0001). However, no significant association between AD and maternal shift work was found. Working in professional or technical occupations increased the risk of childhood AD in addition to work stress during pregnancy. © 2013 The Authors. BJD © 2013 British Association of Dermatologists.

Multifactorial Analysis of a Biomarker Pool for Alzheimer Disease Risk in a North Indian Population.

PubMed

Talwar, Puneet; Grover, Sandeep; Sinha, Juhi; Chandna, Puneet; Agarwal, Rachna; Kushwaha, Suman; Kukreti, Ritushree

2017-01-01

Alzheimer disease (AD) is a progressive neurodegenerative disease with a complex multifactorial etiology. Here, we aim to identify a biomarker pool comprised of genetic variants and blood biomarkers as predictor of AD risk. We performed a case-control study involving 108 cases and 159 non-demented healthy controls to examine the association of multiple biomarkers with AD risk. The APOE genotyping revealed that ε4 allele frequency was significantly high (p value = 0.0001, OR = 2.66, 95% CI 1.58-4.46) in AD as compared to controls, whereas ε2 (p = 0.0430, OR = 0.29, CI 0.07-1.10) was overrepresented in controls. In biochemical assays, significant differences in levels of total copper, free copper, zinc, copper/zinc ratio, iron, epidermal growth factor receptor (EGFR), leptin, and albumin were also observed. The AD risk score (ADRS) as a linear combination of 6 candidate markers involving age, education status, APOE ε4 allele, levels of iron, Cu/Zn ratio, and EGFR was created using stepwise linear discriminant analysis. The area under the ROC curve of the ADRS panel for predicting AD risk was significantly high (AUC = 0.84, p < 0.0001, 95% CI 0.78-0.89, sensitivity = 70.0%, specificity = 83.8%) compared to individual parameters. These findings support the multifactorial etiology of AD and demonstrate the ability of a panel involving 6 biomarkers to discriminate AD cases from non-demented healthy controls. © 2017 S. Karger AG, Basel.

Identification of genetic risk factors in the Chinese population implicates a role of immune system in Alzheimer's disease pathogenesis.

PubMed

Zhou, Xiaopu; Chen, Yu; Mok, Kin Y; Zhao, Qianhua; Chen, Keliang; Chen, Yuewen; Hardy, John; Li, Yun; Fu, Amy K Y; Guo, Qihao; Ip, Nancy Y

2018-02-20

Alzheimer's disease (AD) is a leading cause of mortality among the elderly. We performed a whole-genome sequencing study of AD in the Chinese population. In addition to the variants identified in or around the APOE locus (sentinel variant rs73052335, P = 1.44 × 10 -14 ), two common variants, GCH1 (rs72713460, P = 4.36 × 10 -5 ) and KCNJ15 (rs928771, P = 3.60 × 10 -6 ), were identified and further verified for their possible risk effects for AD in three small non-Asian AD cohorts. Genotype-phenotype analysis showed that KCNJ15 variant rs928771 affects the onset age of AD, with earlier disease onset in minor allele carriers. In addition, altered expression level of the KCNJ15 transcript can be observed in the blood of AD subjects. Moreover, the risk variants of GCH1 and KCNJ15 are associated with changes in their transcript levels in specific tissues, as well as changes of plasma biomarkers levels in AD subjects. Importantly, network analysis of hippocampus and blood transcriptome datasets suggests that the risk variants in the APOE , GCH1 , and KCNJ15 loci might exert their functions through their regulatory effects on immune-related pathways. Taking these data together, we identified common variants of GCH1 and KCNJ15 in the Chinese population that contribute to AD risk. These variants may exert their functional effects through the immune system. Copyright © 2018 the Author(s). Published by PNAS.

Sleep, Cognitive impairment, and Alzheimer's disease: A Systematic Review and Meta-Analysis.

PubMed

Bubu, Omonigho M; Brannick, Michael; Mortimer, James; Umasabor-Bubu, Ogie; Sebastião, Yuri V; Wen, Yi; Schwartz, Skai; Borenstein, Amy R; Wu, Yougui; Morgan, David; Anderson, William M

2017-01-01

Mounting evidence implicates disturbed sleep or lack of sleep as one of the risk factors for Alzheimer's disease (AD), but the extent of the risk is uncertain. We conducted a broad systematic review and meta-analysis to quantify the effect of sleep problems/disorders on cognitive impairment and AD. Original published literature assessing any association of sleep problems or disorders with cognitive impairment or AD was identified by searching PubMed, Embase, Web of Science, and the Cochrane library. Effect estimates of individual studies were pooled and relative risks (RR) and 95% confidence intervals (CI) were calculated using random effects models. We also estimated the population attributable risk. Twenty-seven observational studies (n = 69216 participants) that provided 52 RR estimates were included in the meta-analysis. Individuals with sleep problems had a 1.55 (95% CI: 1.25-1.93), 1.65 (95% CI: 1.45-1.86), and 3.78 (95% CI: 2.27-6.30) times higher risk of AD, cognitive impairment, and preclinical AD than individuals without sleep problems, respectively. The overall meta-analysis revealed that individuals with sleep problems had a 1.68 (95% CI: 1.51-1.87) times higher risk for the combined outcome of cognitive impairment and/or AD. Approximately 15% of AD in the population may be attributed to sleep problems. This meta-analysis confirmed the association between sleep and cognitive impairment or AD and, for the first time, consolidated the evidence to provide an "average" magnitude of effect. As sleep problems are of a growing concern in the population, these findings are of interest for potential prevention of AD. © Sleep Research Society 2016. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.

Bioinformatics Identification of Modules of Transcription Factor Binding Sites in Alzheimer's Disease-Related Genes by In Silico Promoter Analysis and Microarrays

PubMed Central

Augustin, Regina; Lichtenthaler, Stefan F.; Greeff, Michael; Hansen, Jens; Wurst, Wolfgang; Trümbach, Dietrich

2011-01-01

The molecular mechanisms and genetic risk factors underlying Alzheimer's disease (AD) pathogenesis are only partly understood. To identify new factors, which may contribute to AD, different approaches are taken including proteomics, genetics, and functional genomics. Here, we used a bioinformatics approach and found that distinct AD-related genes share modules of transcription factor binding sites, suggesting a transcriptional coregulation. To detect additional coregulated genes, which may potentially contribute to AD, we established a new bioinformatics workflow with known multivariate methods like support vector machines, biclustering, and predicted transcription factor binding site modules by using in silico analysis and over 400 expression arrays from human and mouse. Two significant modules are composed of three transcription factor families: CTCF, SP1F, and EGRF/ZBPF, which are conserved between human and mouse APP promoter sequences. The specific combination of in silico promoter and multivariate analysis can identify regulation mechanisms of genes involved in multifactorial diseases. PMID:21559189

Association of traumatic brain injury and Alzheimer disease onset: A systematic review.

PubMed

Julien, J; Joubert, S; Ferland, M-C; Frenette, L C; Boudreau-Duhaime, M M; Malo-Véronneau, L; de Guise, E

2017-09-01

Inconsistencies regarding the risk of developing Alzheimer disease after traumatic brain injury (TBI) remain in the literature. Indeed, why AD develops in certain TBI patients while others are unaffected is still unclear. The aim of this study was to performed a systematic review to investigate whether certain variables related to TBI, such as TBI severity, loss of consciousness (LOC) and post-traumatic amnesia (PTA), are predictors of risk of AD in adults. From 841 citations retrieved from MEDLINE via PubMed, EMBASE, PSYINFO and Cochrane Library databases, 18 studies were eligible for the review. The review revealed that about 55.5% of TBI patients may show deteriorated condition, from acute post-TBI cognitive deficits to then meeting diagnostic criteria for AD, but whether TBI is a risk factor for AD remains elusive. Failure to establish such a link may be related to methodological problems in the studies. To shed light on this dilemma, future studies should use a prospective design, define the types and severities of TBI and use standardized AD and TBI diagnostic criteria. Ultimately, an AD prediction model, based on several variables, would be useful for clinicians detecting TBI patients at risk of AD. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Postmenopausal hormone therapy and Alzheimer disease

PubMed Central

Tuppurainen, Marjo; Rikkonen, Toni; Kivipelto, Miia; Soininen, Hilkka; Kröger, Heikki; Tolppanen, Anna-Maija

2017-01-01

Objective: To explore the association between postmenopausal hormone therapy (HT) and Alzheimer disease (AD). Methods: Twenty-year follow-up data from the Kuopio Osteoporosis Risk Factor and Prevention study cohort were used. Self-administered questionnaires were sent to all women aged 47–56 years, residing in Kuopio Province starting in 1989 until 2009, every 5th year. Register-based information on HT prescriptions was available since 1995. Probable AD cases, based on DSM-IV and National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer's Disease and Related Disorders Association criteria, were identified from the special reimbursement register (1999–2009). The study population included 8,195 women (227 cases of incident AD). Results: Postmenopausal estrogen use was not associated with AD risk in register-based or self-reported data (hazard ratio/95% confidence interval 0.92/0.68–1.2, 0.99/0.75–1.3, respectively). Long-term self-reported postmenopausal HT was associated with reduced AD risk (0.53/0.31–0.91). Similar results were obtained with any dementia diagnosis in the hospital discharge register as an outcome. Conclusions: Our results do not provide strong evidence for a protective association between postmenopausal HT use and AD or dementia, although we observed a reduced AD risk among those with long-term self-reported HT use. PMID:28202700

Combining risk markers improves cardiovascular risk prediction in women.

PubMed

Holewijn, Suzanne; den Heijer, Martin; Kiemeney, Lambertus A; Stalenhoef, Anton F H; de Graaf, Jacqueline

2014-01-01

Cardiovascular risk stratification could be improved by adding measures of atherosclerosis to current risk scores, especially in intermediate-risk individuals. We prospectively evaluated the additive value of different non-invasive risk markers (both individual and combined) for gender-specific cardiovascular risk stratification on top of traditional risk factors in a middle-aged population-based cohort. Carotid-plaques, IMT (intima-media thickness), ABI (ankle-brachial index), PWV (pulse-wave velocity), AIx (augmentation index), CAP (central augmented pressure) and CSP (central-systolic pressure) were measured in 1367 CVD (cardiovascular disease)-free participants aged 50-70 years old. Cardiovascular events were validated after a mean follow-up of 3.8 years. AUC (area-under-the-curve) and NRI (net reclassification improvement) analyses (total-NRI for all and clinical-NRI for intermediate-risk groups) were used to determine the additive value of individual and combined risk markers. Cardiovascular events occurred in 32 women and 39 men. Traditional cardiovascular risk factors explained 6.2% and 12.5% of the variance in CVD in women and men respectively. AUCs did not substantially increase by adding individual or combined non-invasive risk markers. Individual risk markers only improved reclassification in intermediate-risk women and more than in men; clinical-NRIs ranged between 48.0 and 173.1% in women and 8.9 and 20% in men. Combined non-invasive-risk markers improved reclassification in all women and even more in those at intermediate risk; 'IMT-presence-thickness-of-plaques' showed largest reclassification [total-NRI=33.8%, P=0.012; IDI (integrated-discrimination-improvement)=0.048, P=0.066; clinical-NRI=168.0%]. In men, combined non-invasive risk markers improved reclassification only in those at intermediate risk; 'PWV-AIx-CSP-CAP-IMT' showed the largest reclassification (total-NRI=14.5%, P=0.087; IDI=0.016, P=0.148; clinical-NRI=46.0%). In all women, cardiovascular risk stratification improved by adding combinations and in women at intermediate risk also by adding individual non-invasive risk markers. The additive value of individual and combined non-invasive risk markers in men is limited to men at intermediate risk only, and to a lesser extent than in women.

Sex and the development of Alzheimer’s disease

PubMed Central

Pike, Christian J.

2016-01-01

Men and women exhibit differences in the development and progression of Alzheimer’s disease (AD). The factors underlying the sex differences in AD are not well understood. This review emphasizes the contributions of sex steroid hormones to the relationship between sex and AD. In women, events that decrease lifetime exposure to estrogens are generally associated with increased AD risk, whereas estrogen-based hormone therapy administered near the time of menopause may reduce AD risk. In men, estrogens do not exhibit age-related reduction and are not significantly associated with AD risk. Rather, normal age-related depletions of testosterone in plasma and brain predict enhanced vulnerability to AD. Both estrogens and androgens exert numerous protective actions in the adult brain that increase neural functioning and resilience as well as specifically attenuate multiple aspects of AD-related neuropathology. Aging diminishes the activational effects of sex hormones in sex-specific manners, which is hypothesized to contribute to the relationship between aging and AD. Sex steroid hormones may also drive sex differences in AD through their organizational effects during developmental sexual differentiation of the brain. Specifically, sex hormone actions during early development may confer inherent vulnerability of the female brain to development of AD in advanced age. The combined effects of organizational and activational effects of sex steroids yield distinct sex differences in AD pathogenesis, a significant variable that must be more rigorously considered in future research. PMID:27870425

Influence of family history of dementia in the development and progression of late-onset Alzheimer's disease.

PubMed

Scarabino, Daniela; Gambina, Giuseppe; Broggio, Elisabetta; Pelliccia, Franca; Corbo, Rosa Maria

2016-03-01

Family history of dementia (FH) is a recognized risk factor for developing late-onset Alzheimer's disease (AD). We asked whether having FH increases AD risk and influences disease severity (age at onset and cognitive impairment) in 420 AD patients and 109 controls with (FH+) or without (FH-). The relationships of APOE and other AD risk genes with FH were analyzed as well. The proportion of APOE e4 allele carriers was higher among the FH+ than the FH- AD patients (49.6% vs. 38.9%; P = 0.04). The distribution of the risk genotypes of nine AD susceptibility genes previously examined (CHAT, CYP17, CYP19, ESR1, FSHR, P53, P73, P21, PPARG) did not differ between the FH+ and the FH- AD patients, indicating that none contributed significantly to familial clustering of disease. FH was associated with an increased AD risk (odds ratio [OR] 2.71, 95% confidence interval [CI] 1.44-5.09; P = 0.002) independent of carrying the APOE e4 allele (OR 2.61, 95%CI 1.53-4.44; P = 0.0004). Having a first-degree relative or a parent with dementia was significantly associated with AD risk (OR 2.9, 95%CI 1.3-6.4; P = 0.009 and OR 2.7, 95%CI 1.1-6.2; P = 0.02) but having a sibling with dementia was not (OR 1.7, 95%CI 0.2 to 14.7; P = 0.6). Among the FH+ AD patients, having one or both parents affected seemed to raise the risk of earlier onset age (P = 0.02) and greater cognitive impairment (P = 0.02) than having only an affected sibling, whereas having two or more affected relatives did not. © 2015 Wiley Periodicals, Inc.

Using anti-tobacco industry messages to prevent smoking among high-risk adolescents.

PubMed

Thrasher, James F; Niederdeppe, Jeffrey D; Jackson, Christine; Farrelly, Matthew C

2006-06-01

Media campaigns to prevent adolescent tobacco use in the United States increasingly focus on the deceitful practices of the tobacco industry; however, little is known about how adolescents at elevated smoking risk respond to this strategy. This study used data from a nationally representative survey of 10,035 adolescents, ages 12-17 years, in order to test whether reactions to anti-industry advertisements (ads), the attitudes these ads target, and the relationship between these attitudes and smoking differed by social bonding and sensation-seeking risk factors. Results indicated that anti-industry ad reactions and the strength of anti-industry attitudes were comparable between high- and low-sensation seeking adolescents, whereas weakly bonded adolescents had less favorable ad reactions and weaker anti-industry attitudes than strongly bonded adolescents. Social bonding also moderated the influence of sensation seeking on anti-industry ad reactions, such that sensation seeking had a positive influence among more strongly bonded adolescents and no influence among weakly bonded adolescents. Finally, the relationship between anti-industry attitudes and smoking appeared consistent across risk groups, whether risk was defined using social bonding, sensation seeking or the interaction between them. Overall, these results suggest that anti-industry messages are a promising strategy for preventing smoking among high- and low-risk adolescents alike.

Maternal sensitivity and social support protect against childhood atopic dermatitis.

PubMed

Letourneau, Nicole L; Kozyrskyj, Anita L; Cosic, Nela; Ntanda, Henry N; Anis, Lubna; Hart, Martha J; Campbell, Tavis S; Giesbrecht, Gerald F

2017-01-01

Many studies have identified associations between qualities of maternal-child relationships and childhood asthma, but few have examined associations with childhood atopic dermatitis (AD), a common precursor to asthma. Moreover, maternal psychological distress, including prenatal and postnatal depression, anxiety and stress, may increase risk, while social support from partners may reduce risk for childhood AD. We sought to uncover the association between maternal-infant relationship qualities (maternal sensitivity towards infant behavioral signals, controlling behavior, and unresponsiveness) and child AD after accounting for risk (i.e., prenatal and postnatal maternal depression, anxiety and stress) and protective (i.e., social support) factors. We conducted a secondary analysis of data collected on a subsample of 242 women and their infants enrolled during pregnancy in the ongoing Alberta Pregnancy Outcomes and Nutrition cohort study. Inclusion criteria required mothers to be >16 years of age, English speaking and <22 weeks gestational age at enrollment. Data on depression, anxiety and stress in the prenatal and postnatal periods and physician diagnosis of childhood AD at 18 months were gathered via maternal report. Maternal sensitivity, unresponsiveness and controlling behaviours were assessed via videotaped observations using the Child-Adult Relationship Experimental (CARE)-Index at 6 months of infant age. Higher maternal sensitivity, or the inability of the mother to appropriately understand and respond to infant needs based on behavioral signals, predicted reduced odds of AD independent of and in combination with low prenatal and postnatal anxiety and high paternal support. After adjustment, higher maternal controlling behaviours and unresponsiveness also predicted greater odds of AD. Low maternal sensitivity is a risk factor for childhood AD, independently and in combination with perinatal anxiety and low social support. Thus, interventions that improve maternal-infant relationship quality, especially sensitivity, reduce anxiety and improve social support from partners could reduce odds of childhood AD.

Safety of Nonoperative Management After Acute Diverticulitis

PubMed Central

Amoza Pais, Sonia; Batlle Marin, Xavi; Oronoz Martinez, Begoña; Balen Ribera, Enrique; Yarnoz Irazabal, Concepción

2014-01-01

Purpose The role of surgery in the management of diverticular disease after an episode of acute diverticulitis (AD) managed in a conservative form is evolving. Age, number of episodes of AD, type of episode, and symptoms after the episodes are factors related to the need for elective surgery. The aim of this study is to evaluate the safety of conservative management and the risk factors for emergency surgery after a first episode of AD managed without surgery. Methods We retrospectively evaluated 405 patients diagnosed as having had a first episode of AD. Sixty-nine patients underwent emergency surgery on the first admission, and 69 patients had an elective operation in the follow-up (group A). The remaining 267 patients were managed initially without surgery (group B). Thirteen of these 267 patients needed a further urgent surgical procedure. Factors involved in the decision of elective surgery and the probability of emergency surgery after the first episode of AD managed without surgery were evaluated in relation to demographic factors, risk factors, presence of recurrences, and type of the first episode. Results Patients, mean age was 62.7 years, 71 were aged less than 51, and 151 were males. The mean follow-up for patients with nonoperative management was 91.2 months. An elective operation was performed in 69 patients. Compared to patients in group B, those in group A more frequently had a first episode of complicated acute diverticulitis (CAD) (37.1% vs. 16.4%; P = 0.000) and were more likely to be smokers (46.3% vs. 19.3%; P = 0.000) and to suffer more than one episode of AD (42% vs. 26.9%; P = 0.027). Nonoperative management was chosen for 267 patients, but 13 patients needed an emergency operation later. In the multivariate analysis, we found a significant relation between the presence of CAD in the first episode and the need for emergency surgery. There were no differences in surgical mortality between the patients in the two groups, but patients treated with elective surgery had a higher rate of stoma than patients treated non-operatively (7.2% vs. 1.4%; P = 0.028); this difference was not observed in the subgroup of patients with CAD (15.3% vs. 6.8%; P = 0.458). Conclusion After an episode of AD, nonoperative management is safe because fewer than 5% of patients will need an emergent procedure in a subsequent attack of AD. A first episode of CAD is the only risk factor for emergency surgery in patients managed conservatively. PMID:25360428

SPECTRAL GRAPH THEORY AND GRAPH ENERGY METRICS SHOW EVIDENCE FOR THE ALZHEIMER’S DISEASE DISCONNECTION SYNDROME IN APOE-4 RISK GENE CARRIERS

PubMed Central

Daianu, Madelaine; Mezher, Adam; Jahanshad, Neda; Hibar, Derrek P.; Nir, Talia M.; Jack, Clifford R.; Weiner, Michael W.; Bernstein, Matt A.; Thompson, Paul M.

2015-01-01

Our understanding of network breakdown in Alzheimer’s disease (AD) is likely to be enhanced through advanced mathematical descriptors. Here, we applied spectral graph theory to provide novel metrics of structural connectivity based on 3-Tesla diffusion weighted images in 42 AD patients and 50 healthy controls. We reconstructed connectivity networks using whole-brain tractography and examined, for the first time here, cortical disconnection based on the graph energy and spectrum. We further assessed supporting metrics - link density and nodal strength - to better interpret our results. Metrics were analyzed in relation to the well-known APOE-4 genetic risk factor for late-onset AD. The number of disconnected cortical regions increased with the number of copies of the APOE-4 risk gene in people with AD. Each additional copy of the APOE-4 risk gene may lead to more dysfunctional networks with weakened or abnormal connections, providing evidence for the previously hypothesized “disconnection syndrome”. PMID:26413205

SPECTRAL GRAPH THEORY AND GRAPH ENERGY METRICS SHOW EVIDENCE FOR THE ALZHEIMER'S DISEASE DISCONNECTION SYNDROME IN APOE-4 RISK GENE CARRIERS.

PubMed

Daianu, Madelaine; Mezher, Adam; Jahanshad, Neda; Hibar, Derrek P; Nir, Talia M; Jack, Clifford R; Weiner, Michael W; Bernstein, Matt A; Thompson, Paul M

2015-04-01

Our understanding of network breakdown in Alzheimer's disease (AD) is likely to be enhanced through advanced mathematical descriptors. Here, we applied spectral graph theory to provide novel metrics of structural connectivity based on 3-Tesla diffusion weighted images in 42 AD patients and 50 healthy controls. We reconstructed connectivity networks using whole-brain tractography and examined, for the first time here, cortical disconnection based on the graph energy and spectrum. We further assessed supporting metrics - link density and nodal strength - to better interpret our results. Metrics were analyzed in relation to the well-known APOE -4 genetic risk factor for late-onset AD. The number of disconnected cortical regions increased with the number of copies of the APOE -4 risk gene in people with AD. Each additional copy of the APOE -4 risk gene may lead to more dysfunctional networks with weakened or abnormal connections, providing evidence for the previously hypothesized "disconnection syndrome".

Capsaicinoids Modulating Cardiometabolic Syndrome Risk Factors: Current Perspectives

PubMed Central

2016-01-01

Capsaicinoids are bioactive nutrients present within red hot peppers reported to cut ad libitum food intake, to increase energy expenditure (thermogenesis) and lipolysis, and to result in weight loss over time. In addition it has shown more benefits such as improvement in reducing oxidative stress and inflammation, improving vascular health, improving endothelial function, lowering blood pressure, reducing endothelial cytokines, cholesterol lowering effects, reducing blood glucose, improving insulin sensitivity, and reducing inflammatory risk factors. All these beneficial effects together help to modulate cardiometabolic syndrome risk factors. The early identification of cardiometabolic risk factors can help try to prevent obesity, hypertension, diabetes, and cardiovascular disease. PMID:27313880

Loss-of-Function PCSK9 Mutations Are Not Associated With Alzheimer Disease.

PubMed

Paquette, Martine; Saavedra, Yascara Grisel Luna; Poirier, Judes; Théroux, Louise; Dea, Doris; Baass, Alexis; Dufour, Robert

2018-03-01

Hypercholesterolemia is a major risk factor for the late-onset form of Alzheimer disease (AD). Loss-of-function (LOF) mutations of PCSK9 and PCSK9 inhibitors lower low-density lipoprotein cholesterol (LDL-C) and have been associated with a reduced risk of cardiovascular disease. The aim of this study was to examine the effect of PCSK9 LOF variants on risk and age of onset of AD. A total of 878 participants (410 controls and 468 AD cases) from the Quebec Founder Population were included in the study. Fifty-four (6.2%) participants carried the R46L mutation, whereas 226 (26.2%) participants carried the InsLEU mutation. There was no protective or no deleterious effect of carrying PCSK9 LOF mutations on AD prevalence nor on age of onset, even when stratified by apolipoprotein E epsilon 4 genotype or by gender. Our data indicate that carrying PCSK9 LOF mutations has a neutral effect on neurocognitive health and the prevalence of AD.

Alzheimer, mitochondria and gender.

PubMed

Grimm, Amandine; Mensah-Nyagan, Ayikoe Guy; Eckert, Anne

2016-08-01

Epidemiological studies revealed that two-thirds of Alzheimer's disease (AD) patients are women and the drop of sex steroid hormones after the menopause has been proposed to be one risk factor in AD. Similarly, the decrease of circulating testosterone levels with aging may also increase the risk of AD in men. Studies attest the neuroprotective effects of sex hormones in animal models of AD, but clinical trial data remain controversial. Here, we discuss the implication of mitochondria in gender differences observed in AD patients and animal models of AD. We summarize the role of mitochondria in aging and AD, pointing to the potential correlation between the loss of sex hormones and changes in the brain redox status. We discuss the protective effects of the sex hormones, estradiol, progesterone and testosterone with a specific focus on mitochondrial dysfunction in AD. The understanding of pathological processes linking the loss of sex hormones with mitochondrial dysfunction and mechanisms that initiate the disease onset may open new avenues for the development of gender-specific therapeutic approaches. Copyright © 2016. Published by Elsevier Ltd.

Blood type gene locus has no influence on ACE association with Alzheimer's disease.

PubMed

Braae, Anne; Medway, Christopher; Carrasquillo, Minerva; Younkin, Steven; Kehoe, Patrick G; Morgan, Kevin

2015-04-01

The ABO blood group locus was recently found to contribute independently and via interactions with angiotensin-converting enzyme (ACE) gene variation to plasma levels of ACE. Variation in ACE has previously been not only implicated as individually conferring susceptibility for Alzheimer's disease (AD) but also proposed to confer risk via interactions with other as yet unknown genes. More recently, larger studies have not supported ACE as a risk factor for AD, whereas the role of ACE pathway in AD has come under increased levels of scrutiny with respect to various aspects of AD pathology and possible therapies. We explored the potential combined involvement of ABO and ACE variations in the genetic susceptibility of 2067 AD cases compared with 1376 nondemented elderly. Including the effects of ABO haplotype did not provide any evidence for the genetic association of ACE with AD. Copyright © 2015 Elsevier Inc. All rights reserved.

The Latent Structure and Test-Retest Stability of Connected Language Measures in the Wisconsin Registry for Alzheimer's Prevention (WRAP).

PubMed

Mueller, Kimberly D; Koscik, Rebecca L; Clark, Lindsay R; Hermann, Bruce P; Johnson, Sterling C; Turkstra, Lyn S

2017-11-24

While it is well known that discourse-related language functions are impaired in the dementia phase of Alzheimer's Disease (AD), the presymptomatic temporal course of discourse dysfunction are not known earlier in the course of AD. To conduct discourse-related studies in this phase of AD, validated psychometric instruments are needed. This study investigates the latent structure, validity, and test-retest stability of discourse measures in a late-middle-aged normative group who are relatively free from sporadic AD risk factors. Using a normative sample of 399 participants (mean age = 61), exploratory factor analyses (EFA) and confirmatory factor analyses (CFA) were conducted on 18 measures of connected language derived from picture descriptions. Factor invariance across sex and family history and longitudinal test-retest stability measures were calculated. The EFA revealed a four-factor solution, consisting of semantic, syntax, fluency, and lexical constructs. The CFA model substantiated the structure, and factors were invariant across sex and parental history of AD status. Test-retest stability measures were within acceptable ranges. Results confirm a factor structure that is invariant across sex and parental AD history. The factor structure could be useful in similar cohorts designed to detect early language decline in investigations of preclinical or clinical AD or as outcome measures in clinical prevention trials. © The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Physician perspectives and compliance with patient advance directives: the role external factors play on physician decision making.

PubMed

Burkle, Christopher M; Mueller, Paul S; Swetz, Keith M; Hook, C Christopher; Keegan, Mark T

2012-11-21

Following passage of the Patient Self Determination Act in 1990, health care institutions that receive Medicare and Medicaid funding are required to inform patients of their right to make their health care preferences known through execution of a living will and/or to appoint a surrogate-decision maker. We evaluated the impact of external factors and perceived patient preferences on physicians' decisions to honor or forgo previously established advance directives (ADs). In addition, physician views regarding legal risk, patients' ability to comprehend complexities involved with their care, and impact of medical costs related to end-of-life care decisions were explored. Attendees of two Mayo Clinic continuing medical education courses were surveyed. Three scenarios based in part on previously court-litigated matters assessed impact of external factors and perceived patient preferences on physician compliance with patient-articulated wishes regarding resuscitation. General questions measured respondents' perception of legal risk, concerns over patient knowledge of idiosyncrasies involved with their care, and impact medical costs may have on compliance with patient preferences. Responses indicating strength of agreement or disagreement with statements were treated as ordinal data and analyzed using the Cochran Armitage trend test. Three hundred eighty-eight of 951 surveys were completed (41% response rate). Eighty percent reported they were likely to honor a patient's AD despite its 5 year age. Fewer than half (41%) would honor the AD of a patient in ventricular fibrillation who had expressed a desire to "pass away in peace." Few (17%) would forgo an AD following a family's request for continued resuscitative treatment. A majority (52%) considered risk of liability to be lower when maintaining someone alive against their wishes than mistakenly failing to provide resuscitative efforts. A large percentage (74%) disagreed that patients could not appreciate complexities surrounding their care while 69% agreed that costs should never impact a physician's decision as to whether to comply with a patient's AD. Our findings highlight the impact, albeit small, external factors have on physician AD compliance. Most respondents based their decision on the clinical situation at hand and interpretation of the patient's initial wishes and preferences expressed by the AD.

Risk Factors and Pathological Substrates Associated with Agitation/Aggression in Alzheimer's Disease: A Preliminary Study using NACC Data.

PubMed

Sennik, Simrin; Schweizer, Tom A; Fischer, Corinne E; Munoz, David G

2017-01-01

Neuropsychiatric symptoms are common manifestations of Alzheimer's disease (AD). A number of studies have targeted psychosis, i.e., hallucinations and delusions in AD, but few have assessed agitation/aggression in AD. To investigate the risk factors and pathological substrates associated with presence [A(+)] and absence [A(-)] of agitation/aggression (A) in autopsy-confirmed AD. Data was collected from the UDS data as of 2015 on the NACC database. Patients were stratified as intermediate (IAD) or high (HAD) pathological load of AD. Clinical diagnoses were not considered; additional pathological diagnoses were treated as variables. Analysis of data did not include a control group or corrections for multiple comparisons. 1,716 patients met the eligibility criteria; 31.2% of the IAD and 47.8% of the HAD patients were A(+), indicating an association with severity of pathology (p = 0.001). Risk factors for A(+) included: age at initial visit, age at death, years of education, smoking (in females), recent cardiac events (in males), and clinical history of traumatic brain injury (TBI) (in males). A history of hypertension was not related to A(+). In terms of comorbidity, clinical diagnosis of Lewy body dementia syndrome was associated with A(+) but the association was not confirmed when pathological diagnosis based on demonstration of Lewy bodies was used as the criterion. The additional presence of phosphorylated TDP-43, but not tau pathologies, was associated with A(+)HAD. Vascular lesions, including lacunes, large arterial infarcts, and severity of atherosclerosis were negatively associated with A(+). Associated symptoms included delusions, hallucinations, and depression, but not irritability, aberrant motor behavior, sleep and night time behavioral changes, or changes in appetite and eating habits. Smoking, TBI, and phosphorylated TDP-43 are associated with A(+)AD in specific groups, respectively. A(+) is directly associated with AD pathology load and inversely with vascular lesions.

Residential Risk Factors for Atopic Dermatitis in 3- to 6-Year Old Children: A Cross-Sectional Study in Shanghai, China

PubMed Central

Xu, Feng; Yan, Shuxian; Zheng, Qile; Li, Fei; Chai, Weihan; Wu, Minmin; Kan, Haidong; Norback, Dan; Xu, Jinhua; Zhao, Zhuohui

2016-01-01

Background: Atopic dermatitis (AD) is common among pre-school children in Shanghai. This study aimed to identify the risk factors for childhood AD from the perspectives of home environment, demographics and parents-grandparents’ atopic disease. Methods: A cross-sectional study was conducted in Shanghai in April–June, 2010. Preschool children’s parents or guardians were invited to participate a questionnaire survey in six districts (two urban and four suburban/rural) and 6624 children were finally recruited (51.3% boys). AD diagnosis was based on the U.K. Working Party’s (UKWP) criteria. Adjusted odds ratios (AOR) with 95% confidence intervals (95% CI) were calculated by multiple logistic regression. Results: A total of 8.5% of children ever had AD. Around 10.2% of the mothers had lived in newly renovated/decorated homes (NRDH) during the prenatal period (one year before or during pregnancy) and 9.5% got new home furniture (NHF) during the same period. AD was more common in children when mothers had lived in NRDH homes during the prenatal period (AOR = 1.41; 95% CI 1.03–1.93), the current home had indoor mold (2.00, 1.48–2.70), parents-grandparents’ had atopic diseases (3.85, 3.05–4.87), the children had food allergy (3.40, 2.63–4.40) or children lived in urban area (1.52, 1.18–1.96). Associations between AD and NRDH, NHF and indoor molds were only significant in children without parents-grandparents’ atopic diseases. There was an interaction effect between parents-grandparents’ atopic diseases and NRDH (p < 0.05). Conclusions: Home renovation/ redecoration, new furniture and indoor mold, urban residency, heredity disposition and food allergy can be risk factors for childhood AD in Shanghai. PMID:27240388

Polymorphisms of CHAT but not TFAM or VR22 are Associated with Alzheimer Disease Risk.

PubMed

Gao, Lili; Zhang, Yan; Deng, Jinghua; Yu, Wenbing; Yu, Yunxia

2016-06-07

BACKGROUND Alzheimer disease (AD) is a chronic neurodegenerative disease that is one of the most prevalent health problems among seniors. The cause of AD has not yet been elucidated, but many risk factors have been identified that might contribute to the pathogenesis and prognosis of AD. We conducted a meta-analysis of studies involving CHAT, TFAM, and VR22 polymorphisms and AD susceptibility to further understand the pathogenesis of AD. MATERIAL AND METHODS PubMed/Medline, Embase, Web of Science, the Cochrane Library, and Google Scholar were searched for relevant articles. Rs1880676, rs2177369, rs3810950, and rs868750 of CHAT; rs1937 and rs2306604 of TFAM; and rs10997691 and rs7070570 of VR22 are studied in this meta-analysis. RESULTS A total of 51 case-control studies with 16 446 cases and 16 057 controls were enrolled. For CHAT, rs2177369 (G>A) in whites and rs3810950 (G>A) in Asians were found to be associated with AD susceptibility. No association was detected between rs1880676 and rs868750 and AD risk. For TFAM and VR22, no significant association was detected in studied single-nucleotide polymorphisms (SNPs). CONCLUSIONS Rs2177369 and rs3810950 of CHAT are associated with AD susceptibility, but rs1880676 and rs868750 are not. Rs1937 and rs2306604 of TFAM, and rs10997691 and rs7070570 of VR22 are not significantly associated with AD risk.

Obstructive Sleep Apnea Syndrome: An Emerging Risk Factor for Dementia.

PubMed

Buratti, Laura; Luzzi, Simona; Petrelli, Cristina; Baldinelli, Sara; Viticchi, Giovanna; Provinciali, Leandro; Altamura, Claudia; Vernieri, Fabrizio; Silvestrini, Mauro

2016-01-01

Epidemiological studies have suggested that obstructive sleep apnea syndrome (OSAS) may increase the risk of developing cognitive impairment. In patients with Alzheimer's disease (AD), the prevalence of OSAS is much higher than that expected in cognitively healthy subjects. A deeper knowledge of the pathophysiological link between OSAS and AD and the demonstration that OSAS may directly influence the development of cognitive alterations, would increase prevention and treatment strategies for AD patients. In this article, we discuss the evidence of the association between OSAS and dementia. Moreover, we present data about the functional and anatomic cerebral changes induced by OSAS and the possible effects on cognitive activities and on AD pathogenesis. The possibility to positively influence cognitive impairment by OSAS treatment will be also discussed.

Mammographic density, breast cancer risk and risk prediction

PubMed Central

Vachon, Celine M; van Gils, Carla H; Sellers, Thomas A; Ghosh, Karthik; Pruthi, Sandhya; Brandt, Kathleen R; Pankratz, V Shane

2007-01-01

In this review, we examine the evidence for mammographic density as an independent risk factor for breast cancer, describe the risk prediction models that have incorporated density, and discuss the current and future implications of using mammographic density in clinical practice. Mammographic density is a consistent and strong risk factor for breast cancer in several populations and across age at mammogram. Recently, this risk factor has been added to existing breast cancer risk prediction models, increasing the discriminatory accuracy with its inclusion, albeit slightly. With validation, these models may replace the existing Gail model for clinical risk assessment. However, absolute risk estimates resulting from these improved models are still limited in their ability to characterize an individual's probability of developing cancer. Promising new measures of mammographic density, including volumetric density, which can be standardized using full-field digital mammography, will likely result in a stronger risk factor and improve accuracy of risk prediction models. PMID:18190724

Hypertension, cerebrovascular impairment, and cognitive decline in aged AβPP/PS1 mice.

PubMed

Wiesmann, Maximilian; Zerbi, Valerio; Jansen, Diane; Lütjohann, Dieter; Veltien, Andor; Heerschap, Arend; Kiliaan, Amanda J

2017-01-01

Cardiovascular risk factors, especially hypertension, are also major risk factors for Alzheimer's disease (AD). To elucidate the underlying vascular origin of neurodegenerative processes in AD, we investigated the relation between systolic blood pressure (SBP) cerebral blood flow (CBF) and vasoreactivity with brain structure and function in a 16-18 months old double transgenic AβPP swe /PS1 dE9 (AβPP/PS1) mouse model for AD. These aging AβPP/PS1 mice showed an increased SBP linked to a declined regional CBF. Furthermore, using advanced MRI techniques, decline of functional and structural connectivity was revealed in the AD-like mice coupled to impaired cognition, increased locomotor activity, and anxiety-related behavior. Post mortem analyses demonstrated also increased neuroinflammation, and both decreased synaptogenesis and neurogenesis in the AβPP/PS1 mice. Additionally, deviant levels of fatty acids and sterols were present in the brain tissue of the AβPP/PS1 mice indicating maladapted brain fatty acid metabolism. Our findings suggest a link between increased SBP, decreased cerebral hemodynamics and connectivity in an AD mouse model during aging, leading to behavioral and cognitive impairments. As these results mirror the complex clinical symptomatology in the prodromal phase of AD, we suggest that this AD-like murine model could be used to investigate prevention and treatment strategies for early AD patients. Moreover, this study helps to develop more efficient therapies and diagnostics for this very early stage of AD.

Alzheimer disease: epidemiology, diagnostic criteria, risk factors and biomarkers.

PubMed

Reitz, Christiane; Mayeux, Richard

2014-04-15

The global prevalence of dementia is as high as 24 million, and has been predicted to quadruple by the year 2050. In the US alone, Alzheimer disease (AD) - the most frequent cause of dementia characterized by a progressive decline in cognitive function in particular the memory domain - causes estimated health-care costs of $ 172 billion per year. Key neuropathological hallmarks of the AD brain are diffuse and neuritic extracellular amyloid plaques - often surrounded by dystrophic neurites - and intracellular neurofibrillary tangles. These pathological changes are frequently accompanied by reactive microgliosis and loss of neurons, white matter and synapses. The etiological mechanisms underlying these neuropathological changes remain unclear, but are probably caused by both environmental and genetic factors. In this review article, we provide an overview of the epidemiology of AD, review the biomarkers that may be used for risk assessment and in diagnosis, and give suggestions for future research. Copyright © 2014 Elsevier Inc. All rights reserved.

Mathematical modeling of atopic dermatitis reveals "double-switch" mechanisms underlying 4 common disease phenotypes.

PubMed

Domínguez-Hüttinger, Elisa; Christodoulides, Panayiotis; Miyauchi, Kosuke; Irvine, Alan D; Okada-Hatakeyama, Mariko; Kubo, Masato; Tanaka, Reiko J

2017-06-01

The skin barrier acts as the first line of defense against constant exposure to biological, microbial, physical, and chemical environmental stressors. Dynamic interplay between defects in the skin barrier, dysfunctional immune responses, and environmental stressors are major factors in the development of atopic dermatitis (AD). A systems biology modeling approach can yield significant insights into these complex and dynamic processes through integration of prior biological data. We sought to develop a multiscale mathematical model of AD pathogenesis that describes the dynamic interplay between the skin barrier, environmental stress, and immune dysregulation and use it to achieve a coherent mechanistic understanding of the onset, progression, and prevention of AD. We mathematically investigated synergistic effects of known genetic and environmental risk factors on the dynamic onset and progression of the AD phenotype, from a mostly asymptomatic mild phenotype to a severe treatment-resistant form. Our model analysis identified a "double switch," with 2 concatenated bistable switches, as a key network motif that dictates AD pathogenesis: the first switch is responsible for the reversible onset of inflammation, and the second switch is triggered by long-lasting or frequent activation of the first switch, causing irreversible onset of systemic T H 2 sensitization and worsening of AD symptoms. Our mathematical analysis of the bistable switch predicts that genetic risk factors decrease the threshold of environmental stressors to trigger systemic T H 2 sensitization. This analysis predicts and explains 4 common clinical AD phenotypes from a mild and reversible phenotype through to severe and recalcitrant disease and provides a mechanistic explanation for clinically demonstrated preventive effects of emollient treatments against development of AD. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Oxidative stress and APO E polymorphisms in Alzheimer's disease and in mild cognitive impairment.

PubMed

Chico, L; Simoncini, C; Lo Gerfo, A; Rocchi, A; Petrozzi, L; Carlesi, C; Volpi, L; Tognoni, G; Siciliano, G; Bonuccelli, U

2013-08-01

A number of evidences indicates oxidative stress as a relevant pathogenic factor in Alzheimer's disease (AD) and mild cognitive impairment (MCI). Considering its recognized major genetic risk factors in AD, apolipoprotein (APO E) has been investigated in several experimental settings regarding its role in the process of reactive oxygen species (ROS) generation. The aim of this work has been to evaluate possible relationships between APO E genotype and plasma levels of selected oxidative stress markers in both AD and MCI patients. APO E genotypes were determined using restriction enzyme analysis. Plasma levels of oxidative markers, advanced oxidation protein products, iron-reducing ability of plasma and, in MCI, activity of superoxide dismutases were evaluated using spectrophotometric analysis. We found, compared to controls, increased levels of oxidized proteins and decreased values of plasma-reducing capacity in both AD patients (p < 0.0001) and MCI patients (p < 0.001); the difference between AD and MCI patients was significant only for plasma-reducing capacity (p < 0.0001), the former showing the lowest values. Superoxide dismutase activity was reduced, although not at statistical level, in MCI compared with that in controls. E4 allele was statistically associated (p < 0.05) with AD patients. When comparing different APO E genotype subgroups, no difference was present, as far as advanced oxidation protein products and iron-reducing ability of plasma levels were concerned, between E4 and non-E4 carriers, in both AD and MCI; on the contrary, E4 carriers MCI patients showed significantly decreased (p < 0.05) superoxide dismutase activity with respect to non-E4 carriers. This study, in confirming the occurrence of oxidative stress in AD and MCI patients, shows how it can be related, at least for superoxide dismutase activity in MCI, to APO E4 allele risk factor.

Cross-national validation of prognostic models predicting sickness absence and the added value of work environment variables.

PubMed

Roelen, Corné A M; Stapelfeldt, Christina M; Heymans, Martijn W; van Rhenen, Willem; Labriola, Merete; Nielsen, Claus V; Bültmann, Ute; Jensen, Chris

2015-06-01

To validate Dutch prognostic models including age, self-rated health and prior sickness absence (SA) for ability to predict high SA in Danish eldercare. The added value of work environment variables to the models' risk discrimination was also investigated. 2,562 municipal eldercare workers (95% women) participated in the Working in Eldercare Survey. Predictor variables were measured by questionnaire at baseline in 2005. Prognostic models were validated for predictions of high (≥30) SA days and high (≥3) SA episodes retrieved from employer records during 1-year follow-up. The accuracy of predictions was assessed by calibration graphs and the ability of the models to discriminate between high- and low-risk workers was investigated by ROC-analysis. The added value of work environment variables was measured with Integrated Discrimination Improvement (IDI). 1,930 workers had complete data for analysis. The models underestimated the risk of high SA in eldercare workers and the SA episodes model had to be re-calibrated to the Danish data. Discrimination was practically useful for the re-calibrated SA episodes model, but not the SA days model. Physical workload improved the SA days model (IDI = 0.40; 95% CI 0.19-0.60) and psychosocial work factors, particularly the quality of leadership (IDI = 0.70; 95% CI 053-0.86) improved the SA episodes model. The prognostic model predicting high SA days showed poor performance even after physical workload was added. The prognostic model predicting high SA episodes could be used to identify high-risk workers, especially when psychosocial work factors are added as predictor variables.

Intakes of whole grains, bran, and germ and the risk of coronary heart disease in men.

PubMed

Jensen, Majken K; Koh-Banerjee, Pauline; Hu, Frank B; Franz, Mary; Sampson, Laura; Grønbaek, Morten; Rimm, Eric B

2004-12-01

Previous studies have suggested that a daily intake of 3 servings of whole-grain foods is associated with a reduced risk of coronary heart disease (CHD). However, methods for the assessment of whole-grain intake differ. Furthermore, any additional effects of added bran and germ, which are components of whole grains, have not been reported. The objective was to evaluate the association of whole-grain, bran, and germ intakes (with the use of new quantitative measures) with the incidence of CHD. This was a prospective cohort study of 42,850 male health professionals aged 40-75 y at baseline in 1986 who were free from cardiovascular disease, cancer, and diabetes. Daily whole-grain, bran, and germ intakes were derived in grams per day from a detailed semiquantitative dietary questionnaire. During 14 y of follow-up, we documented 1818 incident cases of CHD. After cardiovascular disease risk factors and the intakes of bran and germ added to foods were controlled for, the hazard ratio of CHD between extreme quintiles of whole-grain intake was 0.82 (95% CI: 0.70, 0.96; P for trend=0.01). The hazard ratio of CHD in men with the highest intake of added bran was 0.70 (95% CI: 0.60, 0.82) compared with men with no intake of added bran (P for trend < or = 0.001). Added germ was not associated with CHD risk. This study supports the reported beneficial association of whole-grain intake with CHD and suggests that the bran component of whole grains could be a key factor in this relation.

Candy consumption was not associated with body weight measures, risk factors for cardiovascular disease, or metabolic syndrome in US adults: NHANES 1999-2004

USDA-ARS?s Scientific Manuscript database

There is limited research examining the relationship of candy consumption by adults on diet and health. The purpose of this study was to determine total, chocolate, or sugar candy consumption and their effect on energy, saturated fatty acid and added sugar intake, weight, risk factors for cardiovasc...

Smoking Risk Factors and Gender Differences among Spanish High School Students

ERIC Educational Resources Information Center

Garcia-Rodriguez, Olaya; Suarez-Vazquez, Rosa; Secades-Villa, Roberto; Fernandez-Hermida, Jose R.

2010-01-01

The objectives of the present study were to analyze the pattern of tobacco use among Spanish adolescents, as well as to determine gender differences in specific risk factors of cigarette use. The study sample was made up of 1,483 boys and 1,358 girls, aged 12-16 (M = 14). Participants were asked to answer an "ad-hoc" instrument to…

Sex and gender differences in the causes of dementia: a narrative review.

PubMed

Rocca, Walter A; Mielke, Michelle M; Vemuri, Prashanthi; Miller, Virginia M

2014-10-01

This is a narrative review of new ideas and concepts related to differences between men and women in their risk of developing dementia or Alzheimer's disease (AD). We introduce the concept of dimorphic neurology and the distinction between sex and gender. We then provide three examples of risk factors related to sex and gender from the literature. Apolipoprotein E genotype is equally common in men and women but has a stronger effect in women. Apolipoprotein E genotype is a biological factor that cannot be modified but interacts with sex or gender related factors that can be modified. Low education has a similar harmful effect in men and women but has been historically more common in women. Education is a social factor related to gender that can be modified. Finally, bilateral oophorectomy is a factor restricted to women. Bilateral oophorectomy is a surgical practice related to sex that can be modified. Consideration of risk and protective factors in men and women separately may accelerate etiologic research for neurological diseases in general, and for dementia and AD in particular. Similarly, future preventive interventions for dementia should be tailored to men and women separately. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Associations between feedlot management practices and bovine respiratory disease in Australian feedlot cattle.

PubMed

Hay, K E; Morton, J M; Clements, A C A; Mahony, T J; Barnes, T S

2016-06-01

Bovine respiratory disease (BRD) is the major cause of clinical disease and death in feedlot cattle. A prospective longitudinal study was conducted in a population of Australian feedlot cattle to assess associations between factors related to feedlot management and risk of BRD. In total, 35,131 animals in 170 pens (cohorts) inducted into 14 feedlots were included in statistical analyses. Causal diagrams were used to inform model building to allow separate estimation of total and direct effects. Multilevel mixed effects logistic regression models were fitted within the Bayesian framework. The placement of pen water troughs such that they could be accessed by animals in adjoining pens was associated with markedly increased risk of BRD (OR 4.3, 95% credible interval: 1.4-10.3). Adding animals to pens over multiple days was associated with increased risk of BRD across all animals in those pens compared to placing all animals in the pen on a single day (total effect: OR 1.9, 95% credible interval: 1.2-2.8). The much attenuated direct effect indicated that this was primarily mediated via factors on indirect pathways so it may be possible to ameliorate the adverse effects of adding animals to pens over multiple days by altering exposure to these intervening factors (e.g. mixing history). In pens in which animals were added to the pen over multiple days, animals added ≥7 days (OR: 0.7, credible interval: 0.5-0.9) or 1-6 days (OR: 0.8, credible interval: 0.7-1.0) before the last animal was added were at modestly reduced risk of BRD compared to the animals that were added to the pen on the latest day. Further research is required to disentangle effects of cohort formation patterns at animal-level and higher levels on animal-level risk of BRD. Vaccination against Bovine herpesvirus 1 at feedlot entry was investigated but results were inconclusive and further research is required to evaluate vaccine efficacy. We conclude that there are practical interventions available to feedlot managers to reduce the risk of cattle developing BRD at the feedlot. We recommend placement of water troughs in feedlot pens so that they cannot be accessed by animals in adjoining pens. Further research is required to identify practical and cost-effective management strategies that allow longer adaption times for cattle identified prior to induction as being at higher risk of developing BRD. Copyright © 2016 Elsevier B.V. All rights reserved.

Association between Asymptomatic Urinary Tract Infection and Postoperative Spine Infection in Elderly Women : A Retrospective Analysis Study

PubMed Central

Lee, Seung-Eun; Park, Yong-Sook; Kim, Young-Baeg

2010-01-01

Objective The purpose of this study is to identify the relationship between asymptomatic urinary tract infection (aUTI) and postoperative spine infection. Methods A retrospective review was done in 355 women more than 65 years old who had undergone laminectomy and/or discectomy, and spinal fusion, between January 2004 and December 2008. Previously postulated risk factors (i.e., instrumentation, diabetes, prior corticosteroid therapy, previous spinal surgery, and smoking) were investigated. Furthermore, we added aUTI that was not previously considered. Results Among 355 patients, 42 met the criteria for aUTI (Bacteriuria ≥ 105 CFU/mL and no associated symptoms). A postoperative spine infection was evident in 15 of 355 patients. Of the previously described risk factors, multi-levels (p < 0.05), instrumentation (p < 0.05) and diabetes (p < 0.05) were proven risk factors, whereas aUTI (p > 0.05) was not statistically significant. However, aUTI with Foley catheterization was statistically significant when Foley catheterization was added as a variable to the all existing risk factors. Conclusion aUTI is not rare in elderly women admitted to the hospital for lumbar spine surgery. The results of this study suggest that aUTI with Foley catheterization may be considered a risk factor for postoperative spine infection in elderly women. Therefore, we would consider treating aUTI before operating on elderly women who will need Foley catheterization. PMID:20461166

Postmenopausal hormone therapy and Alzheimer disease: A prospective cohort study.

PubMed

Imtiaz, Bushra; Tuppurainen, Marjo; Rikkonen, Toni; Kivipelto, Miia; Soininen, Hilkka; Kröger, Heikki; Tolppanen, Anna-Maija

2017-03-14

To explore the association between postmenopausal hormone therapy (HT) and Alzheimer disease (AD). Twenty-year follow-up data from the Kuopio Osteoporosis Risk Factor and Prevention study cohort were used. Self-administered questionnaires were sent to all women aged 47-56 years, residing in Kuopio Province starting in 1989 until 2009, every 5th year. Register-based information on HT prescriptions was available since 1995. Probable AD cases, based on DSM-IV and National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria, were identified from the special reimbursement register (1999-2009). The study population included 8,195 women (227 cases of incident AD). Postmenopausal estrogen use was not associated with AD risk in register-based or self-reported data (hazard ratio/95% confidence interval 0.92/0.68-1.2, 0.99/0.75-1.3, respectively). Long-term self-reported postmenopausal HT was associated with reduced AD risk (0.53/0.31-0.91). Similar results were obtained with any dementia diagnosis in the hospital discharge register as an outcome. Our results do not provide strong evidence for a protective association between postmenopausal HT use and AD or dementia, although we observed a reduced AD risk among those with long-term self-reported HT use. Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

C-reactive protein and serum creatinine, but not haemoglobin A1c, are independent predictors of coronary heart disease risk in non-diabetic Chinese.

PubMed

Salim, Agus; Tai, E Shyong; Tan, Vincent Y; Welsh, Alan H; Liew, Reginald; Naidoo, Nasheen; Wu, Yi; Yuan, Jian-Min; Koh, Woon P; van Dam, Rob M

2016-08-01

In western populations, high-sensitivity C-reactive protein (hsCRP), and to a lesser degree serum creatinine and haemoglobin A1c, predict risk of coronary heart disease (CHD). However, data on Asian populations that are increasingly affected by CHD are sparse and it is not clear whether these biomarkers can be used to improve CHD risk classification. We conducted a nested case-control study within the Singapore Chinese Health Study cohort, with incident 'hard' CHD (myocardial infarction or CHD death) as an outcome. We used data from 965 men (298 cases, 667 controls) and 528 women (143 cases, 385 controls) to examine the utility of hsCRP, serum creatinine and haemoglobin A1c in improving the prediction of CHD risk over and above traditional risk factors for CHD included in the ATP III model. For each sex, the performance of models with only traditional risk factors used in the ATP III model was compared with models with the biomarkers added using weighted Cox proportional hazards analysis. The impact of adding these biomarkers was assessed using the net reclassification improvement index. For men, loge hsCRP (hazard ratio 1.25, 95% confidence interval: 1.05; 1.49) and loge serum creatinine (hazard ratio 4.82, 95% confidence interval: 2.10; 11.04) showed statistically significantly associations with CHD risk when added to the ATP III model. We did not observe a significant association between loge haemoglobin A1c and CHD risk (hazard ratio 1.83, 95% confidence interval: 0.21; 16.06). Adding hsCRP and serum creatinine to the ATP III model improved risk classification in men with a net gain of 6.3% of cases (p-value = 0.001) being reclassified to a higher risk category, while it did not significantly reduce the accuracy of classification for non-cases. For women, squared hsCRP was borderline significantly (hazard ratio 1.01, 95% confidence interval: 1.00; 1.03) and squared serum creatinine was significantly (hazard ratio 1.81, 95% confidence interval: 1.49; 2.21) associated with CHD risk. However, the association between squared haemoglobin A1c and CHD risk was not significant (hazard ratio 1.05, 95% confidence interval: 0.99; 1.12). The addition of hsCRP and serum creatinine to the ATP III model resulted in 3.7% of future cases being reclassified to a higher risk category (p-value = 0.025), while it did not significantly reduce the accuracy of classification for non-cases. Adding hsCRP and serum creatinine, but not haemoglobin A1c, to traditional risk factors improved CHD risk prediction among non-diabetic Singaporean Chinese. The improved risk estimates will allow better identification of individuals at high risk of CHD than existing risk calculators such as the ATP III model. © The European Society of Cardiology 2016.

Cardiorespiratory fitness and classification of risk of cardiovascular disease mortality.

PubMed

Gupta, Sachin; Rohatgi, Anand; Ayers, Colby R; Willis, Benjamin L; Haskell, William L; Khera, Amit; Drazner, Mark H; de Lemos, James A; Berry, Jarett D

2011-04-05

Cardiorespiratory fitness (fitness) is associated with cardiovascular disease (CVD) mortality. However, the extent to which fitness improves risk classification when added to traditional risk factors is unclear. Fitness was measured by the Balke protocol in 66 371 subjects without prior CVD enrolled in the Cooper Center Longitudinal Study between 1970 and 2006; follow-up was extended through 2006. Cox proportional hazards models were used to estimate the risk of CVD mortality with a traditional risk factor model (age, sex, systolic blood pressure, diabetes mellitus, total cholesterol, and smoking) with and without the addition of fitness. The net reclassification improvement and integrated discrimination improvement were calculated at 10 and 25 years. Ten-year risk estimates for CVD mortality were categorized as <1%, 1% to <5%, and ≥5%, and 25-year risk estimates were categorized as <8%, 8% to 30%, and ≥30%. During a median follow-up period of 16 years, there were 1621 CVD deaths. The addition of fitness to the traditional risk factor model resulted in reclassification of 10.7% of the men, with significant net reclassification improvement at both 10 years (net reclassification improvement=0.121) and 25 years (net reclassification improvement=0.041) (P<0.001 for both). The integrated discrimination improvement was 0.010 at 10 years (P<0.001), and the relative integrated discrimination improvement was 29%. Similar findings were observed for women at 25 years. A single measurement of fitness significantly improves classification of both short-term (10-year) and long-term (25-year) risk for CVD mortality when added to traditional risk factors.

Association of Cancer History with Alzheimer's Disease Dementia and Neuropathology.

PubMed

Yarchoan, Mark; James, Bryan D; Shah, Raj C; Arvanitakis, Zoe; Wilson, Robert S; Schneider, Julie; Bennett, David A; Arnold, Steven E

2017-01-01

Cancer and Alzheimer's disease (AD) are common diseases of aging and share many risk factors. Surprisingly, however, epidemiologic data from several recent independent cohort studies suggest that there may be an inverse association between these diseases. To determine the relationship between history of cancer and odds of dementia proximate to death and neuropathological indices of AD. Using data from two separate clinical-pathologic cohort studies of aging and AD, the Religious Orders Study (ROS) and the Rush Memory and Aging Project (MAP), we compared odds of AD dementia proximate to death among participants with and without a history of cancer. We then examined the relation of history of cancer with measures of AD pathology at autopsy, i.e., paired helical filament tau (PHFtau) neurofibrillary tangles and amyloid-β load. Participants reporting a history of cancer had significantly lower odds of AD (OR 0.70 [0.55-0.89], p = 0.0040) proximate to death as compared to participants reporting no prior history of cancer. The results remained significant after adjusting for multiple risk factors including age, sex, race, education, and presence of an APOEɛ4 allele. At autopsy, participants with a history of cancer had significantly fewer PHFtau tangles (p < 0.001) than participants without a history of cancer, but similar levels of amyloid-β. Cancer survivors have reduced odds of developing AD and a lower burden of neurofibrillary tangle deposition.

Examining the Relationship between Trace Lithium in Drinking Water and the Rising Rates of Age-Adjusted Alzheimer's Disease Mortality in Texas.

PubMed

Fajardo, Val Andrew; Fajardo, Val Andrei; LeBlanc, Paul J; MacPherson, Rebecca E K

2018-01-01

Alzheimer's disease (AD) mortality rates have steadily increased over time. Lithium, the current gold standard treatment for bipolar disorder, can exert neuroprotective effects against AD. We examined the relationship between trace levels of lithium in drinking water and changes in AD mortality across several Texas counties. 6,180 water samples from public wells since 2007 were obtained and averaged for 234 of 254 Texas counties. Changes in AD mortality rates were calculated by subtracting aggregated age-adjusted mortality rates obtained between 2000-2006 from those obtained between 2009-2015. Using aggregated rates maximized the number of counties with reliable mortality data. Correlational analyses between average lithium concentrations and changes in AD mortality were performed while also adjusting for gender, race, education, rural living, air pollution, physical inactivity, obesity, and type 2 diabetes. Age-adjusted AD mortality rate was significantly increased over time (+27%, p < 0.001). Changes in AD mortality were negatively correlated with trace lithium levels (p = 0.01, r = -0.20), and statistical significance was maintained after controlling for most risk factors except for physical inactivity, obesity, and type 2 diabetes. Furthermore, the prevalence of obesity and type 2 diabetes positively correlated with changes in AD mortality (p = 0.01 and 0.03, respectively), but also negatively correlated with trace lithium in drinking water (p = 0.05 and <0.0001, respectively). Trace lithium in water is negatively linked with changes in AD mortality, as well as obesity and type 2 diabetes, which are important risk factors for AD.

Gender-specific association of ATP-binding cassette transporter 1 (ABCA1) polymorphisms with the risk of late-onset Alzheimer's disease.

PubMed

Sundar, Purnima Desai; Feingold, Eleanor; Minster, Ryan L; DeKosky, Steven T; Kamboh, M Ilyas

2007-06-01

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder caused by a complex interaction of genetic and environmental factors. Increasing evidence highlights a potential role for cholesterol in the pathophysiology of AD. The ABCA1 gene, located in close vicinity to the 9q linkage peaks identified by genome-wide AD linkage studies, plays an important role in cellular cholesterol efflux, and is likely a good candidate gene. However, results from published genetic association studies between ABCA1 and AD are ambiguous. In the present study, we examined the role of two ABCA1 polymorphisms, R219K (rs2230806) and G-17C (rs2740483) in modifying the risk of late-onset AD (LOAD) in a large American white cohort of 992 AD cases and 699 controls. We observed significant gender x R219K interaction (p=0.00008). Female carriers of the 219K allele showed a 1.75-fold increased risk of developing AD compared to non-219K carrier females (95% CI 1.34-2.29; p=0.00004). The overall two-site haplotype distribution was also significant between female AD cases and controls (p=0.017). The risk associated with the R219K polymorphism was independent of the recently reported significant association in the ubiquilin (UBQLN1) gene in this region on chromosome 9q. Our data suggest a gender-specific and APOE and UBQLN1 independent association between the ABCA1/R219K polymorphism and LOAD.

The relationship between fasting serum glucose and cerebral glucose metabolism in late-life depression and normal aging

PubMed Central

Marano, Christopher M.; Workman, Clifford I.; Lyman, Christopher H.; Kramer, Elisse; Hermann, Carol R.; Ma, Yilong; Dhawan, Vijay; Chaly, Thomas; Eidelberg, David; Smith, Gwenn S.

2015-01-01

Evidence exists for late-life depression (LLD) as both a prodrome of and risk factor for Alzheimer’s disease (AD). The underlying neurobiological mechanisms are poorly understood. Impaired peripheral glucose metabolism may explain the association between depression and AD given the connection between type 2 diabetes mellitus with both depression and AD. Positron emission tomography (PET) measures of cerebral glucose metabolism are sensitive to detecting changes in neural circuitry in LLD and AD. Fasting serum glucose (FSG) in non-diabetic young (YC; n=20) and elderly controls (EC; n=12) and LLD patients (n=16) was correlated with PET scans of cerebral glucose metabolism on a voxel-wise basis. The negative correlations were more extensive in EC versus YC and in LLD patients versus EC. Increased FSG correlated with decreased cerebral glucose metabolism in LLD patients to a greater extent than in EC in heteromodal association cortices involved in mood symptoms and cognitive deficits observed in LLD and dementia. Negative correlations in YC were observed in sensory and motor regions. Understanding the neurobiological consequences of diabetes and associated conditions will have substantial public health significance given that this is a modifiable risk factor for which prevention strategies could have an important impact on lowering dementia risk. PMID:24650451

Genetic dissection of Alzheimer disease, a heterogeneous disorder.

PubMed

Schellenberg, G D

1995-09-12

The genetics of Alzheimer disease (AD) are complex and not completely understood. Mutations in the amyloid precursor protein gene (APP) can cause early-onset autosomal dominant AD. In vitro studies indicate that cells expressing mutant APPs overproduce pathogenic forms of the A beta peptide, the major component of AD amyloid. However, mutations in the APP gene are responsible for 5% or less of all early-onset familial AD. A locus on chromosome 14 is responsible for AD in other early-onset AD families and represents the most severe form of the disease in terms of age of onset and rate of decline. Attempts to identify the AD3 gene by positional cloning methods are underway. At least one additional early-onset AD locus remains to be located. In late-onset AD, the apolipoprotein E gene allele epsilon 4 is a risk factor for AD. This allele appears to act as a dose-dependent age-of-onset modifier. The epsilon 2 allele of this gene may be protective. Other late-onset susceptibility factors remain to be identified.

Sex Differences in Risk for Alzheimer's Disease Related to Neurotrophin Gene Polymorphisms: The Cache County Memory Study.

PubMed

Matyi, Joshua; Tschanz, JoAnn T; Rattinger, Gail B; Sanders, Chelsea; Vernon, Elizabeth K; Corcoran, Chris; Kauwe, John S K; Buhusi, Mona

2017-11-09

Neurotrophins, including nerve-growth factor and brain-derived neurotrophic factor, have been implicated in Alzheimer's disease (AD). Associations between AD and neurotrophin signaling genes have been inconsistent, with few studies examining sex differences in risk. We examined four single-nucleotide polymorphisms (SNPs) involved in neurotrophin signaling (rs6265, rs56164415, rs2289656, rs2072446) and risk for AD by sex in a population-based sample of older adults. Three thousand four hundred and ninety-nine individuals without dementia at baseline [mean (standard deviation) age = 74.64 (6.84), 58% female] underwent dementia screening and assessment over four triennial waves. Cox regression was used to examine time to AD or right censoring for each SNP. Female carriers of the minor T allele for rs2072446 and rs56164415 had a 60% (hazard ratio [HR] = 1.60, 95% confidence interval [CI] = 1.02-2.51) and 93% (HR = 1.93, 95% CI = 1.30-2.84) higher hazard for AD, respectively, than male noncarriers of the T allele. Furthermore, male carriers of the T allele of rs2072446 had a 61% lower hazard (HR = 0.39, 95% CI = 0.14-1.06) than male noncarriers at trend-level significance (p = .07). The association between certain neurotrophin gene polymorphisms and AD differs by sex and may explain inconsistent findings in the literature. © The Author 2017. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Habitual sugar intake and cognitive function among middle-aged and older Puerto Ricans without diabetes

USDA-ARS?s Scientific Manuscript database

Intake of added sugars, mainly fructose and sucrose, has been associated with risk factors for cognitive impairment, such as obesity, the metabolic syndrome and type 2 diabetes. The objective of this analysis was to examine whether habitual intakes of total sugars, added sugars, sugar-sweetened bev...

Association of Radon Background and Total Background Ionizing Radiation with Alzheimer's Disease Deaths in U.S. States.

PubMed

Lehrer, Steven; Rheinstein, Peter H; Rosenzweig, Kenneth E

2017-01-01

Exposure of the brain to ionizing radiation might promote the development of Alzheimer's disease (AD). Analysis of AD death rates versus radon background radiation and total background radiation in U.S. states. Total background, radon background, cosmic and terrestrial background radiation measurements are from Assessment of Variations in Radiation Exposure in the United States and Report No. 160 - Ionizing Radiation Exposure of the Population of the United States. 2013 AD death rates by U.S. state are from the Alzheimer's Association. Radon background ionizing radiation was significantly correlated with AD death rate in 50 states and the District of Columbia (r = 0.467, p = 0.001). Total background ionizing radiation was also significantly correlated with AD death rate in 50 states and the District of Columbia (r = 0.452, p = 0.001). Multivariate linear regression weighted by state population demonstrated that AD death rate was significantly correlated with radon background (β= 0.169, p < 0.001), age (β= 0.231, p < 0.001), hypertension (β= 0.155, p < 0.001), and diabetes (β= 0.353, p < 0.001). Our findings, like other studies, suggest that ionizing radiation is a risk factor for AD. Intranasal inhalation of radon gas could subject the rhinencephalon and hippocampus to damaging radiation that initiates AD. The damage would accumulate over time, causing age to be a powerful risk factor.

Causes of oral cancer--an appraisal of controversies.

PubMed

Warnakulasuriya, S

2009-11-28

Major risk factors for oral cancer are cigarette smoking and alcohol misuse. Among Asian populations, regular use of betel quid (with or without added tobacco) increases oral cancer risks. Dentists should be aware of some emerging risk factors for oral, and particularly oropharyngeal cancer such as the role of the human papillomavirus infection (HPV). Decreases in risk could be achieved by encouraging high fruit and vegetable consumption. Some controversies related to the aetiology of this disease also need clarification. The objective of this paper is to provide an opinion on these debated controversies.

Risk Factors for Nursing Home Placement in Alzheimer's Disease: A Longitudinal Study of Cognition, ADL, Service Utilization, and Cholinesterase Inhibitor Treatment

ERIC Educational Resources Information Center

Wattmo, Carina; Wallin, Asa K.; Londos, Elisabet; Minthon, Lennart

2011-01-01

Purpose of the Study: To identify risk factors for early nursing home placement (NHP) in Alzheimer's disease (AD), focusing on the impact of longitudinal change in cognition, activities of daily living (ADL), service utilization, and cholinesterase inhibitor treatment (ChEI). Design and Methods: In an open, 3-year, prospective, multicenter study…

The genetics of Alzheimer disease: back to the future.

PubMed

Bertram, Lars; Lill, Christina M; Tanzi, Rudolph E

2010-10-21

Three decades of genetic research in Alzheimer disease (AD) have substantially broadened our understanding of the pathogenetic mechanisms leading to neurodegeneration and dementia. Positional cloning led to the identification of rare, disease-causing mutations in APP, PSEN1, and PSEN2 causing early-onset familial AD, followed by the discovery of APOE as the single most important risk factor for late-onset AD. Recent genome-wide association approaches have delivered several additional AD susceptibility loci that are common in the general population, but exert only very small risk effects. As a result, a large proportion of the heritability of AD continues to remain unexplained by the currently known disease genes. It seems likely that much of this "missing heritability" may be accounted for by rare sequence variants, which, owing to recent advances in high-throughput sequencing technologies, can now be assessed in unprecedented detail. Copyright © 2010 Elsevier Inc. All rights reserved.

Alzheimer's Disease and Exercise: A Literature Review.

PubMed

Cass, Shane P

Alzheimer's disease (AD) is a progressive neurodegenerative disease that impairs memory and cognitive judgment. It is the leading cause of dementia in late adult life and is associated with a significant social burden and increased morbidity and mortality in the elderly. Because of mixed effectiveness of medications, exercise has been considered as a treatment for pre-clinical AD, late stage AD, and as a prevention strategy. Exercise appears to improve brain blood flow, increase hippocampal volume, and improve neurogenesis. Prospective studies indicate that physical inactivity is one of the most common preventable risk factors for developing AD and that higher physical activity levels are associated with a reduced risk of development of disease. Exercise as a treatment for AD shows improvement in cognitive function, decreased neuropsychiatric symptoms, and a slower decline in activities of daily living (ADL). Exercise has been shown to have fewer side effects and better adherence compared to medications.

Preclinical Alzheimer's Disease: Implications for Refinement of the Concept.

PubMed

Vos, Stephanie J B; Visser, Pieter Jelle

2018-05-23

Increasing interest in clinical trials and clinical research settings to identify Alzheimer's disease (AD) in the earliest stages of the disease has led to the concept of preclinical AD. Individuals with preclinical AD have AD pathology without clinical symptoms yet. Accumulating evidence has shown that biomarkers can identify preclinical AD and that preclinical AD is associated with a poor clinical outcome. Little is known yet about the role of vascular and lifestyle risk factors in the development of preclinical AD. In order to better understand preclinical AD pathology and clinical progression rates, there is a need to refine the concept of preclinical AD. This will be of great value for advancements in future research, clinical trials, and eventually clinical practice.

Association between chronic periodontitis and the risk of Alzheimer's disease: a retrospective, population-based, matched-cohort study.

PubMed

Chen, Chang-Kai; Wu, Yung-Tsan; Chang, Yu-Chao

2017-08-08

Although recent short-term cross-sectional studies have revealed that chronic periodontitis (CP) may be a risk factor for increased cognitive impairment in patients with Alzheimer's disease (AD), systematic reviews and long-term longitudinal studies have provided less clear evidence regarding the relationship between CP and AD. Therefore, we conducted a retrospective cohort study using the National Health Insurance Research Database (NHIRD) of Taiwan to determine whether patients with CP are at increased risk of developing AD. We conducted a retrospective matched-cohort study using the NHIRD of Taiwan. We identified 9291 patients newly diagnosed with CP between 1997 and 2004. A total of 18,672 patients without CP were matched to the patient cohort according to sex, age, index year, co-morbidity and urbanisation level. Cox proportional hazards regression analyses were performed to evaluate the subsequent risk of AD. Patients with CP had a higher prevalence of hyperlipidaemia, depression, traumatic brain injury and co-morbidities, as well as higher urbanisation levels, than those in the unexposed cohort (all p < 0.01). At the final follow-up, totals of 115 (1.24%) and 208 (1.11%) individuals in the CP exposed and unexposed groups, respectively, had developed AD. Patients with 10 years of CP exposure exhibited a higher risk of developing AD than unexposed groups (adjusted HR 1.707, 95% CI 1.152-2.528, p = 0.0077). Our findings demonstrate that 10-year CP exposure was associated with a 1.707-fold increase in the risk of developing AD. These findings highlight the need to prevent progression of periodontal disease and promote healthcare service at the national level.

Suicidal Tendency Among Adolescents With Adjustment Disorder.

PubMed

Ferrer, Laia; Kirchner, Teresa

2015-01-01

Adolescents with adjustment disorder (AD) are at risk of presenting suicidal symptoms. Certain personality traits are linked to suicidal tendencies. There is a lack of information about the link between suicide and personality patterns in adolescents with AD. To identify the personality characteristics that predispose to or prevent the development of suicidal ideation and behavior among adolescents with AD. We recruited 108 adolescents with AD at a public mental health center near Barcelona (Spain). They were administered the Inventario de Riesgo Suicida para Adolescentes (IRIS) to assess suicidal symptoms, as well as the Millon Adolescent Clinical Inventory (MACI) and the 16PF Adolescent Personality Questionnaire (16PF-APQ) to appraise personality features. Doleful personality emerged as the principal risk for suicidal symptoms. The conforming personality pattern exerted a protective effect, and emotional stability was associated with low levels of suicidal tendencies. Among the Big Five factors, anxiety had the highest explanatory power for suicidal tendencies. Certain personality characteristics are associated with heightened or reduced risk of suicidal tendencies in adolescents with AD. Their identification is important for clinicians designing treatment programs for these patients.

Association of apolipoprotein E allele {epsilon}4 with late-onset sporadic Alzheimer`s disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lucotte, G.; David, F.; Berriche, S.

1994-09-15

Apolipoprotein E, type {epsilon}4 allele (ApoE {epsilon}4), is associated with late-onset sporadic Alzheimer`s disease (AD) in French patients. The association is highly significant (0.45 AD versus 0.12 controls for {epsilon}4 allele frequencies). These data support the involvement of ApoE {epsilon}4 allele as a very important risk factor for the clinical expression of AD. 22 refs., 1 fig., 3 tabs.

Linkage of sleep-disordered breathing and acute aortic dissection with patent false lumen.

PubMed

Inami, Toru; Seino, Yoshihiko; Shimura, Tetsuro; Kurihara, Osamu; Kimata, Nakahisa; Murakami, Daisuke; Munakata, Ryo; Takano, Masamichi; Ohba, Takayoshi; Shimizu, Wataru

2016-07-01

Sleep-disordered breathing (SDB) is known as a cardiovascular risk factor and has high prevalence in hypertension, which is a major risk factor of aortic dissection (AD). However, the impact of SDB on AD has not been fully clarified. The aim of this study is to elucidate the impact of SDB on AD, especially on the type of false lumen in AD. We enrolled twenty-three consecutive patients with acute AD (mean age: 66 ± 13 years). All subjects were evaluated by an ambulatory polygraphic sleep monitoring within 1 month from the onset. AD was evaluated by axial images of computed tomography. We comparatively analyzed SDB and AD. 35 % of the subjects presented severe OSA (apnea-hypopnea index: AHI ≥30). The patent false lumen group showed significantly higher systolic and diastolic blood pressure (BP) on arrival and AHI, and lower percutaneous oxygen saturation (SaO2) compared with those in the thrombosed false lumen group. The prevalence of severe SDB was higher in the patent false lumen group (60 vs 15 %, p = 0.039). Systolic BP on arrival was significantly correlated with AHI (r = 0.457, p = 0.033) and the minimum SaO2 (r = -0.537, p = 0.010). The present study revealed close linkage between SDB and AD, and a high prevalence of SDB among AD patients. Severe SDB was related to the development of AD, especially for the patent false lumen type through highly elevated BP which might be easily evoked in the presence of severe SDB. Repetitive occurrence of intrathoracic negative pressure also might influence the repair or closure of false lumen of AD, although the present analysis did not reach statistical significance.

Fine-mapping of the human leukocyte antigen locus as a risk factor for Alzheimer disease: A case–control study

PubMed Central

Steele, Natasha Z. R.; Geier, Ethan G.; Damotte, Vincent; Boehme, Kevin L.; Mukherjee, Shubhabrata; Crane, Paul K.; Kauwe, John S. K.; Kramer, Joel H.; Miller, Bruce L.; Hollenbach, Jill A.; Huang, Yadong

2017-01-01

Background Alzheimer disease (AD) is a progressive disorder that affects cognitive function. There is increasing support for the role of neuroinflammation and aberrant immune regulation in the pathophysiology of AD. The immunoregulatory human leukocyte antigen (HLA) complex has been linked to susceptibility for a number of neurodegenerative diseases, including AD; however, studies to date have failed to consistently identify a risk HLA haplotype for AD. Contributing to this difficulty are the complex genetic organization of the HLA region, differences in sequencing and allelic imputation methods, and diversity across ethnic populations. Methods and findings Building on prior work linking the HLA to AD, we used a robust imputation method on two separate case–control cohorts to examine the relationship between HLA haplotypes and AD risk in 309 individuals (191 AD, 118 cognitively normal [CN] controls) from the San Francisco-based University of California, San Francisco (UCSF) Memory and Aging Center (collected between 1999–2015) and 11,381 individuals (5,728 AD, 5,653 CN controls) from the Alzheimer’s Disease Genetics Consortium (ADGC), a National Institute on Aging (NIA)-funded national data repository (reflecting samples collected between 1984–2012). We also examined cerebrospinal fluid (CSF) biomarker measures for patients seen between 2005–2007 and longitudinal cognitive data from the Alzheimer’s Disease Neuroimaging Initiative (n = 346, mean follow-up 3.15 ± 2.04 y in AD individuals) to assess the clinical relevance of identified risk haplotypes. The strongest association with AD risk occurred with major histocompatibility complex (MHC) haplotype A*03:01~B*07:02~DRB1*15:01~DQA1*01:02~DQB1*06:02 (p = 9.6 x 10−4, odds ratio [OR] [95% confidence interval] = 1.21 [1.08–1.37]) in the combined UCSF + ADGC cohort. Secondary analysis suggested that this effect may be driven primarily by individuals who are negative for the established AD genetic risk factor, apolipoprotein E (APOE) ɛ4. Separate analyses of class I and II haplotypes further supported the role of class I haplotype A*03:01~B*07:02 (p = 0.03, OR = 1.11 [1.01–1.23]) and class II haplotype DRB1*15:01- DQA1*01:02- DQB1*06:02 (DR15) (p = 0.03, OR = 1.08 [1.01–1.15]) as risk factors for AD. We followed up these findings in the clinical dataset representing the spectrum of cognitively normal controls, individuals with mild cognitive impairment, and individuals with AD to assess their relevance to disease. Carrying A*03:01~B*07:02 was associated with higher CSF amyloid levels (p = 0.03, β ± standard error = 47.19 ± 21.78). We also found a dose-dependent association between the DR15 haplotype and greater rates of cognitive decline (greater impairment on the 11-item Alzheimer’s Disease Assessment Scale cognitive subscale [ADAS11] over time [p = 0.03, β ± standard error = 0.7 ± 0.3]; worse forgetting score on the Rey Auditory Verbal Learning Test (RAVLT) over time [p = 0.02, β ± standard error = −0.2 ± 0.06]). In a subset of the same cohort, dose of DR15 was also associated with higher baseline levels of chemokine CC-4, a biomarker of inflammation (p = 0.005, β ± standard error = 0.08 ± 0.03). The main study limitations are that the results represent only individuals of European-ancestry and clinically diagnosed individuals, and that our study used imputed genotypes for a subset of HLA genes. Conclusions We provide evidence that variation in the HLA locus—including risk haplotype DR15—contributes to AD risk. DR15 has also been associated with multiple sclerosis, and its component alleles have been implicated in Parkinson disease and narcolepsy. Our findings thus raise the possibility that DR15-associated mechanisms may contribute to pan-neuronal disease vulnerability. PMID:28350795

What is the Relationship of Traumatic Brain Injury to Dementia?

PubMed

Mendez, Mario F

2017-01-01

There is a long history linking traumatic brain injury (TBI) with the development of dementia. Despite significant reservations, such as recall bias or concluding causality for TBI, a summary of recent research points to several conclusions on the TBI-dementia relationship. 1) Increasing severity of a single moderate-to-severe TBI increases the risk of subsequent Alzheimer's disease (AD), the most common type of dementia. 2) Repetitive, often subconcussive, mild TBIs increases the risk for chronic traumatic encephalopathy (CTE), a degenerative neuropathology. 3) TBI may be a risk factor for other neurodegenerative disorders that can be associated with dementia. 4) TBI appears to lower the age of onset of TBI-related neurocognitive syndromes, potentially adding "TBI cognitive-behavioral features". The literature further indicates several specific risk factors for TBI-associated dementia: 5) any blast or blunt physical force to the head as long as there is violent head displacement; 6) decreased cognitive and/or neuronal reserve and the related variable of older age at TBI; and 7) the presence of apolipoprotein E ɛ4 alleles, a genetic risk factor for AD. Finally, there are neuropathological features relating TBI with neurocognitive syndromes: 8) acute TBI results in amyloid pathology and other neurodegenerative proteinopathies; 9) CTE shares features with neurodegenerative dementias; and 10) TBI results in white matter tract and neural network disruptions. Although further research is needed, these ten findings suggest that dose-dependent effects of violent head displacement in vulnerable brains predispose to dementia; among several potential mechanisms is the propagation of abnormal proteins along damaged white matter networks.

Additive effect between IL-13 polymorphism and cesarean section delivery/prenatal antibiotics use on atopic dermatitis: a birth cohort study (COCOA).

PubMed

Lee, So-Yeon; Yu, Jinho; Ahn, Kang-Mo; Kim, Kyung Won; Shin, Youn Ho; Lee, Kyung-Shin; Hong, Seo Ah; Jung, Young-Ho; Lee, Eun; Yang, Song-I; Seo, Ju-Hee; Kwon, Ji-Won; Kim, Byoung-Ju; Kim, Hyo-Bin; Kim, Woo-Kyung; Song, Dae Jin; Jang, Gwang Cheon; Shim, Jung Yeon; Lee, Soo-Young; Kwon, Ja-Young; Choi, Suk-Joo; Lee, Kyung-Ju; Park, Hee Jin; Won, Hye-Sung; Yoo, Ho-Sung; Kang, Mi-Jin; Kim, Hyung-Young; Hong, Soo-Jong

2014-01-01

Although cesarean delivery and prenatal exposure to antibiotics are likely to affect the gut microbiome in infancy, their effect on the development of atopic dermatitis (AD) in infancy is unclear. The influence of individual genotypes on these relationships is also unclear. To evaluate with a prospective birth cohort study whether cesarean section, prenatal exposure to antibiotics, and susceptible genotypes act additively to promote the development of AD in infancy. The Cohort for Childhood of Asthma and Allergic Diseases (COCOA) was selected from the general Korean population. A pediatric allergist assessed 412 infants for the presence of AD at 1 year of age. Their cord blood DNA was subjected to interleukin (IL)-13 (rs20541) and cluster-of-differentiation (CD)14 (rs2569190) genotype analysis. The combination of cesarean delivery and prenatal exposure to antibiotics associated significantly and positively with AD (adjusted odds ratio, 5.70; 95% CI, 1.19-27.3). The association between cesarean delivery and AD was significantly modified by parental history of allergic diseases or risk-associated IL-13 (rs20541) and CD14 (rs2569190) genotypes. There was a trend of interaction between IL-13 (rs20541) and delivery mode with respect to the subsequent risk of AD. (P for interaction = 0.039) Infants who were exposed prenatally to antibiotics and were born by cesarean delivery had a lower total microbiota diversity in stool samples at 6 months of age than the control group. As the number of these risk factors increased, the AD risk rose (trend p<0.05). Cesarean delivery and prenatal antibiotic exposure may affect the gut microbiota, which may in turn influence the risk of AD in infants. These relationships may be shaped by the genetic predisposition.

The influence of childhood atopic dermatitis on health of mothers, and its impact on Asian families.

PubMed

Ho, Roger C M; Giam, Y C; Ng, T P; Mak, Anselm; Goh, Daniel; Zhang, Melvyn W B; Cheak, Alicia; Van Bever, Hugo P

2010-05-01

This study examines maternal perceptions of paediatric atopic dermatitis (AD) on family and determines risk factors including severity of AD, maternal physical and mental health (MH), quality of life of patients and sociodemographics which predict a negative family impact. A cross-sectional assessment using the Dermatitis Family Impact Questionnaire Scale to assess the impact of AD on family, Infant's Dermatitis Quality of Life Index (<5-yrs old) or Children's Dermatitis Life Quality Index (5-17 yrs old) was used to measure health-related quality of life (HRQOL) of paediatric patients with AD. A 12-item Short-Form Health Survey (SF-12) was used to assess physical and MH of their mothers. Risk factors of adverse family impact were assessed using multiple regression analysis. One hundred and four patients with AD and their mothers were studied. Their mean ages (+/-s.d.) were respectively 6.4 +/- 4.3 and 37.2 +/- 6.6 yrs. In multiple regression analysis, Severity Scoring of Atopic Dermatitis (SCORAD) appeared to be associated with negative family impact and the association remained significant after adjustment for bio-psycho-social factors and HRQOL of patients. The association remained insignificant after adjustment for physical and MH of the mothers. Our results show that the severity of paediatric AD leads to negative family impact through reduction of physical and MH of the mothers, and is independent of patients' HRQOL and sociodemographics. The current approach for managing paediatric AD in Asian society could include early multidisciplinary intervention, aiming at enhancing physical and MH of mothers while minimizing negative impact on family and social isolation. Further research will be welcomed as the results of this study mainly applied to Asian society which could be different to populations from other geographic areas.

Alzheimer’s and Dementia in the Oldest-Old: A Century of Challenges

PubMed Central

Kawas, Claudia H.; Corrada, Maria M.

2012-01-01

Alzheimer’s disease (AD) is the most common type of dementia in the US and much of the world with rates increasing exponentially from age 65. Increases in life expectancy in the last century have resulted in a large number of people living to old ages and will result in a quadrupling of AD cases by the middle of the century. Preventing or delaying the onset of AD could have a huge impact in the number of cases expected to develop. The oldest-old are the fastest growing segment of the population and are estimated to account for 12% of the population over 65. Establishing accurate estimates of dementia and AD rates in this group is crucial for public health planning. Prevalence and incidence estimates above age 85 are imprecise and inconsistent because of the lack of very old individuals in most studies. Moreover, risk and protective factors in our oldest citizens have been studied little, and clinical-pathological correlations appear to be poor. We introduce The 90+ Study, established to address some of the unanswered questions about AD and dementia in the oldest-old. Our preliminary results show that close to half of demented oldest-old do not have known cerebral pathology to account for their cognitive deficits. Furthermore, the APOE-e4 allele appears to be a risk factor for AD only in the women in our study. In addition to the challenge of preventing and treating AD, the oldest-old will require major investigative energy to better understand the concomitants of longevity, the causes of dementia, and the factors that promote successful aging in oldest citizens. PMID:17168640

[Radiotherapy with androgen deprivation in high-risk prostate cancer: what outcomes on a Caribbean population?].

PubMed

Foahom Kamwa, A D; Vian, E; Agoua, G; Sénéchal, C; Bentaleb, Y; Fofana, M; Manip-M'ebobisse, N; Blanchet, P

2012-11-01

To analyze in a Caribbean population at 90% of African descent, the results of radiotherapy with androgen deprivation (AD) in high-risk prostate cancer (PCa). Fifty-nine consecutive patients with a high-risk PCa as defined by the D'AMICO classification and treated by radiotherapy with AD between January 2003 and April 2009 in our center were analyzed. The median dose of radiation and the median duration of AD were 70Gy and 37months respectively. Biochemical recurrence (BF), as primary outcome was defined according to the PHOENIX criteria (nadir PSA+2ng/mL). Multivariate analysis was performed to identify predictive factors of BF. The median follow-up was 47months. Eight (13.6%) patients had BF and four (6.8%) developed metastases. Six (10.2%) died during the follow-up. The 5years acturial biochemical disease-free survival was 79.7%. Multivariate analyses have shown that Gleason sum (GS) superior to 7 (P=0.029), AD duration less than 24months (P=0.004) and the rate of Nadir PSA greater or equal to 0.5ng/mL (P=0.011) were independent predictive factors of BF. This study was the first to our knowledge, to provide that radiotherapy associate with AD for HRPC among Caribbean men is effective as observed in other populations. Patients with GS superior to 7 could be considered for more aggressive treatments in clinical trials. Copyright © 2012 Elsevier Masson SAS. All rights reserved.

Association between Repeated Unpredictable Chronic Mild Stress (UCMS) Procedures with a High Fat Diet: A Model of Fluoxetine Resistance in Mice

PubMed Central

Isingrini, Elsa; Camus, Vincent; Le Guisquet, Anne-Marie; Pingaud, Maryse; Devers, Séverine; Belzung, Catherine

2010-01-01

Major depressive disorder is a debilitating disease. Unfortunately, treatment with antidepressants (ADs) has limited therapeutic efficacy since resistance to AD is common. Research in this field is hampered by the lack of a reliable natural animal model of AD resistance. Depression resistance is related to various factors, including the attendance of cardiovascular risk factors and past depressive episodes. We aimed to design a rodent model of depression resistance to ADs, associating cardiovascular risk factors with repeated unpredicted chronic mild stress (UCMS). Male BALB/c mice were given either a regular (4% fat) or a high fat diet (45% fat) and subjected to two 7-week periods of UCMS separated by 6 weeks. From the second week of each UCMS procedure, vehicle or fluoxetine (10 mg/kg, i.p.) was administrated daily. The effects of the UCMS and fluoxetine in both diet conditions were assessed using physical (coat state and body weight) and behavioural tests (the reward maze test and the splash test). The results demonstrate that during the second procedure, UCMS induced behavioural changes, including coat state degradation, disturbances in self-care behaviour (splash test) and anhedonia (reward maze test) and these were reversed by fluoxetine in the regular diet condition. In contrast, the high-fat diet regimen prevented the AD fluoxetine from abolishing the UCMS-induced changes. In conclusion, by associating UCMS—an already validated animal model of depression—with high-fat diet regimen, we designed a naturalistic animal model of AD resistance related to a sub-nosographic clinical entity of depression. PMID:20436931

Improving Global Vascular Risk Prediction with Behavioral and Anthropometric Factors: The Multi-ethnic Northern Manhattan Cohort Study

PubMed Central

Sacco, Ralph L.; Khatri, Minesh; Rundek, Tatjana; Xu, Qiang; Gardener, Hannah; Boden-Albala, Bernadette; Di Tullio, Marco R.; Homma, Shunichi; Elkind, Mitchell SV; Paik, Myunghee C

2010-01-01

Objective To improve global vascular risk prediction with behavioral and anthropometric factors. Background Few cardiovascular risk models are designed to predict the global vascular risk of MI, stroke, or vascular death in multi-ethnic individuals, and existing schemes do not fully include behavioral risk factors. Methods A randomly-derived, population-based, prospective cohort of 2737 community participants free of stroke and coronary artery disease were followed annually for a median of 9.0 years in the Northern Manhattan Study (mean age 69 years; 63.2% women; 52.7% Hispanic, 24.9% African-American, 19.9% white). A global vascular risk score (GVRS) predictive of stroke, myocardial infarction, or vascular death was developed by adding variables to the traditional Framingham cardiovascular variables based on the likelihood ratio criterion. Model utility was assessed through receiver operating characteristics, calibration, and effect on reclassification of subjects. Results Variables which significantly added to the traditional Framingham profile included waist circumference, alcohol consumption, and physical activity. Continuous measures for blood pressure and fasting blood sugar were used instead of hypertension and diabetes. Ten -year event-free probabilities were 0.95 for the first quartile of GVRS, 0.89 for the second quartile, 0.79 for the third quartile, and 0.56 for the fourth quartile. The addition of behavioral factors in our model improved prediction of 10 -year event rates compared to a model restricted to the traditional variables. Conclusion A global vascular risk score that combines both traditional, behavioral, and anthropometric risk factors, uses continuous variables for physiological parameters, and is applicable to non-white subjects could improve primary prevention strategies. PMID:19958966

Effects of Family History and APOE ε4 Status on Cognitive Decline in the Absence of AD: The Cache County Study

PubMed Central

Hayden, Kathleen M.; Zandi, Peter P.; West, Nancy A.; Tschanz, JoAnn T.; Norton, Maria C.; Corcoran, Chris; Breitner, John C. S.; Welsh-Bohmer, Kathleen A.

2010-01-01

Context Studies have shown that the APOE ε4 genotype is associated with cognitive decline and increased risk of Alzheimer’s dementia (AD). Other genes are probably associated with both outcomes. Family history of AD (FhxAD) may represent genetic factors or shared environmental factors that increase the risk of cognitive decline. Objective To evaluate the influences of FhxAD and APOE ε4 on cognitive decline. Design, Setting, and Participants Residents of Cache County, Utah, aged 65+ were invited to participate. At baseline 2,957 participants provided DNA for genotyping at APOE and a detailed family history of AD. They also completed the Modified Mini-Mental State Examination (3MS). Cognitive status was re-examined after three and seven years. We used mixed models to examine the association between FhxAD, APOE ε4, and cognitive trajectories. Main Outcome Measure 3MS score trajectories over time. Results Compared with participants who had neither APOE ε4 nor FhxAD, those with APOE ε4 scored lower at baseline (−0.70 points on 3MS, 95% confidence interval (CI) −1.15 to −0.24). Participants with both FhxAD and APOE ε4 differed less, if at all, in baseline score (−0.46, 95% CI −1.09 to 0.16) but declined faster over 7 years (− 9.75, CI −10.82 -- 8.67) vs.(−2.91, CI −3.37 to −2.44). After exclusion of participants who developed prodromal AD or incident dementia, the group with FhxAD and APOE ε4 declined much less over 7 years (−1.54, CI −2.59 to −0.50). Conclusions These results suggest that much of the association between FhxAD, APOE ε4, and cognitive decline is attributed to undetected incipient (latent) disease. Absent this association, the two factors do not appear individually to be associated with cognitive decline although they may be additive. PMID:19901170

Predictors of Cognitive and Functional Decline in Patients With Alzheimer Disease Dementia From Brazil.

PubMed

Oliveira, Fabricio F; Chen, Elizabeth S; Smith, Marilia C; Bertolucci, Paulo H F

2016-01-01

Little is known on how risk factors for Alzheimer disease (AD) dementia affect disease progression, much less for populations with low mean schooling, whereas the transcription of APOE may be regulated by nongenetic factors. In this 44-month cohort study, 214 consecutive outpatients with late-onset AD were assessed for rates of cognitive and functional decline by way of Clinical Dementia Rating and Mini-Mental State Examination (MMSE) scores, keeping blinded assessment of APOE haplotypes. Subjects were evaluated for sex, schooling, age of dementia onset, and cerebrovascular risk factors (including Framingham risk scores). Of the 214 patients, there were 146 (68.2%) women and 113 (52.8%) APOE4+ carriers. The mean age of AD onset was 73.4±6.5 years-old, negatively correlated with time to Clinical Dementia Rating >1.0 (β=-0.132; ρ<0.001), MMSE=20 (β=-0.105; ρ<0.001), and MMSE=15 (β=-0.124; ρ=0.003), more significantly for women and APOE4+ carriers. Mean schooling was 4.18±3.7 years, correlated with time to MMSE=20 and MMSE=15 for women and APOE4+ carriers. Body mass index was correlated with time to MMSE=20 only for men (ρ=0.006). The 10-year coronary heart disease risk was correlated with time to MMSE=20 only for APOE4+ carriers (ρ=0.015). These outcomes suggest interactions among genomic effects of cognitive reserve, cerebral perfusion, and hormonal changes over mechanisms of neurodegeneration.

Interaction between Cytomegalovirus and Herpes Simplex Virus Type 1 Associated with the Risk of Alzheimer's Disease Development.

PubMed

Lövheim, Hugo; Olsson, Jan; Weidung, Bodil; Johansson, Anders; Eriksson, Sture; Hallmans, Göran; Elgh, Fredrik

2018-01-01

Several environmental factors, including infectious agents, have been suggested to cause Alzheimer's disease (AD). Cytomegalovirus (CMV) has been associated with AD in several recent studies. To investigate whether carriage of CMV, alone or in combination with Herpes simplex virus (HSV), increased the risk of developing AD. Plasma samples from 360 AD cases (75.3% women, mean age 61.2 years), taken an average of 9.6 years before AD diagnosis, and 360 age-, sex-, cohort-, and sampling date matched dementia-free controls were analyzed to detect anti-CMV (immunoglobulin [Ig] G and IgM), group-specific anti-HSV (IgG and IgM), and specific anti-HSV1 and HSV2 IgG antibodies by enzyme-linked immunosorbent assays. AD cases and dementia-free controls were compared using conditional logistic regression analyses. The presence of anti-CMV IgG antibodies did not increase the risk of AD (odds ratio [OR], 0.857; p = 0.497). Among AD cases, an association between CMV and HSV1 carriage was detected (OR 7.145, p < 0.001); in a conditional logistic regression model, the interaction between CMV and HSV1 was associated with AD development (OR 5.662; p = 0.007). The present findings do not support a direct relationship between CMV infection and the development of AD; however, an interaction between CMV and HSV1 was found to be associated significantly with AD development. These findings suggest that CMV infection facilitates the development of HSV1-associated AD, possibly via its effects on the immune system.

Chronic obstructive pulmonary disease is associated with altered neuropsychological performance in young adults.

PubMed

De Carolis, Antonella; Giubilei, Franco; Caselli, Giulio; Casolla, Barbara; Cavallari, Michele; Vanacore, Nicola; Leonori, Rita; Scrocchia, Ilaria; Fersini, Anna; Quercia, Augusto; Orzi, Francesco

2011-01-01

Subjects with ischemic lesions have an increased risk of dementia. In addition, Alzheimer's disease (AD) and vascular cognitive impairment share many risk factors. These observations suggest that different diseases that cause altered blood perfusion of the brain or hypoxia promote AD neurodegeneration. In this case-control, cross-sectional study, we sought to test the hypothesis that hypoxia facilitates cognitive decline. We looked for altered neuropsychological performance in subjects with chronic obstructive pulmonary disease (COPD) without apparent cardio- or cerebrovascular diseases or risk factors for atherosclerosis. A selected, homogeneous group of workers from two ceramic factories in a small town of central Italy was enrolled in this study. The COPD patients had a slightly, but significantly worse performance than controls in a number of neuropsychological tests. The findings are consistent with the working hypothesis that chronic hypoxia facilitates cognitive decline.

Short-term modern life-like stress exacerbates Aβ-pathology and synapse loss in 3xTg-AD mice

PubMed Central

Baglietto-Vargas, David; Chen, Yuncai; Suh, Dongjin; Ager, Rahasson R.; Rodriguez-Ortiz, Carlos J.; Mederios, Rodrigo; Myczek, Kristoffer; Green, Kim N.; Baram, Tallie Z.; LaFerla, Frank M.

2016-01-01

Alzheimer’s disease (AD) is a progressive neurological disorder that impairs memory and other cognitive functions in the elderly. The social and financial impacts of AD are overwhelming and are escalating exponentially as a result of population aging. Therefore, identifying AD-related risk factors and the development of more efficacious therapeutic approaches are critical to cure this neurological disorder. Current epidemiological evidence indicates that life experiences, including chronic stress, are a risk for AD. However, it is unknown if short-term stress, lasting for hours, influences the onset or progression of AD. Here, we determined the effect of short-term, multi-modal ‘modern life-like’ stress on AD pathogenesis and synaptic plasticity in mice bearing three AD mutations (the 3xTg-AD mouse model). We found that combined emotional and physical stress lasting 5 h severely impaired memory in wild-type mice and tended to impact it in already low-performing 3xTg-AD mice. This stress reduced the number of synapse-bearing dendritic spines in 3xTg-AD mice and increased Aβ levels by augmenting AβPP processing. Thus, short-term stress simulating modern-life conditions may exacerbate cognitive deficits in preclinical AD by accelerating amyloid pathology and reducing synapse numbers. PMID:26077803

Epidemiologic studies of modifiable factors associated with cognition and dementia: systematic review and meta-analysis

PubMed Central

2014-01-01

Background Cognitive impairment, including dementia, is a major health concern with the increasing aging population. Preventive measures to delay cognitive decline are of utmost importance. Alzheimer’s disease (AD) is the most frequent cause of dementia, increasing in prevalence from <1% below the age of 60 years to >40% above 85 years of age. Methods We systematically reviewed selected modifiable factors such as education, smoking, alcohol, physical activity, caffeine, antioxidants, homocysteine (Hcy), n-3 fatty acids that were studied in relation to various cognitive health outcomes, including incident AD. We searched MEDLINE for published literature (January 1990 through October 2012), including cross-sectional and cohort studies (sample sizes > 300). Analyses compared study finding consistency across factors, study designs and study-level characteristics. Selecting studies of incident AD, our meta-analysis estimated pooled risk ratios (RR), population attributable risk percent (PAR%) and assessed publication bias. Results In total, 247 studies were retrieved for systematic review. Consistency analysis for each risk factor suggested positive findings ranging from ~38.9% for caffeine to ~89% for physical activity. Education also had a significantly higher propensity for “a positive finding” compared to caffeine, smoking and antioxidant-related studies. Meta-analysis of 31 studies with incident AD yielded pooled RR for low education (RR = 1.99; 95% CI: 1.30-3.04), high Hcy (RR = 1.93; 95% CI: 1.50-2.49), and current/ever smoking status (RR = 1.37; 95% CI: 1.23-1.52) while indicating protective effects of higher physical activity and n-3 fatty acids. Estimated PAR% were particularly high for physical activity (PAR% = 31.9; 95% CI: 22.7-41.2) and smoking (PAR%=31.09%; 95% CI: 17.9-44.3). Overall, no significant publication bias was found. Conclusions Higher Hcy levels, lower educational attainment, and decreased physical activity were particularly strong predictors of incident AD. Further studies are needed to support other potential modifiable protective factors, such as caffeine. PMID:24962204

Pathology supported genetic testing and treatment of cardiovascular disease in middle age for prevention of Alzheimer's disease.

PubMed

Kotze, Maritha J; van Rensburg, Susan J

2012-09-01

Chronic, multi-factorial conditions caused by a complex interaction between genetic and environmental risk factors frequently share common disease mechanisms, as evidenced by an overlap between genetic risk factors for cardiovascular disease (CVD) and Alzheimer's disease (AD). Single nucleotide polymorphisms (SNPs) in several genes including ApoE, MTHFR, HFE and FTO are known to increase the risk of both conditions. The E4 allele of the ApoE polymorphism is the most extensively studied risk factor for AD and increases the risk of coronary heart disease by approximately 40%. It furthermore displays differential therapeutic responses with use of cholesterol-lowering statins and acetylcholinesterase inhibitors, which may also be due to variation in the CYP2D6 gene in some patients. Disease expression may be triggered by gene-environment interaction causing conversion of minor metabolic abnormalities into major brain disease due to cumulative risk. A growing body of evidence supports the assessment and treatment of CVD risk factors in midlife as a preventable cause of cognitive decline, morbidity and mortality in old age. In this review, the concept of pathology supported genetic testing (PSGT) for CVD is described in this context. PSGT combines DNA testing with biochemical measurements to determine gene expression and to monitor response to treatment. The aim is to diagnose treatable disease subtypes of complex disorders, facilitate prevention of cumulative risk and formulate intervention strategies guided from the genetic background. CVD provides a model to address the lifestyle link in most chronic diseases with a genetic component. Similar preventative measures would apply for optimisation of heart and brain health.

17 CFR 240.17i-2 - Notice of intention to be supervised by the Commission as a supervised investment bank holding...

Code of Federal Regulations, 2011 CFR

2011-04-01

... correlations across risk factors, a description of the process used to measure those correlations; (D) A... risk, credit risk, and operational risk made in accordance with § 240.17i-7(a)-(d); (vi) A list of the... and credit risk on those categories of positions pursuant to § 240.17i-7(b) and (c); (vii) A...

Endometrial cancer risk prediction including serum-based biomarkers: results from the EPIC cohort.

PubMed

Fortner, Renée T; Hüsing, Anika; Kühn, Tilman; Konar, Meric; Overvad, Kim; Tjønneland, Anne; Hansen, Louise; Boutron-Ruault, Marie-Christine; Severi, Gianluca; Fournier, Agnès; Boeing, Heiner; Trichopoulou, Antonia; Benetou, Vasiliki; Orfanos, Philippos; Masala, Giovanna; Agnoli, Claudia; Mattiello, Amalia; Tumino, Rosario; Sacerdote, Carlotta; Bueno-de-Mesquita, H B As; Peeters, Petra H M; Weiderpass, Elisabete; Gram, Inger T; Gavrilyuk, Oxana; Quirós, J Ramón; Maria Huerta, José; Ardanaz, Eva; Larrañaga, Nerea; Lujan-Barroso, Leila; Sánchez-Cantalejo, Emilio; Butt, Salma Tunå; Borgquist, Signe; Idahl, Annika; Lundin, Eva; Khaw, Kay-Tee; Allen, Naomi E; Rinaldi, Sabina; Dossus, Laure; Gunter, Marc; Merritt, Melissa A; Tzoulaki, Ioanna; Riboli, Elio; Kaaks, Rudolf

2017-03-15

Endometrial cancer risk prediction models including lifestyle, anthropometric and reproductive factors have limited discrimination. Adding biomarker data to these models may improve predictive capacity; to our knowledge, this has not been investigated for endometrial cancer. Using a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, we investigated the improvement in discrimination gained by adding serum biomarker concentrations to risk estimates derived from an existing risk prediction model based on epidemiologic factors. Serum concentrations of sex steroid hormones, metabolic markers, growth factors, adipokines and cytokines were evaluated in a step-wise backward selection process; biomarkers were retained at p < 0.157 indicating improvement in the Akaike information criterion (AIC). Improvement in discrimination was assessed using the C-statistic for all biomarkers alone, and change in C-statistic from addition of biomarkers to preexisting absolute risk estimates. We used internal validation with bootstrapping (1000-fold) to adjust for over-fitting. Adiponectin, estrone, interleukin-1 receptor antagonist, tumor necrosis factor-alpha and triglycerides were selected into the model. After accounting for over-fitting, discrimination was improved by 2.0 percentage points when all evaluated biomarkers were included and 1.7 percentage points in the model including the selected biomarkers. Models including etiologic markers on independent pathways and genetic markers may further improve discrimination. © 2016 UICC.

Risk of falls in Alzheimer's disease: a prospective study.

PubMed

Horikawa, Etsuo; Matsui, Toshifumi; Arai, Hiroyuki; Seki, Takashi; Iwasaki, Koh; Sasaki, Hidetada

2005-07-01

Falls are common in patients with Alzheimer's disease (AD). Identification of the potential risk factors and developing preventive strategies for falls will have a significant impact in maintaining the quality of life in AD. Clinical follow-up of 124 (74.1+/-6.1 years, range 62-88) mild to moderate AD patients in an outpatient memory clinic. Postural sway, cognitive function, use of neuroleptics, severity of periventricular and deep white matter lesions, and the presence or absence of silent brain infarctions on magnetic resonance imaging were assessed at baseline. A total of 104 patients (84%) completed the study. Fall events were confirmed in 42.3% (44/104). After adjustment for age, gender, and cognitive status, a high grade of periventricular white matter lesions (odds ratio 8.7 [95%CI 1.5 to 51.8], p = 0.017) and neuroleptic drug use (odds ratio 3.5 [95%CI 1.2 to 10.5], p = 0.027) were significantly associated with an increased risk of falls. Our results suggest that periventricular white matter lesions and the use of neuroleptics may be related to falls in mild to moderate AD. A comprehensive risk management of brain ischemia as well as the use of the smallest efficacious dose of neuroleptics in the treatment of behavioral and psychiatric symptoms of AD should be recommended to help reduce the risk of unexpected falls.

Association of candy consumption with body weight measures, other health risk factors for cardiovascular disease, and diet quality in US children and adolescents: NHANES 1999-2004

USDA-ARS?s Scientific Manuscript database

The purpose of this study was to determine the effects of total, chocolate, or sugar candy consumption on intakes of total energy, fat, and added sugars; diet quality; weight/adiposity parameters; and risk factors for cardiovascular disease in children 2–13 years of age (n=7,049) and adolescents 14–...

Neuroimaging Characteristics of Small-Vessel Disease in Older Adults with Normal Cognition, Mild Cognitive Impairment, and Alzheimer Disease.

PubMed

Mimenza-Alvarado, Alberto; Aguilar-Navarro, Sara G; Yeverino-Castro, Sara; Mendoza-Franco, César; Ávila-Funes, José Alberto; Román, Gustavo C

2018-01-01

Cerebral small-vessel disease (SVD) represents the most frequent type of vascular brain lesions, often coexisting with Alzheimer disease (AD). By quantifying white matter hyperintensities (WMH) and hippocampal and parietal atrophy, we aimed to describe the prevalence and severity of SVD among older adults with normal cognition (NC), mild cognitive impairment (MCI), and probable AD and to describe associated risk factors. This study included 105 older adults evaluated with magnetic resonance imaging and clinical and neuropsychological tests. We used the Fazekas scale (FS) for quantification of WMH, the Scheltens scale (SS) for hippocampal atrophy, and the Koedam scale (KS) for parietal atrophy. Logistic regression models were performed to determine the association between FS, SS, and KS scores and the presence of NC, MCI, or probable AD. Compared to NC subjects, SVD was more prevalent in MCI and probable AD subjects. After adjusting for confounding factors, logistic regression showed a positive association between higher scores on the FS and probable AD (OR = 7.6, 95% CI 2.7-20, p < 0.001). With the use of the SS and KS (OR = 4.5, 95% CI 3.5-58, p = 0.003 and OR = 8.9, 95% CI 1-72, p = 0.04, respectively), the risk also remained significant for probable AD. These results suggest an association between severity of vascular brain lesions and neurodegeneration.

Effect of Alzheimer disease risk on brain function during self-appraisal in healthy middle-aged adults.

PubMed

Johnson, Sterling C; Ries, Michele L; Hess, Timothy M; Carlsson, Cynthia M; Gleason, Carey E; Alexander, Andrew L; Rowley, Howard A; Asthana, Sanjay; Sager, Mark A

2007-10-01

Asymptomatic middle-aged adult children of patients with Alzheimer disease (AD) recently were found to exhibit functional magnetic resonance imaging (fMRI) deficits in the mesial temporal lobe during an encoding task. Whether this effect will be observed on other fMRI tasks is yet unknown. This study examines the neural substrates of self-appraisal (SA) in persons at risk for AD. Accurate appraisal of deficits is a problem for many patients with AD, and prior fMRI studies of healthy young adults indicate that brain areas vulnerable to AD such as the anterior mesial temporal lobe and posterior cingulate are involved during SA tasks. To determine whether parental family history of AD (hereafter referred to as FH) or presence of the epsilon4 allele of the apolipoprotein E gene (APOE4) exerts independent effects on brain function during SA. Cross-sectional factorial design in which APOE4 status (present vs absent) was one factor and FH was the other. All participants received cognitive testing, genotyping, and an fMRI task that required subjective SA decisions regarding trait adjective words in comparison with semantic decisions about the same words. An academic medical center with a research-dedicated 3.0-T MR imaging facility. Cognitively normal middle-aged adults (n = 110), 51 with an FH and 59 without an FH. Blood oxygen-dependent contrast measured using T2*-weighted echo-planar imaging. Parental family history of AD and APOE4 status interacted in the posterior cingulate and left superior and medial frontal regions. There were main effects of FH (FH negative > FH positive) in the left hippocampus and ventral posterior cingulate. There were no main effects of APOE genotype. Our results suggest that FH may affect brain function during subjective SA in regions commonly affected by AD. Although the participants in this study were asymptomatic and middle-aged, the findings suggest that there may be subtle alterations in brain function attributable to AD risk factors.

Association of Severe Atopic Dermatitis with month of birth in Armenian pediatric patients.

PubMed

Sargsyan, Anna; Gupta, Jayanta; Ghosh, Debajyoti

2018-04-26

Atopic dermatitis (AD) is a chronic relapsing skin disease which affects 15-20% of children worldwide.(1) It is also considered as a major risk factor for developing other atopic diseases including food allergy, asthma and allergic rhinitis later in life - a phenomenon known as the "atopic march". Multiple factors, including season of birth and associated perinatal environmental conditions, have been known to play important roles in the manifestation of AD.(2) Moreover, about 20% of patients with AD have moderate-to-severe disease, which is associated with significantly lower quality of life, imposing considerable burden on the nation's health-care resources.(3) Therefore, studying severe AD patients might be very important in managing overall AD-related disease burden. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Inverse occurrence of cancer and Alzheimer disease: a population-based incidence study.

PubMed

Musicco, Massimo; Adorni, Fulvio; Di Santo, Simona; Prinelli, Federica; Pettenati, Carla; Caltagirone, Carlo; Palmer, Katie; Russo, Antonio

2013-07-23

To evaluate the incidence of cancer in persons with Alzheimer disease (AD) and the incidence of AD dementia in persons with cancer. This was a cohort study in Northern Italy on more than 1 million residents. Cancer incidence was derived from the local health authority (ASL-Mi1) tumor registry and AD dementia incidence from registries of drug prescriptions, hospitalizations, and payment exemptions. Expected cases of AD dementia were calculated by applying the age-, sex-, and calendar year-specific incidence rates observed in the whole population to the subgroup constituted of persons with newly diagnosed cancers during the observation period (2004-2009). The same calculations were carried out for cancers in patients with AD dementia. Separate analyses were carried out for the time period preceding or following the index diagnosis for survivors and nonsurvivors until the end of 2009 and for different types and sites of cancer. The risk of cancer in patients with AD dementia was halved, and the risk of AD dementia in patients with cancer was 35% reduced. This relationship was observed in almost all subgroup analyses, suggesting that some anticipated potential confounding factors did not significantly influence the results. The occurrence of both cancer and AD dementia increases exponentially with age, but with an inverse relationship; older persons with cancer have a reduced risk of AD dementia and vice versa. As AD dementia and cancer are negative hallmarks of aging and senescence, we suggest that AD dementia, cancer, and senescence could be manifestations of a unique phenomenon related to human aging.

The Role of Genetics in Advancing Precision Medicine for Alzheimer's Disease-A Narrative Review.

PubMed

Freudenberg-Hua, Yun; Li, Wentian; Davies, Peter

2018-01-01

Alzheimer's disease (AD) is the most common type of dementia, which has a substantial genetic component. AD affects predominantly older people. Accordingly, the prevalence of dementia has been rising as the population ages. To date, there are no effective interventions that can cure or halt the progression of AD. The only available treatments are the management of certain symptoms and consequences of dementia. The current state-of-the-art medical care for AD comprises three simple principles: prevent the preventable, achieve early diagnosis, and manage the manageable symptoms. This review provides a summary of the current state of knowledge of risk factors for AD, biological diagnostic testing, and prospects for treatment. Special emphasis is given to recent advances in genetics of AD and the way genomic data may support prevention, early intervention, and development of effective pharmacological treatments. Mutations in the APP, PSEN1 , and PSEN2 genes cause early onset Alzheimer's disease (EOAD) that follows a Mendelian inheritance pattern. For late onset Alzheimer's disease (LOAD), APOE4 was identified as a major risk allele more than two decades ago. Population-based genome-wide association studies of late onset AD have now additionally identified common variants at roughly 30 genetic loci. Furthermore, rare variants (allele frequency <1%) that influence the risk for LOAD have been identified in several genes. These genetic advances have broadened our insights into the biological underpinnings of AD. Moreover, the known genetic risk variants could be used to identify presymptomatic individuals at risk for AD and support diagnostic assessment of symptomatic subjects. Genetic knowledge may also facilitate precision medicine. The goal of precision medicine is to use biological knowledge and other health information to predict individual disease risk, understand disease etiology, identify disease subcategories, improve diagnosis, and provide personalized treatment strategies. We discuss the potential role of genetics in advancing precision medicine for AD along with its ethical challenges. We outline strategies to implement genomics into translational clinical research that will not only improve accuracy of dementia diagnosis, thus enabling more personalized treatment strategies, but may also speed up the discovery of novel drugs and interventions.

The Role of Genetics in Advancing Precision Medicine for Alzheimer’s Disease—A Narrative Review

PubMed Central

Freudenberg-Hua, Yun; Li, Wentian; Davies, Peter

2018-01-01

Alzheimer’s disease (AD) is the most common type of dementia, which has a substantial genetic component. AD affects predominantly older people. Accordingly, the prevalence of dementia has been rising as the population ages. To date, there are no effective interventions that can cure or halt the progression of AD. The only available treatments are the management of certain symptoms and consequences of dementia. The current state-of-the-art medical care for AD comprises three simple principles: prevent the preventable, achieve early diagnosis, and manage the manageable symptoms. This review provides a summary of the current state of knowledge of risk factors for AD, biological diagnostic testing, and prospects for treatment. Special emphasis is given to recent advances in genetics of AD and the way genomic data may support prevention, early intervention, and development of effective pharmacological treatments. Mutations in the APP, PSEN1, and PSEN2 genes cause early onset Alzheimer’s disease (EOAD) that follows a Mendelian inheritance pattern. For late onset Alzheimer’s disease (LOAD), APOE4 was identified as a major risk allele more than two decades ago. Population-based genome-wide association studies of late onset AD have now additionally identified common variants at roughly 30 genetic loci. Furthermore, rare variants (allele frequency <1%) that influence the risk for LOAD have been identified in several genes. These genetic advances have broadened our insights into the biological underpinnings of AD. Moreover, the known genetic risk variants could be used to identify presymptomatic individuals at risk for AD and support diagnostic assessment of symptomatic subjects. Genetic knowledge may also facilitate precision medicine. The goal of precision medicine is to use biological knowledge and other health information to predict individual disease risk, understand disease etiology, identify disease subcategories, improve diagnosis, and provide personalized treatment strategies. We discuss the potential role of genetics in advancing precision medicine for AD along with its ethical challenges. We outline strategies to implement genomics into translational clinical research that will not only improve accuracy of dementia diagnosis, thus enabling more personalized treatment strategies, but may also speed up the discovery of novel drugs and interventions. PMID:29740579

Cancer linked to Alzheimer disease but not vascular dementia

PubMed Central

Roe, C M.; Fitzpatrick, A L.; Xiong, C; Sieh, W; Kuller, L; Miller, J P.; Williams, M M.; Kopan, R; Behrens, M I.; Morris, J C.

2010-01-01

Objective: To investigate whether cancer is associated with Alzheimer disease (AD) and vascular dementia (VaD). Methods: Cox proportional hazards models were used to test associations between prevalent dementia and risk of future cancer hospitalization, and associations between prevalent cancer and risk of subsequent dementia. Participants in the Cardiovascular Health Study–Cognition Substudy, a prospective cohort study, aged 65 years or older (n = 3,020) were followed a mean of 5.4 years for dementia and 8.3 years for cancer. Results: The presence of any AD (pure AD + mixed AD/VaD; hazard ratio [HR] = 0.41, 95% confidence interval [CI] = 0.20–0.84) and pure AD (HR = 0.31, 95% CI = 0.12–0.86) was associated with a reduced risk of future cancer hospitalization, adjusted for demographic factors, smoking, obesity, and physical activity. No significant associations were found between dementia at baseline and rate of cancer hospitalizations for participants with diagnoses of VaD. Prevalent cancer was associated with reduced risk of any AD (HR = 0.72; 95% CI = 0.52–0.997) and pure AD (HR = 0.57; 95% CI = 0.36–0.90) among white subjects after adjustment for demographics, number of APOE ε4 alleles, hypertension, diabetes, and coronary heart disease; the opposite association was found among minorities, but the sample size was too small to provide stable estimates. No significant association was found between cancer and subsequent development of VaD. Conclusions: In white older adults, prevalent Alzheimer disease (AD) was longitudinally associated with a reduced risk of cancer, and a history of cancer was associated with a reduced risk of AD. Together with other work showing associations between cancer and Parkinson disease, these findings suggest the possibility that cancer is linked to neurodegeneration. GLOSSARY 3MSE = modified Mini-Mental State Examination; AD = Alzheimer disease; ADDTC = Alzheimer Disease Diagnostic and Treatment Centers; CHD = coronary heart disease; CHS = Cardiovascular Health Study; CI = confidence interval; HR = hazard ratio; ICD-9 = International Classification of Diseases–Ninth Revision; MCI = mild cognitive impairment; NINCDS-ADRDA = National Institute of Neurological and Communicative Diseases and Stroke–Alzheimer's Disease and Related Disorders Association; PD = Parkinson disease; VaD = vascular dementia. PMID:20032288

Down-Regulation of Olfactory Receptors in Response to Traumatic Brain Injury Promotes Risk for Alzheimer’s Disease

DTIC Science & Technology

2014-10-01

SUPPLEMENTARY NOTES 14. ABSTRACT Traumatic Brain Injury (TBI) is a risk factor for subsequent development of Alzheimer’s disease (AD). Abnormal tau...Special Reporting Requirements……………………………………10 9. Appendices……………………………………………………………10 1. INTRODUCTION Traumatic Brain Injury (TBI) is a risk factor for... risk factor for Alzheimer’s disease, Neurosci. Biobehav. Rev. 36(5), 1376-81. Teague SJ, Davis AM, Leeson PD, Oprea T (1999) The Design of Leadlike

Differences in ABCA1 R219K Polymorphisms and Serum Indexes in Alzheimer and Parkinson Diseases in Northern China

PubMed Central

Ya, Lagai; Lu, Zuneng

2017-01-01

Background ABCA1 R219K single-nucleotide polymorphisms (SNPs) was related to Alzheimer disease (AD) but not Parkinson disease (PD). Here, we analyzed the associations among ABCA1 R219K distribution, serum biomarkers, AD, and PD in a population in northern China. Material/Methods We used the Mini-Mental State Examination (MMSE) and the Hoehn and Yahr scale (H-Y) to evaluate AD and PD progression, separately. ABCA1 R219K was analyzed by matrix-assisted laser desorption ionization time of flight time mass spectrometry (MALDI-TOF-MS). Serum indexes were determined by enzyme-linked immunosorbent assay (ELISA). Results ABCA1 R219K RR+RK genotype frequency in AD and PD patients was lower than that in normal controls (NC), while ABCA1 R219K KK genotype frequency was significantly higher. ABCA1 R219K RR genotype frequency in AD patients and NC was lower than that in PD patients, while ABCA1 R219K RK+KK genotype frequency was significantly higher. ABCA1 R219K RR genotype was positively correlated to MMSE value in AD patients, while ABCA1 R219K KK genotype was negatively correlated to H-Y value in PD patients. Serum factors were significantly different among AD and PD patients and NC. Serum ABCA1, ApoA1, ApoA2, ApoB, HDL, TC, IL-1β, IL-6, and TNF-α were significantly different between AD and PD patients. Conclusions ABCA1 R219K R allele was the risk factor inducing abnormal serum levels of ApoA2, LDL, and TG in AD patients, and abnormal levels of serum ABCA1, HDL, IL-1β, IL-6, and TNF-α in PD patients, while ABCA1 R219K K allele was the risk factor inducing lower ABCA1 in AD patients. IL-1β, IL-6, and TNF-α were negatively correlated to MMSE in AD patients but positively correlated to H-Y in PD patients, while HDL was positively related to H-Y in PD patients. PMID:28943632

Differences in ABCA1 R219K Polymorphisms and Serum Indexes in Alzheimer and Parkinson Diseases in Northern China.

PubMed

Ya, Lagai; Lu, Zuneng

2017-09-25

BACKGROUND ABCA1 R219K single-nucleotide polymorphisms (SNPs) was related to Alzheimer disease (AD) but not Parkinson disease (PD). Here, we analyzed the associations among ABCA1 R219K distribution, serum biomarkers, AD, and PD in a population in northern China. MATERIAL AND METHODS We used the Mini-Mental State Examination (MMSE) and the Hoehn and Yahr scale (H-Y) to evaluate AD and PD progression, separately. ABCA1 R219K was analyzed by matrix-assisted laser desorption ionization time of flight time mass spectrometry (MALDI-TOF-MS). Serum indexes were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS ABCA1 R219K RR+RK genotype frequency in AD and PD patients was lower than that in normal controls (NC), while ABCA1 R219K KK genotype frequency was significantly higher. ABCA1 R219K RR genotype frequency in AD patients and NC was lower than that in PD patients, while ABCA1 R219K RK+KK genotype frequency was significantly higher. ABCA1 R219K RR genotype was positively correlated to MMSE value in AD patients, while ABCA1 R219K KK genotype was negatively correlated to H-Y value in PD patients. Serum factors were significantly different among AD and PD patients and NC. Serum ABCA1, ApoA1, ApoA2, ApoB, HDL, TC, IL-1β, IL-6, and TNF-α were significantly different between AD and PD patients. CONCLUSIONS ABCA1 R219K R allele was the risk factor inducing abnormal serum levels of ApoA2, LDL, and TG in AD patients, and abnormal levels of serum ABCA1, HDL, IL-1b, IL-6, and TNF-α in PD patients, while ABCA1 R219K K allele was the risk factor inducing lower ABCA1 in AD patients. IL-1β, IL-6, and TNF-α were negatively correlated to MMSE in AD patients but positively correlated to H-Y in PD patients, while HDL was positively related to H-Y in PD patients.

Associations Between Genetic Variants in 19p13 and 19q13 Regions and Susceptibility to Alzheimer Disease: A Meta-Analysis.

PubMed

Bao, Jie; Wang, Xiao-jie; Mao, Zong-fu

2016-01-22

Alzheimer disease (AD) has become an epidemic within the growing elderly population and effective therapies of AD have not been discovered. Genetic factors accounted for over 70% of the incidence of AD and the disease-related polymorphisms are located on chromosome 19, which is one of several prominent chromosomes related to the development of AD. Many inconsistent associations between polymorphisms in ABCA7, CD33, and TOMM40 genes and the susceptibility to AD have been suggested by several independent studies. A comprehensive literature search for studies involving the association between gene polymorphisms and AD was performed, and we finally selected 3 genes (4 polymorphisms) for the meta-analysis: ABCA7 (rs3764650), CD33 (rs3865444), and TOMM40 (rs157580, rs2075650). A total of 25 articles investigating 3 genes (4 polymorphisms) were included in the meta-analysis. The pooled results of 4 polymorphisms were all significantly associated with the susceptibility to AD. The pooled effect of ABCA7 rs3764605 allele G was significantly associated with an increased the risk of AD (OR=1.20, 95% CI: 1.14-1.26, P value <0.001). Similarly, our evidence suggested that allele A of TOMM40 rs2075650 polymorphism was a risk factor for AD (OR=2.87, 95% CI: 2.46-3.34, P value <0.001). Alleles A of CD33 rs3865444 and A of TOMM40 rs157580 were both protective factors for AD onset (OR=0.94, 95% CI: 0.90-0.98, P value=0.003; OR=0.62, 95% CI: 0.57-0.66, P value <0.001). CONCLUSIONS" Results from the meta-analysis revealed that the pooled ABCA7 rs376465, CD33 rs3865444, TOMM40 rs157580, and rs2075650 variants were significantly associated with the susceptibility to AD. However, the association differed significantly between Asian and Caucasian groups for SNPs of CD33 rs3865444, TOMM40 rs157580, and rs2075650.

Adipocyte-derived factors in age-related dementia and their contribution to vascular and Alzheimer pathology.

PubMed

Ishii, Makoto; Iadecola, Costantino

2016-05-01

Age-related dementia is increasingly recognized as having a mixed pathology, with contributions from both cerebrovascular factors and pathogenic factors associated with Alzheimer's disease (AD). Furthermore, there is accumulating evidence that vascular risk factors in midlife, e.g., obesity, diabetes, and hypertension, increase the risk of developing late-life dementia. Since obesity and changes in body weight/adiposity often drive diabetes and hypertension, understanding the relationship between adiposity and age-related dementia may reveal common underlying mechanisms. Here we offer a brief appraisal of how changes in body weight and adiposity are related to both AD and dementia on vascular basis, and examine the involvement of two key adipocyte-derived hormones: leptin and adiponectin. The evidence suggests that in midlife increased body weight/adiposity and subsequent changes in adipocyte-derived hormones may increase the long-term susceptibility to dementia. On the other hand, later in life, decreases in body weight/adiposity and related hormonal changes are early manifestations of disease that precede the onset of dementia and may promote AD and vascular pathology. Understanding the contribution of adiposity to age-related dementia may help identify the underlying pathological mechanisms common to both vascular dementia and AD, and provide new putative targets for early diagnosis and therapy. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia, edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock. Copyright © 2015 Elsevier B.V. All rights reserved.

Treatment for Rheumatoid Arthritis and Risk of Alzheimer's Disease: A Nested Case-Control Analysis.

PubMed

Chou, Richard C; Kane, Michael; Ghimire, Sanjay; Gautam, Shiva; Gui, Jiang

2016-11-01

It is increasingly becoming accepted that inflammation may play an important role in the pathogenesis of Alzheimer's disease (AD), as several immune-related genes have been associated with AD. Among these is tumor necrosis factor (TNF)-α, a proinflammatory cytokine known to play an important role in autoimmune disorders, including rheumatoid arthritis (RA). Although AD and RA appear to involve similar pathological mechanisms through the production of TNF-α, the relationship between AD and RA remains unknown. To determine the relative risk of AD among RA patients and non-RA patients, and whether anti-TNF therapy for RA was associated with a lower risk of AD in RA patients. We performed a nested case-control study of more than 8.5 million commercially insured adults (aged ≥18 years) in all 50 US states, Puerto Rico, and US Virgin Islands in the Verisk Health claims database. We derived a sub-cohort of subjects with a diagnosis of RA (controls), or RA and AD (cases), matching cases and controls based on age, sex, exposure assessment period, and methotrexate treatment. We also assessed relative risk of AD following exposure to standard RA therapies, including anti-TNF agents (infliximab, adalimumab, etanercept), methotrexate, prednisone, sulfasalazine, and rituximab. Odds ratios were adjusted for comorbidities, including coronary artery disease, diabetes mellitus, and peripheral vascular disease. AD was more prevalent (p < 0.0001) among RA patients (0.79 %) than among those without RA (0.11 %). Chronic conditions such as coronary artery disease (odds ratio [OR] 1.48; 95 % confidence interval [CI] 1.04-2.05; p = 0.03), diabetes (OR 1.86; 95 % CI 1.32-2.62; p = 0.0004), and peripheral vascular disease (OR 1.61; 95 % CI 1.06-2.43; p = 0.02) significantly increased the relative risk of AD among RA patients. Exposure to anti-TNF agents as a class, but not other immunosuppressive drugs studied, was associated with lowered risk of AD among RA patients (unadjusted OR 0.44; 95 % CI 0.22-0.87; p = 0.02; adjusted OR 0.45; 95 % CI 0.23-0.90; p = 0.02). Sub-group analysis demonstrated that of the three anti-TNF agents studied, only etanercept (unadjusted OR, 0.33; 95 % CI 0.08-0.94; p = 0.03; adjusted OR 0.30; 95 % CI 0.08-0.89; p = 0.02) was associated with a decreased risk of AD in RA patients. There is an increased risk of AD in the studied RA population. The relative risk of AD among RA subjects was lowered in those exposed to etanercept. Anti-TNF therapy with etanercept shows promise as a potential treatment for AD.

Family history of autoimmune diseases is associated with an increased risk of autism in children: A systematic review and meta-analysis.

PubMed

Wu, Shunquan; Ding, Yingying; Wu, Fuquan; Li, Ruisheng; Xie, Guoming; Hou, Jun; Mao, Panyong

2015-08-01

We conducted a systematic review and meta-analysis to summarize the current evidence on the relationship between family history of autoimmune diseases (ADs) and risk of autism in children, as current evidence suggests inconsistent results. We identified relevant studies by searching PubMed, EmBase, and Web of Science databases up to Dec 2014. Risk estimates from individual studies were pooled using random-effects models. Sub-groups analyses were conducted by some study-level factors. Publication bias was assessed by funnel plots, Egger's regression test and Begg-Mazumdar test. A total of 11 articles were included in the meta-analysis, including 3 cohort studies, 6 case-control studies, and 2 cross-sectional studies. The meta-analysis showed that family history of all ADs combined was associated with a 28% (95% CI: 12-48%) higher risk of autism in children. For some specific ADs, evidence synthesis for risk of autism in children showed a statistically significant association with family history of hypothyroidism (OR=1.64, 95% CI: 1.07-2.50), type 1 diabetes (OR=1.49, 95% CI: 1.23-1.81), rheumatoid arthritis (OR=1.51, 95% CI: 1.19-1.91), and psoriasis (OR=1.59, 95% CI: 1.28-1.97). The results varied in some subgroups. An overall increased risk of autism in children with family history of ADs was identified. More mechanistic studies are needed to further explain the association between family history of ADs and increased risk of autism in children. Copyright © 2015. Published by Elsevier Ltd.

Effect of breast-feeding on the development of atopic dermatitis during the first 3 years of life--results from the GINI-birth cohort study.

PubMed

Laubereau, Birgit; Brockow, Inken; Zirngibl, Angelika; Koletzko, Sibylle; Gruebl, Armin; von Berg, Andrea; Filipiak-Pittroff, Birgit; Berdel, Dietrich; Bauer, Carl Peter; Reinhardt, Dietrich; Heinrich, Joachim; Wichmann, H-Erich

2004-05-01

To investigate if exclusive breast-feeding for 4 months is associated with atopic dermatitis during the first 3 years of life. Data on 3903 children were taken from yearly parental-administered questionnaires from a birth cohort study in Germany (recruited 1995-1998) comprised of a noninterventional (NI) and an interventional (I) subgroup. Outcomes were physician-diagnosed atopic dermatitis (AD) and itchy rash. Multiple logistic regression was performed for the entire cohort and stratified by family history of allergy and by study group adjusting for a fixed set of risk factors for allergies. Exclusive breast-feeding (52 % of children) was not associated with higher risk for AD either in the entire cohort (OR(adj,) 0.95; 95% CI, 0.79-1.14) or if stratified by family history of AD. In the I subgroup, but not in the NI subgroup, exclusive breast-feeding showed a significant protective effect on AD if compared with conventional cow's milk formula (OR(adj), 0.64; 95% CI, 0.45-0.90). These findings do not support the hypothesis that exclusive breast-feeding is a risk factor for development of atopic dermatitis but is protective if compared with conventional cow's milk. Observational studies might not be able to effectively control for selection bias and reverse causation.

Type 2 diabetes aggravates Alzheimer's disease-associated vascular alterations of the aorta in mice.

PubMed

Sena, Cristina M; Pereira, Ana M; Carvalho, Cristina; Fernandes, Rosa; Seiça, Raquel M; Oliveira, Catarina R; Moreira, Paula I

2015-01-01

Vascular risk factors are associated with a higher incidence of dementia. In fact, diabetes mellitus is considered a main risk factor for Alzheimer's disease (AD) and both diseases are characterized by vascular dysfunction. However, the underlying mechanisms remain largely unknown. Here, the effects of high-sucrose-induced type 2 diabetes (T2D) in the aorta of wild type (WT) and triple-transgenic AD (3xTg-AD) mice were investigated. 3xTg-AD mice showed a significant decrease in body weight and an increase in postprandial glycemia, glycated hemoglobin (HbA1c), and vascular nitrotyrosine, superoxide anion (O2•-), receptor for the advanced glycation end products (RAGE) protein, and monocyte chemoattractant protein-1 (MCP-1) levels when compared to WT mice. High-sucrose intake caused a significant increase in body weight, postprandial glycemia, HbA1c, triglycerides, plasma vascular cell adhesion molecule 1 (VCAM-1), and vascular nitrotyrosine, O2•-, RAGE, and MCP-1 levels in both WT and 3xTg-AD mice when compared to the respective control group. Also, a significant decrease in nitric oxide-dependent vasorelaxation was observed in 3xTg-AD and sucrose-treated WT mice. In conclusion, AD and T2D promote similar vascular dysfunction of the aorta, this effect being associated with elevated oxidative and nitrosative stress and inflammation. Also, AD-associated vascular alterations are potentiated by T2D. These findings support the idea that metabolic alterations predispose to the onset and progression of dementia.

Factors influencing accuracy of cortical thickness in the diagnosis of Alzheimer's disease.

PubMed

Belathur Suresh, Mahanand; Fischl, Bruce; Salat, David H

2018-04-01

There is great value to use of structural neuroimaging in the assessment of Alzheimer's disease (AD). However, to date, predictive value of structural imaging tend to range between 80% and 90% in accuracy and it is unclear why this is the case given that structural imaging should parallel the pathologic processes of AD. There is a possibility that clinical misdiagnosis relative to the gold standard pathologic diagnosis and/or additional brain pathologies are confounding factors contributing to reduced structural imaging classification accuracy. We examined potential factors contributing to misclassification of individuals with clinically diagnosed AD purely from cortical thickness measures. Correctly classified and incorrectly classified groups were compared across a range of demographic, biological, and neuropsychological data including cerebrospinal fluid biomarkers, amyloid imaging, white matter hyperintensity (WMH) volume, cognitive, and genetic factors. Individual subject analyses suggested that at least a portion of the control individuals misclassified as AD from structural imaging additionally harbor substantial AD biomarker pathology and risk, yet are relatively resistant to cognitive symptoms, likely due to "cognitive reserve," and therefore clinically unimpaired. In contrast, certain clinical control individuals misclassified as AD from cortical thickness had increased WMH volume relative to other controls in the sample, suggesting that vascular conditions may contribute to classification accuracy from cortical thickness measures. These results provide examples of factors that contribute to the accuracy of structural imaging in predicting a clinical diagnosis of AD, and provide important information about considerations for future work aimed at optimizing structural based diagnostic classifiers for AD. © 2017 Wiley Periodicals, Inc.

Framingham risk score can predict cognitive decline progression in Alzheimer's disease.

PubMed

Viticchi, Giovanna; Falsetti, Lorenzo; Buratti, Laura; Boria, Cristiano; Luzzi, Simona; Bartolini, Marco; Provinciali, Leandro; Silvestrini, Mauro

2015-11-01

The role of vascular factors in influencing cognitive decline has been extensively investigated, and some difficulties in defining their weight in dementia pathogenesis have emerged. The aim of the study was to investigate the relevance of the Framingham cardiovascular risk profile (FCRP) in influencing cognitive deterioration in a population of Alzheimer's disease (AD) patients. Two hundred eighty-four consecutive AD patients were enrolled. For each patient, FCRP score was calculated. We did a 1-year follow-up to quantify the cognitive decline by recording changes in the Clinical Dementia Rating score. The FCRP score predicted cognitive deterioration with an area under the curve of 0.63 (95% confidence interval: 0.57-0.69; p < 0.0001). In the subpopulation of patients with a genetic increased predisposition to develop cognitive deterioration and with an advanced vascular impairment, the FCRP predictive value significantly increased with an area under the curve of 0.77 (95% confidence interval: 0.52-0.93; p < 0.05). Our findings show that FCRP can predict the progression of deterioration in AD patients. This was particularly evident in patients with major genetic and atherosclerotic risk factors. Copyright © 2015 Elsevier Inc. All rights reserved.

A prospective birth cohort study of different risk factors for development of allergic diseases in offspring of non-atopic parents

PubMed Central

Lee, Ming-Tsung; Wu, Chih-Chiang; Ou, Chia-Yu; Chang, Jen-Chieh; Liu, Chieh-An; Wang, Chih-Lu; Chuang, Hau; Kuo, Ho-Chang; Hsu, Te-Yao; Chen, Chie-Pein; Yang, Kuender D.

2017-01-01

Background: Allergic diseases are thought to be inherited. Prevalence of allergic diseases has, however, increased dramatically in last decades, suggesting environmental causes for the development of allergic diseases. Objective: We studied risk factors associated with the development of atopic dermatitis (AD), allergic rhinitis (AR) and asthma (AS) in children of non-atopic parents in a subtropical country. Methods: In a birth cohort of 1,497 newborns, parents were prenatally enrolled and validated for allergic diseases by questionnaire, physician-verified and total or specific Immunoglobulin E (IgE) levels; 1,236 and 756 children, respectively, completed their 3-year and 6-year follow-up. Clinical examination, questionnaire, and blood samples for total and specific IgE of the children were collected at each follow-up visit. Results: Prevalence of AD, AR and AS was, respectively, 8.2%, 30.8% and 12.4% in children of non-atopic parents. Prevalence of AR (p<.001) and AS (p=.018) was significantly higher in children of parents who were both atopic. A combination of Cesarean section (C/S) and breastfeeding for more than 1 month showed the highest risk for AD (OR=3.111, p=.006). Infants living in homes with curtains and no air filters had the highest risk for AR (OR=2.647, p<.001), and male infants of non-atopic parents living in homes without air filters had the highest risk for AS (OR=1.930, p=.039). Conclusions: Breastfeeding and C/S affect development of AD. Gender, use of curtains and/or air filters affect AR and AS, suggesting that control of the perinatal environment is necessary for the prevention of atopic diseases in children of non-atopic parents. PMID:28086237

A prospective birth cohort study of different risk factors for development of allergic diseases in offspring of non-atopic parents.

PubMed

Lee, Ming-Tsung; Wu, Chih-Chiang; Ou, Chia-Yu; Chang, Jen-Chieh; Liu, Chieh-An; Wang, Chih-Lu; Chuang, Hau; Kuo, Ho-Chang; Hsu, Te-Yao; Chen, Chie-Pein; Yang, Kuender D

2017-02-14

Allergic diseases are thought to be inherited. Prevalence of allergic diseases has, however, increased dramatically in last decades, suggesting environmental causes for the development of allergic diseases. We studied risk factors associated with the development of atopic dermatitis (AD), allergic rhinitis (AR) and asthma (AS) in children of non-atopic parents in a subtropical country. In a birth cohort of 1,497 newborns, parents were prenatally enrolled and validated for allergic diseases by questionnaire, physician-verified and total or specific Immunoglobulin E (IgE) levels; 1,236 and 756 children, respectively, completed their 3-year and 6-year follow-up. Clinical examination, questionnaire, and blood samples for total and specific IgE of the children were collected at each follow-up visit. Prevalence of AD, AR and AS was, respectively, 8.2%, 30.8% and 12.4% in children of non-atopic parents. Prevalence of AR (p<.001) and AS (p=.018) was significantly higher in children of parents who were both atopic. A combination of Cesarean section (C/S) and breastfeeding for more than 1 month showed the highest risk for AD (OR=3.111, p=.006). Infants living in homes with curtains and no air filters had the highest risk for AR (OR=2.647, p<.001), and male infants of non-atopic parents living in homes without air filters had the highest risk for AS (OR=1.930, p=.039). Breastfeeding and C/S affect development of AD. Gender, use of curtains and/or air filters affect AR and AS, suggesting that control of the perinatal environment is necessary for the prevention of atopic diseases in children of non-atopic parents.

Physical activity and dementia risk in the elderly: findings from a prospective Italian study.

PubMed

Ravaglia, G; Forti, P; Lucicesare, A; Pisacane, N; Rietti, E; Bianchin, M; Dalmonte, E

2008-05-06

To examine the effect of physical activity on risk of developing Alzheimer disease (AD) and vascular dementia (VaD) in the elderly. Data are from a prospective population-based cohort of 749 Italian subjects aged 65 and older who, in 1999/2000, were cognitively normal at an extensive assessment for clinically overt and preclinical dementia and, in 2003/2004, underwent follow-up for incident dementia. Baseline physical activity was measured as energy expenditure on activities of different intensity (walking, stair climbing, moderate activities, vigorous activities, and total physical activity). Over 3.9 +/- 0.7 years of follow-up there were 86 incident dementia cases (54 AD, 27 VaD). After adjustment for sociodemographic and genetic confounders, VaD risk was significantly lower for the upper tertiles of walking (hazard ratio [HR] 0.27, 95% CI 0.12 to 0.63), moderate (HR 0.29, 95% CI 0.12 to 0.66), and total physical activity (HR 0.24, 95% 0.11 to 0.56) compared to the corresponding lowest tertile. The association persisted after accounting for vascular risk factors and overall health status. After adjustment for sociodemographic and genetic confounders, AD risk was not associated with measures of physical activity and results did not change after further adjustment for vascular risk factors and overall health and functional status. In this cohort, physical activity is associated with a lower risk of vascular dementia but not of Alzheimer disease. Further research is needed about the biologic mechanisms operating between physical activity and cognition.

The Folate-Vitamin B12 Interaction, Low Hemoglobin, and the Mortality Risk from Alzheimer's Disease.

PubMed

Min, Jin-Young; Min, Kyoung-Bok

2016-03-21

Abnormal hemoglobin levels are a risk factor for Alzheimer's disease (AD). Although the mechanism underlying these associations is elusive, inadequate micronutrients, particularly folate and vitamin B12, may increase the risk for anemia, cognitive impairment, and AD. In this study, we investigated whether the nutritional status of folate and vitamin B12 is involved in the association between low hemoglobin levels and the risk of AD mortality. Data were obtained from the 1999-2006 National Health and Nutrition Examination Survey (NHANES) and the NHANES (1999-2006) Linked Mortality File. A total of 4,688 participants aged ≥60 years with available baseline data were included in this study. We categorized three groups based on the quartiles of folate and vitamin B12 as follows: Group I (low folate and vitamin B12); Group II (high folate and low vitamin B12 or low folate and high vitamin B12); and Group III (high folate and vitamin B12). Of 4,688 participants, 49 subjects died due to AD. After adjusting for age, sex, ethnicity, education, smoking history, body mass index, the presence of diabetes or hypertension, and dietary intake of iron, significant increases in the AD mortality were observed in Quartile1 for hemoglobin (HR: 8.4, 95% CI: 1.4-50.8), and the overall risk of AD mortality was significantly reduced with increases in the quartile of hemoglobin (p for trend = 0.0200), in subjects with low levels of both folate and vitamin B12 at baseline. This association did not exist in subjects with at least one high level of folate and vitamin B12. Our finding shows the relationship between folate and vitamin B12 levels with respect to the association between hemoglobin levels and AD mortality.

Genetically decreased vitamin D and risk of Alzheimer disease.

PubMed

Mokry, Lauren E; Ross, Stephanie; Morris, John A; Manousaki, Despoina; Forgetta, Vincenzo; Richards, J Brent

2016-12-13

To test whether genetically decreased vitamin D levels are associated with Alzheimer disease (AD) using mendelian randomization (MR), a method that minimizes bias due to confounding or reverse causation. We selected single nucleotide polymorphisms (SNPs) that are strongly associated with 25-hydroxyvitamin D (25OHD) levels (p < 5 × 10 -8 ) from the Study of Underlying Genetic Determinants of Vitamin D and Highly Related Traits (SUNLIGHT) Consortium (N = 33,996) to act as instrumental variables for the MR study. We measured the effect of each of these SNPs on 25OHD levels in the Canadian Multicentre Osteoporosis Study (CaMos; N = 2,347) and obtained the corresponding effect estimates for each SNP on AD risk from the International Genomics of Alzheimer's Project (N = 17,008 AD cases and 37,154 controls). To produce MR estimates, we weighted the effect of each SNP on AD by its effect on 25OHD and meta-analyzed these estimates using a fixed-effects model to provide a summary effect estimate. The SUNLIGHT Consortium identified 4 SNPs to be genome-wide significant for 25OHD, which described 2.44% of the variance in 25OHD in CaMos. All 4 SNPs map to genes within the vitamin D metabolic pathway. MR analyses demonstrated that a 1-SD decrease in natural log-transformed 25OHD increased AD risk by 25% (odds ratio 1.25, 95% confidence interval 1.03-1.51, p = 0.021). After sensitivity analysis in which we removed SNPs possibly influenced by pleiotropy and population stratification, the results were largely unchanged. Our results provide evidence supporting 25OHD as a causal risk factor for AD. These findings provide further rationale to understand the effect of vitamin D supplementation on cognition and AD risk in randomized controlled trials. © 2016 American Academy of Neurology.

Vascular disease and risk factors are associated with cognitive decline in the alzheimer disease spectrum.

PubMed

Lorius, Natacha; Locascio, Joseph J; Rentz, Dorene M; Johnson, Keith A; Sperling, Reisa A; Viswanathan, Anand; Marshall, Gad A

2015-01-01

We investigated the relationship between vascular disease and risk factors versus cognitive decline cross-sectionally and longitudinally in normal older control, mild cognitive impairment, and mild Alzheimer disease (AD) dementia subjects. A total of 812 participants (229 normal older control, 395 mild cognitive impairment, 188 AD) underwent cognitive testing, brain magnetic resonance imaging, and clinical evaluations at baseline and over a period of 3 years. General linear, longitudinal mixed-effects, and Cox proportional hazards models were used. Greater homocysteine level and white matter hyperintensity volume were associated with processing speed impairment (homocysteine: P=0.02; white matter hyperintensity: P<0.0001); greater Vascular Index score was associated with memory impairment (P=0.007); and greater number of apolipoprotein E ε4 (APOE4) alleles was associated with global cognitive impairment (P=0.007) at baseline. Apolipoprotein E ε4 was associated with greater rate of increase in global cognitive impairment (P=0.002) and processing speed impairment (P=0.001) over time, whereas higher total cholesterol was associated with greater rate of increase in global cognitive impairment (P=0.02) and memory impairment (P=0.06) over time. These results suggest a significant association of increased vascular disease and risk factors with cognitive impairment at baseline and over time in the AD spectrum in a sample that was selected to have low vascular burden at baseline.

Sex modifies the APOE-related risk of developing Alzheimer disease.

PubMed

Altmann, Andre; Tian, Lu; Henderson, Victor W; Greicius, Michael D

2014-04-01

The APOE4 allele is the strongest genetic risk factor for sporadic Alzheimer disease (AD). Case-control studies suggest the APOE4 link to AD is stronger in women. We examined the APOE4-by-sex interaction in conversion risk (from healthy aging to mild cognitive impairment (MCI)/AD or from MCI to AD) and cerebrospinal fluid (CSF) biomarker levels. Cox proportional hazards analysis was used to compute hazard ratios (HRs) for an APOE-by-sex interaction on conversion in controls (n = 5,496) and MCI patients (n = 2,588). The interaction was also tested in CSF biomarker levels of 980 subjects from the Alzheimer's Disease Neuroimaging Initiative. Among controls, male and female carriers were more likely to convert to MCI/AD, but the effect was stronger in women (HR = 1.81 for women; HR = 1.27 for men; interaction: p = 0.011). The interaction remained significant in a predefined subanalysis restricted to APOE3/3 and APOE3/4 genotypes. Among MCI patients, both male and female APOE4 carriers were more likely to convert to AD (HR = 2.16 for women; HR = 1.64 for men); the interaction was not significant (p = 0.14). In the subanalysis restricted to APOE3/3 and APOE3/4 genotypes, the interaction was significant (p = 0.02; HR = 2.17 for women; HR = 1.51 for men). The APOE4-by-sex interaction on biomarker levels was significant for MCI patients for total tau and the tau-to-Aβ ratio (p = 0.009 and p = 0.02, respectively; more AD-like in women). APOE4 confers greater AD risk in women. Biomarker results suggest that increased APOE-related risk in women may be associated with tau pathology. These findings have important clinical implications and suggest novel research approaches into AD pathogenesis. © 2014 American Neurological Association.

Added sugar and sugar-sweetened foods and beverages and the risk of pancreatic cancer in the National Institutes of Health-AARP Diet and Health Study.

PubMed

Bao, Ying; Stolzenberg-Solomon, Rachael; Jiao, Li; Silverman, Debra T; Subar, Amy F; Park, Yikyung; Leitzmann, Michael F; Hollenbeck, Albert; Schatzkin, Arthur; Michaud, Dominique S

2008-08-01

Although it has been hypothesized that hyperglycemia, hyperinsulinemia, and insulin resistance are involved in the development of pancreatic cancer, results from epidemiologic studies of added sugar intake are inconclusive. Our objective was to investigate whether the consumption of total added sugar and sugar-sweetened foods and beverages is associated with pancreatic cancer risk. In 1995 and 1996, we prospectively examined 487 922 men and women aged 50-71 y and free of cancer and diabetes. Total added dietary sugar intake (in tsp/d; based on the US Department of Agriculture's Pyramid Servings Database) was assessed with a food-frequency questionnaire. Relative risks (RRs) and 95% CIs were calculated with adjustment for total energy and potential confounding factors. During an average 7.2 y of follow-up, 1258 incident pancreatic cancer cases were ascertained. The median intakes for the lowest and highest quintiles of total added sugar intake were 12.6 (3 tsp/d) and 96.2 (22.9 tsp/d) g/d, respectively. No overall greater risk of pancreatic cancer was observed in men or women with high intake of total added sugar or sugar-sweetened foods and beverages. For men and women combined, the multivariate RRs of the highest versus lowest intake categories were 0.85 (95% CI: 0.68, 1.06; P for trend = 0.07) for total added sugar, 1.01 (0.82,1.23; P for trend = 0.58) for sweets, 0.98 (0.82,1.18; P for trend = 0.49) for dairy desserts, 1.12 (0.91,1.39; P for trend = 0.35) for sugar added to coffee and tea, and 1.01 (0.77,1.31; P for trend = 0.76) for regular soft drinks. Our results do not support the hypothesis that consumption of added sugar or of sugar-sweetened foods and beverages is associated with overall risk of pancreatic cancer.

Antenatal depressive symptoms among pregnant women: Evidence from a Southern Brazilian population-based cohort study.

PubMed

Coll, Carolina de Vargas Nunes; da Silveira, Mariângela Freitas; Bassani, Diego Garcia; Netsi, Elena; Wehrmeister, Fernando César; Barros, Fernando César; Stein, Alan

2017-02-01

Antenatal depression (AD) is a major public health issue but evidence regarding its prevalence and associated factors in low and middle-income countries (LMICs) is limited. The aim of the study was to estimate the prevalence and identify risk factors for AD among Brazilian pregnant women. All women living in the urban area of the city of Pelotas, Southern Brazil, with confirmed pregnancy and estimated delivery date in the year 2015, were invited to take part. Eligible pregnant women were recruited from health services. Symptoms of antenatal depression were assessed using the Edinburgh Postnatal Depression Scale (EPDS) by face-to-face interviews. A cutoff-point of 13 or more was used to define probable AD. EPDS scores were available for 4130 women. The prevalence of AD was 16% (95%CI 14·9-17·1). After adjustment for potential confounders, the factors most strongly associated with higher EPDS scores were a previous history of depression (PR 2·81; 95%CI 2·44-3·25), high parity (PR 1·72; 95%CI 1·38-2·15 - ≥2 children vs. 1 child) and maternal education (PR 5·47; 95%CI 4·22-7·09 - 0-4 vs. ≥12 years of formal education). EPDS was administered through face-to-face interviews rather than questionnaires and some women may have felt uncomfortable reporting their symptoms leading to underreporting and consequently underestimation of the prevalence found. AD prevalence is substantially higher in Brazil than in high-income countries (HICs) but similar to other LMICs. Our study identified relevant risk factors that may be potential targets to plan interventions, particularly a history of depression. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Plasma cortisol in Alzheimer’s disease with or without depressive symptoms

PubMed Central

Zvěřová, Martina; Fišar, Zdeněk; Jirák, Roman; Kitzlerová, Eva; Hroudová, Jana; Raboch, Jiří

2013-01-01

Background Cortisol is presumed to be a risk factor for stress- and age-related disorders, such as depressive disorder and Alzheimer’s disease (AD). The aim of this study was to investigate the association of plasma cortisol concentration with AD in presence or absence of comorbid depressive symptoms. Material/Methods Plasma cortisol concentration was measured in 80 AD patients (35 of them with depressive symptoms), 27 elderly depressive patients without AD, and 37 elderly controls. Results Compared to controls, a significant increase of mean plasma cortisol was found in AD patients but not in depressive patients. Plasma cortisol was positively correlated with cognitive impairment in AD patients. We confirmed a U-shaped association between plasma cortisol and major depression and a linear association between plasma cortisol and AD without depressive symptoms. Significantly increased relative risk of disease in people with high plasma cortisol was found for AD with depressive symptoms and for AD with mild dementia. Conclusions Plasma cortisol reflects the degree of cognitive impairment in AD rather than the severity of comorbid depression. We confirmed that both hypercortisolemia and hypocortisolemia are associated with depressive disorder. Significant association between high plasma cortisol and AD was found, supporting the use of high plasma cortisol as a component of a panel of biochemical markers for AD with depressive symptoms as well as AD in the early stage of dementia development. PMID:23955525

Reductive stress in young healthy individuals at risk of Alzheimer disease.

PubMed

Badía, Mari-Carmen; Giraldo, Esther; Dasí, Francisco; Alonso, Dolores; Lainez, Jose M; Lloret, Ana; Viña, Jose

2013-10-01

Oxidative stress is a hallmark of Alzheimer disease (AD) but this has not been studied in young healthy persons at risk of the disease. Carrying an Apo ε4 allele is the major genetic risk factor for AD. We have observed that lymphocytes from young, healthy persons carrying at least one Apo ε4 allele suffer from reductive rather than oxidative stress, i.e., lower oxidized glutathione and P-p38 levels and higher expression of enzymes involved in antioxidant defense, such as glutamylcysteinyl ligase and glutathione peroxidase. In contrast, in the full-blown disease, the situation is reversed and oxidative stress occurs, probably because of the exhaustion of the antioxidant mechanisms just mentioned. These results provide insights into the early events of the progression of the disease that may allow us to find biomarkers of AD at its very early stages. Copyright © 2013 Elsevier Inc. All rights reserved.

GUIDELINES OF CARE FOR THE MANAGEMENT OF ATOPIC DERMATITIS

PubMed Central

Eichenfield, Lawrence F.; Tom, Wynnis L.; Chamlin, Sarah L.; Feldman, Steven R.; Hanifin, Jon M.; Simpson, Eric L.; Berger, Timothy G.; Bergman, James N.; Cohen, David E.; Cooper, Kevin D.; Cordoro, Kelly M.; Davis, Dawn M.; Krol, Alfons; Margolis, David J.; Paller, Amy S.; Schwarzenberger, Kathryn; Silverman, Robert A.; Williams, Hywel C.; Elmets, Craig A.; Block, Julie; Harrod, Christopher G.; Begolka, Wendy Smith; Sidbury, Robert

2014-01-01

Atopic dermatitis (AD) is a chronic, pruritic inflammatory dermatosis that affects up to 25% of children and 2–3% of adults. This guideline addresses important clinical questions that arise in AD management and care, providing updated and expanded recommendations based on the available evidence. In this first of four sections, methods for diagnosis and monitoring of disease, outcomes measures for assessment and common clinical associations that affect patients with AD are discussed. Known risk factors for the development of disease are also reviewed. PMID:24290431

Role of APOE Isforms in the Pathogenesis of TBI Induced Alzheimer’s Disease

DTIC Science & Technology

2014-10-01

the inheritance of APOe4 is the only proven genetic risk factor for sporadic Alzheimer disease (AD). Importantly, TBI is a risk factor for the...mice on human APOE genetic background were exceptionally difficult to generate. We are considering changes in the genotype of those particular groups...mediated through ABCA1. 2 Keywords Traumatic brain injury, APOE isoforms, ABCA1, Alzheimer disease, APPmice, amyloid beta, axonal injury, inflamma

Alzheimer's disease, cerebrovascular dysfunction and the benefits of exercise: from vessels to neurons.

PubMed

Lange-Asschenfeldt, Christian; Kojda, Georg

2008-06-01

Exercise training promotes extensive cardiovascular changes and adaptive mechanisms in both the peripheral and cerebral vasculature, such as improved organ blood flow, induction of antioxidant pathways, and enhanced angiogenesis and vascular regeneration. Clinical studies have demonstrated a reduction of morbidity and mortality from cardiovascular disease among exercising individuals. However, evidence from recent large clinical trials also suggests a substantial reduction of dementia risk - particularly regarding Alzheimer's disease (AD) - with regular exercise. Enhanced neurogenesis and improved synaptic plasticity have been implicated in this beneficial effect. However, recent research has revealed that vascular and specifically endothelial dysfunction is essentially involved in the disease process and profoundly aggravates underlying neurodegeneration. Moreover, vascular risk factors (VRFs) are probably determinants of incidence and course of AD. In this review, we emphasize the interconnection between AD and VRFs and the impact of cerebrovascular and endothelial dysfunction on AD pathophysiology. Furthermore, we describe the molecular mechanisms of the beneficial effects of exercise on the vasculature such as activation of the vascular nitric oxide (NO)/endothelial NO synthase (eNOS) pathway, upregulation of antioxidant enzymes, and angiogenesis. Finally, recent prospective clinical studies dealing with the effect of exercise on the risk of incident AD are briefly reviewed. We conclude that, next to upholding neuronal plasticity, regular exercise may counteract AD pathophysiology by building a vascular reserve.

Alzheimer's disease in people with Down's syndrome: the prospects for and the challenges of developing preventative treatments.

PubMed

Castro, Paula; Zaman, Shahid; Holland, Anthony

2017-04-01

People with Down's syndrome (DS) are at high risk for developing Alzheimer's disease (AD) at a relatively young age. This increased risk is not observed in people with intellectual disabilities for reasons other than DS and for this reason it is unlikely to be due to non-specific effects of having a neurodevelopmental disorder but, instead, a direct consequence of the genetics of DS (trisomy 21). Given the location of the amyloid precursor protein (APP) gene on chromosome 21, the amyloid cascade hypothesis is the dominant theory accounting for this risk, with other genetic and environmental factors modifying the age of onset and the course of the disease. Several potential therapies targeting the amyloid pathway and aiming to modify the course of AD are currently being investigated, which may also be useful for treating AD in DS. However, given that the neuropathology associated with AD starts many years before dementia manifests, any preventative treatment must start well before the onset of symptoms. To enable trials of such interventions, plasma, CSF, brain, and retinal biomarkers are being studied as proxy early diagnostic and outcome measures for AD. In this systematic review, we consider the prospects for the development of potential preventative treatments of AD in the DS population and their evaluation.

Prediction of breast cancer risk by genetic risk factors, overall and by hormone receptor status.

PubMed

Hüsing, Anika; Canzian, Federico; Beckmann, Lars; Garcia-Closas, Montserrat; Diver, W Ryan; Thun, Michael J; Berg, Christine D; Hoover, Robert N; Ziegler, Regina G; Figueroa, Jonine D; Isaacs, Claudine; Olsen, Anja; Viallon, Vivian; Boeing, Heiner; Masala, Giovanna; Trichopoulos, Dimitrios; Peeters, Petra H M; Lund, Eiliv; Ardanaz, Eva; Khaw, Kay-Tee; Lenner, Per; Kolonel, Laurence N; Stram, Daniel O; Le Marchand, Loïc; McCarty, Catherine A; Buring, Julie E; Lee, I-Min; Zhang, Shumin; Lindström, Sara; Hankinson, Susan E; Riboli, Elio; Hunter, David J; Henderson, Brian E; Chanock, Stephen J; Haiman, Christopher A; Kraft, Peter; Kaaks, Rudolf

2012-09-01

There is increasing interest in adding common genetic variants identified through genome wide association studies (GWAS) to breast cancer risk prediction models. First results from such models showed modest benefits in terms of risk discrimination. Heterogeneity of breast cancer as defined by hormone-receptor status has not been considered in this context. In this study we investigated the predictive capacity of 32 GWAS-detected common variants for breast cancer risk, alone and in combination with classical risk factors, and for tumours with different hormone receptor status. Within the Breast and Prostate Cancer Cohort Consortium, we analysed 6009 invasive breast cancer cases and 7827 matched controls of European ancestry, with data on classical breast cancer risk factors and 32 common gene variants identified through GWAS. Discriminatory ability with respect to breast cancer of specific hormone receptor-status was assessed with the age adjusted and cohort-adjusted concordance statistic (AUROC(a)). Absolute risk scores were calculated with external reference data. Integrated discrimination improvement was used to measure improvements in risk prediction. We found a small but steady increase in discriminatory ability with increasing numbers of genetic variants included in the model (difference in AUROC(a) going from 2.7% to 4%). Discriminatory ability for all models varied strongly by hormone receptor status. Adding information on common polymorphisms provides small but statistically significant improvements in the quality of breast cancer risk prediction models. We consistently observed better performance for receptor-positive cases, but the gain in discriminatory quality is not sufficient for clinical application.

Assistive Device Use as a Dynamic Acquisition Process in Later Life

ERIC Educational Resources Information Center

Pressler, Karis A.; Ferraro, Kenneth F.

2010-01-01

Purpose: This study identifies risk factors, including incident disability, for the use of assistive devices (ADs) among older people. Design and Methods: Three waves of data from the National Long-Term Care Survey (NLTCS) are used to examine whether upper and lower body disability lead to use of ADs (both number of devices used and number of…

Is the exposure to antidepressant drugs in early pregnancy a risk factor for spontaneous abortion? A review of available evidences.

PubMed

Santone, Giovanni; Ricchi, Gianmatteo; Rocchetti, David; Tofani, Stefania; Bellantuono, Cesario

2009-01-01

To review studies conducted to establish the risk of spontaneous abortion (SA) in women exposed to antidepressant drugs (ADs) during early pregnancy. By using different search terms, PubMed, Toxline, EMBASE, PsychINFO, and the Cochrane library databases were searched from January 1980 to March 2008, to identify studies assessing the risk of SA in women exposed to different classes of ADs during the first trimester of pregnancy. Ten studies over 21 identified were selected for the analysis. All were performed prospectively and included as control group unexposed women, or exposed to non-teratogenic drugs or to placebo. In seven studies a depressive episode was specified as the reason for which the drug was prescribed, while the time of exposure was in nine. Only three studies over ten selected reported a significant association between an increased rate of SAs and early pregnancy exposure to some ADs. Many methodological flaws in the study design were found in all studies considered. Given this background and a lack of strong evidence on this issue, further prospective and better designed studies are needed to assess the risk of SA in pregnant women exposed to ADs against the risk of an untreated maternal depression.

Alzheimer Disease: Scientific Breakthroughs and Translational Challenges.

PubMed

Caselli, Richard J; Beach, Thomas G; Knopman, David S; Graff-Radford, Neill R

2017-06-01

Alzheimer disease (AD) was originally conceived as a rare disease that caused presenile dementia but has come to be understood as the most prevalent cause of dementia at any age worldwide. It has an extended preclinical phase characterized by sequential changes in imaging and cerebrospinal fluid biomarkers with subtle memory decline beginning more than a decade before the emergence of symptomatic memory loss heralding the beginning of the mild cognitive impairment stage. The apolipoprotein E ε4 allele is a prevalent and potent risk factor for AD that has facilitated research into its preclinical phase. Cerebral Aβ levels build from preclinical through early dementia stages followed by hyperphosphorylated tau-related pathology, the latter driving cognitive deficits and dementia severity. Structural and molecular imaging can now recapitulate the neuropathology of AD antemortem. Autosomal dominant forms of early-onset familial AD gave rise to the amyloid hypothesis of AD, which, in turn, has led to therapeutic trials of immunotherapy designed to clear cerebral amyloid, but to date results have been disappointing. Genome-wide association studies have identified multiple additional risk factors, but to date none have yielded an effective alternate therapeutic target. Current and future trials aimed at presymptomatic individuals either harboring cerebral amyloid or at genetically high risk offer the hope that earlier intervention might yet succeed where trials in patients with established dementia have failed. A major looming challenge will be that of expensive, incompletely effective disease-modifying therapy: who and when to treat, and how to pay for it. Copyright © 2017 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

Insulin deprivation induces PP2A inhibition and tau hyperphosphorylation in hTau mice, a model of Alzheimer’s disease-like tau pathology

PubMed Central

Gratuze, Maud; Julien, Jacinthe; Petry, Franck R.; Morin, Françoise; Planel, Emmanuel

2017-01-01

Abnormally hyperphosphorylated tau aggregated as intraneuronal neurofibrillary tangles is one of the two neuropathological hallmarks of Alzheimer’s disease (AD). The majority of AD cases are sporadic with numerous environmental, biological and genetic risks factors. Interestingly, insulin dysfunction and hyperglycaemia are both risk factors for sporadic AD. However, how hyperglycaemia and insulin dysfunction affect tau pathology, is not well understood. In this study, we examined the effects of insulin deficiency on tau pathology in transgenic hTau mice by injecting different doses of streptozotocin (STZ), a toxin that destroys insulin-producing cells in the pancreas. One high dose of STZ resulted in marked diabetes, and five low doses led to a milder diabetes. Both groups exhibited brain tau hyperphosphorylation but no increased aggregation. Tau hyperphosphorylation correlated with inhibition of Protein Phosphatase 2A (PP2A), the main tau phosphatase. Interestingly, insulin injection 30 minutes before sacrifice partially restored tau phosphorylation to control levels in both STZ-injected groups. Our results confirm a link between insulin homeostasis and tau phosphorylation, which could explain, at least in part, a higher incidence of AD in diabetic patients. PMID:28402338

Insulin deprivation induces PP2A inhibition and tau hyperphosphorylation in hTau mice, a model of Alzheimer's disease-like tau pathology.

PubMed

Gratuze, Maud; Julien, Jacinthe; Petry, Franck R; Morin, Françoise; Planel, Emmanuel

2017-04-12

Abnormally hyperphosphorylated tau aggregated as intraneuronal neurofibrillary tangles is one of the two neuropathological hallmarks of Alzheimer's disease (AD). The majority of AD cases are sporadic with numerous environmental, biological and genetic risks factors. Interestingly, insulin dysfunction and hyperglycaemia are both risk factors for sporadic AD. However, how hyperglycaemia and insulin dysfunction affect tau pathology, is not well understood. In this study, we examined the effects of insulin deficiency on tau pathology in transgenic hTau mice by injecting different doses of streptozotocin (STZ), a toxin that destroys insulin-producing cells in the pancreas. One high dose of STZ resulted in marked diabetes, and five low doses led to a milder diabetes. Both groups exhibited brain tau hyperphosphorylation but no increased aggregation. Tau hyperphosphorylation correlated with inhibition of Protein Phosphatase 2A (PP2A), the main tau phosphatase. Interestingly, insulin injection 30 minutes before sacrifice partially restored tau phosphorylation to control levels in both STZ-injected groups. Our results confirm a link between insulin homeostasis and tau phosphorylation, which could explain, at least in part, a higher incidence of AD in diabetic patients.

Sleep Modifies the Relation of APOE to the Risk of Alzheimer Disease and Neurofibrillary Tangle Pathology

PubMed Central

Lim, Andrew S.P.; Yu, Lei; Kowgier, Matthew; Schneider, Julie A.; Buchman, Aron S.; Bennett, David A.

2013-01-01

IMPORTANCE The Apolipoprotein E (APOE) ε4 allele is a common and well-established genetic risk factor for Alzheimer Disease (AD). Sleep consolidation is also associated with AD risk and previous work suggests that APOE genotype and sleep may interact to influence cognitive function. OBJECTIVE To determine whether better sleep consolidation attenuates the relation of the APOE genotype to the risk of incident AD and the burden of AD pathology. DESIGN Prospective longitudinal cohort study with up to 6 years of follow-up. SETTING Community-based. PARTICIPANTS We studied a volunteer sample of 698 community dwelling older adults without dementia (average age 81.7 years; 77% female) in the Rush Memory and Aging Project followed for up to 6 years. EXPOSURES We used up to 10 days of actigraphic recording to quantify the degree of sleep consolidation, and ascertained APOE genotype. MAIN OUTCOME MEASURES Subjects underwent annual evaluation for AD over a follow-up period of up to 6 years. Autopsies were performed on 201 deceased participants, and Aβ and neurofibrillary tangle (NFT) pathology were identified by immunohistochemistry and quantified. RESULTS Over a follow-up period, 98 individuals developed AD. In a series of Cox proportional hazards models, better sleep consolidation attenuated the effect of the ε4 allele on the risk of incident AD (HR 0.67 95%CI 0.46–0.97 p=0.036 per allele per 1SD increase in sleep consolidation). In a series of linear mixed effect models, better sleep consolidation also attenuated the effect of the ε4 allele on the annual rate of cognitive decline (interaction estimate +0.048 SE=0.012 p<0.001). In deceased individuals, better sleep consolidation attenuated the effect of the ε4 allele on NFT density (interaction estimate −0.42 SE=0.17 p=0.016), which accounted for the effect of sleep consolidation on the association between APOE genotype and cognition proximate to death. CONCLUSIONS AND RELEVANCE Better sleep consolidation attenuates the effect of APOE genotype on incident AD and NFT pathology. Assessment of sleep consolidation may identify APOE positive individuals at high risk for incident AD, and interventions to enhance sleep consolidation should be studied as potentially useful means to reduce the risk of AD and NFT pathology in APOE ε4+ individuals. PMID:24145819

Buying time: a rationale for examining the use of circadian rhythm and sleep interventions to delay progression of mild cognitive impairment to Alzheimer's disease.

PubMed

Landry, Glenn J; Liu-Ambrose, Teresa

2014-01-01

As of 2010, the worldwide economic impact of dementia was estimated at $604 billion USD; and without discovery of a cure or effective interventions to delay disease progression, dementia's annual global economic impact is expected to surpass $1 trillion USD as early as 2030. Alzheimer's disease (AD) is the leading cause of dementia accounting for over 75% of all cases. Toxic accumulation of amyloid beta (Aβ), either by overproduction or some clearance failure, is thought to be an underlying mechanism of the neuronal cell death characteristic of AD-though this amyloid hypothesis has been increasingly challenged in recent years. A compelling alternative hypothesis points to chronic neuroinflammation as a common root in late-life degenerative diseases including AD. Apolipoprotein-E (APOE) genotype is the strongest genetic risk factor for AD: APOE-ε4 is proinflammatory and individuals with this genotype accumulate more Aβ, are at high risk of developing AD, and almost half of all AD patients have at least one ε4 allele. Recent studies suggest a bidirectional relationship exists between sleep and AD pathology. Sleep may play an important role in Aβ clearance, and getting good quality sleep vs. poor quality sleep might reduce the AD risk associated with neuroinflammation and the ε4 allele. Taken together, these findings are particularly important given the sleep disruptions commonly associated with AD and the increased burden disrupted sleep poses for AD caregivers. The current review aims to: (1) identify individuals at high risk for dementia who may benefit most from sleep interventions; (2) explore the role poor sleep quality plays in exacerbating AD type dementia; (3) examine the science of sleep interventions to date; and (4) provide a road map in pursuit of comprehensive sleep interventions, specifically targeted to promote cognitive function and delay progression of dementia.

Improving risk prediction accuracy for new soldiers in the U.S. Army by adding self-report survey data to administrative data.

PubMed

Bernecker, Samantha L; Rosellini, Anthony J; Nock, Matthew K; Chiu, Wai Tat; Gutierrez, Peter M; Hwang, Irving; Joiner, Thomas E; Naifeh, James A; Sampson, Nancy A; Zaslavsky, Alan M; Stein, Murray B; Ursano, Robert J; Kessler, Ronald C

2018-04-03

High rates of mental disorders, suicidality, and interpersonal violence early in the military career have raised interest in implementing preventive interventions with high-risk new enlistees. The Army Study to Assess Risk and Resilience in Servicemembers (STARRS) developed risk-targeting systems for these outcomes based on machine learning methods using administrative data predictors. However, administrative data omit many risk factors, raising the question whether risk targeting could be improved by adding self-report survey data to prediction models. If so, the Army may gain from routinely administering surveys that assess additional risk factors. The STARRS New Soldier Survey was administered to 21,790 Regular Army soldiers who agreed to have survey data linked to administrative records. As reported previously, machine learning models using administrative data as predictors found that small proportions of high-risk soldiers accounted for high proportions of negative outcomes. Other machine learning models using self-report survey data as predictors were developed previously for three of these outcomes: major physical violence and sexual violence perpetration among men and sexual violence victimization among women. Here we examined the extent to which this survey information increases prediction accuracy, over models based solely on administrative data, for those three outcomes. We used discrete-time survival analysis to estimate a series of models predicting first occurrence, assessing how model fit improved and concentration of risk increased when adding the predicted risk score based on survey data to the predicted risk score based on administrative data. The addition of survey data improved prediction significantly for all outcomes. In the most extreme case, the percentage of reported sexual violence victimization among the 5% of female soldiers with highest predicted risk increased from 17.5% using only administrative predictors to 29.4% adding survey predictors, a 67.9% proportional increase in prediction accuracy. Other proportional increases in concentration of risk ranged from 4.8% to 49.5% (median = 26.0%). Data from an ongoing New Soldier Survey could substantially improve accuracy of risk models compared to models based exclusively on administrative predictors. Depending upon the characteristics of interventions used, the increase in targeting accuracy from survey data might offset survey administration costs.

Concurrence of High Fat Diet and APOE Gene Induces Allele Specific Metabolic and Mental Stress Changes in a Mouse Model of Alzheimer's Disease.

PubMed

Segev, Yifat; Livne, Adva; Mints, Meshi; Rosenblum, Kobi

2016-01-01

Aging is the main risk factor for neurodegenerative diseases, including Alzheimer's disease (AD). However, evidence indicates that the pathological process begins long before actual cognitive or pathological symptoms are apparent. The long asymptomatic phase and complex integration between genetic, environmental and metabolic factors make it one of the most challenging diseases to understand and cure. In the present study, we asked whether an environmental factor such as high-fat (HF) diet would synergize with a genetic factor to affect the metabolic and cognitive state in the Apolipoprotein E (ApoE4) mouse model of AD. Our data suggest that a HF diet induces diabetes mellitus (DM)-like metabolism in ApoE4 mice, as well as changes in β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) protein levels between the two ApoE strains. Furthermore, HF diet induces anxiety in this AD mouse model. Our results suggest that young ApoE4 carriers are prone to psychological stress and metabolic abnormalities related to AD, which can easily be triggered via HF nutrition.

Feasibility of Predicting MCI/AD Using Neuropsychological Tests and Serum β-Amyloid

PubMed Central

Luis, Cheryl A.; Abdullah, Laila; Ait-Ghezala, Ghania; Mouzon, Benoit; Keegan, Andrew P.; Crawford, Fiona; Mullan, Michael

2011-01-01

We examined the usefulness of brief neuropsychological tests and serum Aβ as a predictive test for detecting MCI/AD in older adults. Serum Aβ levels were measured from 208 subjects who were cognitively normal at enrollment and blood draw. Twenty-eight of the subjects subsequently developed MCI (n = 18) or AD (n = 10) over the follow-up period. Baseline measures of global cognition, memory, language fluency, and serum Aβ1–42 and the ratio of serum Aβ1–42/Aβ1–40 were significant predictors for future MCI/AD using Cox regression with demographic variables, APOE ε4, vascular risk factors, and specific medication as covariates. An optimal sensitivity of 85.2% and specificity of 86.5% for predicting MCI/AD was achieved using ROC analyses. Brief neuropsychological tests and measurements of Aβ1–42 obtained via blood warrants further study as a practical and cost effective method for wide-scale screening for identifying older adults who may be at-risk for pathological cognitive decline. PMID:21660215

Clinical Significance of Cerebrovascular Biomarkers and White Matter Tract Integrity in Alzheimer Disease: Clinical correlations With Neurobehavioral Data in Cross-Sectional and After 18 Months Follow-ups.

PubMed

Wu, Ming-Kung; Lu, Yan-Ting; Huang, Chi-Wei; Lin, Pin-Hsuan; Chen, Nai-Ching; Lui, Chun-Chung; Chang, Wen-Neng; Lee, Chen-Chang; Chang, Ya-Ting; Chen, Sz-Fan; Chang, Chiung-Chih

2015-07-01

Cerebrovascular risk factors and white matter (WM) damage lead to worse cognitive performance in Alzheimer dementia (AD). This study investigated WM microstructure using diffusion tensor imaging in patients with mild to moderate AD and investigated specific fiber tract involvement with respect to predefined cerebrovascular risk factors and neurobehavioral data prediction cross-sectionally and after 18 months. To identify the primary pathoanatomic relationships of risk biomarkers to fiber tract integrity, we predefined 11 major association tracts and calculated tract specific fractional anisotropy (FA) values. Eighty-five patients with AD underwent neurobehavioral assessments including the minimental state examination (MMSE) and 12-item neuropsychiatric inventory twice with a 1.5-year interval to represent major outcome factors. In the cross-sectional data, total cholesterol, low-density lipoprotein, vitamin B12, and homocysteine levels correlated variably with WM FA values. After entering the biomarkers and WM FA into a regression model to predict neurobehavioral outcomes, only fiber tract FA or homocysteine level predicted the MMSE score, and fiber tract FA or age predicted the neuropsychiatric inventory total scores and subdomains of apathy, disinhibition, and aberrant motor behavior. In the follow-up neurobehavioral data, the mean global FA value predicted the MMSE and aberrant motor behavior subdomain, while age predicted the anxiety and elation subdomains. Cerebrovascular risk biomarkers may modify WM microstructural organization, while the association with fiber integrity showed greater clinical significance to the prediction of neurobehavioral outcomes both cross-sectionally and longitudinally.

Assessing the presence of shared genetic architecture between Alzheimer's disease and major depressive disorder using genome-wide association data

PubMed Central

Gibson, J; Russ, T C; Adams, M J; Clarke, T-K; Howard, D M; Hall, L S; Fernandez-Pujals, A M; Wigmore, E M; Hayward, C; Davies, G; Murray, A D; Smith, B H; Porteous, D J; Deary, I J; McIntosh, A M

2017-01-01

Major depressive disorder (MDD) and Alzheimer's disease (AD) are both common in older age and frequently co-occur. Numerous phenotypic studies based on clinical diagnoses suggest that a history of depression increases risk of subsequent AD, although the basis of this relationship is uncertain. Both illnesses are polygenic, and shared genetic risk factors could explain some of the observed association. We used genotype data to test whether MDD and AD have an overlapping polygenic architecture in two large population-based cohorts, Generation Scotland's Scottish Family Health Study (GS:SFHS; N=19 889) and UK Biobank (N=25 118), and whether age of depression onset influences any relationship. Using two complementary techniques, we found no evidence that the disorders are influenced by common genetic variants. Using linkage disequilibrium score regression with genome-wide association study (GWAS) summary statistics from the International Genomics of Alzheimer's Project, we report no significant genetic correlation between AD and MDD (rG=−0.103, P=0.59). Polygenic risk scores (PRS) generated using summary data from International Genomics of Alzheimer's Project (IGAP) and the Psychiatric Genomics Consortium were used to assess potential pleiotropy between the disorders. PRS for MDD were nominally associated with participant-recalled AD family history in GS:SFHS, although this association did not survive multiple comparison testing. AD PRS were not associated with depression status or late-onset depression, and a survival analysis showed no association between age of depression onset and genetic risk for AD. This study found no evidence to support a common polygenic structure for AD and MDD, suggesting that the comorbidity of these disorders is not explained by common genetic variants. PMID:28418403

Assessing the presence of shared genetic architecture between Alzheimer's disease and major depressive disorder using genome-wide association data.

PubMed

Gibson, J; Russ, T C; Adams, M J; Clarke, T-K; Howard, D M; Hall, L S; Fernandez-Pujals, A M; Wigmore, E M; Hayward, C; Davies, G; Murray, A D; Smith, B H; Porteous, D J; Deary, I J; McIntosh, A M

2017-04-18

Major depressive disorder (MDD) and Alzheimer's disease (AD) are both common in older age and frequently co-occur. Numerous phenotypic studies based on clinical diagnoses suggest that a history of depression increases risk of subsequent AD, although the basis of this relationship is uncertain. Both illnesses are polygenic, and shared genetic risk factors could explain some of the observed association. We used genotype data to test whether MDD and AD have an overlapping polygenic architecture in two large population-based cohorts, Generation Scotland's Scottish Family Health Study (GS:SFHS; N=19 889) and UK Biobank (N=25 118), and whether age of depression onset influences any relationship. Using two complementary techniques, we found no evidence that the disorders are influenced by common genetic variants. Using linkage disequilibrium score regression with genome-wide association study (GWAS) summary statistics from the International Genomics of Alzheimer's Project, we report no significant genetic correlation between AD and MDD (r G =-0.103, P=0.59). Polygenic risk scores (PRS) generated using summary data from International Genomics of Alzheimer's Project (IGAP) and the Psychiatric Genomics Consortium were used to assess potential pleiotropy between the disorders. PRS for MDD were nominally associated with participant-recalled AD family history in GS:SFHS, although this association did not survive multiple comparison testing. AD PRS were not associated with depression status or late-onset depression, and a survival analysis showed no association between age of depression onset and genetic risk for AD. This study found no evidence to support a common polygenic structure for AD and MDD, suggesting that the comorbidity of these disorders is not explained by common genetic variants.

European Prevention of Alzheimer's Dementia Registry: Recruitment and prescreening approach for a longitudinal cohort and prevention trials.

PubMed

Vermunt, Lisa; Veal, Colin D; Ter Meulen, Lea; Chrysostomou, Charalambos; van der Flier, Wiesje; Frisoni, Giovanni B; Guessous, Idris; Kivipelto, Miia; Marizzoni, Moira; Martinez-Lage, Pablo; Molinuevo, José Luis; Porteous, David; Ritchie, Karen; Scheltens, Philip; Ousset, Pierre-Jean; Ritchie, Craig W; Luscan, Gerald; Brookes, Anthony J; Visser, Pieter Jelle

2018-06-01

It is a challenge to find participants for Alzheimer's disease (AD) prevention trials within a short period of time. The European Prevention of Alzheimer's Dementia Registry (EPAD) aims to facilitate recruitment by preselecting subjects from ongoing cohort studies. This article introduces this novel approach. A virtual registry, with access to risk factors and biomarkers for AD through minimal data sets of ongoing cohort studies, was set up. To date, ten cohorts have been included in the EPAD. Around 2500 participants have been selected, using variables associated with the risk for AD. Of these, 15% were already recruited in the EPAD longitudinal cohort study, which serves as a trial readiness cohort. This study demonstrates that a virtual registry can be used for the preselection of participants for AD studies. Copyright © 2018 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Social and Behavioral Risk Marker Clustering Associated with Biological Risk Factors for Coronary Heart Disease: NHANES 2001–2004

PubMed Central

Everage, Nicholas J.; Linkletter, Crystal D.; Gjelsvik, Annie; McGarvey, Stephen T.; Loucks, Eric B.

2014-01-01

Background. Social and behavioral risk markers (e.g., physical activity, diet, smoking, and socioeconomic position) cluster; however, little is known whether clustering is associated with coronary heart disease (CHD) risk. Objectives were to determine if sociobehavioral clustering is associated with biological CHD risk factors (total cholesterol, HDL cholesterol, systolic blood pressure, body mass index, waist circumference, and diabetes) and whether associations are independent of individual clustering components. Methods. Participants included 4,305 males and 4,673 females aged ≥20 years from NHANES 2001–2004. Sociobehavioral Risk Marker Index (SRI) included a summary score of physical activity, fruit/vegetable consumption, smoking, and educational attainment. Regression analyses evaluated associations of SRI with aforementioned biological CHD risk factors. Receiver operator curve analyses assessed independent predictive ability of SRI. Results. Healthful clustering (SRI = 0) was associated with improved biological CHD risk factor levels in 5 of 6 risk factors in females and 2 of 6 risk factors in males. Adding SRI to models containing age, race, and individual SRI components did not improve C-statistics. Conclusions. Findings suggest that healthful sociobehavioral risk marker clustering is associated with favorable CHD risk factor levels, particularly in females. These findings should inform social ecological interventions that consider health impacts of addressing social and behavioral risk factors. PMID:24719858

Sugars in diet and risk of cancer in the NIH-AARP Diet and Health Study

PubMed Central

Tasevska, Nataša; Jiao, Li; Cross, Amanda J.; Kipnis, Victor; Subar, Amy F.; Hollenbeck, Albert; Schatzkin, Arthur; Potischman, Nancy

2012-01-01

Prospective epidemiologic data on the effects of different types of dietary sugars on cancer incidence have been limited. In this report, we investigated the association of total sugars, sucrose, fructose, added sugars, added sucrose and added fructose in the diet with risk of 24 malignancies. Participants (n = 435,674) aged 50–71 years from the NIH-AARP Diet and Health Study were followed for 7.2 years. The intake of individual sugars was assessed using a 124-item food frequency questionnaire (FFQ). Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) in multivariable models adjusted for confounding factors pertinent to individual cancers. We identified 29,099 cancer cases in men and 13,355 cases in women. In gender-combined analyses, added sugars were positively associated with risk of esophageal adenocarcinoma (HRQ5 vs. Q1: 1.62, 95% CI: 1.07–2.45; Ptrend = 0.01); added fructose was associated with risk of small intestine cancer (HRQ5 vs. Q1: 2.20, 95% CI: 1.16–4.16; Ptrend = 0.009); and all investigated sugars were associated with increased risk of pleural cancer. In women, all investigated sugars were inversely associated with ovarian cancer. We found no association between dietary sugars and risk of colorectal or any other major cancer. Measurement error in FFQ-reported dietary sugars may have limited our ability to obtain more conclusive findings. Statistically significant associations observed for the rare cancers are of interest and warrant further investigation. PMID:21328345

Sugars in diet and risk of cancer in the NIH-AARP Diet and Health Study.

PubMed

Tasevska, Nataša; Jiao, Li; Cross, Amanda J; Kipnis, Victor; Subar, Amy F; Hollenbeck, Albert; Schatzkin, Arthur; Potischman, Nancy

2012-01-01

Prospective epidemiologic data on the effects of different types of dietary sugars on cancer incidence have been limited. In this report, we investigated the association of total sugars, sucrose, fructose, added sugars, added sucrose and added fructose in the diet with risk of 24 malignancies. Participants (n = 435,674) aged 50-71 years from the NIH-AARP Diet and Health Study were followed for 7.2 years. The intake of individual sugars was assessed using a 124-item food frequency questionnaire (FFQ). Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) in multivariable models adjusted for confounding factors pertinent to individual cancers. We identified 29,099 cancer cases in men and 13,355 cases in women. In gender-combined analyses, added sugars were positively associated with risk of esophageal adenocarcinoma (HR(Q5 vs. Q1) : 1.62, 95% CI: 1.07-2.45; p(trend) = 0.01), added fructose was associated with risk of small intestine cancer (HR(Q5 vs. Q1) : 2.20, 95% CI: 1.16-4.16; p(trend) = 0.009) and all investigated sugars were associated with increased risk of pleural cancer. In women, all investigated sugars were inversely associated with ovarian cancer. We found no association between dietary sugars and risk of colorectal or any other major cancer. Measurement error in FFQ-reported dietary sugars may have limited our ability to obtain more conclusive findings. Statistically significant associations observed for the rare cancers are of interest and warrant further investigation. Copyright © 2011 UICC.

Alzheimer’s Disease Risk Gene CD33 Inhibits Microglial Uptake of Amyloid Beta

PubMed Central

Griciuc, Ana; Serrano-Pozo, Alberto; Parrado, Antonio R.; Lesinski, Andrea N.; Asselin, Caroline N.; Mullin, Kristina; Hooli, Basavaraj; Choi, Se Hoon; Hyman, Bradley T.; Tanzi, Rudolph E.

2013-01-01

SUMMARY The transmembrane protein CD33 is a sialic acid-binding immunoglobulin-like lectin that regulates innate immunity but has no known functions in the brain. We have previously shown that the CD33 gene is a risk factor for Alzheimer’s disease (AD). Here, we observed increased expression of CD33 in microglial cells in AD brain. The minor allele of the CD33 SNP rs3865444, which confers protection against AD, was associated with reductions in both CD33 expression and insoluble amyloid beta 42 (Aβ42) levels in AD brain. Furthermore, the numbers of CD33-immunoreactive microglia were positively correlated with insoluble Aβ42 levels and plaque burden in AD brain. CD33 inhibited uptake and clearance of Aβ42 in microglial cell cultures. Finally, brain levels of insoluble Aβ42 as well as amyloid plaque burden were markedly reduced in APPSwe/PS1ΔE9/CD33−/− mice. Therefore, CD33 inactivation mitigates Aβ pathology and CD33 inhibition could represent a novel therapy for AD. PMID:23623698

Alzheimer's disease risk gene CD33 inhibits microglial uptake of amyloid beta.

PubMed

Griciuc, Ana; Serrano-Pozo, Alberto; Parrado, Antonio R; Lesinski, Andrea N; Asselin, Caroline N; Mullin, Kristina; Hooli, Basavaraj; Choi, Se Hoon; Hyman, Bradley T; Tanzi, Rudolph E

2013-05-22

The transmembrane protein CD33 is a sialic acid-binding immunoglobulin-like lectin that regulates innate immunity but has no known functions in the brain. We have previously shown that the CD33 gene is a risk factor for Alzheimer's disease (AD). Here, we observed increased expression of CD33 in microglial cells in AD brain. The minor allele of the CD33 SNP rs3865444, which confers protection against AD, was associated with reductions in both CD33 expression and insoluble amyloid beta 42 (Aβ42) levels in AD brain. Furthermore, the numbers of CD33-immunoreactive microglia were positively correlated with insoluble Aβ42 levels and plaque burden in AD brain. CD33 inhibited uptake and clearance of Aβ42 in microglial cell cultures. Finally, brain levels of insoluble Aβ42 as well as amyloid plaque burden were markedly reduced in APP(Swe)/PS1(ΔE9)/CD33(-/-) mice. Therefore, CD33 inactivation mitigates Aβ pathology and CD33 inhibition could represent a novel therapy for AD. Copyright © 2013 Elsevier Inc. All rights reserved.

Autism Spectrum Disorders and Race, Ethnicity, and Nativity: A Population-Based Study

PubMed Central

Becerra, Tracy A.; von Ehrenstein, Ondine S.; Heck, Julia E.; Olsen, Jorn; Arah, Onyebuchi A.; Jeste, Shafali S.; Rodriguez, Michael

2014-01-01

OBJECTIVE: Our understanding of the influence of maternal race/ethnicity and nativity and childhood autistic disorder (AD) in African Americans/blacks, Asians, and Hispanics in the United States is limited. Phenotypic differences in the presentation of childhood AD in minority groups may indicate etiologic heterogeneity or different thresholds for diagnosis. We investigated whether the risk of developing AD and AD phenotypes differed according to maternal race/ethnicity and nativity. METHODS: Children born in Los Angeles County with a primary AD diagnosis at ages 3 to 5 years during 1998–2009 were identified and linked to 1995–2006 California birth certificates (7540 children with AD from a cohort of 1 626 354 births). We identified a subgroup of children with AD and a secondary diagnosis of mental retardation and investigated heterogeneity in language and behavior. RESULTS: We found increased risks of being diagnosed with AD overall and specifically with comorbid mental retardation in children of foreign-born mothers who were black, Central/South American, Filipino, and Vietnamese, as well as among US-born Hispanic and African American/black mothers, compared with US-born whites. Children of US African American/black and foreign-born black, foreign-born Central/South American, and US-born Hispanic mothers were at higher risk of exhibiting an AD phenotype with both severe emotional outbursts and impaired expressive language than children of US-born whites. CONCLUSIONS: Maternal race/ethnicity and nativity are associated with offspring’s AD diagnosis and severity. Future studies need to examine factors related to nativity and migration that may play a role in the etiology as well as identification and diagnosis of AD in children. PMID:24958588

Autism spectrum disorders and race, ethnicity, and nativity: a population-based study.

PubMed

Becerra, Tracy A; von Ehrenstein, Ondine S; Heck, Julia E; Olsen, Jorn; Arah, Onyebuchi A; Jeste, Shafali S; Rodriguez, Michael; Ritz, Beate

2014-07-01

Our understanding of the influence of maternal race/ethnicity and nativity and childhood autistic disorder (AD) in African Americans/blacks, Asians, and Hispanics in the United States is limited. Phenotypic differences in the presentation of childhood AD in minority groups may indicate etiologic heterogeneity or different thresholds for diagnosis. We investigated whether the risk of developing AD and AD phenotypes differed according to maternal race/ethnicity and nativity. Children born in Los Angeles County with a primary AD diagnosis at ages 3 to 5 years during 1998-2009 were identified and linked to 1995-2006 California birth certificates (7540 children with AD from a cohort of 1,626,354 births). We identified a subgroup of children with AD and a secondary diagnosis of mental retardation and investigated heterogeneity in language and behavior. We found increased risks of being diagnosed with AD overall and specifically with comorbid mental retardation in children of foreign-born mothers who were black, Central/South American, Filipino, and Vietnamese, as well as among US-born Hispanic and African American/black mothers, compared with US-born whites. Children of US African American/black and foreign-born black, foreign-born Central/South American, and US-born Hispanic mothers were at higher risk of exhibiting an AD phenotype with both severe emotional outbursts and impaired expressive language than children of US-born whites. Maternal race/ethnicity and nativity are associated with offspring's AD diagnosis and severity. Future studies need to examine factors related to nativity and migration that may play a role in the etiology as well as identification and diagnosis of AD in children. Copyright © 2014 by the American Academy of Pediatrics.

Unified theory of Alzheimer's disease (UTAD): implications for prevention and curative therapy.

PubMed

Nehls, Michael

2016-01-01

The aim of this review is to propose a Unified Theory of Alzheimer's disease (UTAD) that integrates all key behavioural, genetic and environmental risk factors in a causal chain of etiological and pathogenetic events. It is based on three concepts that emanate from human's evolutionary history: (1) The grandmother-hypothesis (GMH), which explains human longevity due to an evolutionary advantage in reproduction by trans-generational transfer of acquired knowledge. Consequently it is argued that mental health at old-age must be the default pathway of humans' genetic program and not development of AD. (2) Therefore, mechanism like neuronal rejuvenation (NRJ) and adult hippocampal neurogenesis (AHN) that still function efficiently even at old age provide the required lifelong ability to memorize personal experiences important for survival. Cumulative evidence from a multitude of experimental and epidemiological studies indicate that behavioural and environmental risk factors, which impair productive AHN, result in reduced episodic memory performance and in reduced psychological resilience. This leads to avoidance of novelty, dysregulation of the hypothalamic-pituitary-adrenal (HPA)-axis and cortisol hypersecretion, which drives key pathogenic mechanisms of AD like the accumulation and oligomerization of synaptotoxic amyloid beta, chronic neuroinflammation and neuronal insulin resistance. (3) By applying to AHN the law of the minimum (LOM), which defines the basic requirements of biological growth processes, the UTAD explains why and how different lifestyle deficiencies initiate the AD process by impairing AHN and causing dysregulation of the HPA-axis, and how environmental and genetic risk factors such as toxins or ApoE4, respectively, turn into disease accelerators under these unnatural conditions. Consequently, the UTAD provides a rational strategy for the prevention of mental decline and a system-biological approach for the causal treatment of AD, which might even be curative if the systemic intervention is initiated early enough in the disease process. Hence an individualized system-biological treatment of patients with early AD is proposed as a test for the validity of UTAD and outlined in this review.

A Kernel Machine Method for Detecting Effects of Interaction Between Multidimensional Variable Sets: An Imaging Genetics Application

PubMed Central

Ge, Tian; Nichols, Thomas E.; Ghosh, Debashis; Mormino, Elizabeth C.

2015-01-01

Measurements derived from neuroimaging data can serve as markers of disease and/or healthy development, are largely heritable, and have been increasingly utilized as (intermediate) phenotypes in genetic association studies. To date, imaging genetic studies have mostly focused on discovering isolated genetic effects, typically ignoring potential interactions with non-genetic variables such as disease risk factors, environmental exposures, and epigenetic markers. However, identifying significant interaction effects is critical for revealing the true relationship between genetic and phenotypic variables, and shedding light on disease mechanisms. In this paper, we present a general kernel machine based method for detecting effects of interaction between multidimensional variable sets. This method can model the joint and epistatic effect of a collection of single nucleotide polymorphisms (SNPs), accommodate multiple factors that potentially moderate genetic influences, and test for nonlinear interactions between sets of variables in a flexible framework. As a demonstration of application, we applied the method to data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to detect the effects of the interactions between candidate Alzheimer's disease (AD) risk genes and a collection of cardiovascular disease (CVD) risk factors, on hippocampal volume measurements derived from structural brain magnetic resonance imaging (MRI) scans. Our method identified that two genes, CR1 and EPHA1, demonstrate significant interactions with CVD risk factors on hippocampal volume, suggesting that CR1 and EPHA1 may play a role in influencing AD-related neurodegeneration in the presence of CVD risks. PMID:25600633

Sex hormones, aging, and Alzheimer’s disease

PubMed Central

Barron, Anna M.; Pike, Christian J.

2012-01-01

A promising strategy to delay and perhaps prevent Alzheimer’s disease (AD) is to identify the age-related changes that put the brain at risk for the disease. A significant normal age change known to result in tissue-specific dysfunction is the depletion of sex hormones. In women, menopause results in a relatively rapid loss of estradiol and progesterone. In men, aging is associated with a comparatively gradual yet significant decrease in testosterone. We review a broad literature that indicates age-related losses of estrogens in women and testosterone in men are risk factors for AD. Both estrogens and androgens exert a wide range of protective actions that improve multiple aspects of neural health, suggesting that hormone therapies have the potential to combat AD pathogenesis. However, translation of experimental findings into effective therapies has proven challenging. One emerging treatment option is the development of novel hormone mimetics termed selective estrogen and androgen receptor modulators. Continued research of sex hormones and their roles in the aging brain is expected to yield valuable approaches to reducing the risk of AD. PMID:22201929

Asset Mapping: A Course Assignment and Community Assessment

ERIC Educational Resources Information Center

Crozier, Mary; Melchior, Florence

2013-01-01

Asset mapping is a relatively new data collection strategy to identify services, staff capacity, programs, resources, values, and other protective factors in a geographic area that can be juxtaposed to risk factors when initiating community planning. A substance abuse prevention course for undergraduates added an assignment of assessing community…

Association between environmental factors and emergency hospital admissions due to Alzheimer's disease in Madrid.

PubMed

Culqui, D R; Linares, C; Ortiz, C; Carmona, R; Díaz, J

2017-08-15

There are scarce studies of time series that analysed the short-term association between emergency hospital admissions due to Alzheimer's disease (AD) and environmental factors. The objective is to analyse the effect of heat waves, noise and air pollutants on urgent hospital admissions due to AD in Madrid. Longitudinal ecological time series study was performed. The dependent variable was the emergency AD hospital admissions occurred in Madrid during the period 2001-2009. Independent variables were: Daily mean concentrations (μg/m3) of air pollutants (PM 2.5 and PM 10 ; O3 and NO2); maximum daily temperature (°C) and daily and night noise levels (dB(A)). Relative Risk (RR) for an increment in interquartile range, and Attributable Risk (AR) values were calculated through GLM with Poisson link. Our findings indicated that only PM 2.5 concentrations at lag 2 with a RR: 1.38 (95% CI: 1.15-1.65); AR 27.5% (95% CI: 13.0-39.4); and heat wave days at lag 3 with a RR: 1.30 (95% CI: 1.12-1.52); AR 23.1% (95% CI: 10.7-34.2) were associated with AD hospital admissions. A reduction in AD patients' exposure levels to PM 2.5 and special care of such patients during heat wave periods could result in a decrease in both emergency AD admissions and the related health care costs. Copyright © 2017 Elsevier B.V. All rights reserved.

Polygenic risk score of sporadic late-onset Alzheimer's disease reveals a shared architecture with the familial and early-onset forms.

PubMed

Cruchaga, Carlos; Del-Aguila, Jorge L; Saef, Benjamin; Black, Kathleen; Fernandez, Maria Victoria; Budde, John; Ibanez, Laura; Deming, Yuetiva; Kapoor, Manav; Tosto, Giuseppe; Mayeux, Richard P; Holtzman, David M; Fagan, Anne M; Morris, John C; Bateman, Randall J; Goate, Alison M; Harari, Oscar

2018-02-01

To determine whether the extent of overlap of the genetic architecture among the sporadic late-onset Alzheimer's Disease (sLOAD), familial late-onset AD (fLOAD), sporadic early-onset AD (sEOAD), and autosomal dominant early-onset AD (eADAD). Polygenic risk scores (PRSs) were constructed using previously identified 21 genome-wide significant loci for LOAD risk. We found that there is an overlap in the genetic architecture among sEOAD, fLOAD, and sLOAD. The highest association of the PRS and risk (odds ratio [OR] = 2.27; P = 1.29 × 10 -7 ) was observed in sEOAD, followed by fLOAD (OR = 1.75; P = 1.12 × 10 -7 ) and sLOAD (OR = 1.40; P = 1.21 × 10 -3 ). The PRS was associated with cerebrospinal fluid ptau 181 -Aβ 42 on eADAD (P = 4.36 × 10 -2 ). Our analysis confirms that the genetic factors identified for LOAD modulate risk in sLOAD and fLOAD and also sEOAD cohorts. Specifically, our results suggest that the burden of these risk variants is associated with familial clustering and earlier onset of AD. Although these variants are not associated with risk in the eADAD, they may be modulating age at onset. Copyright © 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Risk factors for medical complications after long-level internal fixation in the treatment of adult degenerative scoliosis.

PubMed

Zhang, Xi-Nuo; Sun, Xiang-Yao; Meng, Xiang-Long; Hai, Yong

2018-04-13

This study evaluates baseline patient characteristics and surgical parameters for risk factors of medical complications in ASD patients received posterior long level internal fixation. Analysis of consecutive patients who underwent posterior long-level instruction fixation for adult degenerative scoliosis (ADS) with a minimum of two year follow-up was performed. Pre-operative risk factors, intraoperative variables, peri-operative radiographic parameters, and surgical-related risk factors were collected to analyze the effect of risk factors on medical complications. Patients were separated into groups with and without medical complication. Then, complication group was further classified as major or minor medical complications. Potential risk factors were identified by univariate testing. Multivariate logistic regression was used to evaluate independent predictors of medical complications. One hundred and thirty-one ADS patients who underwent posterior long segment pedicle screws fixation were included. Total medical complication incidence was 25.2%, which included infection (12.2%), neurological (11.5%), cardiopulmonary (7.6%), gastrointestinal (6.1%), and renal (1.5%) complications. Overall, 7.6% of patients developed major medical complications, and 17.6% of patients developed minor medical complications. The radiographic parameters of pre-operative and last follow-up had no significant difference between the groups of medical complications and the major or minor medical complications subgroups. However, the incidence of cerebrospinal fluid leak (CFL) in patients who without medical complications was much lower than that with medical complications (18.4 vs. 42.4%, P = 0.005). Independent risk factors for development of medical complications included smoking (OR = 6.45, P = 0.012), heart disease (OR = 10.07, P = 0.012), fusion level (OR = 2.12, P = 0.001), and length of hospital stay (LOS) (OR = 2.11, P = 0.000). Independent risk factors for development of major medical complications were diabetes (OR 6.81, P = 0.047) and heart disease (OR = 5.99, P = 0.049). Except for the last follow-up, Oswestry Disability Index and visual analog scale of the patient experienced medical complications trend higher score; the clinical outcomes have no significant difference between the medical and major complications groups. Heart disease comorbidity is an independent risk factor for both medical and major medical complications. Smoking, fusion level, and LOS are independent risk factors for medical complication. Diabetes is the independent risk factors for major medical complications.

New Insights on the Risk for Cardiovascular Disease in African Americans: The Role of Added Sugars

PubMed Central

Saab, Karim R.; Kendrick, Jessica; Yracheta, Joseph M.; Lanaspa, Miguel A.; Pollard, Maisha

2015-01-01

African Americans are at increased risk for cardiovascular and metabolic diseases, including obesity, high BP, diabetes, CKD, myocardial infarction, and stroke. Here we summarize the current risks and provide an overview of the underlying risk factors that may account for these associations. By reviewing the relationship between cardiovascular and renal diseases and the African-American population during the early 20th century, the historic and recent associations of African heritage with cardiovascular disease, and modern population genetics, it is possible to assemble strong hypotheses for the primary underlying mechanisms driving the increased frequency of disease in African Americans. Our studies suggest that underlying genetic mechanisms may be responsible for the increased frequency of high BP and kidney disease in African Americans, with particular emphasis on the role of APOL1 polymorphisms in causing kidney disease. In contrast, the Western diet, particularly the relatively high intake of fructose-containing sugars and sweetened beverages, appears to be the dominant force driving the increased risk of diabetes, obesity, and downstream complications. Given that intake of added sugars is a remediable risk factor, we recommend clinical trials to examine the reduction of sweetened beverages as a primary means for reducing cardiovascular risk in African Americans. PMID:25090991

Buying time: a rationale for examining the use of circadian rhythm and sleep interventions to delay progression of mild cognitive impairment to Alzheimer’s disease

PubMed Central

Landry, Glenn J.; Liu-Ambrose, Teresa

2014-01-01

As of 2010, the worldwide economic impact of dementia was estimated at $604 billion USD; and without discovery of a cure or effective interventions to delay disease progression, dementia’s annual global economic impact is expected to surpass $1 trillion USD as early as 2030. Alzheimer’s disease (AD) is the leading cause of dementia accounting for over 75% of all cases. Toxic accumulation of amyloid beta (Aβ), either by overproduction or some clearance failure, is thought to be an underlying mechanism of the neuronal cell death characteristic of AD—though this amyloid hypothesis has been increasingly challenged in recent years. A compelling alternative hypothesis points to chronic neuroinflammation as a common root in late-life degenerative diseases including AD. Apolipoprotein-E (APOE) genotype is the strongest genetic risk factor for AD: APOE-ε4 is proinflammatory and individuals with this genotype accumulate more Aβ, are at high risk of developing AD, and almost half of all AD patients have at least one ε4 allele. Recent studies suggest a bidirectional relationship exists between sleep and AD pathology. Sleep may play an important role in Aβ clearance, and getting good quality sleep vs. poor quality sleep might reduce the AD risk associated with neuroinflammation and the ε4 allele. Taken together, these findings are particularly important given the sleep disruptions commonly associated with AD and the increased burden disrupted sleep poses for AD caregivers. The current review aims to: (1) identify individuals at high risk for dementia who may benefit most from sleep interventions; (2) explore the role poor sleep quality plays in exacerbating AD type dementia; (3) examine the science of sleep interventions to date; and (4) provide a road map in pursuit of comprehensive sleep interventions, specifically targeted to promote cognitive function and delay progression of dementia. PMID:25538616

Environmental pollutants as risk factors for neurodegenerative disorders: Alzheimer and Parkinson diseases

PubMed Central

Chin-Chan, Miguel; Navarro-Yepes, Juliana; Quintanilla-Vega, Betzabet

2015-01-01

Neurodegenerative diseases including Alzheimer (AD) and Parkinson (PD) have attracted attention in last decades due to their high incidence worldwide. The etiology of these diseases is still unclear; however the role of the environment as a putative risk factor has gained importance. More worryingly is the evidence that pre- and post-natal exposures to environmental factors predispose to the onset of neurodegenerative diseases in later life. Neurotoxic metals such as lead, mercury, aluminum, cadmium and arsenic, as well as some pesticides and metal-based nanoparticles have been involved in AD due to their ability to increase beta-amyloid (Aβ) peptide and the phosphorylation of Tau protein (P-Tau), causing senile/amyloid plaques and neurofibrillary tangles (NFTs) characteristic of AD. The exposure to lead, manganese, solvents and some pesticides has been related to hallmarks of PD such as mitochondrial dysfunction, alterations in metal homeostasis and aggregation of proteins such as α-synuclein (α-syn), which is a key constituent of Lewy bodies (LB), a crucial factor in PD pathogenesis. Common mechanisms of environmental pollutants to increase Aβ, P-Tau, α-syn and neuronal death have been reported, including the oxidative stress mainly involved in the increase of Aβ and α-syn, and the reduced activity/protein levels of Aβ degrading enzyme (IDE)s such as neprilysin or insulin IDE. In addition, epigenetic mechanisms by maternal nutrient supplementation and exposure to heavy metals and pesticides have been proposed to lead phenotypic diversity and susceptibility to neurodegenerative diseases. This review discusses data from epidemiological and experimental studies about the role of environmental factors in the development of idiopathic AD and PD, and their mechanisms of action. PMID:25914621

Apolipoprotein E: Risk factor for Alzheimer disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tsai, M.S.; Thibodeau, S.N.; Tangalos, E.G.

1994-04-01

The apolipoprotein E gene (APOE) has three common alleles (E2, E3, and E4) that determine six genotypes in the general population. In this study, the authors examined 77 patients with late-onset Alzheimer disease (AD), along with an equal number of age- and sex-matched controls, for an association with the APOE-E4 allele. They show that the frequency of this allele among AD patients was significantly higher than that among the control population (.351 vs. .130, P = .000006). The genotype frequencies also differed between the two groups (P = .0002), with the APOE-E4/E3 genotype being the most common in the ADmore » group and the APOE-E3/E3 being the most common in the control group. In the AD group, homozygosity for E4 was found in nine individuals, whereas none was found in the control group. The odds ratio for AD, when associated with one or two E4 alleles, was 4.6 (95% confidence interval [CI] 1.9-12.3), while the odds ratio for AD, when associated with heterozygosity for APOE-E4, was 3.6 (05% CI 1.5-9.8). Finally, the median age at onset among the AD patients decreased from 83 to 78 to 74 years as the number of APOE-E4 alleles increased from 0 to 1 to 2, respectively (test for trend, P = .001). The data, which are in agreement with recent reports, suggest that the APOE-E4 allele is associated with AD and that this allelic variant may be an important risk factor for susceptibility to AD in the general population. 30 refs., 5 tabs.« less

Blood-derived integration-free iPS cell line UKBi011-A from a diagnosed male Alzheimer's disease patient with APOE ɛ4/ɛ4 genotype.

PubMed

Peitz, Michael; Bechler, Tamara; Thiele, Catrin Cornelia; Veltel, Monika; Bloschies, Melanie; Fliessbach, Klaus; Ramirez, Alfredo; Brüstle, Oliver

2018-04-23

Alzheimer's disease (AD) is most the frequent neurodegenerative disease, and the APOE ε4 allele is the most prominent risk factor for late-onset AD. Here, we present an iPSC line generated from peripheral blood cells of a male AD patient employing Sendai virus vectors encoding the transcription factors OCT4, SOX2, KLF4 and c-MYC. The characterized iPSC line expresses typical human pluripotency markers and shows differentiation into all three germ layers, complete reprogramming vector clearance, a normal SNP genotype and maintenance of the APOE ε4/ε4 allele. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

The 32-year relationship between cholesterol and dementia from midlife to late life.

PubMed

Mielke, M M; Zandi, P P; Shao, H; Waern, M; Östling, S; Guo, X; Björkelund, C; Lissner, L; Skoog, I; Gustafson, D R

2010-11-23

Cellular and animal studies suggest that hypercholesterolemia contributes to Alzheimer disease (AD). However, the relationship between cholesterol and dementia at the population level is less clear and may vary over the lifespan. The Prospective Population Study of Women, consisting of 1,462 women without dementia aged 38-60 years, was initiated in 1968-1969 in Gothenburg, Sweden. Follow-ups were conducted in 1974-1975, 1980-1981, 1992-1993, and 2000-2001. All-cause dementia was diagnosed according to DSM-III-R criteria and AD according to National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria. Cox proportional hazards regression examined baseline, time-dependent, and change in cholesterol levels in relation to incident dementia and AD among all participants. Analyses were repeated among participants who survived to the age of 70 years or older and participated in the 2000-2001 examination. Higher cholesterol level in 1968 was not associated with an increased risk of AD (highest vs lowest quartile: hazard ratio [HR] 2.82, 95% confidence interval [CI] 0.94-8.43) among those who survived to and participated in the 2000-2001 examination. While there was no association between cholesterol level and dementia when considering all participants over 32 years, a time-dependent decrease in cholesterol over the follow-up was associated with an increased risk of dementia (HR 2.35, 95% CI 1.22-4.58). These data suggest that midlife cholesterol level is not associated with an increased risk of AD. However, there may be a slight risk among those surviving to an age at risk for dementia. Declining cholesterol levels from midlife to late life may better predict AD risk than levels obtained at one timepoint prior to dementia onset. Analytic strategies examining this and other risk factors across the lifespan may affect interpretation of results.

Short-term modern life-like stress exacerbates Aβ-pathology and synapse loss in 3xTg-AD mice.

PubMed

Baglietto-Vargas, David; Chen, Yuncai; Suh, Dongjin; Ager, Rahasson R; Rodriguez-Ortiz, Carlos J; Medeiros, Rodrigo; Myczek, Kristoffer; Green, Kim N; Baram, Tallie Z; LaFerla, Frank M

2015-09-01

Alzheimer's disease (AD) is a progressive neurological disorder that impairs memory and other cognitive functions in the elderly. The social and financial impacts of AD are overwhelming and are escalating exponentially as a result of population aging. Therefore, identifying AD-related risk factors and the development of more efficacious therapeutic approaches are critical to cure this neurological disorder. Current epidemiological evidence indicates that life experiences, including chronic stress, are a risk for AD. However, it is unknown if short-term stress, lasting for hours, influences the onset or progression of AD. Here, we determined the effect of short-term, multi-modal 'modern life-like' stress on AD pathogenesis and synaptic plasticity in mice bearing three AD mutations (the 3xTg-AD mouse model). We found that combined emotional and physical stress lasting 5 h severely impaired memory in wild-type mice and tended to impact it in already low-performing 3xTg-AD mice. This stress reduced the number of synapse-bearing dendritic spines in 3xTg-AD mice and increased Aβ levels by augmenting AβPP processing. Thus, short-term stress simulating modern-life conditions may exacerbate cognitive deficits in preclinical AD by accelerating amyloid pathology and reducing synapse numbers. Epidemiological evidence indicates that life experiences, including chronic stress, are a risk for Alzheimer disease (AD). However, it is unknown if short stress in the range of hours influences the onset or progression of AD. Here, we determined the effect of short, multi-modal 'modern-lifelike'stress on AD pathogenesis and synaptic plasticity in mice bearing three AD mutations (the 3xTg-AD mouse model). We found that combined emotional and physical stress lasting 5 h severely impaired memory in wild-type mice and tended to impact it in already low-performing 3xTg-AD mice. This stress reduced the number of synapse-bearing dendritic spines in 3xTg-AD mice and increased Aβ levels by augmenting AβPP processing. Thus, short stress simulating modern-life conditions may exacerbate cognitive deficits in preclinical AD by accelerating amyloid pathology and reducing synapse numbers. © 2015 International Society for Neurochemistry.

Accelerated failure time models for semi-competing risks data in the presence of complex censoring.

PubMed

Lee, Kyu Ha; Rondeau, Virginie; Haneuse, Sebastien

2017-12-01

Statistical analyses that investigate risk factors for Alzheimer's disease (AD) are often subject to a number of challenges. Some of these challenges arise due to practical considerations regarding data collection such that the observation of AD events is subject to complex censoring including left-truncation and either interval or right-censoring. Additional challenges arise due to the fact that study participants under investigation are often subject to competing forces, most notably death, that may not be independent of AD. Towards resolving the latter, researchers may choose to embed the study of AD within the "semi-competing risks" framework for which the recent statistical literature has seen a number of advances including for the so-called illness-death model. To the best of our knowledge, however, the semi-competing risks literature has not fully considered analyses in contexts with complex censoring, as in studies of AD. This is particularly the case when interest lies with the accelerated failure time (AFT) model, an alternative to the traditional multiplicative Cox model that places emphasis away from the hazard function. In this article, we outline a new Bayesian framework for estimation/inference of an AFT illness-death model for semi-competing risks data subject to complex censoring. An efficient computational algorithm that gives researchers the flexibility to adopt either a fully parametric or a semi-parametric model specification is developed and implemented. The proposed methods are motivated by and illustrated with an analysis of data from the Adult Changes in Thought study, an on-going community-based prospective study of incident AD in western Washington State. © 2017, The International Biometric Society.

Atopic dermatitis increases the effect of exposure to peanut antigen in dust on peanut sensitization and likely peanut allergy

PubMed Central

Brough, Helen A.; Liu, Andrew H.; Sicherer, Scott; Makinson, Kerry; Douiri, Abdel; Brown, Sara J.; Stephens, Alick C.; Irwin McLean, W.H.; Turcanu, Victor; Wood, Robert A.; Jones, Stacie M.; Burks, Wesley; Dawson, Peter; Stablein, Donald; Sampson, Hugh; Lack, Gideon

2015-01-01

Background History and severity of atopic dermatitis (AD) are risk factors for peanut allergy. Recent evidence suggests that children can become sensitized to food allergens through an impaired skin barrier. Household peanut consumption, which correlates strongly with peanut protein levels in household dust, is a risk factor for peanut allergy. Objective We sought to assess whether environmental peanut exposure (EPE) is a risk for peanut sensitization and allergy and whether markers of an impaired skin barrier modify this risk. Methods Peanut protein in household dust (in micrograms per gram) was assessed in highly atopic children (age, 3-15 months) recruited to the Consortium of Food Allergy Research Observational Study. History and severity of AD, peanut sensitization, and likely allergy (peanut-specific IgE, ≥5 kUA/mL) were assessed at recruitment into the Consortium of Food Allergy Research study. Results There was an exposure-response relationship between peanut protein levels in household dust and peanut skin prick test (SPT) sensitization and likely allergy. In the final multivariate model an increase in 4 log2 EPE units increased the odds of peanut SPT sensitization (1.71-fold; 95% CI, 1.13- to 2.59-fold; P = .01) and likely peanut allergy (PA; 2.10-fold; 95% CI, 1.20- to 3.67-fold; P < .01). The effect of EPE on peanut SPT sensitization was augmented in children with a history of AD (OR, 1.97; 95% CI, 1.26-3.09; P < .01) and augmented even further in children with a history of severe AD (OR, 2.41; 95% CI, 1.30-4.47; P < .01); the effect of EPE on PA was also augmented in children with a history of AD (OR, 2.34; 95% CI, 1.31-4.18; P < .01). Conclusion Exposure to peanut antigen in dust through an impaired skin barrier in atopically inflamed skin is a plausible route for peanut SPT sensitization and PA. PMID:25457149

Genetic susceptibility for Alzheimer disease neuritic plaque pathology.

PubMed

Shulman, Joshua M; Chen, Kewei; Keenan, Brendan T; Chibnik, Lori B; Fleisher, Adam; Thiyyagura, Pradeep; Roontiva, Auttawut; McCabe, Cristin; Patsopoulos, Nikolaos A; Corneveaux, Jason J; Yu, Lei; Huentelman, Matthew J; Evans, Denis A; Schneider, Julie A; Reiman, Eric M; De Jager, Philip L; Bennett, David A

2013-09-01

While numerous genetic susceptibility loci have been identified for clinical Alzheimer disease (AD), it is important to establish whether these variants are risk factors for the underlying disease pathology, including neuritic plaques. To investigate whether AD susceptibility loci from genome-wide association studies affect neuritic plaque pathology and to additionally identify novel risk loci for this trait. Candidate analysis of single-nucleotide polymorphisms and genome-wide association study in a joint clinicopathologic cohort, including 725 deceased subjects from the Religious Orders Study and the Rush Memory and Aging Project (2 prospective, community-based studies), followed by targeted validation in an independent neuroimaging cohort, including 114 subjects from multiple clinical and research centers. A quantitative measure of neuritic plaque pathologic burden, based on assessments of silver-stained tissue averaged from multiple brain regions. Validation based on β-amyloid load by immunocytochemistry, and replication with fibrillar β-amyloid positron emission tomographic imaging with Pittsburgh Compound B or florbetapir. Besides the previously reported APOE and CR1 loci, we found that the ABCA7 (rs3764650; P = .02) and CD2AP (rs9349407; P = .03) AD susceptibility loci are associated with neuritic plaque burden. In addition, among the top results of our genome-wide association study, we discovered a novel variant near the amyloid precursor protein gene (APP, rs2829887) that is associated with neuritic plaques (P = 3.3 × 10-6). This polymorphism was associated with postmortem β-amyloid load as well as fibrillar β-amyloid in 2 independent cohorts of adults with normal cognition. These findings enhance understanding of AD risk factors by relating validated susceptibility alleles to increased neuritic plaque pathology and implicate common genetic variation at the APP locus in the earliest, presymptomatic stages of AD.

Importance and management of micronutrient deficiencies in patients with Alzheimer’s disease

PubMed Central

Cardoso, Bárbara Rita; Cominetti, Cristiane; Cozzolino, Silvia Maria Franciscato

2013-01-01

Alzheimer’s disease (AD) is the most common form of dementia, and it generally affects the elderly. It has been suggested that diet is an intensively modifiable lifestyle factor that might reduce the risk of AD. Because epidemiological studies generally report the potential neuronal protective effects of various micronutrients, the aim of this study was to perform a literature review on the major nutrients that are related to AD, including selenium, vitamins C and E, transition metals, vitamin D, B-complex vitamins, and omega-3 fatty acids. PMID:23696698

Association of Insulin Resistance With Cerebral Glucose Uptake in Late Middle-Aged Adults at Risk for Alzheimer Disease.

PubMed

Willette, Auriel A; Bendlin, Barbara B; Starks, Erika J; Birdsill, Alex C; Johnson, Sterling C; Christian, Bradley T; Okonkwo, Ozioma C; La Rue, Asenath; Hermann, Bruce P; Koscik, Rebecca L; Jonaitis, Erin M; Sager, Mark A; Asthana, Sanjay

2015-09-01

Converging evidence suggests that Alzheimer disease (AD) involves insulin signaling impairment. Patients with AD and individuals at risk for AD show reduced glucose metabolism, as indexed by fludeoxyglucose F 18-labeled positron emission tomography (FDG-PET). To determine whether insulin resistance predicts AD-like global and regional glucose metabolism deficits in late middle-aged participants at risk for AD and to examine whether insulin resistance-predicted variation in regional glucose metabolism is associated with worse cognitive performance. This population-based, cross-sectional study included 150 cognitively normal, late middle-aged (mean [SD] age, 60.7 [5.8] years) adults from the Wisconsin Registry for Alzheimer's Prevention (WRAP) study, a general community sample enriched for AD parental history. Participants underwent cognitive testing, fasting blood draw, and FDG-PET at baseline. We used the homeostatic model assessment of peripheral insulin resistance (HOMA-IR). Regression analysis tested the statistical effect of HOMA-IR on global glucose metabolism. We used a voxelwise analysis to determine whether HOMA-IR predicted regional glucose metabolism. Finally, predicted variation in regional glucose metabolism was regressed against cognitive factors. Covariates included age, sex, body mass index, apolipoprotein E ε4 genotype, AD parental history status, and a reference region used to normalize regional uptake. Regional glucose uptake determined using FDG-PET and neuropsychological factors. Higher HOMA-IR was associated with lower global glucose metabolism (β = -0.29; P < .01) and lower regional glucose metabolism across large portions of the frontal, lateral parietal, lateral temporal, and medial temporal lobes (P < .05, familywise error corrected). The association was especially robust in the left medial temporal lobe (R2 = 0.178). Lower glucose metabolism in the left medial temporal lobe predicted by HOMA-IR was significantly related to worse performance on the immediate memory (β = 0.317; t148 = 4.08; P < .001) and delayed memory (β = 0.305; t148 = 3.895; P < .001) factor scores. Our results show that insulin resistance, a prevalent and increasingly common condition in developed countries, is associated with significantly lower regional cerebral glucose metabolism, which in turn may predict worse memory performance. Midlife may be a critical period for initiating treatments to lower peripheral insulin resistance to maintain neural metabolism and cognitive function.

Genome-wide association analysis of age-at-onset in Alzheimer’s disease

PubMed Central

Kamboh, M. Ilyas; Barmada, M. Michael; Demirci, F. Yesim; Minster, Ryan L.; Carrasquillo, Minerva M.; Pankratz, V. Shane; Younkin, Steven G.; Saykin, Andrew J.; Sweet, Robert A.; Feingold, Eleanor; DeKosky, Steven T.; Lopez, Oscar L.

2011-01-01

The risk of Alzheimer’s disease (AD) is strongly determined by genetic factors and recent genome-wide association studies (GWAS) have identified several genes for the disease risk. In addition to the disease risk, age-at-onset (AAO) of AD has also strong genetic component with an estimated heritability of 42%. Identification of AAO genes may help to understand the biological mechanisms that regulate the onset of the disease. Here we report the first GWAS focused on identifying genes for the AAO of AD. We performed a genome-wide meta analysis on 3 samples comprising a total of 2,222 AD cases. A total of ~2.5 million directly genotyped or imputed SNPs were analyzed in relation to AAO of AD. As expected, the most significant associations were observed in the APOE region on chromosome 19 where several SNPs surpassed the conservative genome-wide significant threshold (P<5E-08). The most significant SNP outside the APOE region was located in the DCHS2 gene on chromosome 4q31.3 (rs1466662; P=4.95E-07). There were 19 additional significant SNPs in this region at P<1E-04 and the DCHS2 gene is expressed in the cerebral cortex and thus is a potential candidate for affecting AAO in AD. These findings need to be confirmed in additional well-powered samples. PMID:22005931

Genome-wide association analysis of age-at-onset in Alzheimer's disease.

PubMed

Kamboh, M I; Barmada, M M; Demirci, F Y; Minster, R L; Carrasquillo, M M; Pankratz, V S; Younkin, S G; Saykin, A J; Sweet, R A; Feingold, E; DeKosky, S T; Lopez, O L

2012-12-01

The risk of Alzheimer's disease (AD) is strongly determined by genetic factors and recent genome-wide association studies (GWAS) have identified several genes for the disease risk. In addition to the disease risk, age-at-onset (AAO) of AD has also strong genetic component with an estimated heritability of 42%. Identification of AAO genes may help to understand the biological mechanisms that regulate the onset of the disease. Here we report the first GWAS focused on identifying genes for the AAO of AD. We performed a genome-wide meta-analysis on three samples comprising a total of 2222 AD cases. A total of ~2.5 million directly genotyped or imputed single-nucleotide polymorphisms (SNPs) were analyzed in relation to AAO of AD. As expected, the most significant associations were observed in the apolipoprotein E (APOE) region on chromosome 19 where several SNPs surpassed the conservative genome-wide significant threshold (P<5E-08). The most significant SNP outside the APOE region was located in the DCHS2 gene on chromosome 4q31.3 (rs1466662; P=4.95E-07). There were 19 additional significant SNPs in this region at P<1E-04 and the DCHS2 gene is expressed in the cerebral cortex and thus is a potential candidate for affecting AAO in AD. These findings need to be confirmed in additional well-powered samples.

Social relationships and risk of dementia: a population-based study.

PubMed

Sörman, Daniel Eriksson; Rönnlund, Michael; Sundström, Anna; Adolfsson, Rolf; Nilsson, Lars-Göran

2015-08-01

The objective was to examine whether aspects of social relationships in old age are associated with all-cause dementia and Alzheimer's disease (AD). We studied 1,715 older adults (≥ 65 years) who were dementia-free at baseline over a period of up to 16 years. Data on living status, contact/visit frequency, satisfaction with contact frequency, and having/not having a close friend were analyzed using Cox proportional hazards regressions with all-cause dementia or AD as the dependent variable. To control for reverse causality and to identify potential long-term effects, we additionally performed analyses with delayed entry. We identified 373 incident cases of dementia (207 with AD) during follow-up. The variable visiting/visits from friends was associated with reduced risk of all-cause dementia. Further, a higher value on the relationships index (sum of all variables) was associated with reduced risk of all-cause dementia and AD. However, in analyses with delayed entry, restricted to participants with a survival time of three years or more, none of the social relationship variables was associated with all-cause dementia or AD. The results indicate that certain aspects of social relationships are associated with incident dementia or AD, but also that these associations may reflect reverse causality. Future studies aimed at identifying other factors of a person's social life that may have the potential to postpone dementia should consider the effects of reverse causality.

Apolipoprotein E gene polymorphism and Alzheimer's disease in Chinese population: a meta-analysis

NASA Astrophysics Data System (ADS)

Liu, Mengying; Bian, Chen; Zhang, Jiqiang; Wen, Feng

2014-03-01

The relationship between Apolipoprotein E (ApoE) genotype and the risk of Alzheimer's disease (AD) is relatively well established in Caucasians, but less established in other ethnicities. To examine the association between ApoE polymorphism and the onset of AD in Chinese population, we searched the commonly used electronic databases between January 2000 and November 2013 for relevant studies. Total 20 studies, including 1576 cases and 1741 controls, were retrieved. The results showed statistically significant positive association between risk factor ɛ4 allele carriers and AD in Chinese population (OR = 3.93, 95% CI = 3.37-4.58, P < 0.00001). Genotype ApoE ɛ4/ɛ4 and ɛ4/ɛ3 have statistically significant association with AD as well (ɛ4/ɛ4: OR = 11.76, 95% CI = 6.38-21.47, P < 0.00001; ɛ4/ɛ3: OR = 3.08, 95% CI = 2.57-3.69, P < 0.00001). Furthermore, the frequency of the ApoE ɛ3 is lower in AD than that in the health controls, and the difference of ɛ3 allele is also statistically significant (OR = 0.42, 95% CI = 0.37-0.47, P < 0.00001). No significant heterogeneity was observed among all studies. This meta-analysis suggests that the subject with at least one ApoE ɛ4 allele has higher risk suffering from AD than controls in Chinese population. The results also provide a support for the protection effect of ApoE ɛ3 allele in developing AD.

Candidate gene analysis for Alzheimer's disease in adults with Down syndrome.

PubMed

Lee, Joseph H; Lee, Annie J; Dang, Lam-Ha; Pang, Deborah; Kisselev, Sergey; Krinsky-McHale, Sharon J; Zigman, Warren B; Luchsinger, José A; Silverman, Wayne; Tycko, Benjamin; Clark, Lorraine N; Schupf, Nicole

2017-08-01

Individuals with Down syndrome (DS) overexpress many genes on chromosome 21 due to trisomy and have high risk of dementia due to the Alzheimer's disease (AD) neuropathology. However, there is a wide range of phenotypic differences (e.g., age at onset of AD, amyloid β levels) among adults with DS, suggesting the importance of factors that modify risk within this particularly vulnerable population, including genotypic variability. Previous genetic studies in the general population have identified multiple genes that are associated with AD. This study examined the contribution of polymorphisms in these genes to the risk of AD in adults with DS ranging from 30 to 78 years of age at study entry (N = 320). We used multiple logistic regressions to estimate the likelihood of AD using single-nucleotide polymorphisms (SNPs) in candidate genes, adjusting for age, sex, race/ethnicity, level of intellectual disability and APOE genotype. This study identified multiple SNPs in APP and CST3 that were associated with AD at a gene-wise level empirical p-value of 0.05, with odds ratios in the range of 1.5-2. SNPs in MARK4 were marginally associated with AD. CST3 and MARK4 may contribute to our understanding of potential mechanisms where CST3 may contribute to the amyloid pathway by inhibiting plaque formation, and MARK4 may contribute to the regulation of the transition between stable and dynamic microtubules. Copyright © 2017 Elsevier Inc. All rights reserved.

FABP4 predicts atherogenic dyslipidemia development. The PREDIMED study.

PubMed

Cabré, Anna; Babio, Nancy; Lázaro, Iolanda; Bulló, Mònica; Garcia-Arellano, Ana; Masana, Lluís; Salas-Salvadó, Jordi

2012-05-01

Atherogenic dyslipidemia (AD), characterized by high plasma triglycerides and low HDL particles, is considered one of the main effectors of vascular damage associated with obesity, metabolic syndrome (MS) and type 2 diabetes. Adipocyte fatty acid-binding protein (FABP4) plasma concentrations have been linked to metabolic alterations that are associated with adiposity. The aim of the present study was to prospectively analyze the predictive value of baseline FABP4 plasma concentrations for the development of AD. In the frame of the PREDIMED study, a multicenter dietary interventional trial, we prospectively measured the baseline plasma FABP4 levels and AD incidence over a six-year follow-up period (median 4 [IQR, 3-5 years]) in 578 volunteers who visited their general practitioners because of their cardiovascular risk factors. During follow-up, 103 participants developed AD. Baseline plasma FABP4 levels were associated with new onset AD over the follow-up period (OR 1.03 [95% IC: 1.00-1.05], p=0.020). This increased risk was observed in women but not in men. Among women, those in the highest tertile of FABP4 had a 2.54-fold increased relative risk of developing AD compared to the lowest tertile (HR 2.54 [95% CI, 1.31-4.93], p for trend=0.008). Elevated plasma FABP4 concentrations should be considered as a potential marker of metabolic derangement, which may predict the development of AD in women. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Hospital-treated mental and behavioral disorders and risk of Alzheimer's disease: A nationwide nested case-control study.

PubMed

Tapiainen, V; Hartikainen, S; Taipale, H; Tiihonen, J; Tolppanen, A-M

2017-06-01

Studies investigating psychiatric disorders as Alzheimer's disease (AD) risk factors have yielded heterogeneous findings. Differences in time windows between the exposure and outcome could be one explanation. We examined whether (1) mental and behavioral disorders in general or (2) specific mental and behavioral disorder categories increase the risk of AD and (3) how the width of the time window between the exposure and outcome affects the results. A nationwide nested case-control study of all Finnish clinically verified AD cases, alive in 2005 and their age, sex and region of residence matched controls (n of case-control pairs 27,948). History of hospital-treated mental and behavioral disorders was available since 1972. Altogether 6.9% (n=1932) of the AD cases and 6.4% (n=1784) of controls had a history of any mental and behavioral disorder. Having any mental and behavioral disorder (adjusted OR=1.07, 95% CI=1.00-1.16) or depression/other mood disorder (adjusted OR=1.17, 95% CI=1.05-1.30) were associated with higher risk of AD with 5-year time window but not with 10-year time window (adjusted OR, 95% CI 0.99, 0.91-1.08 for any disorder and 1.08, 0.96-1.23 for depression). The associations between mental and behavioral disorders and AD were modest and dependent on the time window. Therefore, some of the disorders may represent misdiagnosed prodromal symptoms of AD, which underlines the importance of proper differential diagnostics among older persons. These findings also highlight the importance of appropriate time window in psychiatric and neuroepidemiology research. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Traditional used Plants against Cognitive Decline and Alzheimer Disease

PubMed Central

Eckert, Gunter Peter

2010-01-01

Alzheimer's disease (AD) is a neurodegenerative disorder characterized clinically by progressive memory deficits, impaired cognitive function, and altered and inappropriate behavior. Aging represents the most important risk factor for AD and the global trend in the phenomenon of population aging has dramatic consequences for public health, healthcare financing, and delivery systems in the word and, especially in developing countries. Mounting evidence obtained in in vitro and in vivo studies, suggests that various traditionally used plants in Asia, India, and Europe significantly affect key metabolic alterations culminating in AD-typical neurodegeneration. The present article aims to bring the reader up-to-date on the most recent studies and advances describing the direct and indirect activities of traditional used plants and its constituents possibly relieving features of AD. A variety of traditional used plants and its extracts exerted activities on AD related drug targets including AChE activity, antioxidative activity, modulation of Aβ-producing secretase activities, Aβ-degradation, heavy metal chelating, induction of neurotrophic factors, and cell death mechanisms. Although pre-clinical investigations identified promising drug candidates for AD, clinical evidences are still pending. PMID:21833177

Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer's disease

PubMed Central

Small, Gary W.; Ercoli, Linda M.; Silverman, Daniel H. S.; Huang, S.-C.; Komo, Scott; Bookheimer, Susan Y.; Lavretsky, Helen; Miller, Karen; Siddarth, Prabha; Rasgon, Natalie L.; Mazziotta, John C.; Saxena, Sanjaya; Wu, H. M.; Mega, Michael S.; Cummings, Jeffrey L.; Saunders, Ann M.; Pericak-Vance, Margaret A.; Roses, Allen D.; Barrio, Jorge R.; Phelps, Michael E.

2000-01-01

The major known genetic risk for Alzheimer's disease (AD), apolipoprotein E-4 (APOE-4), is associated with lowered parietal, temporal, and posterior cingulate cerebral glucose metabolism in patients with a clinical diagnosis of AD. To determine cognitive and metabolic decline patterns according to genetic risk, we investigated cerebral metabolic rates by using positron emission tomography in middle-aged and older nondemented persons with normal memory performance. A single copy of the APOE-4 allele was associated with lowered inferior parietal, lateral temporal, and posterior cingulate metabolism, which predicted cognitive decline after 2 years of longitudinal follow-up. For the 20 nondemented subjects followed longitudinally, memory performance scores did not decline significantly, but cortical metabolic rates did. In APOE-4 carriers, a 4% left posterior cingulate metabolic decline was observed, and inferior parietal and lateral temporal regions demonstrated the greatest magnitude (5%) of metabolic decline after 2 years. These results indicate that the combination of cerebral metabolic rates and genetic risk factors provides a means for preclinical AD detection that will assist in response monitoring during experimental treatments. PMID:10811879

Metabolic Syndrome and Cognitive Decline in Early Alzheimer’s Disease and Healthy Older Adults

PubMed Central

Watts, Amber S.; Loskutova, Natalia; Burns, Jeffrey M.; Johnson, David K.

2013-01-01

Metabolic syndrome (MetS) is a cluster of risk factors (i.e., abdominal obesity, hypertension, dyslipidemia, glucose and insulin dysregulation) that is associated with cardiovascular disease, diabetes, and dementia. Recent studies addressing the association of MetS with cognitive performance and risk for dementia report mixed results. An important step in clarifying these conflicting results is determining whether cognition is influenced by the effects of individual MetS components versus the additive effects of multiple components. We assessed the effect of MetS on cognitive performance and decline over two years in 75 cases of early Alzheimer’s disease (AD) and 73 healthy older adult controls in the Brain Aging Project. Using factor analytic techniques, we compared the effect of a combined MetS factor to the effect of individual MetS components on change in attention, verbal memory, and mental status. In healthy controls, a combined MetS factor did not significantly predict cognitive performance, though higher insulin predicted poorer cognitive performance outcomes. In the AD group, higher scores on a combined MetS factor predicted better cognitive outcomes. Our findings suggest that MetS does not have the same association with cognitive decline in healthy older adults and those with early AD. We suggest that individual MetS components should not be evaluated in isolation and that careful methodological approaches are needed to understand the timing and non-linear relationships among these components over time. PMID:23388170

Potential Therapeutics for Vascular Cognitive Impairment and Dementia.

PubMed

Sun, Miao-Kun

2017-10-16

As the human lifespan increases, the number of people affected by age-related dementia is growing at an epidemic pace. Vascular pathology dramatically affects cognitive profiles, resulting in dementia and cognitive impairment. While vascular dementia itself constitutes a medical challenge, hypoperfusion/vascular risk factors enhance amyloid toxicity and other memory-damaging factors and hasten Alzheimer's disease (AD) and other memory disorders' progression, as well as negatively affect treatment outcome. Few therapeutic options are, however, currently available to improve the prognosis of patients with vascular dementia and cognitive impairment, mixed AD dementia with vascular pathology, or other memory disorders. Emerging evidence, however, indicates that, like AD and other memory disorders, synaptic impairment underlies much of the memory impairment in the cognitive decline of vascular cognitive impairment and vascular dementia. Effective rescues of the memory functions might be achieved through synaptic and memory therapeutics, targeting distinct molecular signaling pathways that support the formation of new synapses and maintaining their connections. Potential therapeutic agents include: 1) memory therapeutic agents that rescue synaptic and memory functions after the brain insults; 2) anti-pathologic therapeutics and an effective management of vascular risk factors; and 3) preventative therapeutic agents that achieve memory therapy through functional enhancement. Their development and potential as clinically effective memory therapeutics for vascular cognitive impairment and dementia are discussed in this review. These therapeutic agents are also likely to benefit patients with AD and/or other types of memory disorders. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Gene-based rare allele analysis identified a risk gene of Alzheimer's disease.

PubMed

Kim, Jong Hun; Song, Pamela; Lim, Hyunsun; Lee, Jae-Hyung; Lee, Jun Hong; Park, Sun Ah

2014-01-01

Alzheimer's disease (AD) has a strong propensity to run in families. However, the known risk genes excluding APOE are not clinically useful. In various complex diseases, gene studies have targeted rare alleles for unsolved heritability. Our study aims to elucidate previously unknown risk genes for AD by targeting rare alleles. We used data from five publicly available genetic studies from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the database of Genotypes and Phenotypes (dbGaP). A total of 4,171 cases and 9,358 controls were included. The genotype information of rare alleles was imputed using 1,000 genomes. We performed gene-based analysis of rare alleles (minor allele frequency≤3%). The genome-wide significance level was defined as meta P<1.8×10(-6) (0.05/number of genes in human genome = 0.05/28,517). ZNF628, which is located at chromosome 19q13.42, showed a genome-wide significant association with AD. The association of ZNF628 with AD was not dependent on APOE ε4. APOE and TREM2 were also significantly associated with AD, although not at genome-wide significance levels. Other genes identified by targeting common alleles could not be replicated in our gene-based rare allele analysis. We identified that rare variants in ZNF628 are associated with AD. The protein encoded by ZNF628 is known as a transcription factor. Furthermore, the associations of APOE and TREM2 with AD were highly significant, even in gene-based rare allele analysis, which implies that further deep sequencing of these genes is required in AD heritability studies.

Longitudinal Changes in Serum Glucose Levels are Associated with Metabolic Changes in Alzheimer's Disease Related Brain Regions.

PubMed

Burns, Christine M; Kaszniak, Alfred W; Chen, Kewei; Lee, Wendy; Bandy, Daniel J; Caselli, Richard J; Reiman, Eric M

2018-01-01

The association between longitudinal changes in serum glucose level and longitudinal changes in [18F] Fluorodeoxyglucose-PET (FDG PET) measurements of Alzheimer's disease (AD) risk are unknown. To investigate whether variation in serum glucose levels across time are associated with changes in FDG PET measurements of cerebral metabolic rate for glucose (rCMRgl) in brain regions preferentially affected by Alzheimer's disease (AD). Participants are a subset of a prospective cohort study investigating FDG PET, apolipoprotein E (APOE) ɛ4, and risk for AD which includes data from baseline, interim, and follow up visits over 4.4±1.0-years. An automated brain-mapping algorithm was utilized to characterize and compare associations between longitudinal changes in serum glucose levels and longitudinal changes in rCMRgl. This study included 80 adults aged 61.5±5 years, including 38 carriers and 42 non-carriers of the APOE ɛ4 allele. Longitudinal increases in serum glucose levels were associated with longitudinal CMRgl decline in the vicinity of parietotemporal, precuneus/posterior cingulate, and prefrontal brain regions preferentially affected by AD (p < 0.05, corrected for multiple comparisons). Findings remained significant when controlled for APOE ɛ4 status and baseline and advancing age. Additional studies are needed to clarify and confirm the relationship between longitudinal changes in peripheral glucose and FDG PET measurements of AD risk. Future findings will set the stage on the use of FDG PET in the evaluation of possible interventions that target risk factors for the development of AD.

Occupational exposure to mineral turpentine and heavy fuels: a possible risk factor for Alzheimer's disease.

PubMed

Helou, Rafik; Jaecker, Pierre

2014-05-01

The association between solvents and Alzheimer's disease (AD) has been the subject of several studies. Yet, only few studies have examined the various solvents separately, and the controls have rarely been monitored long enough. For these reasons and others, we believe that further studies are required. The objective of this study was to identify solvents associated with the clinicoradiological diagnostic of AD or mixed-type dementia (MD). A retrospective case-control study was performed in 156 patients followed up at the Memory Diagnostic Center of Bertinot Juel Hospital (France). The inclusion criteria were known occupation(s), a Mini-Mental State Examination (MMSE) score ≥10 at the first visit, a neuropsychological evaluation performed and a diagnosis established in our Memory Diagnostic Center. The diagnostics were crossed with 9 solvents belonging to two classes of solvents. Exposure was evaluated using French national job-exposure matrices. Certain petroleum-based solvents and fuels (i.e. mineral turpentine, diesel fuel, fuel oil and kerosene) were associated with a diagnosis of AD or MD. This association was still significant after adjustment for age, sex and education (adjusted OR: 6.5; 95% CI: 2-20). Occupational exposure to mineral turpentine and heavy fuels may be a risk factor for AD and MD.

Mild cognitive impairment: an opportunity to identify patients at high risk for progression to Alzheimer's disease.

PubMed

Levey, Allan; Lah, James; Goldstein, Felicia; Steenland, Kyle; Bliwise, Donald

2006-07-01

There is increasing evidence that subtle losses in cognitive function may be symptomatic of a transition to early Alzheimer's disease (AD). Ongoing research is focusing on the identification of those individuals with mild cognitive impairment (MCI) who are most likely to convert to AD. Of the MCI subtypes, patients with amnestic MCI (a-MCI) are at greatest risk. The objectives of this article were to review the relationship between MCI, normal aging, and AD, and to summarize recent research on the diagnosis and potential treatment of MCI. Relevant articles were identified through searches of MEDLINE and EMBASE using the terms mild cognitive impairment; cognitive impairment, no dementia; and dementia prodrome, with no restrictions as to year. Additional papers of interest were identified from the reference lists of the identified articles. The search was current as of February 2006. Guidelines and recommendations are being developed to assist physicians in diagnosing MCI, identifying its subtype and etiology, understanding the risks for conversion to AD, and managing disease progression. Given the existence of a subset of individuals with a-MCI, who are at greatest risk for progression to AD but still have high levels of cognition and function, the ability to improve symptoms and delay progression to AD would be particularly beneficial. In a 3-year, randomized, double-blind, placebo-controlled study in 769 patients with a-MCI, treatment with the cholinesterase inhibitor donepezil was associated with a significantly lower rate of progression to AD compared with placebo during the first 12 months of treatment (hazard ratio=0.42; 95% CI, 0.24-0.76; P=0.004) but not at later time points. Of other types of agents that have been investigated (antioxidants, estrogen replacement therapy, cyclooxygenase-2-selective inhibitors), none have shown significant beneficial effects in delaying cognitive decline or progression to AD. New drugs such as secretase inhibitors, small molecules that disrupt amyloid aggregation, and immunotherapies are in preclinical development. MCI involves more substantial cognitive and memory decline than normal aging and represents a significant risk factor for the development of dementia. Further research is needed into treatments to delay the conversion from MCI to AD.

Interleukin-1β Promoter Polymorphism Enhances the Risk of Sleep Disturbance in Alzheimer's Disease.

PubMed

Yin, You; Liu, Yan; Pan, Xiao; Chen, Rui; Li, Peng; Wu, Hui-Juan; Zhao, Zheng-Qing; Li, Yan-Peng; Huang, Liu-Qing; Zhuang, Jian-Hua; Zhao, Zhong-Xin

2016-01-01

Sleep alleviates Alzheimer's disease (AD)-related neuropathological processes, whereas sleep disturbance in AD patients is associated with elevated peripheral inflammatory cytokine levels. In the present study, we assessed interleukin (IL)-1β and APOEε4 polymorphisms for association with susceptibility of sleep disturbances in AD patients. A total of 123 pretreated AD patients and 120 age-, gender- and education level-matched healthy controls were recruited for two consecutive full-night polysomnography and measurement of Epworth Sleepiness Scale (ESS) scores for sleep-wake disturbance. Their genomic DNA was analyzed for IL-1β and APOEε4 SNPs using ligase detection reaction (LDR) technology. Blood levels of IL-1β, IL-6, and tumor necrosis factor alpha (TNF-α) were measured using ELISA after lipopolysaccharide (LPS) stimulation. The odds ratio and 95% confidence interval for genotype-specific risk were calculated using an unconditional logistic regression model and adjusted by age, gender, educational levels, body mass index (BMI), and activities of daily living (ADL). Compared to the non-APOEε4/ε4 genotype, APOEε4/ε4 significantly increased the risk of AD (APOEε4/ε4 vs. non-APOEε4/ε4, adjusted OR = 4.33, 95% CI = 1.33-14.10, p = 0.015). Compared to the IL-1β CC genotype (-31), the TT genotype significantly increased the risk of AD (TT vs. CC, adjusted OR = 1.72, 95% CI = 1.13-2.61, p = 0.010). AD patients carrying the APOEε4 allele and the IL-1β TT genotype showed less time in bed, longer sleep latency and REM latency, more awakenings, and a lower SWS percentage than those carrying CC/CT combined genotypes. In addition, blood IL-1β levels were significantly greater in AD patients carrying both the APOEε4 allele and the IL-1β-31TT genotype than in those carrying the APOEε4 allele and the -31 TC or CC genotype. In conclusion, this study provides the first evidence indicating that the IL-1β-31TT genotype and homozygous APOEε4 combined are associated with increased risk of developing AD with sleep disturbance.

48 CFR 215.404-71-3 - Contract type risk and working capital adjustment.

Code of Federal Regulations, 2014 CFR

2014-10-01

... varying contract types. The working capital adjustment is an adjustment added to the profit objective for... Base (item 20) Profit objective 24. CONTRACT type risk (1) (2) (3) Cost financed Length factor Interest... money. (3) Multiply (1) by (2). (4) Only complete this block when the prospective contract is a fixed...

48 CFR 215.404-71-3 - Contract type risk and working capital adjustment.

Code of Federal Regulations, 2013 CFR

2013-10-01

... varying contract types. The working capital adjustment is an adjustment added to the profit objective for... Base (item 20) Profit objective 24. CONTRACT type risk (1) (2) (3) Cost financed Length factor Interest... money. (3) Multiply (1) by (2). (4) Only complete this block when the prospective contract is a fixed...

48 CFR 215.404-71-3 - Contract type risk and working capital adjustment.

Code of Federal Regulations, 2012 CFR

2012-10-01

... varying contract types. The working capital adjustment is an adjustment added to the profit objective for... Base (item 20) Profit objective 24. CONTRACT type risk (1) (2) (3) Cost financed Length factor Interest... money. (3) Multiply (1) by (2). (4) Only complete this block when the prospective contract is a fixed...

A dose-response of consuming high fructose corn syrup-sweetened beverages on lipid/lipoprotein risk factors for cardiovascular disease in young adults

USDA-ARS?s Scientific Manuscript database

National Health and Nutrition Examination Survey data show increased risk of cardiovascular disease (CVD) mortality with increased intake of added sugar across quintiles. Objective: To determine the dose response effects of consuming beverages sweetened with high fructose corn syrup (HFCS) at zero, ...

Cytomegalovirus infection and risk of Alzheimer disease in older black and white individuals.

PubMed

Barnes, Lisa L; Capuano, Ana W; Aiello, Alison E; Turner, Arlener D; Yolken, Robert H; Torrey, E Fuller; Bennett, David A

2015-01-15

Human cytomegalovirus (CMV) is prevalent in older adults and has been implicated in many chronic diseases of aging. This study investigated the relation between CMV and the risk of Alzheimer disease (AD). Data come from 3 cohort studies that included 849 participants (mean age [±SD], 78.6 ± 7.2 years; mean education duration [±SD], 15.4 ± 3.3 years; 25% black). A solid-phase enzyme-linked immunosorbent assay was used for detecting type-specific immunoglobulin G antibody responses to CMV and herpes simplex virus type 1 (HSV-1) measured in archived serum samples. Of 849 participants, 73.4% had serologic evidence of exposure to CMV (89.0% black and 68.2% white; P < .001). During an average of 5.0 years of follow-up, 93 persons developed AD. CMV seropositivity was associated with an increased risk of AD (relative risk, 2.15; 95% confidence interval, 1.42-3.27) and a faster rate of decline in global cognition (estimate [±standard error], -0.02 ± 0.01; P = .03) in models that controlled for age, sex, education duration, race, vascular risk factors, vascular diseases, and apolipoprotein ε4 level. Results were similar in black and white individuals for both incident AD and change in cognitive function and were independent of HSV-1 status. These results suggest that CMV infection is associated with an increased risk of AD and a faster rate of cognitive decline in older diverse populations. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Relative risk of Alzheimer disease and age-at-onset distributions, based on APOE genotypes among elderly African Americans, caucasians, and hispanics in New York City

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tang, M.X.; Liu, X.H.; Stern, Y.

1996-03-01

Apolipoprotein-E {epsilon}4 (APOE-{epsilon}4) has been consistently associated with Alzheimer disease (AD) and may be responsible for an earlier age at onset. We have previously reported a diminished association between APOE-{epsilon}4 and AD in African Americans. Using a new method, which allows inclusion of censored information, we compared relative risks by APOE genotypes in an expanded collection of cases and controls from three ethnic groups in a New York community. The relative risk for AD associated with APOE-{epsilon}4 homozygosity was increased in all ethnic groups (African American relative risk [RR] = 3.0; 95% confidence interval [CI] = 1.5-5.9; Caucasian RR =more » 7.3, 95% CI = 2.5-21.6; and Hispanic RR = 2.5, 95% CI = 1.1-5.7), compared with those with APOE-{epsilon}3/{epsilon}3 genotypes. The risk was also increased for APOE-{epsilon}4 heterozygous Caucasians (RR = 2.9, 95% CI = 1.7-5.1) and Hispanics (RR = 1.6,95% CI = 1.1-2.3), but not for African Americans (RR = 0.6, 95% CI = 0.4-0.9). The age distribution of the proportion of Caucasians and Hispanics without AD was consistently lower for APOE-{epsilon}4 homozygous and APOE-{epsilon}4 heterozygous individuals than for those with other APOE genotypes. In African Americans this relationship was observed only in APOE-{epsilon}4 homozygotes. These results confirm that APOE genotypes influence the RR of AD in Caucasians and Hispanics. Differences in risk among APOE-{epsilon}4 heterozygote African Americans suggest that other genetic or environmental factors may modify the effect of APOE-{epsilon}4 in some populations. 58 refs., 3 figs., 4 tabs.« less

Combined effect of educational status and cardiovascular risk factors on the incidence of coronary heart disease and stroke in European cohorts: Implications for prevention.

PubMed

Veronesi, Giovanni; Tunstall-Pedoe, Hugh; Ferrario, Marco M; Kee, Frank; Kuulasmaa, Kari; Chambless, Lloyd E; Amouyel, Philippe; Arveiler, Dominique; Bobak, Martin; Ferrieres, Jean; Giampaoli, Simona; Jørgensen, Torben; Peters, Annette; Salomaa, Veikko; Soderberg, Stefan; Tamosiunas, Abdonas; Cesana, Giancarlo

2017-03-01

Background The combined effect of social status and risk factors on the absolute risk of cardiovascular disease has been insufficiently investigated, but results provide guidance on who could benefit most through prevention. Methods We followed 77,918 cardiovascular disease-free individuals aged 35-74 years at baseline, from 38 cohorts covering Nordic and Baltic countries, the UK and Central Europe, for a median of 12 years. Using Fine-Gray models in a competing-risks framework we estimated the effect of the interaction of education with smoking, blood pressure and body weight on the cumulative risk of incident acute coronary heart disease and stroke. Results Compared with more educated smokers, the less educated had an added increase in absolute risk of cardiovascular disease of 3.1% (95% confidence interval + 0.1%, +6.2%) in men and of 1.5% (-1.9%, +5.0%) in women, consistent across smoking categories. Conversely, the interaction was negative for overweight: -2.6% (95% CI: -5.6%, +0.3%) and obese: -3.6% (-7.6%, +0.4%) men, suggesting that the more educated would benefit more from the same reduction in body weight. A weaker interaction was observed for body weight in women, and for blood pressure in both genders. Less educated men and women with a cluster of two or more risk factors had an added cardiovascular disease risk of 3.6% (+0.1%, +7.0%) and of 2.6% (-0.5%, +5.6%), respectively, compared with their more educated counterparts. Conclusions Socially disadvantaged subjects have more to gain from lifestyle and blood pressure modification, hopefully reducing both their risk and also social inequality in disease.

Using eye-tracking to examine how embedding risk corrective statements improves cigarette risk beliefs: Implications for tobacco regulatory policy.

PubMed

Lochbuehler, Kirsten; Tang, Kathy Z; Souprountchouk, Valentina; Campetti, Dana; Cappella, Joseph N; Kozlowski, Lynn T; Strasser, Andrew A

2016-07-01

Tobacco companies have deliberately used explicit and implicit misleading information in marketing campaigns. The aim of the current study was to experimentally investigate whether the editing of explicit and implicit content of a print advertisement improves smokers' risk beliefs and smokers' knowledge of explicit and implicit information. Using a 2(explicit/implicit)×2(accurate/misleading) between-subject design, 203 smokers were randomly assigned to one of four advertisement conditions. The manipulation of graphic content was examined as an implicit factor to convey product harm. The inclusion of a text corrective in the body of the ad was defined as the manipulated explicit factor. Participants' eye movements and risk beliefs/recall were measured during and after ad exposure, respectively. Results indicate that exposure to a text corrective decreases false beliefs about the product (p<.01) and improves correct recall of information provided by the corrective (p<.05). Accurate graphic content did not alter the harmfulness of the product. Independent of condition, smokers who focused longer on the warning label made fewer false inferences about the product (p=.01) and were more likely to correctly recall the warning information (p<.01). Nonetheless, most smokers largely ignored the text warning. Embedding a corrective statement in the body of the ad is an effective strategy to convey health information to consumers, which can be mandated under the Tobacco Control Act. Eye-tracking results objectively demonstrate that text-only warnings are not viewed by smokers, thus minimizing their effectiveness for conveying risk information. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Using Eye-tracking to Examine How Embedding Risk Corrective Statements Improves Cigarette Risk Beliefs: Implications for Tobacco Regulatory Policy

PubMed Central

Lochbuehler, Kirsten; Tang, Kathy Z.; Souprountchouk, Valentina; Campetti, Dana; Cappella, Joseph N.; Kozlowski, Lynn T.; Strasser, Andrew A.

2016-01-01

Background Tobacco companies have deliberately used explicit and implicit misleading information in marketing campaigns. The aim of the current study was to experimentally investigate whether the editing of explicit and implicit content of a print advertisement improves smokers’ risk beliefs and smokers’ knowledge of explicit and implicit information. Methods Using a 2(explicit/implicit) x 2(accurate/misleading) between-subject design, 203 smokers were randomly assigned to one of four advertisement conditions. The manipulation of graphic content was examined as an implicit factor to convey product harm. The inclusion of a text corrective in the body of the ad was defined as the manipulated explicit factor. Participants’ eye movements and risk beliefs/recall were measured during and after ad exposure, respectively. Results Results indicate that exposure to a text corrective decreases false beliefs about the product (p < .01) and improves correct recall of information provided by the corrective (p < .05). Accurate graphic content did not alter the harmfulness of the product. Independent of condition, smokers who focused longer on the warning label made fewer false inferences about the product (p = .01) and were more likely to correctly recall the warning information (p < .01). Nonetheless, most smokers largely ignored the text warning. Conclusions Embedding a corrective statement in the body of the ad is an effective strategy to convey health information to consumers, which can be mandated under the Tobacco Control Act (2009). Eye-tracking results objectively demonstrate that text-only warnings are not viewed by smokers, thus minimizing their effectiveness for conveying risk information. PMID:27160034

Concurrence of High Fat Diet and APOE Gene Induces Allele Specific Metabolic and Mental Stress Changes in a Mouse Model of Alzheimer’s Disease

PubMed Central

Segev, Yifat; Livne, Adva; Mints, Meshi; Rosenblum, Kobi

2016-01-01

Aging is the main risk factor for neurodegenerative diseases, including Alzheimer’s disease (AD). However, evidence indicates that the pathological process begins long before actual cognitive or pathological symptoms are apparent. The long asymptomatic phase and complex integration between genetic, environmental and metabolic factors make it one of the most challenging diseases to understand and cure. In the present study, we asked whether an environmental factor such as high-fat (HF) diet would synergize with a genetic factor to affect the metabolic and cognitive state in the Apolipoprotein E (ApoE4) mouse model of AD. Our data suggest that a HF diet induces diabetes mellitus (DM)-like metabolism in ApoE4 mice, as well as changes in β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) protein levels between the two ApoE strains. Furthermore, HF diet induces anxiety in this AD mouse model. Our results suggest that young ApoE4 carriers are prone to psychological stress and metabolic abnormalities related to AD, which can easily be triggered via HF nutrition. PMID:27656136

Intrinsic Brain Activity of Cognitively Normal Older Persons Resembles More That of Patients Both with and at Risk for Alzheimer's Disease Than That of Healthy Younger Persons

PubMed Central

Pasquini, Lorenzo; Tonch, Annika; Plant, Claudia; Zherdin, Andrew; Ortner, Marion; Kurz, Alexander; Förstl, Hans; Zimmer, Claus; Grimmer, Timo; Wohlschäger, Afra; Riedl, Valentin

2014-01-01

Abstract In Alzheimer's disease (AD), recent findings suggest that amyloid-β (Aβ)-pathology might start 20–30 years before first cognitive symptoms arise. To account for age as most relevant risk factor for sporadic AD, it has been hypothesized that lifespan intrinsic (i.e., ongoing) activity of hetero-modal brain areas with highest levels of functional connectivity triggers Aβ-pathology. This model induces the simple question whether in older persons without any cognitive symptoms intrinsic activity of hetero-modal areas is more similar to that of symptomatic patients with AD or to that of younger healthy persons. We hypothesize that due to advanced age and therefore potential impact of pre-clinical AD, intrinsic activity of older persons resembles more that of patients than that of younger controls. We tested this hypothesis in younger (ca. 25 years) and older healthy persons (ca. 70 years) and patients with mild cognitive impairment and AD-dementia (ca. 70 years) by the use of resting-state functional magnetic resonance imaging, distinct measures of intrinsic brain activity, and different hierarchical clustering approaches. Independently of applied methods and involved areas, healthy older persons' intrinsic brain activity was consistently more alike that of patients than that of younger controls. Our result provides evidence for larger similarity in intrinsic brain activity between healthy older persons and patients with or at-risk for AD than between older and younger ones, suggesting a significant proportion of pre-clinical AD cases in the group of cognitively normal older people. The observed link of aging and AD with intrinsic brain activity supports the view that lifespan intrinsic activity may contribute critically to the pathogenesis of AD. PMID:24689864

The Incidence and Recurrence of Getting Lost in Community-Dwelling People with Alzheimer’s Disease: A Two and a Half-Year Follow-Up

PubMed Central

2016-01-01

Getting lost (GL) is a serious problem for people living with Alzheimer’s disease (PwAD), causing psychological distress in both PwAD and caregivers, and increasing the odds of being institutionalized. It is thus important to identify risk factors for the GL events in PwAD. Between April 2009 and March 2012, we invited 185 community-dwelling PwAD and their caregivers to participate in this study. At the baseline, 95 had experienced GL (Group B); the remaining 90 (Group A) had not. We focused on the incidence of GL events and the associated factors by way of demographic data, cognitive function assessed by the Cognitive Ability Screening Instrument (CASI), and spatial navigation abilities as assessed by the Questionnaire of Everyday Navigational Ability (QuENA). After a 2.5-year period, the incidence of GL in Group A was 33.3% and the recurrence of GL in Group B was 40%. Multiple logistic regression analysis revealed that the inattention item on the QuENA and orientation item on the CASI had independent effects on the GL incidence, while the absence of a safety range was associated with the risk of GL recurrence. During the 2.5 years, the PwAD with GL incidence deteriorated more in the mental manipulation item on the CASI than those without. We suggest that before the occurrence of GL, the caregivers of PwAD should refer to the results of cognitive assessment and navigation ability evaluation to enhance the orientation and attention of the PwAD. Once GL occurs, the caregivers must set a safety range to prevent GL recurrence, especially for younger people. PMID:27183297

A kernel machine method for detecting effects of interaction between multidimensional variable sets: an imaging genetics application.

PubMed

Ge, Tian; Nichols, Thomas E; Ghosh, Debashis; Mormino, Elizabeth C; Smoller, Jordan W; Sabuncu, Mert R

2015-04-01

Measurements derived from neuroimaging data can serve as markers of disease and/or healthy development, are largely heritable, and have been increasingly utilized as (intermediate) phenotypes in genetic association studies. To date, imaging genetic studies have mostly focused on discovering isolated genetic effects, typically ignoring potential interactions with non-genetic variables such as disease risk factors, environmental exposures, and epigenetic markers. However, identifying significant interaction effects is critical for revealing the true relationship between genetic and phenotypic variables, and shedding light on disease mechanisms. In this paper, we present a general kernel machine based method for detecting effects of the interaction between multidimensional variable sets. This method can model the joint and epistatic effect of a collection of single nucleotide polymorphisms (SNPs), accommodate multiple factors that potentially moderate genetic influences, and test for nonlinear interactions between sets of variables in a flexible framework. As a demonstration of application, we applied the method to the data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to detect the effects of the interactions between candidate Alzheimer's disease (AD) risk genes and a collection of cardiovascular disease (CVD) risk factors, on hippocampal volume measurements derived from structural brain magnetic resonance imaging (MRI) scans. Our method identified that two genes, CR1 and EPHA1, demonstrate significant interactions with CVD risk factors on hippocampal volume, suggesting that CR1 and EPHA1 may play a role in influencing AD-related neurodegeneration in the presence of CVD risks. Copyright © 2015 Elsevier Inc. All rights reserved.

Impact of the Alzheimer's Disease Neuroimaging Initiative, 2004 to 2014.

PubMed

Weiner, Michael W; Veitch, Dallas P; Aisen, Paul S; Beckett, Laurel A; Cairns, Nigel J; Cedarbaum, Jesse; Donohue, Michael C; Green, Robert C; Harvey, Danielle; Jack, Clifford R; Jagust, William; Morris, John C; Petersen, Ronald C; Saykin, Andrew J; Shaw, Leslie; Thompson, Paul M; Toga, Arthur W; Trojanowski, John Q

2015-07-01

The Alzheimer's Disease Neuroimaging Initiative (ADNI) was established in 2004 to facilitate the development of effective treatments for Alzheimer's disease (AD) by validating biomarkers for AD clinical trials. We searched for ADNI publications using established methods. ADNI has (1) developed standardized biomarkers for use in clinical trial subject selection and as surrogate outcome measures; (2) standardized protocols for use across multiple centers; (3) initiated worldwide ADNI; (4) inspired initiatives investigating traumatic brain injury and post-traumatic stress disorder in military populations, and depression, respectively, as an AD risk factor; (5) acted as a data-sharing model; (6) generated data used in over 600 publications, leading to the identification of novel AD risk alleles, and an understanding of the relationship between biomarkers and AD progression; and (7) inspired other public-private partnerships developing biomarkers for Parkinson's disease and multiple sclerosis. ADNI has made myriad impacts in its first decade. A competitive renewal of the project in 2015 would see the use of newly developed tau imaging ligands, and the continued development of recruitment strategies and outcome measures for clinical trials. Copyright © 2015 The Alzheimer's Association. All rights reserved.

Impact of the Alzheimer’s Disease Neuroimaging Initiative, 2004 to 2014

PubMed Central

Weiner, Michael W.; Veitch, Dallas P.; Aisen, Paul S.; Beckett, Laurel A.; Cairns, Nigel J.; Cedarbaum, Jesse; Donohue, Michael C.; Green, Robert C.; Harvey, Danielle; Jack, Clifford R.; Jagust, William; Morris, John C.; Petersen, Ronald C.; Saykin, Andrew J.; Shaw, Leslie; Thompson, Paul M.; Toga, Arthur W.; Trojanowski, John Q.

2015-01-01

Introduction The Alzheimer’s Disease Neuroimaging Initiative (ADNI) was established in 2004 to facilitate the development of effective treatments for Alzheimer’s disease (AD) by validating biomarkers for AD clinical trials. Methods We searched for ADNI publications using established methods. Results ADNI has (1) developed standardized biomarkers for use in clinical trial subject selection and as surrogate outcome measures; (2) standardized protocols for use across multiple centers; (3) initiated worldwide ADNI; (4) inspired initiatives investigating traumatic brain injury and post-traumatic stress disorder in military populations, and depression, respectively, as an AD risk factor; (5) acted as a data-sharing model; (6) generated data used in over 600 publications, leading to the identification of novel AD risk alleles, and an understanding of the relationship between biomarkers and AD progression; and (7) inspired other public-private partnerships developing biomarkers for Parkinson’s disease and multiple sclerosis. Discussion ADNI has made myriad impacts in its first decade. A competitive renewal of the project in 2015 would see the use of newly developed tau imaging ligands, and the continued development of recruitment strategies and outcome measures for clinical trials. PMID:26194320

Brain injury, neuroinflammation and Alzheimer's disease.

PubMed

Breunig, Joshua J; Guillot-Sestier, Marie-Victoire; Town, Terrence

2013-01-01

With as many as 300,000 United States troops in Iraq and Afghanistan having suffered head injuries (Miller, 2012), traumatic brain injury (TBI) has garnered much recent attention. While the cause and severity of these injuries is variable, severe cases can lead to lifelong disability or even death. While aging is the greatest risk factor for Alzheimer's disease (AD), it is now becoming clear that a history of TBI predisposes the individual to AD later in life (Sivanandam and Thakur, 2012). In this review article, we begin by defining hallmark pathological features of AD and the various forms of TBI. Putative mechanisms underlying the risk relationship between these two neurological disorders are then critically considered. Such mechanisms include precipitation and 'spreading' of cerebral amyloid pathology and the role of neuroinflammation. The combined problems of TBI and AD represent significant burdens to public health. A thorough, mechanistic understanding of the precise relationship between TBI and AD is of utmost importance in order to illuminate new therapeutic targets. Mechanistic investigations and the development of preclinical therapeutics are reliant upon a clearer understanding of these human diseases and accurate modeling of pathological hallmarks in animal systems.

Impaired mitochondrial energy metabolism as a novel risk factor for selective onset and progression of dementia in oldest-old subjects

PubMed Central

Zhao, Wei; Wang, Jun; Varghese, Merina; Ho, Lap; Mazzola, Paolo; Haroutunian, Vahram; Katsel, Pavel L; Gibson, Gary E; Levine, Samara; Dubner, Lauren; Pasinetti, Giulio Maria

2015-01-01

Recent evidence shows that Alzheimer disease (AD) dementia in the oldest-old subjects was associated with significantly less amyloid plaque and fibrillary tangle neuropathology than in the young-old population. In this study, using quantitative (q) PCR studies, we validated genome-wide microarray RNA studies previously conducted by our research group. We found selective downregulation of mitochondrial energy metabolism genes in the brains of oldest-old, but not young-old, AD dementia cases, despite a significant lack of classic AD neuropathology features. We report a significant decrease of genes associated with mitochondrial pyruvate metabolism, the tricarboxylic acid cycle (TCA), and glycolytic pathways. Moreover, significantly higher levels of nitrotyrosylated (3-NT)-proteins and 4-hydroxy-2-nonenal (HNE) adducts, which are indexes of cellular protein oxidation and lipid peroxidation, respectively, were detected in the brains of oldest-old subjects at high risk of developing AD, possibly suggesting compensatory mechanisms. These findings support the hypothesis that although oldest-old AD subjects, characterized by significantly lower AD neuropathology than young-old AD subjects, have brain mitochondrial metabolism impairment, which we hypothesize may selectively contribute to the development of dementia. Outcomes from this study provide novel insights into the molecular mechanisms underlying clinical dementia in young-old and oldest-old AD subjects and provide novel strategies for AD prevention and treatment in oldest-old dementia cases. PMID:25784811

Impaired mitochondrial energy metabolism as a novel risk factor for selective onset and progression of dementia in oldest-old subjects.

PubMed

Zhao, Wei; Wang, Jun; Varghese, Merina; Ho, Lap; Mazzola, Paolo; Haroutunian, Vahram; Katsel, Pavel L; Gibson, Gary E; Levine, Samara; Dubner, Lauren; Pasinetti, Giulio Maria

2015-01-01

Recent evidence shows that Alzheimer disease (AD) dementia in the oldest-old subjects was associated with significantly less amyloid plaque and fibrillary tangle neuropathology than in the young-old population. In this study, using quantitative (q) PCR studies, we validated genome-wide microarray RNA studies previously conducted by our research group. We found selective downregulation of mitochondrial energy metabolism genes in the brains of oldest-old, but not young-old, AD dementia cases, despite a significant lack of classic AD neuropathology features. We report a significant decrease of genes associated with mitochondrial pyruvate metabolism, the tricarboxylic acid cycle (TCA), and glycolytic pathways. Moreover, significantly higher levels of nitrotyrosylated (3-NT)-proteins and 4-hydroxy-2-nonenal (HNE) adducts, which are indexes of cellular protein oxidation and lipid peroxidation, respectively, were detected in the brains of oldest-old subjects at high risk of developing AD, possibly suggesting compensatory mechanisms. These findings support the hypothesis that although oldest-old AD subjects, characterized by significantly lower AD neuropathology than young-old AD subjects, have brain mitochondrial metabolism impairment, which we hypothesize may selectively contribute to the development of dementia. Outcomes from this study provide novel insights into the molecular mechanisms underlying clinical dementia in young-old and oldest-old AD subjects and provide novel strategies for AD prevention and treatment in oldest-old dementia cases.

NASA Models of Space Radiation Induced Cancer, Circulatory Disease, and Central Nervous System Effects

NASA Technical Reports Server (NTRS)

Cucinotta, Francis A.; Chappell, Lori J.; Kim, Myung-Hee Y.

2013-01-01

The risks of late effects from galactic cosmic rays (GCR) and solar particle events (SPE) are potentially a limitation to long-term space travel. The late effects of highest concern have significant lethality including cancer, effects to the central nervous system (CNS), and circulatory diseases (CD). For cancer and CD the use of age and gender specific models with uncertainty assessments based on human epidemiology data for low LET radiation combined with relative biological effectiveness factors (RBEs) and dose- and dose-rate reduction effectiveness factors (DDREF) to extrapolate these results to space radiation exposures is considered the current "state-of-the-art". The revised NASA Space Risk Model (NSRM-2014) is based on recent radio-epidemiology data for cancer and CD, however a key feature of the NSRM-2014 is the formulation of particle fluence and track structure based radiation quality factors for solid cancer and leukemia risk estimates, which are distinct from the ICRP quality factors, and shown to lead to smaller uncertainties in risk estimates. Many persons exposed to radiation on earth as well as astronauts are life-time never-smokers, which is estimated to significantly modify radiation cancer and CD risk estimates. A key feature of the NASA radiation protection model is the classification of radiation workers by smoking history in setting dose limits. Possible qualitative differences between GCR and low LET radiation increase uncertainties and are not included in previous risk estimates. Two important qualitative differences are emerging from research studies. The first is the increased lethality of tumors observed in animal models compared to low LET radiation or background tumors. The second are Non- Targeted Effects (NTE), which include bystander effects and genomic instability, which has been observed in cell and animal models of cancer risks. NTE's could lead to significant changes in RBE and DDREF estimates for GCR particles, and the potential effectiveness of radiation mitigator's. The NSRM- 2014 approaches to model radiation quality dependent lethality and NTE's will be described. CNS effects include both early changes that may occur during long space missions and late effects such as Alzheimer's disease (AD). AD effects 50% of the population above age 80-yr, is a degenerative disease that worsens with time after initial onset leading to death, and has no known cure. AD is difficult to detect at early stages and the small number of low LET epidemiology studies undertaken have not identified an association with low dose radiation. However experimental studies in mice suggest GCR may lead to early onset AD. We discuss modeling approaches to consider mechanisms whereby radiation would lead to earlier onset of occurrence of AD. Biomarkers of AD include amyloid beta (A(Beta)) plaques, and neurofibrillary tangles (NFT) made up of aggregates of the hyperphosphorylated form of the micro-tubule associated, tau protein. Related markers include synaptic degeneration, dentritic spine loss, and neuronal cell loss through apoptosis. Radiation may affect these processes by causing oxidative stress, aberrant signaling following DNA damage, and chronic neuroinflammation. Cell types to be considered in multi-scale models are neurons, astrocytes, and microglia. We developed biochemical and cell kinetics models of DNA damage signaling related to glycogen synthase kinase-3(Beta) (GSK3(Beta)) and neuroinflammation, and considered multi-scale modeling approaches to develop computer simulations of cell interactions and their relationships to A(Beta) plaques and NFTs. Comparison of model results to experimental data for the age specific development of A(Beta) plaques in transgenic mice will be discussed.

Endothelial dysfunction and amyloid-β-induced neurovascular alterations

PubMed Central

Koizumi, Kenzo; Wang, Gang; Park, Laibaik

2015-01-01

Alzheimer's disease (AD) and cerebrovascular diseases share common vascular risk factors that have disastrous effects on cerebrovascular regulation. Endothelial cells, lining inner walls of cerebral blood vessels, form a dynamic interface between the blood and the brain and are critical for the maintenance of neurovascular homeostasis. Accordingly, injury in endothelial cells is regarded as one of the earliest symptoms of impaired vasoregulatory mechanisms. Extracellular buildup of amyloid-β (Aβ) is a central pathogenic factor in AD. Aβ exerts potent detrimental effects on cerebral blood vessels and impairs endothelial structure and function. Recent evidence implicates vascular oxidative stress and activation of the nonselective cationic channel transient receptor potential melastatin (TRPM)-2 on endothelial cells in the mechanisms of Aβ-induced neurovascular dysfunction. Thus, Aβ triggers opening of TRPM2 channels in endothelial cells leading to intracellular Ca2+ overload and vasomotor dysfunction. The cerebrovascular dysfunction may contribute to AD pathogenesis by reducing the cerebral blood supply, leading to increased susceptibility to vascular insufficiency, and by promoting Aβ accumulation. The recent realization that vascular factors contribute to AD pathobiology suggests new targets for the prevention and treatment of this devastating disease. PMID:26328781

Factors influencing commencement and adherence to a home-based balance exercise program for reducing risk of falls: perceptions of people with Alzheimer's disease and their caregivers.

PubMed

Suttanon, Plaiwan; Hill, Keith D; Said, Catherine M; Byrne, Karin N; Dodd, Karen J

2012-07-01

Balance exercise is an important component of falls-prevention interventions, with growing evidence that it can be beneficial for people with Alzheimer's disease (AD). However, to implement a balance exercise program successfully for people with AD it is important to consider factors that can affect commencement and adherence to the program. This qualitative study explored these factors. Ten participants with AD, who had completed a six-month home-based balance exercise program, and their caregivers (n = 9) participated. A phenomenological theoretical framework with semi-structured interviews was used for data collection and analysis. Factors influencing the decision to commence the program were: possible benefits of the program, recommendations from health professionals, value of research, positive attitude towards exercise, and minimizing caregivers' burden. Factors influencing adherence to the program were grouped under 11 themes: six themes facilitated completion (program characteristics, physiotherapist, exercise recording sheet, caregivers' support, sense of commitment, and perceived benefit) and five themes were barriers (pre-existing conditions, dislike of structured exercise, absence from home, caregiver's health or commitment, and bad weather). A home-based exercise program with regular support from a physiotherapist and caregiver are key elements facilitating continuing program adherence in people with AD.

Diversity and Disparity in Dementia: The Impact of Ethnoracial Differences in Alzheimer’s Disease

PubMed Central

Chin, Alexander L.; Negash, Selamawit; Hamilton, Roy

2012-01-01

Debate exists regarding differences in the prevalence of Alzheimer’s disease (AD) in African Americans and Hispanics in the United States, with some evidence suggesting that the prevalence of AD may be considerably higher in these groups than in non-Hispanic whites. Despite this possible disparity, patients of minority ethnoracial groups often receive delayed diagnosis or inadequate treatment for dementia. This review investigates these disparities by conceptualizing the dementia disease process as a product of both biological and cultural factors. Ethnoracial differences in biological risk factors, such as genetics and cardiovascular disease, may help to explain disparities in the incidence and prevalence of AD, while race-specific cultural factors may impact diagnosis and treatment. Cultural factors include differences in perceptions about what is normal aging and what is not, lack of adequate access to medical care, and issues of trust between minority groups and the medical establishment. The diagnosis of AD in diverse populations may also be complicated by racial biases inherent in cognitive screening tools widely used by clinicians, but controlling for literacy level or using savings scores in psychometric analyses has the potential to mitigate these biases. We also suggest that emerging biomarker-based diagnostic tools may be useful in further characterizing diverse populations with AD. Recognizing the gap in communication that exists between minority communities and the medical research community, we propose that education and outreach are a critical next step in the effort to understand AD as it relates to diverse populations. PMID:21399486

Diversity and disparity in dementia: the impact of ethnoracial differences in Alzheimer disease.

PubMed

Chin, Alexander L; Negash, Selamawit; Hamilton, Roy

2011-01-01

Debate exists regarding differences in the prevalence of Alzheimer disease (AD) in African Americans and Hispanics in the United States, with some evidence suggesting that the prevalence of AD may be considerably higher in these groups than in non-Hispanic whites. Despite this possible disparity, patients of minority ethnoracial groups often receive delayed diagnosis or inadequate treatment for dementia. This review investigates these disparities by conceptualizing the dementia disease process as a product of both biological and cultural factors. Ethnoracial differences in biological risk factors, such as genetics and cardiovascular disease, may help to explain disparities in the incidence and prevalence of AD, whereas race-specific cultural factors may impact diagnosis and treatment. Cultural factors include differences in perceptions about what is normal aging and what is not, lack of adequate access to medical care, and issues of trust between minority groups and the medical establishment. The diagnosis of AD in diverse populations may also be complicated by racial biases inherent in cognitive screening tools widely used by clinicians, but controlling for literacy level or using savings scores in psychometric analyses has the potential to mitigate these biases. We also suggest that emerging biomarker-based diagnostic tools may be useful in further characterizing diverse populations with AD. Recognizing the gap in communication that exists between minority communities and the medical research community, we propose that education and outreach are a critical next step in the effort to understand AD as it relates to diverse populations.

APOε2 and education in cognitively normal older subjects with high levels of AD pathology at autopsy: findings from the Nun Study.

PubMed

Iacono, Diego; Zandi, Peter; Gross, Myron; Markesbery, William R; Pletnikova, Olga; Rudow, Gay; Troncoso, Juan C

2015-06-10

Asymptomatic Alzheimer's disease (ASYMAD) subjects are individuals characterized by preserved cognition before death despite substantial AD pathology at autopsy. ASYMAD subjects show comparable levels of AD pathology, i.e. β-amyloid neuritic plaques (Aβ-NP) and tau-neurofibrillary tangles (NFT), to those observed in mild cognitive impairment (MCI) and some definite AD cases. Previous clinicopathologic studies on ASYMAD subjects have shown specific phenomena of hypertrophy in the cell bodies, nuclei, and nucleoli of hippocampal pyramidal neurons and other cerebral areas. Since it is well established that the allele APOε4 is a major genetic risk factor for AD, we examined whether specific alleles of APOE could be associated with the different clinical outcomes between ASYMAD and MCI subjects despite equivalent AD pathology. A total of 523 brains from the Nun Study were screened for this investigation. The results showed higher APOε2 frequency (p < 0.001) in ASYMAD (19.2%) vs. MCI (0%) and vs. AD (4.7%). Furthermore, higher education in ASYMAD vs. MCI and AD (p < 0.05) was found. These novel autopsy-verified findings support the hypothesis of the beneficial effect of APOε2 and education, both which seem to act as contributing factors in delaying or forestalling the clinical manifestations of AD despite consistent levels of AD pathology.

APOε2 and education in cognitively normal older subjects with high levels of AD pathology at autopsy: findings from the Nun Study

PubMed Central

Iacono, Diego; Zandi, Peter; Gross, Myron; Markesbery, William R.; Pletnikova, Olga; Rudow, Gay; Troncoso, Juan C.

2015-01-01

Asymptomatic Alzheimer's disease (ASYMAD) subjects are individuals characterized by preserved cognition before death despite substantial AD pathology at autopsy. ASYMAD subjects show comparable levels of AD pathology, i.e. β-amyloid neuritic plaques (Aβ-NP) and tau-neurofibrillary tangles (NFT), to those observed in mild cognitive impairment (MCI) and some definite AD cases. Previous clinicopathologic studies on ASYMAD subjects have shown specific phenomena of hypertrophy in the cell bodies, nuclei, and nucleoli of hippocampal pyramidal neurons and other cerebral areas. Since it is well established that the allele APOε4 is a major genetic risk factor for AD, we examined whether specific alleles of APOE could be associated with the different clinical outcomes between ASYMAD and MCI subjects despite equivalent AD pathology. A total of 523 brains from the Nun Study were screened for this investigation. The results showed higher APOε2 frequency (p < 0.001) in ASYMAD (19.2%) vs. MCI (0%) and vs. AD (4.7%). Furthermore, higher education in ASYMAD vs. MCI and AD (p < 0.05) was found. These novel autopsy-verified findings support the hypothesis of the beneficial effect of APOε2 and education, both which seem to act as contributing factors in delaying or forestalling the clinical manifestations of AD despite consistent levels of AD pathology. PMID:26101858

Risk factors for sporadic listeriosis in the Netherlands, 2008 to 2013.

PubMed

Friesema, I H; Kuiling, S; van der Ende, A; Heck, M E; Spanjaard, L; van Pelt, W

2015-08-06

Although the disease burden of listeriosis on population level is low, on individual level the impact is high, largely due to severe illness and a high case fatality. Identification of risk factors supports and specifies public health actions needed for prevention. We performed a case–control study to determine host- and food-related risk factors for non-perinatal listeriosis in the Netherlands. Patients with non-perinatal listeriosis reported between July 2008 and December 2013 were compared with controls from a periodic control survey who completed a questionnaire in the same period. Higher age, male sex, underlying disease, especially cancer and kidney disease, and use of immunosuppressive medicine were strong risk factors for acquiring non-perinatal listeriosis. Analysis of the food consumption in the group of cases and controls with underlying diseases did not reveal any high-risk food products. Information and advice should continue to be given to persons at risk of severe listeriosis. Univariate analyses indicate that patients using gastric acid inhibitors are at risk. It is worth adding these patients to the group of susceptible persons.

Survival of Alzheimer's disease patients in Korea.

PubMed

Go, Seok Min; Lee, Kang Soo; Seo, Sang Won; Chin, Juhee; Kang, Sue J; Moon, So Young; Na, Duk L; Cheong, Hae-Kwan

2013-01-01

The natural history of Alzheimer's disease (AD) has rarely been studied in the Korean population. Our study on survival analyses in Korean AD patients potentially provides a basis for cross-cultural comparisons. We studied 724 consecutive patients from a memory disorder clinic in a tertiary hospital in Seoul, who were diagnosed as having AD between April 1995 and December 2005. Deaths were identified by the Statistics Korea database. The Kaplan-Meier method was used for survival analysis, and a Cox proportional hazard model was used to assess factors related to patient survival. The overall median survival from the onset of first symptoms and from the time of diagnosis was 12.6 years (95% confidence interval 11.7-13.4) and 9.3 years (95% confidence interval 8.7-9.9), respectively. The age of onset, male gender, history of diabetes mellitus, lower Mini-Mental State Examination score, and higher Clinical Dementia Rating score were negatively associated with survival. There was a reversal of risk of AD between early-onset and later-onset AD, 9.1 years after onset. The results of our study show a different pattern of survival compared to those studies carried out with western AD populations. Mortality risk of early-onset AD varied depending on the duration of follow-up. Copyright © 2013 S. Karger AG, Basel.

Omega-3 fatty acids and dementia

PubMed Central

Cole, Greg M.; Ma, Qiu-Lan; Frautschy, Sally A.

2014-01-01

More than a dozen epidemiological studies have reported that reduced levels or intake of omega-3 fatty acids or fish consumption is associated with increased risk for age-related cognitive decline or dementia such as Alzheimer's disease (AD). Increased dietary consumption or blood levels of docosahexaenoic acid (DHA) appear protective for AD and other dementia in multiple epidemiological studies; however, three studies suggest that the ApoE4 genotype limits protection. DHA is broadly neuroprotective via multiple mechanisms that include neuroprotective DHA metabolites, reduced arachidonic acid metabolites, and increased trophic factors or downstream trophic signal transduction. DHA is also protective against several risk factors for dementia including head trauma, diabetes, and cardiovascular disease. DHA is specifically protective against AD via additional mechanisms: It limits the production and accumulation of the amyloid β peptide toxin that is widely believed to drive the disease; and it also suppresses several signal transduction pathways induced by Aβ, including two major kinases that phosphorylate the microtubule associated protein tau and promote neurofibrillary tangle pathology. Based on the epidemiological and basic research data, expert panels have recommended the need for clinical trials with omega-3 fatty acids, notably DHA, for the prevention or treatment of age-related cognitive decline—with a focus on the most prevalent cause, AD. Clinical trials are underway to prevent and treat AD. Results to-date suggest that DHA may be more effective if it is begun early or used in conjunction with antioxidants. PMID:19523795

A Study of Cumulative Trauma Disorders of the Upper Extremities and Occupation in Wright-Patterson Adir Force Base Civilian Personnel.

DTIC Science & Technology

1995-09-01

Workers: Individual, Ergonomie and Work Organizational Factors," Ergonomics, 38: 763- 776 (April 1995). Brogmus, G.E. and R. Marko. "The...Naval Health Research Center, San Diego CA, June 1988 (AD-A199920). Keyserling, W. M. and others. "A Checklist For Evaluating Ergonomie Risk Factors

Added Sugar Consumption and Chronic Oral Disease Burden among Adolescents in Brazil.

PubMed

Carmo, C D S; Ribeiro, M R C; Teixeira, J X P; Alves, C M C; Franco, M M; França, A K T C; Benatti, B B; Cunha-Cruz, J; Ribeiro, C C C

2018-05-01

Chronic oral diseases are rarely studied together, especially with an emphasis on their common risk factors. This study examined the association of added sugar consumption on "chronic oral disease burden" among adolescents, with consideration of obesity and systemic inflammation pathways through structural equation modeling. A cross-sectional study was conducted of a complex random sample of adolescent students enrolled at public schools in São Luís, Brazil ( n = 405). The outcome was chronic oral disease burden, a latent variable based on the presence of probing depth ≥4 mm, bleeding on probing, caries, and clinical consequences of untreated caries. The following hypotheses were tested: 1) caries and periodontal diseases among adolescents are correlated with each other; 2) added sugar consumption and obesity are associated with chronic oral disease burden; and 3) chronic oral disease burden is linked to systemic inflammation. Models were adjusted for socioeconomic status, added sugar consumption, oral hygiene behaviors, obesity, and serum levels of interleukin 6 (IL-6). All estimators of the latent variable chronic oral disease burden involved factor loadings ≥0.5 and P values <0.001, indicating good fit. Added sugar consumption (standardized coefficient [SC] = 0.212, P = 0.005), high IL-6 levels (SC = 0.130, P = 0.036), and low socioeconomic status (SC = -0.279, P = 0.001) were associated with increased chronic oral disease burden values. Obesity was associated with high IL-6 levels (SC = 0.232, P = 0.001). Visible plaque index was correlated with chronic oral disease burden (SC = 0.381, P < 0.001). Our finding that caries and periodontal diseases are associated with each other and with added sugar consumption, obesity, and systemic inflammation reinforces the guidance of the World Health Organization that any approach intended to prevent noncommunicable diseases should be directed toward common risk factors.

Exploring the multiple-hit hypothesis of preterm white matter damage using diffusion MRI.

PubMed

Barnett, Madeleine L; Tusor, Nora; Ball, Gareth; Chew, Andrew; Falconer, Shona; Aljabar, Paul; Kimpton, Jessica A; Kennea, Nigel; Rutherford, Mary; David Edwards, A; Counsell, Serena J

2018-01-01

Preterm infants are at high risk of diffuse white matter injury and adverse neurodevelopmental outcome. The multiple hit hypothesis suggests that the risk of white matter injury increases with cumulative exposure to multiple perinatal risk factors. Our aim was to test this hypothesis in a large cohort of preterm infants using diffusion weighted magnetic resonance imaging (dMRI). We studied 491 infants (52% male) without focal destructive brain lesions born at < 34 weeks, who underwent structural and dMRI at a specialist Neonatal Imaging Centre. The median (range) gestational age (GA) at birth was 30 + 1 (23 + 2 -33 + 5 ) weeks and median postmenstrual age at scan was 42 + 1 (38-45) weeks. dMRI data were analyzed using tract based spatial statistics and the relationship between dMRI measures in white matter and individual perinatal risk factors was assessed. We tested the hypothesis that increased exposure to perinatal risk factors was associated with lower fractional anisotropy (FA), and higher radial, axial and mean diffusivity (RD, AD, MD) in white matter. Neurodevelopmental performance was investigated using the Bayley Scales of Infant and Toddler Development, Third Edition (BSITD-III) in a subset of 381 infants at 20 months corrected age. We tested the hypothesis that lower FA and higher RD, AD and MD in white matter were associated with poorer neurodevelopmental performance. Identified risk factors for diffuse white matter injury were lower GA at birth, fetal growth restriction, increased number of days requiring ventilation and parenteral nutrition, necrotizing enterocolitis and male sex. Clinical chorioamnionitis and patent ductus arteriosus were not associated with white matter injury. Multivariate analysis demonstrated that fetal growth restriction, increased number of days requiring ventilation and parenteral nutrition were independently associated with lower FA values. Exposure to cumulative risk factors was associated with reduced white matter FA and FA values at term equivalent age were associated with subsequent neurodevelopmental performance. This study suggests multiple perinatal risk factors have an independent association with diffuse white matter injury at term equivalent age and exposure to multiple perinatal risk factors exacerbates dMRI defined, clinically significant white matter injury. Our findings support the multiple hit hypothesis for preterm white matter injury.

Financial errors in dementia: Testing a neuroeconomic conceptual framework

PubMed Central

Chiong, Winston; Hsu, Ming; Wudka, Danny; Miller, Bruce L.; Rosen, Howard J.

2013-01-01

Financial errors by patients with dementia can have devastating personal and family consequences. We developed and evaluated a neuroeconomic conceptual framework for understanding financial errors across different dementia syndromes, using a systematic, retrospective, blinded chart review of demographically-balanced cohorts of patients with Alzheimer’s disease (AD, n=100) and behavioral variant frontotemporal dementia (bvFTD, n=50). Reviewers recorded specific reports of financial errors according to a conceptual framework identifying patient cognitive and affective characteristics, and contextual influences, conferring susceptibility to each error. Specific financial errors were reported for 49% of AD and 70% of bvFTD patients (p = 0.012). AD patients were more likely than bvFTD patients to make amnestic errors (p< 0.001), while bvFTD patients were more likely to spend excessively (p = 0.004) and to exhibit other behaviors consistent with diminished sensitivity to losses and other negative outcomes (p< 0.001). Exploratory factor analysis identified a social/affective vulnerability factor associated with errors in bvFTD, and a cognitive vulnerability factor associated with errors in AD. Our findings highlight the frequency and functional importance of financial errors as symptoms of AD and bvFTD. A conceptual model derived from neuroeconomic literature identifies factors that influence vulnerability to different types of financial error in different dementia syndromes, with implications for early diagnosis and subsequent risk prevention. PMID:23550884

Causes of Mortality After Dose-Escalated Radiation Therapy and Androgen Deprivation for High-Risk Prostate Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tendulkar, Rahul D., E-mail: tendulr@ccf.org; Hunter, Grant K.; Reddy, Chandana A.

Purpose: Men with high-risk prostate cancer have other competing causes of mortality; however, current risk stratification schema do not account for comorbidities. We aim to identify the causes of death and factors predictive for mortality in this population. Methods and Materials: A total of 660 patients with high-risk prostate cancer were treated with definitive high-dose external beam radiation therapy (≥74 Gy) and androgen deprivation (AD) between 1996 and 2009 at a single institution. Cox proportional hazards regression analysis was conducted to determine factors predictive of survival. Results: The median radiation dose was 78 Gy, median duration of AD was 6more » months, and median follow-up was 74 months. The 10-year overall survival (OS) was 60.6%. Prostate cancer was the leading single cause of death, with 10-year mortality of 14.1% (95% CI 10.7-17.6), compared with other cancers (8.4%, 95% CI 5.7-11.1), cardiovascular disease (7.3%, 95% CI 4.7-9.9), and all other causes (10.4%, 95% CI 7.2-13.6). On multivariate analysis, older age (HR 1.55, P=.002) and Charlson comorbidity index score (CS) ≥1 (HR 2.20, P<.0001) were significant factors predictive of OS, whereas Gleason score, T stage, prostate-specific antigen, duration of AD, radiation dose, smoking history, and body mass index were not. Men younger than 70 years of age with CS = 0 were more likely to die of prostate cancer than any other cause, whereas older men or those with CS ≥1 more commonly suffered non-prostate cancer death. The cumulative incidences of prostate cancer-specific mortality were similar regardless of age or comorbidities (P=.60). Conclusions: Men with high-risk prostate cancer are more likely to die of causes other than prostate cancer, except for the subgroup of men younger than 70 years of age without comorbidities. Only older age and presence of comorbidities significantly predicted for OS, whereas prostate cancer- and treatment-related factors did not.« less

Apolipoprotein E Genotype and Sex Risk Factors for Alzheimer Disease: A Meta-analysis.

PubMed

Neu, Scott C; Pa, Judy; Kukull, Walter; Beekly, Duane; Kuzma, Amanda; Gangadharan, Prabhakaran; Wang, Li-San; Romero, Klaus; Arneric, Stephen P; Redolfi, Alberto; Orlandi, Daniele; Frisoni, Giovanni B; Au, Rhoda; Devine, Sherral; Auerbach, Sanford; Espinosa, Ana; Boada, Mercè; Ruiz, Agustín; Johnson, Sterling C; Koscik, Rebecca; Wang, Jiun-Jie; Hsu, Wen-Chuin; Chen, Yao-Liang; Toga, Arthur W

2017-10-01

It is unclear whether female carriers of the apolipoprotein E (APOE) ε4 allele are at greater risk of developing Alzheimer disease (AD) than men, and the sex-dependent association of mild cognitive impairment (MCI) and APOE has not been established. To determine how sex and APOE genotype affect the risks for developing MCI and AD. Twenty-seven independent research studies in the Global Alzheimer's Association Interactive Network with data on nearly 58 000 participants. Non-Hispanic white individuals with clinical diagnostic and APOE genotype data. Homogeneous data sets were pooled in case-control analyses, and logistic regression models were used to compute risks. Age-adjusted odds ratios (ORs) and 95% confidence intervals for developing MCI and AD were calculated for men and women across APOE genotypes. Participants were men and women between ages 55 and 85 years. Across data sets most participants were white, and for many participants, racial/ethnic information was either not collected or not known. Men (OR, 3.09; 95% CI, 2.79-3.42) and women (OR, 3.31; CI, 3.03-3.61) with the APOE ε3/ε4 genotype from ages 55 to 85 years did not show a difference in AD risk; however, women had an increased risk compared with men between the ages of 65 and 75 years (women, OR, 4.37; 95% CI, 3.82-5.00; men, OR, 3.14; 95% CI, 2.68-3.67; P = .002). Men with APOE ε3/ε4 had an increased risk of AD compared with men with APOE ε3/ε3. The APOE ε2/ε3 genotype conferred a protective effect on women (OR, 0.51; 95% CI, 0.43-0.61) decreasing their risk of AD more (P value = .01) than men (OR, 0.71; 95% CI, 0.60-0.85). There was no difference between men with APOE ε3/ε4 (OR, 1.55; 95% CI, 1.36-1.76) and women (OR, 1.60; 95% CI, 1.43-1.81) in their risk of developing MCI between the ages of 55 and 85 years, but women had an increased risk between 55 and 70 years (women, OR, 1.43; 95% CI, 1.19-1.73; men, OR, 1.07; 95% CI, 0.87-1.30; P = .05). There were no significant differences between men and women in their risks for converting from MCI to AD between the ages of 55 and 85 years. Individuals with APOE ε4/ε4 showed increased risks vs individuals with ε3/ε4, but no significant differences between men and women with ε4/ε4 were seen. Contrary to long-standing views, men and women with the APOE ε3/ε4 genotype have nearly the same odds of developing AD from age 55 to 85 years, but women have an increased risk at younger ages.

Rationale and clinical data supporting nutritional intervention in Alzheimer's disease.

PubMed

Engelborghs, S; Gilles, C; Ivanoiu, A; Vandewoude, M

2014-01-01

Adequate nutrition plays an important role in the maintenance of cognitive function, particularly during aging. Malnutrition is amongst the risk factors for developing mild cognitive impairment (MCI) and Alzheimer's disease (AD). Epidemiological studies have associated deficiencies in some nutrients with a higher risk of cognitive dysfunction and/or AD. Cognitive decline in AD is correlated with synaptic loss and many of the components required to maintain optimal synaptic function are derived from dietary sources. As synapses are part of the neuronal membrane and are continuously being remodelled, the availability of sufficient levels of nutritional precursors (mainly uridine monophosphate, choline and omega-3 fatty acids) to make the phospholipids required to build neuronal membranes may have beneficial effects on synaptic degeneration in AD. In addition, B-vitamins, phospholipids and other micronutrients act as cofactors to enhance the supply of precursors required to make neuronal membranes and synapses. Despite this, no randomized controlled trial has hitherto provided evidence that any single nutrient has a beneficial effect on cognition or lowers the risk for AD. However, a multi-target approach using combinations of (micro)nutrients might have beneficial effects on cognitive function in neurodegenerative brain disorders like AD leading to synaptic degeneration. Here we review the clinical evidence for supplementation, based on a multi-target approach with a focus on key nutrients with a proposed role in synaptic dysfunction. Based on preclinical evidence, a nutrient mixture, Souvenaid(®) (Nutricia N.V., Zoetermeer, The Netherlands) was developed. Clinical trials with Souvenaid(®) have shown improved memory performance in patients with mild AD. Further clinical trials to evaluate the effects of nutritional intervention in MCI and early dementia due to AD are on-going.

Consumption of added sugars from liquid but not solid sources predicts impaired glucose homeostasis and insulin resistance among youth at risk of obesity.

PubMed

Wang, Jiawei; Light, Kelly; Henderson, Mélanie; O'Loughlin, Jennifer; Mathieu, Marie-Eve; Paradis, Gilles; Gray-Donald, Katherine

2014-01-01

Little is known about longitudinal associations between added sugar consumption (solid and liquid sources) and glucose-insulin homeostasis among youth. Caucasian children (8-10 y) with at least one obese biological parent were recruited in the QUébec Adipose and Lifestyle InvesTigation in Youth (QUALITY) cohort (n = 630) and followed-up 2 y later (n = 564). Added sugars were assessed by 3 24-h dietary recalls at baseline. Two-year changes were examined in multivariate linear regression models, adjusting for baseline level, age, sex, Tanner stage, energy intake, fat mass (dual-energy X-ray absorptiometry), and physical activity (7 d accelerometer). Added sugar intake in either liquid or solid sources was not related to changes in adiposity measures (fat mass, body mass index, or waist circumference). However, a higher consumption (10 g/d) of added sugars from liquid sources was associated with 0.04 mmol/L higher fasting glucose, 2.3 pmol/L higher fasting insulin, 0.1 unit higher homeostasis model assessment of insulin resistance (HOMA-IR), and 0.4 unit lower Matsuda-insulin sensitivity index (Matsuda-ISI) in all participants (P < 0.01). No associations were observed with consumption of added sugars from solid sources. Overweight/obese children at baseline had greater increases in adiposity indicators, fasting insulin, and HOMA-IR and decreases in Matsuda-ISI during those 2 y than normal-weight children. Consumption of added sugars from liquid or solid sources was not associated with changes in adiposity, but liquid added sugars were a risk factor for the development of impaired glucose homeostasis and insulin resistance over 2 y among youth at risk of obesity.

Nonlinear analysis of the heartbeats in public patient ECGs using an automated PD2i algorithm for risk stratification of arrhythmic death

PubMed Central

Skinner, James E; Anchin, Jerry M; Weiss, Daniel N

2008-01-01

Heart rate variability (HRV) reflects both cardiac autonomic function and risk of arrhythmic death (AD). Reduced indices of HRV based on linear stochastic models are independent risk factors for AD in post-myocardial infarct cohorts. Indices based on nonlinear deterministic models have a significantly higher sensitivity and specificity for predicting AD in retrospective data. A need exists for nonlinear analytic software easily used by a medical technician. In the current study, an automated nonlinear algorithm, the time-dependent point correlation dimension (PD2i), was evaluated. The electrocardiogram (ECG) data were provided through an National Institutes of Health-sponsored internet archive (PhysioBank) and consisted of all 22 malignant arrhythmia ECG files (VF/VT) and 22 randomly selected arrhythmia files as the controls. The results were blindly calculated by automated software (Vicor 2.0, Vicor Technologies, Inc., Boca Raton, FL) and showed all analyzable VF/VT files had PD2i < 1.4 and all analyzable controls had PD2i > 1.4. Five VF/VT and six controls were excluded because surrogate testing showed the RR-intervals to contain noise, possibly resulting from the low digitization rate of the ECGs. The sensitivity was 100%, specificity 85%, relative risk > 100; p < 0.01, power > 90%. Thus, automated heartbeat analysis by the time-dependent nonlinear PD2i-algorithm can accurately stratify risk of AD in public data made available for competitive testing of algorithms. PMID:18728829

The Empowering Role of Mobile Apps in Behavior Change Interventions: The Gray Matters Randomized Controlled Trial.

PubMed

Hartin, Phillip J; Nugent, Chris D; McClean, Sally I; Cleland, Ian; Tschanz, JoAnn T; Clark, Christine J; Norton, Maria C

2016-08-02

Health education and behavior change programs targeting specific risk factors have demonstrated their effectiveness in reducing the development of future diseases. Alzheimer disease (AD) shares many of the same risk factors, most of which can be addressed via behavior change. It is therefore theorized that a behavior change intervention targeting these risk factors would likely result in favorable rates of AD prevention. The objective of this study was to reduce the future risk of developing AD, while in the short term promoting vascular health, through behavior change. The study was an interventional randomized controlled trial consisting of subjects who were randomly assigned into either treatment (n=102) or control group (n=42). Outcome measures included various blood-based biomarkers, anthropometric measures, and behaviors related to AD risk. The treatment group was provided with a bespoke "Gray Matters" mobile phone app designed to encourage and facilitate behavior change. The app presented evidence-based educational material relating to AD risk and prevention strategies, facilitated self-reporting of behaviors across 6 behavioral domains, and presented feedback on the user's performance, calculated from reported behaviors against recommended guidelines. This paper explores the rationale for a mobile phone-led intervention and details the app's effect on behavior change and subsequent clinical outcomes. Via the app, the average participant submitted 7.3 (SD 3.2) behavioral logs/day (n=122,719). Analysis of these logs against primary outcome measures revealed that participants who improved their high-density lipoprotein cholesterol levels during the study duration answered a statistically significant higher number of questions per day (mean 8.30, SD 2.29) than those with no improvement (mean 6.52, SD 3.612), t97.74=-3.051, P=.003. Participants who decreased their body mass index (BMI) performed significantly better in attaining their recommended daily goals (mean 56.21 SD 30.4%) than those who increased their BMI (mean 40.12 SD 29.1%), t80 = -2.449, P=.017. In total, 69.2% (n=18) of those who achieved a mean performance percentage of 60% or higher, across all domains, reduced their BMI during the study, whereas 60.7% (n=34) who did not, increased their BMI. One-way analysis of variance of systolic blood pressure category changes showed a significant correlation between reported efforts to reduce stress and category change as a whole, P=.035. An exit survey highlighted that respondents (n=83) reported that the app motivated them to perform physical activity (85.4%) and make healthier food choices (87.5%). In this study, the ubiquitous nature of the mobile phone excelled as a delivery platform for the intervention, enabling the dissemination of educational intervention material while simultaneously monitoring and encouraging positive behavior change, resulting in desirable clinical effects. Sustained effort to maintain the achieved behaviors is expected to mitigate future AD risk. ClinicalTrails.gov NCT02290912; https://clinicaltrials.gov/ct2/show/NCT02290912 (Archived by WebCite at http://www.webcitation.org/6ictUEwnm).

The Empowering Role of Mobile Apps in Behavior Change Interventions: The Gray Matters Randomized Controlled Trial

PubMed Central

Nugent, Chris D; McClean, Sally I; Cleland, Ian; Tschanz, JoAnn T; Clark, Christine J; Norton, Maria C

2016-01-01

Background Health education and behavior change programs targeting specific risk factors have demonstrated their effectiveness in reducing the development of future diseases. Alzheimer disease (AD) shares many of the same risk factors, most of which can be addressed via behavior change. It is therefore theorized that a behavior change intervention targeting these risk factors would likely result in favorable rates of AD prevention. Objective The objective of this study was to reduce the future risk of developing AD, while in the short term promoting vascular health, through behavior change. Methods The study was an interventional randomized controlled trial consisting of subjects who were randomly assigned into either treatment (n=102) or control group (n=42). Outcome measures included various blood-based biomarkers, anthropometric measures, and behaviors related to AD risk. The treatment group was provided with a bespoke “Gray Matters” mobile phone app designed to encourage and facilitate behavior change. The app presented evidence-based educational material relating to AD risk and prevention strategies, facilitated self-reporting of behaviors across 6 behavioral domains, and presented feedback on the user’s performance, calculated from reported behaviors against recommended guidelines. Results This paper explores the rationale for a mobile phone–led intervention and details the app’s effect on behavior change and subsequent clinical outcomes. Via the app, the average participant submitted 7.3 (SD 3.2) behavioral logs/day (n=122,719). Analysis of these logs against primary outcome measures revealed that participants who improved their high-density lipoprotein cholesterol levels during the study duration answered a statistically significant higher number of questions per day (mean 8.30, SD 2.29) than those with no improvement (mean 6.52, SD 3.612), t97.74=−3.051, P=.003. Participants who decreased their body mass index (BMI) performed significantly better in attaining their recommended daily goals (mean 56.21 SD 30.4%) than those who increased their BMI (mean 40.12 SD 29.1%), t80 = −2.449, P=.017. In total, 69.2% (n=18) of those who achieved a mean performance percentage of 60% or higher, across all domains, reduced their BMI during the study, whereas 60.7% (n=34) who did not, increased their BMI. One-way analysis of variance of systolic blood pressure category changes showed a significant correlation between reported efforts to reduce stress and category change as a whole, P=.035. An exit survey highlighted that respondents (n=83) reported that the app motivated them to perform physical activity (85.4%) and make healthier food choices (87.5%). Conclusions In this study, the ubiquitous nature of the mobile phone excelled as a delivery platform for the intervention, enabling the dissemination of educational intervention material while simultaneously monitoring and encouraging positive behavior change, resulting in desirable clinical effects. Sustained effort to maintain the achieved behaviors is expected to mitigate future AD risk. Trial Registration ClinicalTrails.gov NCT02290912; https://clinicaltrials.gov/ct2/show/NCT02290912 (Archived by WebCite at http://www.webcitation.org/6ictUEwnm) PMID:27485822

Genetics of psychosis of Alzheimer disease.

PubMed

Shah, Chintan; DeMichele-Sweet, Mary Ann A; Sweet, Robert A

2017-01-01

Psychotic symptoms, comprised of delusions and hallucinations, occur in about half of individuals with Alzheimer disease (AD with psychosis, AD+P). These individuals have greater agitation, aggression, depression, functional impairment, and mortality than individuals without psychosis (AD-P). Although the exact etiopathogenesis of AD+P is unclear, the rapidly developing field of genomics continues to expand our understanding of this disease. Several independent studies have demonstrated familial aggregation and heritability of AD+P. Linkage studies have been suggestive of loci on several chromosomes associated with AD+P. Association studies examining apolipoprotein E gene, the best established genetic risk factor for late-onset AD, did not find any significant association of this gene with AD+P. Other candidate gene studies focusing on monoamine neurotransmitter systems have yielded equivocal results. A genome-wide association study and studies examining copy number variations recently have detected suggestive associations, but have been underpowered. Approaches to increase sizes of AD+P samples for genome wide association studies are discussed. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Genomics of Dementia: APOE- and CYP2D6-Related Pharmacogenetics

PubMed Central

Cacabelos, Ramón; Martínez, Rocío; Fernández-Novoa, Lucía; Carril, Juan C.; Lombardi, Valter; Carrera, Iván; Corzo, Lola; Tellado, Iván; Leszek, Jerzy; McKay, Adam; Takeda, Masatoshi

2012-01-01

Dementia is a major problem of health in developed societies. Alzheimer's disease (AD), vascular dementia, and mixed dementia account for over 90% of the most prevalent forms of dementia. Both genetic and environmental factors are determinant for the phenotypic expression of dementia. AD is a complex disorder in which many different gene clusters may be involved. Most genes screened to date belong to different proteomic and metabolomic pathways potentially affecting AD pathogenesis. The ε4 variant of the APOE gene seems to be a major risk factor for both degenerative and vascular dementia. Metabolic factors, cerebrovascular disorders, and epigenetic phenomena also contribute to neurodegeneration. Five categories of genes are mainly involved in pharmacogenomics: genes associated with disease pathogenesis, genes associated with the mechanism of action of a particular drug, genes associated with phase I and phase II metabolic reactions, genes associated with transporters, and pleiotropic genes and/or genes associated with concomitant pathologies. The APOE and CYP2D6 genes have been extensively studied in AD. The therapeutic response to conventional drugs in patients with AD is genotype specific, with CYP2D6-PMs, CYP2D6-UMs, and APOE-4/4 carriers acting as the worst responders. APOE and CYP2D6 may cooperate, as pleiotropic genes, in the metabolism of drugs and hepatic function. The introduction of pharmacogenetic procedures into AD pharmacological treatment may help to optimize therapeutics. PMID:22482072

How Do Community-Dwelling Persons with Alzheimer Disease Fall? Falls in the FINALEX Study.

PubMed

Perttila, Niko M; Öhman, Hannareeta; Strandberg, Timo E; Kautiainen, Hannu; Raivio, Minna; Laakkonen, Marja-Liisa; Savikko, Niina; Tilvis, Reijo S; Pitkala, Kaisu H

2017-01-01

People with dementia are at high risk for falls. However, little is known of the features causing falls in Alzheimer disease (AD). Our aim was to investigate how participants with AD fall. In the FINALEX (Finnish Alzheimer Disease Exercise Trial) study, participants' ( n = 194) falls were followed up for 1 year by diaries kept by their spouses. The most common reason for falls ( n = 355) was stumbling ( n = 61). Of the falls, 123 led to injuries, 50 to emergency department visits, and 13 to fractures. The participants without falls ( n = 103) were younger and had milder dementia than those with 1 ( n = 34) or ≥2 falls ( n = 57). Participants with a Mini Mental State Examination score of around 10 points were most prone to fall. In adjusted regression models, good nutritional status, good physical functioning, and use of antihypertensive medication (incident rate ratio [IRR] 0.68, 95% confidence interval [CI] 0.54-0.85) protected against falls, whereas fall history (IRR 2.71, 95% CI 2.13-3.44), osteoarthritis, diabetes mellitus, chronic obstructive pulmonary disease, higher number of drugs, drugs with anticholinergic properties, psychotropics, and opioids (IRR 4.27, 95% CI 2.92-6.24) were risk factors for falls. Our study provides a detailed account on how and why people with AD fall, suggesting several risk and protective factors.

Preclinical Alzheimer disease and risk of falls.

PubMed

Stark, Susan L; Roe, Catherine M; Grant, Elizabeth A; Hollingsworth, Holly; Benzinger, Tammie L; Fagan, Anne M; Buckles, Virginia D; Morris, John C

2013-07-30

We determined the rate of falls among cognitively normal, community-dwelling older adults, some of whom had presumptive preclinical Alzheimer disease (AD) as detected by in vivo imaging of fibrillar amyloid plaques using Pittsburgh compound B (PiB) and PET and/or by assays of CSF to identify Aβ₄₂, tau, and phosphorylated tau. We conducted a 12-month prospective cohort study to examine the cumulative incidence of falls. Participants were evaluated clinically and underwent PiB PET imaging and lumbar puncture. Falls were reported monthly using an individualized calendar journal returned by mail. A Cox proportional hazards model was used to test whether time to first fall was associated with each biomarker and the ratio of CSF tau/Aβ₄₂ and CSF phosphorylated tau/Aβ₄₂, after adjustment for common fall risk factors. The sample (n = 125) was predominately female (62.4%) and white (96%) with a mean age of 74.4 years. When controlled for ability to perform activities of daily living, higher levels of PiB retention (hazard ratio = 2.95 [95% confidence interval 1.01-6.45], p = 0.05) and of CSF biomarker ratios (p < 0.001) were associated with a faster time to first fall. Presumptive preclinical AD is a risk factor for falls in older adults. This study suggests that subtle noncognitive changes that predispose older adults to falls are associated with AD and may precede detectable cognitive changes.

How Do Community-Dwelling Persons with Alzheimer Disease Fall? Falls in the FINALEX Study

PubMed Central

Perttila, Niko M.; Öhman, Hannareeta; Strandberg, Timo E.; Kautiainen, Hannu; Raivio, Minna; Laakkonen, Marja-Liisa; Savikko, Niina; Tilvis, Reijo S.; Pitkala, Kaisu H.

2017-01-01

Background People with dementia are at high risk for falls. However, little is known of the features causing falls in Alzheimer disease (AD). Our aim was to investigate how participants with AD fall. Methods In the FINALEX (Finnish Alzheimer Disease Exercise Trial) study, participants' (n = 194) falls were followed up for 1 year by diaries kept by their spouses. Results The most common reason for falls (n = 355) was stumbling (n = 61). Of the falls, 123 led to injuries, 50 to emergency department visits, and 13 to fractures. The participants without falls (n = 103) were younger and had milder dementia than those with 1 (n = 34) or ≥2 falls (n = 57). Participants with a Mini Mental State Examination score of around 10 points were most prone to fall. In adjusted regression models, good nutritional status, good physical functioning, and use of antihypertensive medication (incident rate ratio [IRR] 0.68, 95% confidence interval [CI] 0.54–0.85) protected against falls, whereas fall history (IRR 2.71, 95% CI 2.13–3.44), osteoarthritis, diabetes mellitus, chronic obstructive pulmonary disease, higher number of drugs, drugs with anticholinergic properties, psychotropics, and opioids (IRR 4.27, 95% CI 2.92–6.24) were risk factors for falls. Conclusions Our study provides a detailed account on how and why people with AD fall, suggesting several risk and protective factors. PMID:28690633

New type of hip arthroplasty failure related to modular femoral components: breakage at the neck-stem junction.

PubMed

Wodecki, P; Sabbah, D; Kermarrec, G; Semaan, I

2013-10-01

Total hip replacements (THR) with modular femoral components (stem-neck interface) make it possible to adapt to extramedullary femoral parameters (anteversion, offset, and length) theoretically improving muscle function and stability. Nevertheless, adding a new interface has its disadvantages: reduced mechanical resistance, fretting corrosion and material fatigue fracture. We report the case of a femoral stem fracture of the female part of the component where the modular morse taper of the neck is inserted. An extended trochanteric osteotomy was necessary during revision surgery because the femoral stump could not be grasped for extraction, so that a long stem had to be used. In this case, the patient had the usual risk factors for modular neck failure: he was an active overweight male patient with a long varus neck. This report shows that the female part of the stem of a small femoral component may also be at increased failure risk and should be added to the list of risk factors. To our knowledge, this is the first reported case of this type of failure. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Quantifying links between stroke and risk factors: a study on individual health risk appraisal of stroke in a community of Chongqing.

PubMed

Wu, Yazhou; Zhang, Ling; Yuan, Xiaoyan; Wu, Yamin; Yi, Dong

2011-04-01

The objective of this study is to investigate the risk factors of stroke in a community in Chongqing by setting quantitative criteria for determining the risk factors of stroke. Thus, high-risk individuals can be identified and laid a foundation for predicting individual risk of stroke. 1,034 cases with 1:2 matched controls (2,068) were chosen from five communities in Chongqing including Shapingba, Xiaolongkan, Tianxingqiao, Yubei Road and Ciqikou. Participants were interviewed with a uniform questionnaire. The risk factors of stroke and the odds ratios of risk factors were analyzed with a logistic regression model, and risk exposure factors of different levels were converted into risk scores using statistical models. For men, ten risk factors including hypertension (5.728), family history of stroke (4.599), and coronary heart disease (5.404), among others, were entered into the main effect model. For women, 11 risk factors included hypertension (5.270), family history of stroke (4.866), hyperlipidemia (4.346), among others. The related risk scores were added to obtain a combined risk score to predict the individual's risk of stoke in the future. An individual health risk appraisal model of stroke, which was applicable to individuals of different gender, age, health behavior, disease and family history, was established. In conclusion, personal diseases including hypertension, diabetes mellitus, etc., were very important to the prevalence of stoke. The prevalence of stroke can be effectively reduced by changing unhealthy lifestyles and curing the positive individual disease. The study lays a foundation for health education to persuade people to change their unhealthy lifestyles or behaviors, and could be used in community health services.

Conversion of elderly to Alzheimer's dementia: role of confluence of hypothermia and senescent stigmata--the plausible pathway.

PubMed

Daulatzai, Mak Adam

2010-01-01

Aging is a consequence of progressive decline in special and somatosensory functions and specific brain stem nuclei. Many senescent stigmata, including hypoxia, hypoxemia, depressed cerebral blood flow and glucose metabolism, diseases of senescence, and their medications all enhance hypothermia as do alcohol, cold environment, and malnutrition. Hypothermia is a critical factor having deleterious impact on brain stem and neocortical functions. Additionally, anesthesia in elderly also promotes hypothermia; anesthetics not only cause consciousness (sensory and motor) changes, but memory impairment as well. Anesthesia inhibits cholinergic pathways, reticular and thalamocortical systems, cortico-cortical connectivity, and causes post-operative delirium and cognitive dysfunction. Increasing evidence indicates that anesthetic exposures may contribute to dementia onset and Alzheimer's disease (AD) in hypothermic elderly. Inhaled anesthetics potentiate caspases, BACE, tau hyperphosphorylation, and apoptosis. This paper addresses the important question: "Why do only some elderly fall victim to AD"? Based on information on the pathogenesis of early stages of cognitive dysfunction in elderly (i.e., due to senescent stigmata), and the effects of anesthesia superimposed, a detailed plausible neuropathological substrate (mechanism/pathway) is delineated here that reveals the possible cause(s) of AD. Basically, it encompasses several risk factors for cognitive dysfunction during senescence plus several hypothermia-enhancing routes; they all converge and tip the balance towards dementia onset. This knowledge of the confluence of heterogeneous risk factors in perpetuating dementia relentlessly is of importance in order to: (a) avoid their convergence; (b) take measures to stop/reverse cognitive dysfunction; and (c) to develop therapeutic strategies to enhance cognitive function and attenuate AD.

Barrier function and natural moisturizing factor levels after cumulative exposure to a fruit-derived organic acid and a detergent: different outcomes in atopic and healthy skin and relevance for occupational contact dermatitis in the food industry.

PubMed

Angelova-Fischer, Irena; Hoek, Anne-Karin; Dapic, Irena; Jakasa, Ivone; Kezic, Sanja; Fischer, Tobias W; Zillikens, Detlef

2015-12-01

Fruit-derived organic compounds and detergents are relevant exposure factors for occupational contact dermatitis in the food industry. Although individuals with atopic dermatitis (AD) are at risk for development of occupational contact dermatitis, there have been no controlled studies on the effects of repeated exposure to multiple irritants, relevant for the food industry, in atopic skin. The aim of the study was to investigate the outcomes of repeated exposure to a fruit-derived organic acid and a detergent in AD compared to healthy volunteers. The volunteers were exposed to 2.0% acetic acid (AcA) and/or 0.5% sodium lauryl sulfate (SLS) in controlled tandem repeated irritation test. The outcomes were assessed by measurements of erythema, transepidermal water loss (TEWL) and natural moisturizing factor (NMF) levels. In the AD volunteers, repeated AcA exposure led to barrier disruption and significant TEWL increase; no significant differences after the same exposure in the healthy controls were found. Repeated exposure to SLS and the irritant tandems enhanced the reactions and resulted in a significantly higher increase in TEWL in the AD compared to the control group. Cumulative irritant exposure reduced the NMF levels in both groups. Differences in the severity of irritant-induced barrier impairment in atopic individuals contribute to the risk for occupational contact dermatitis in result of multiple exposures to food-derived irritants and detergents. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Combined assessment of DYRK1A, BDNF and homocysteine levels as diagnostic marker for Alzheimer's disease.

PubMed

Janel, N; Alexopoulos, P; Badel, A; Lamari, F; Camproux, A C; Lagarde, J; Simon, S; Feraudet-Tarisse, C; Lamourette, P; Arbones, M; Paul, J L; Dubois, B; Potier, M C; Sarazin, M; Delabar, J M

2017-06-20

Early identification of Alzheimer's disease (AD) risk factors would aid development of interventions to delay the onset of dementia, but current biomarkers are invasive and/or costly to assess. Validated plasma biomarkers would circumvent these challenges. We previously identified the kinase DYRK1A in plasma. To validate DYRK1A as a biomarker for AD diagnosis, we assessed the levels of DYRK1A and the related markers brain-derived neurotrophic factor (BDNF) and homocysteine in two unrelated AD patient cohorts with age-matched controls. Receiver-operating characteristic curves and logistic regression analyses showed that combined assessment of DYRK1A, BDNF and homocysteine has a sensitivity of 0.952, a specificity of 0.889 and an accuracy of 0.933 in testing for AD. The blood levels of these markers provide a diagnosis assessment profile. Combined assessment of these three markers outperforms most of the previous markers and could become a useful substitute to the current panel of AD biomarkers. These results associate a decreased level of DYRK1A with AD and challenge the use of DYRK1A inhibitors in peripheral tissues as treatment. These measures will be useful for diagnosis purposes.

Mucinous Adenocarcinomas Histotype Can Also be a High-Risk Factor for Stage II Colorectal Cancer Patients.

PubMed

Hu, Xiang; Li, Ya-Qi; Li, Qing-Guo; Ma, Yan-Lei; Peng, Jun-Jie; Cai, Sanjun

2018-05-22

Colorectal mucinous adenocarcinoma (MA) has been associated with a worse prognosis than adenocarcinoma (AD) in advanced stages. Little is known about the prognostic impact of a mucinous histotype on the early stages of colorectal cancer with negative lymph node (LN) metastasis. In contrast to the established prognostic factors such as T stage and grading, the histological subtype is not thought to contribute to the therapeutic outcome, although different subtypes can potentially represent different entities. In this study, we aimed to define the prognostic value of mucinous histology in colorectal cancer with negative LNs. Between 2006 and 2017, a total of 4893 consecutive patients without LN metastasis underwent radical surgery for primary colorectal cancer (MA and AD) in Fudan University Shanghai Cancer Center (FUSCC). Clinical, histopathological, and survival data were analyzed. The incidence of MA was 11% in 4893 colorectal cancer patients without LN metastasis. The MA patients had a higher T category, a greater percentage of LN harvested, larger tumor size and worse grading than the AD patients (p < 0.001 for each). We found that MA histology was correlated with a poor prognosis in terms of relapse in node-negative patients, and MA histology combined with TNM staging may be a feasible method for predicting the relapse rate. Additionally, MA presented as a high-risk factor in patients with negative perineural or vascular invasion and well/moderate-differentiation and showed a more dismal prognosis for stage II patients. Meanwhile, the disease-free survival was identical in MA and AD patients after neo- and adjuvant chemotherapy. MA histology is an independent predictor of poor prognosis due to relapse in LN-negative colorectal cancer patients. Mucinous histology can suggest a possible high risk in early-stage colorectal carcinoma. © 2018 The Author(s). Published by S. Karger AG, Basel.

Association between the APOE ε4 Allele and Late-Onset Alzheimer's Disease in an Ecuadorian Mestizo Population

PubMed Central

Calero, Cristian; Vinueza, Rodrigo; Correa, Patricio; Carrera-Gonzalez, Andrea; Villegas, Franklin; Moreta, Germania; Paredes, Rosario

2017-01-01

Alzheimer's disease (AD) is the most common neurodegenerative disease. It has two main pathological hallmarks: amyloid plaques and neurofibrillary tangles. The APOE ε4 allele has been recognized as the strongest genetic risk factor for late-onset Alzheimer's disease (LOAD) in several populations worldwide, yet the risk varies by region and ethnicity. The aims of this study were to describe APOE allele and genotype frequencies and examine the relationship between the APOE ε4 allele and LOAD risk in an Ecuadorian Mestizo population. We carried out a case-control study comprising 56 individuals clinically diagnosed with probable AD (≥65 years of age) and 58 unrelated healthy control subjects (≥65 years of age). Genotyping was performed using the real-time PCR method. Our data showed that allelic and genotypic frequencies follow the trends observed in most worldwide populations. We also found a high-risk association between APOE ε4 allele carriers and LOAD (OR = 7.286; 95% CI = 2.824–18.799; p < 0.001). Therefore, we concluded that APOE ε4 must be considered an important genetic risk factor for LOAD in the Ecuadorian Mestizo population. Additionally, we suggest that in mixed populations the effects of admixture and ethnic identity should be differentiated when evaluating genetic contributions to Alzheimer's disease risk. PMID:29348964

Consumer perceptions of prescription and over-the-counter drug advertisements with promotional offers.

PubMed

Aikin, Kathryn J; Sullivan, Helen W; O'Donoghue, Amie C; Betts, Kevin R

2016-01-01

Information on the effects of promotional offers in direct-to-consumer prescription drug ads is limited. In two studies, we examined the effect of promotional offers (e.g., money-back guarantee) and ad type (creating prescription and over-the-counter drug ads by varying the presence of benefit and risk information). We found little effect of promotional offers. Adding benefit (risk) information to the ad increased consumers' knowledge of the benefit (risk) information and their efficacy (risk) perceptions. In most cases, adding risk information to an ad with benefit information increased risk knowledge and perceptions without decreasing benefit knowledge or perceptions.

An Application of the Patient Rule-Induction Method for Evaluating the Contribution of the Apolipoprotein E and Lipoprotein Lipase Genes to Predicting Ischemic Heart Disease

PubMed Central

Dyson, Greg; Frikke-Schmidt, Ruth; Nordestgaard, Børge G.; Tybjærg-Hansen, Anne; Sing, Charles F.

2007-01-01

Different combinations of genetic and environmental risk factors are known to contribute to the complex etiology of ischemic heart disease (IHD) in different subsets of individuals. We employed the Patient Rule-Induction Method (PRIM) to select the combination of risk factors and risk factor values that identified each of 16 mutually exclusive partitions of individuals having significantly different levels of risk of IHD. PRIM balances two competing objectives: (1) finding partitions where the risk of IHD is high and (2) maximizing the number of IHD cases explained by the partitions. A sequential PRIM analysis was applied to data on the incidence of IHD collected over 8 years for a sample of 5,455 unrelated individuals from the Copenhagen City Heart Study (CCHS) to assess the added value of variation in two candidate susceptibility genes beyond the traditional, lipid and body mass index risk factors for IHD. An independent sample of 362 unrelated individuals also from the city of Copenhagen was used to test the model obtained for each of the hypothesized partitions. PMID:17436307

Progressive Neuronal Pathology and Synaptic Loss Induced by Prediabetes and Type 2 Diabetes in a Mouse Model of Alzheimer's Disease.

PubMed

Ramos-Rodriguez, Juan Jose; Spires-Jones, Tara; Pooler, Amy M; Lechuga-Sancho, Alfonso Maria; Bacskai, Brian J; Garcia-Alloza, Monica

2017-07-01

Age remains the main risk factor for developing Alzheimer's disease (AD) although certain metabolic alterations, including prediabetes and type 2 diabetes (T2D), may also increase this risk. In order to understand this relationship, we have studied an AD-prediabetes mouse model (APP/PS1) with severe hyperinsulinemia induced by long-term high fat diet (HFD), and an AD-T2D model, generated by crossing APP/PS1 and db/db mice (APP/PS1xdb/db). In both, prediabetic and diabetic AD mice, we have analyzed underlying neuronal pathology and synaptic loss. At 26 weeks of age, when both pathologies were clearly established, we observed severe brain atrophy in APP/PS1xdb/db animals as well as cortical thinning, accompanied by increased caspase activity. Reduced senile plaque burden and elevated soluble Aβ40 and 42 levels were observed in AD-T2D mice. Further assessment revealed a significant increase of neurite curvature in prediabetic-AD mice, and this effect was worsened in AD-T2D animals. Synaptic density loss, analyzed by array tomography, revealed a synergistic effect between T2D and AD, whereas an intermediate state was observed, once more, in prediabetic-AD mice. Altogether, our data suggest that early prediabetic hyperinsulinemia may exacerbate AD pathology, and that fully established T2D clearly worsens these effects. Therefore, it is feasible that early detection of prediabetic state and strict metabolic control could slow or delay progression of AD-associated neuropathological features.

Lipidomic Profiles in Diabetes and Dementia.

PubMed

Huynh, Kevin; Martins, Ralph N; Meikle, Peter J

2017-01-01

Lipids are a diverse class of hydrophobic and amphiphilic molecules which make up the bulk of most biological systems and are essential for human life. The role of lipids in health and disease has been recognized for many decades, as evidenced by the early identification of cholesterol as an important risk factor of heart disease and the development and introduction of statins as a one of the most successful therapeutic interventions to date. While several studies have demonstrated an increased risk of dementia, including Alzheimer's disease (AD), in those with diabetes mellitus, the nature of this risk is not well understood. Recent developments in the field of lipidomics, driven primarily by technological advances in high pressure liquid chromatography and particularly mass spectrometry, have enabled the detailed characterization of the many hundreds of individual lipid species in mammalian systems and their association with disease states. Diabetes mellitus and AD have received particular attention due to their prominence in Western societies as a result of the ongoing obesity epidemic and the aging populations. In this review, we examine how these lipidomic studies are informing on the relationship between lipid metabolism with diabetes and AD and how this may inform on the common pathological pathways that link diabetes risk with dementia.

Classifying Alzheimer's disease with brain imaging and genetic data using a neural network framework.

PubMed

Ning, Kaida; Chen, Bo; Sun, Fengzhu; Hobel, Zachary; Zhao, Lu; Matloff, Will; Toga, Arthur W

2018-08-01

A long-standing question is how to best use brain morphometric and genetic data to distinguish Alzheimer's disease (AD) patients from cognitively normal (CN) subjects and to predict those who will progress from mild cognitive impairment (MCI) to AD. Here, we use a neural network (NN) framework on both magnetic resonance imaging-derived quantitative structural brain measures and genetic data to address this question. We tested the effectiveness of NN models in classifying and predicting AD. We further performed a novel analysis of the NN model to gain insight into the most predictive imaging and genetics features and to identify possible interactions between features that affect AD risk. Data were obtained from the AD Neuroimaging Initiative cohort and included baseline structural MRI data and single nucleotide polymorphism (SNP) data for 138 AD patients, 225 CN subjects, and 358 MCI patients. We found that NN models with both brain and SNP features as predictors perform significantly better than models with either alone in classifying AD and CN subjects, with an area under the receiver operating characteristic curve (AUC) of 0.992, and in predicting the progression from MCI to AD (AUC=0.835). The most important predictors in the NN model were the left middle temporal gyrus volume, the left hippocampus volume, the right entorhinal cortex volume, and the APOE (a gene that encodes apolipoprotein E) ɛ4 risk allele. Furthermore, we identified interactions between the right parahippocampal gyrus and the right lateral occipital gyrus, the right banks of the superior temporal sulcus and the left posterior cingulate, and SNP rs10838725 and the left lateral occipital gyrus. Our work shows the ability of NN models to not only classify and predict AD occurrence but also to identify important AD risk factors and interactions among them. Copyright © 2018 Elsevier Inc. All rights reserved.

Cervical lymph node metastasis in adenoid cystic carcinoma of oral cavity and oropharynx: A collective international review☆

PubMed Central

Suárez, Carlos; Barnes, Leon; Silver, Carl E.; Rodrigo, Juan P.; Shah, Jatin P.; Triantafyllou, Asterios; Rinaldo, Alessandra; Cardesa, Antonio; Pitman, Karen T.; Kowalski, Luiz P.; Robbins, K. Thomas; Hellquist, Henrik; Medina, Jesus E.; de Bree, Remco; Takes, Robert P.; Coca-Pelaz, Andrés; Bradley, Patrick J.; Gnepp, Douglas R.; Teymoortash, Afshin; Strojan, Primož; Mendenhall, William M.; Eloy, Jean Anderson; Bishop, Justin A.; Devaney, Kenneth O.; Thompson, Lester D.R.; Hamoir, Marc; Slootweg, Pieter J.; Poorten, Vincent Vander; Williams, Michelle D.; Wenig, Bruce M.; Skálová, Alena; Ferlito, Alfio

2016-01-01

The purpose of this study was to establish general guidelines in the management of the N0 neck of oral cavity and oropharyngeal adenoid cystic carcinoma (AdCC) in order to improve the survival of these patients and/or reduce the risk of neck recurrences. The incidence of cervical node metastasis at diagnosis of head and neck AdCC is variable, and ranges between 3% and 16%. Metastasis to the cervical lymph nodes of intraoral and oropharyngeal AdCC varies from 2% to 43%, with the lower rates pertaining to palatal AdCC and the higher rates to base of the tongue. Neck node recurrence may happen after treatment in 0–14% of AdCC, is highly dependent on the extent of the treatment and is very rare in patients who have been treated with therapeutic or elective neck dissections, or elective neck irradiation. Lymph node involvement with or without extracapsular extension in AdCC has been shown in most reports to be independently associated with decreased overall and cause-specific survival, probably because lymph node involvement is a risk factor for subsequent distant metastasis. The overall rate of occult neck metastasis in patients with head and neck AdCC ranges from 15% to 44%, but occult neck metastasis from oral cavity and/or oropharynx seems to occur more frequently than from other locations such as the sinonasal tract and major salivary glands. Nevertheless, the benefit of elective neck dissection (END) in AdCC is not comparable to that of squamous cell carcinoma, because the main cause of failure is not related to neck or local recurrence, but rather, to distant failure. Therefore, END should be considered in patients with a cN0 neck with AdCC in some high risk oral and oropharyngeal locations when postoperative RT is not planned, or the rare AdCC-high grade transformation. PMID:27017314

A genetic risk score based on direct associations with coronary heart disease improves coronary heart disease risk prediction in the Atherosclerosis Risk in Communities (ARIC), but not in the Rotterdam and Framingham Offspring, Studies

PubMed Central

Brautbar, Ariel; Pompeii, Lisa A.; Dehghan, Abbas; Ngwa, Julius S.; Nambi, Vijay; Virani, Salim S.; Rivadeneira, Fernando; Uitterlinden, André G.; Hofman, Albert; Witteman, Jacqueline C.M.; Pencina, Michael J.; Folsom, Aaron R.; Cupples, L. Adrienne; Ballantyne, Christie M.; Boerwinkle, Eric

2013-01-01

Objective Multiple studies have identified single-nucleotide polymorphisms (SNPs) that are associated with coronary heart disease (CHD). We examined whether SNPs selected based on predefined criteria will improve CHD risk prediction when added to traditional risk factors (TRFs). Methods SNPs were selected from the literature based on association with CHD, lack of association with a known CHD risk factor, and successful replication. A genetic risk score (GRS) was constructed based on these SNPs. Cox proportional hazards model was used to calculate CHD risk based on the Atherosclerosis Risk in Communities (ARIC) and Framingham CHD risk scores with and without the GRS. Results The GRS was associated with risk for CHD (hazard ratio [HR] = 1.10; 95% confidence interval [CI]: 1.07–1.13). Addition of the GRS to the ARIC risk score significantly improved discrimination, reclassification, and calibration beyond that afforded by TRFs alone in non-Hispanic whites in the ARIC study. The area under the receiver operating characteristic curve (AUC) increased from 0.742 to 0.749 (Δ= 0.007; 95% CI, 0.004–0.013), and the net reclassification index (NRI) was 6.3%. Although the risk estimates for CHD in the Framingham Offspring (HR = 1.12; 95% CI: 1.10–1.14) and Rotterdam (HR = 1.08; 95% CI: 1.02–1.14) Studies were significantly improved by adding the GRS to TRFs, improvements in AUC and NRI were modest. Conclusion Addition of a GRS based on direct associations with CHD to TRFs significantly improved discrimination and reclassification in white participants of the ARIC Study, with no significant improvement in the Rotterdam and Framingham Offspring Studies. PMID:22789513

Factors Associated with Younger Adolescents’ Exposure to Online Alcohol Advertising

PubMed Central

D’Amico, Elizabeth J.; Martino, Steven C.; Collins, Rebecca L.; Shadel, William G.; Tolpadi, Anagha; Kovalchik, Stephanie; Becker, Kirsten M.

2016-01-01

Little is known about the extent and nature of youth exposure to online alcohol advertising, or factors that may be associated with exposure. The current study recruited middle school students who completed a paper survey and then logged each alcohol advertisement that they encountered over a two-week period using cell phones as part of an ecological momentary assessment (EMA) design. We examined the percentage of youth who reported exposure to online alcohol advertising in the past two weeks, average weekly rate of exposure, types of online alcohol advertisements youth reported seeing, and factors that increased youths’ risk of exposure to online alcohol advertising. Analyses are based on 485 participants (47% female; 25% Hispanic, 25% white, 27% black; 6% Asian, 16% other). Youth logged exposures to a total of 3,966 (16,018 weighted for under-reporting) alcohol advertisements across the monitoring period; 154 (568 weighted) or 3.6% were online ads. Seventeen percent of youth reported seeing any online alcohol ad; the majority of online ads seen were video commercials (44.8%) and banner/side ads (26.6%). Factors associated with greater ad exposure were being older, rebellious, and Black race; greater parental monitoring and more hours spent on social media were associated with less exposure. Findings provide important information about adolescents’ exposure to online alcohol advertising and what might contribute to a greater likelihood of exposure. Given that online ad exposure is linked to drinking behavior, prevention programming for younger adolescents should continue to address this issue to help youth make healthy choices regarding alcohol use. PMID:27819430

Factors associated with younger adolescents' exposure to online alcohol advertising.

PubMed

D'Amico, Elizabeth J; Martino, Steven C; Collins, Rebecca L; Shadel, William G; Tolpadi, Anagha; Kovalchik, Stephanie; Becker, Kirsten M

2017-03-01

Little is known about the extent and nature of youth exposure to online alcohol advertising, or factors that may be associated with exposure. The current study recruited middle school students who completed a paper survey and then logged each alcohol advertisement that they encountered over a 2-week period using cell phones as part of an ecological momentary assessment design. We examined the percentage of youth who reported exposure to online alcohol advertising in the past 2 weeks, average weekly rate of exposure, types of online alcohol advertisements youth reported seeing, and factors that increased youths' risk of exposure to online alcohol advertising. Analyses are based on 485 participants (47% female; 25% Hispanic, 25% White, 27% Black; 6% Asian, 16% other). Youth logged exposures to a total of 3,966 (16,018 weighted for underreporting) alcohol advertisements across the monitoring period; 154 (568 weighted) or 3.6% were online ads. Seventeen percent of youth reported seeing any online alcohol ad; the majority of online ads seen were video commercials (44.8%) and banner/side ads (26.6%). Factors associated with greater ad exposure were being older, rebellious, and Black race; greater parental monitoring and more hours spent on social media were associated with less exposure. Findings provide important information about adolescents' exposure to online alcohol advertising and what might contribute to a greater likelihood of exposure. Given that online ad exposure is linked to drinking behavior, prevention programming for younger adolescents should continue to address this issue to help youth make healthy choices regarding alcohol use. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Depression subtypes and 5-year risk of dementia and Alzheimer disease in patients aged 70 years.

PubMed

Vilalta-Franch, Joan; López-Pousa, Secundino; Llinàs-Reglà, Jordi; Calvó-Perxas, Laia; Merino-Aguado, Javier; Garre-Olmo, Josep

2013-04-01

The objective of this study was to estimate several subtypes of depressive disorders as risk factors for dementia and Alzheimer disease (AD) specifically. This is a population-based cohort study using a sample of 451 non-demented older people. Adjusted Cox proportional hazard models were calculated to determine the association of depression with dementia or AD development after 5 years. Baseline evaluation included the Cambridge Mental Disorders of the Elderly Examination (CAMDEX). Depressive disorders (major episode [MD] and minor depressive disorders [MDDIS]) were assessed following DSM-IV criteria and further classified according to the age at onset (early versus late onset). In turn, all late-onset depressions were grouped as with or without depression-executive dysfunction syndrome (DEDS). Dementia (and dementia subtypes) diagnoses were made using the CAMDEX. When the patients were deceased, the Retrospective Collateral Dementia Interview was used. Late-onset depressions (both MD and MDDIS) were associated with increased dementia (hazard ratio [HR] = 2.635; 95% CI = 1.153-6.023; and HR = 2.517; 95% CI = 1.200-5.280, respectively), and AD (HR = 6.262; 95% CI = 2.017-19.446; and HR = 4.208; 95% CI = 1.828-9.685, respectively) after adjustment by age, gender, marital status, education, cognitive impairment, executive function and stroke history. A second model revealed that only late-onset depressions with DEDS increased the risk for both dementia (late-onset MD with DEDS: HR = 6.262; 95% CI = 2.017-19.446; late-onset MDDIS with DEDS: HR = 4.208; 95% CI = 1.828-9.685) and AD (late-onset MD with DEDS: HR = 7.807; 95% CI = 1.567-38.894; late-onset MDDIS with DEDS: HR = 6.099; 95% CI = 2.123-17.524). Late-onset depressive episodes with DEDS are risk factors for dementia and AD development, regardless of the severity of the depression. Copyright © 2012 John Wiley & Sons, Ltd.

Relationship between Added Sugars Consumption and Chronic Disease Risk Factors: Current Understanding.

PubMed

Rippe, James M; Angelopoulos, Theodore J

2016-11-04

Added sugars are a controversial and hotly debated topic. Consumption of added sugars has been implicated in increased risk of a variety of chronic diseases including obesity, cardiovascular disease, diabetes and non-alcoholic fatty liver disease (NAFLD) as well as cognitive decline and even some cancers. Support for these putative associations has been challenged, however, on a variety of fronts. The purpose of the current review is to summarize high impact evidence including systematic reviews, meta-analyses, and randomized controlled trials (RCTs), in an attempt to provide an overview of current evidence related to added sugars and health considerations. This paper is an extension of a symposium held at the Experimental Biology 2015 conference entitled "Sweeteners and Health: Current Understandings, Controversies, Recent Research Findings and Directions for Future Research". We conclude based on high quality evidence from randomized controlled trials (RCT), systematic reviews and meta-analyses of cohort studies that singling out added sugars as unique culprits for metabolically based diseases such as obesity, diabetes and cardiovascular disease appears inconsistent with modern, high quality evidence and is very unlikely to yield health benefits. While it is prudent to consume added sugars in moderation, the reduction of these components of the diet without other reductions of caloric sources seems unlikely to achieve any meaningful benefit.

Relationship between Added Sugars Consumption and Chronic Disease Risk Factors: Current Understanding

PubMed Central

Rippe, James M.; Angelopoulos, Theodore J.

2016-01-01

Added sugars are a controversial and hotly debated topic. Consumption of added sugars has been implicated in increased risk of a variety of chronic diseases including obesity, cardiovascular disease, diabetes and non-alcoholic fatty liver disease (NAFLD) as well as cognitive decline and even some cancers. Support for these putative associations has been challenged, however, on a variety of fronts. The purpose of the current review is to summarize high impact evidence including systematic reviews, meta-analyses, and randomized controlled trials (RCTs), in an attempt to provide an overview of current evidence related to added sugars and health considerations. This paper is an extension of a symposium held at the Experimental Biology 2015 conference entitled “Sweeteners and Health: Current Understandings, Controversies, Recent Research Findings and Directions for Future Research”. We conclude based on high quality evidence from randomized controlled trials (RCT), systematic reviews and meta-analyses of cohort studies that singling out added sugars as unique culprits for metabolically based diseases such as obesity, diabetes and cardiovascular disease appears inconsistent with modern, high quality evidence and is very unlikely to yield health benefits. While it is prudent to consume added sugars in moderation, the reduction of these components of the diet without other reductions of caloric sources seems unlikely to achieve any meaningful benefit. PMID:27827899

Impact of Gene Patents and Licensing Practices on Access to Genetic Testing for Alzheimer’s Disease

PubMed Central

Skeehan, Katie; Heaney, Christopher; Cook-Deegan, Robert

2010-01-01

Genetic testing for Alzheimer’s disease (AD) includes genotyping for apolipoprotein E, for late-onset AD, and three rare autosomal dominant, early-onset forms of AD associated with different genes (APP, PSEN1 and PSEN2). According to researchers, patents have not impeded research in the field, nor were patents an important consideration in the quest for the genetic risk factors. Athena Diagnostics holds exclusive licenses from Duke University for three “method” patents covering APOE genetic testing. Athena offers tests for APOE and genes associated with early onset, autosomal dominant AD. One of those presenilin genes is patented and exclusively licensed to Athena; the other presenilin gene was patented but the patent was allowed to lapse; and one (APP) is patented only as a research tool and patent claims do not cover diagnostic use. Direct-to-consumer testing is available for some AD-related genes, apparently without a license. Athena Diagnostics consolidated its position in the market for AD genetic testing by collecting exclusive rights to patents arising from university research. Duke University also used its licenses to Athena to enforce adherence to clinical guidelines, including elimination of the service from Smart Genetics, which was offering direct-to-consumer risk assessment based on APOE genotyping. PMID:20393312

Maternal and anaesthesia-related risk factors and incidence of spinal anaesthesia-induced hypotension in elective caesarean section: A multinomial logistic regression.

PubMed

Fakherpour, Atousa; Ghaem, Haleh; Fattahi, Zeinabsadat; Zaree, Samaneh

2018-01-01

Although spinal anaesthesia (SA) is nowadays the preferred anaesthesia technique for caesarean section (CS), it is associated with considerable haemodynamic effects, such as maternal hypotension. This study aimed to evaluate a wide range of variables (related to parturient and anaesthesia techniques) associated with the incidence of different degrees of SA-induced hypotension during elective CS. This prospective study was conducted on 511 mother-infant pairs, in which the mother underwent elective CS under SA. The data were collected through preset proforma containing three parts related to the parturient, anaesthetic techniques and a table for recording maternal blood pressure. It was hypothesized that some maternal (such as age) and anaesthesia-related risk factors (such as block height) were associated with occurance of SA-induced hypotension during elective CS. The incidence of mild, moderate and severe hypotension was 20%, 35% and 40%, respectively. Eventually, ten risk factors were found to be associated with hypotension, including age >35 years, body mass index ≥25 kg/m 2 , 11-20 kg weight gain, gravidity ≥4, history of hypotension, baseline systolic blood pressure (SBP) <120 mmHg and baseline heart rate >100 beats/min in maternal modelling, fluid preloading ≥1000 ml, adding sufentanil to bupivacaine and sensory block height >T 4 in anaesthesia-related modelling ( P < 0.05). Age, body mass index, weight gain, gravidity, history of hypotension, baseline SBP and heart rate, fluid preloading, adding sufentanil to bupivacaine and sensory block hieght were the main risk factors identified in the study for SA-induced hypotension during CS.

Analysis of risk factors for and the prognosis of postoperative acute respiratory distress syndrome in patients with Stanford type A aortic dissection.

PubMed

Chen, Mei-Fang; Chen, Liang-Wan; Cao, Hua; Lin, Yong

2016-10-01

To explore the risk factors for and the prognosis of postoperative acute respiratory distress syndrome (ARDS) in patients with Stanford type A aortic dissection (AD). This retrospective nested case-control study included 527 Stanford type A AD patients who were divided into ARDS groups and non-ARDS groups. The clinical features of the groups were examined. The fifty-nine patients in the ARDS group exhibited extended durations of cardiopulmonary bypass (CPB) (P=0.004), deep hypothermic circulatory arrest (DHCA) (P=0.000), ventilator support (P=0.013) and intensive care unit (ICU) stay (P=0.045), higher hospital costs (P=0.000), larger perioperative transfusions volumes [red blood cells (RBC): P=0.002, platelets (PLT): P=0.040, fresh frozen plasma (FFP): P=0.001], more frequent pulmonary infection (P=0.018) and multiple organ dysfunction syndrome (MODS) (P=0.040) and a higher rate of in-hospital mortality (P=0.020). The ARDS group exhibited worse statuses in terms of oxygenation index (OI) values (P=0.000) and Apache II scores (P=0.000). DHCA [P=0.000, odds ratio (OR) =2.589] and perioperative transfusion (RBC: P=0.000, OR =2.573; PLT: P=0.027, OR =1.571; FFP: P=0.002, OR =1.929) were independent risk factors for postoperative ARDS. The survival rates and median survival times after discharge were similar between the two groups (P=0.843). DHCA duration and perioperative transfusion volume were independent risk factors for postoperative ARDS which warrants greater attention by the cardiac surgeons.

Saitohin Q7R polymorphism is associated with late-onset Alzheimer's disease susceptibility among caucasian populations: a meta-analysis.

PubMed

Huang, Rong; Tian, Sai; Cai, Rongrong; Sun, Jie; Xia, Wenqing; Dong, Xue; Shen, Yanjue; Wang, Shaohua

2017-08-01

Saitohin (STH) Q7R polymorphism has been reported to influence the individual's susceptibility to Alzheimer's disease (AD); however, conclusions remain controversial. Therefore, we performed this meta-analysis to explore the association between STH Q7R polymorphism and AD risk. Systematic literature searches were performed in the PubMed, Embase, Cochrane Library and Web of Science for studies published before 31 August 2016. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the strength of the association using a fixed- or random-effects model. Subgroup analyses, Galbraith plot and sensitivity analyses were also performed. All statistical analyses were performed with STATA Version 12.0. A total of 19 case-control studies from 17 publications with 4387 cases and 3972 controls were included in our meta-analysis. The results showed that the Q7R polymorphism was significantly associated with an increased risk of AD in a recessive model (RR versus QQ+QR, OR = 1.27, 95% CI = 1.01-1.60, P = 0.040). After excluding the four studies not carried out in caucasians, the overall association was unchanged in all comparison models. Further subgroup analyses stratified by the time of AD onset, and the quality of included studies provided statistical evidence of significant increased risk of AD in RR versus QQ+QR model only in late-onset subjects (OR = 1.56, 95% CI = 1.07-2.26, P = 0.021) and in studies with high quality (OR = 1.37, 95% CI = 1.01-1.86, P = 0.043). This meta-analysis suggests that the RR genotype in saitohin Q7R polymorphism may be a human-specific risk factor for AD, especially among late-onset AD subjects and caucasian populations. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Normalisation theory: Does it accurately describe temporal changes in adolescent drunkenness and smoking?

PubMed

Sznitman, Sharon R; Zlotnick, Cheryl; Harel-Fisch, Yossi

2016-07-01

The multiple risk model postulates that accumulating risk factors increase adolescent drunkenness and smoking. The normalisation theory adds to this by arguing that the relation between accumulative risk and drunkenness and smoking is dependent on the distribution of these behaviours in the larger population. More concretely, normalisation theory predicts that: (i) when population level use increases, low risk adolescents will be more likely to use alcohol and cigarettes; and (ii) adolescents facing multiple risk factors will be equally likely to use alcohol and cigarettes, regardless of trends in population level use. The current study empirically tests these assumptions on five waves of nationally representative samples of Israeli Jewish youth. Five cross-sectional waves of data from the Israeli Health Behaviour in School-aged Children survey for Jewish 10th graders were used. Logistic regression models measured the impact of changes in population level use across waves on drunkenness and smoking, and their association with differing levels of risk factors. Between zero and two risk factors, the risk of drunkenness and smoking increases for each additional risk factor. When reaching two risk factors, added risk does not significantly increase the likelihood of smoking and drunkenness. Changes in population level drunkenness and smoking did not systematically relate to changes in the individual level relationship between risk factors and smoking and drunkenness. The pattern of results in this study provides strong evidence for the multiple risk factor model and inconsistent evidence for the normalisation theory. [Sznitman SR, Zlotnick C, Harel-Fisch Y. Normalisation theory: Does it accurately describe temporal changes in adolescent drunkenness and smoking? Drug Alcohol Rev 2016;35:424-432]. © 2015 Australasian Professional Society on Alcohol and other Drugs.

Arterial stiffness and cardiovascular events: the Framingham Heart Study.

PubMed

Mitchell, Gary F; Hwang, Shih-Jen; Vasan, Ramachandran S; Larson, Martin G; Pencina, Michael J; Hamburg, Naomi M; Vita, Joseph A; Levy, Daniel; Benjamin, Emelia J

2010-02-02

Various measures of arterial stiffness and wave reflection have been proposed as cardiovascular risk markers. Prior studies have not assessed relations of a comprehensive panel of stiffness measures to prognosis in the community. We used proportional hazards models to analyze first-onset major cardiovascular disease events (myocardial infarction, unstable angina, heart failure, or stroke) in relation to arterial stiffness (pulse wave velocity [PWV]), wave reflection (augmentation index, carotid-brachial pressure amplification), and central pulse pressure in 2232 participants (mean age, 63 years; 58% women) in the Framingham Heart Study. During median follow-up of 7.8 (range, 0.2 to 8.9) years, 151 of 2232 participants (6.8%) experienced an event. In multivariable models adjusted for age, sex, systolic blood pressure, use of antihypertensive therapy, total and high-density lipoprotein cholesterol concentrations, smoking, and presence of diabetes mellitus, higher aortic PWV was associated with a 48% increase in cardiovascular disease risk (95% confidence interval, 1.16 to 1.91 per SD; P=0.002). After PWV was added to a standard risk factor model, integrated discrimination improvement was 0.7% (95% confidence interval, 0.05% to 1.3%; P<0.05). In contrast, augmentation index, central pulse pressure, and pulse pressure amplification were not related to cardiovascular disease outcomes in multivariable models. Higher aortic stiffness assessed by PWV is associated with increased risk for a first cardiovascular event. Aortic PWV improves risk prediction when added to standard risk factors and may represent a valuable biomarker of cardiovascular disease risk in the community.

Maintenance of membrane organization in the aging mouse brain as the determining factor for preventing receptor dysfunction and for improving response to anti-Alzheimer treatments.

PubMed

Colin, Julie; Thomas, Mélanie H; Gregory-Pauron, Lynn; Pinçon, Anthony; Lanhers, Marie-Claire; Corbier, Catherine; Claudepierre, Thomas; Yen, Frances T; Oster, Thierry; Malaplate-Armand, Catherine

2017-06-01

Although a major risk factor for Alzheimer's disease (AD), the "aging" parameter is not systematically considered in preclinical validation of anti-AD drugs. To explore how aging affects neuronal reactivity to anti-AD agents, the ciliary neurotrophic factor (CNTF)-associated pathway was chosen as a model. Comparison of the neuroprotective properties of CNTF in 6- and 18-month old mice revealed that CNTF resistance in the older animals is associated with the exclusion of the CNTF-receptor subunits from rafts and their subsequent dispersion to non-raft cortical membrane domains. This age-dependent membrane remodeling prevented both the formation of active CNTF-receptor complexes and the activation of prosurvival STAT3 and ERK1/2 pathways, demonstrating that age-altered membranes impaired the reactivity of potential therapeutic targets. CNTF-receptor distribution and CNTF signaling responses were improved in older mice receiving dietary docosahexaenoic acid, with CNTF-receptor functionality being similar to those of younger mice, pointing toward dietary intervention as a promising adjuvant strategy to maintain functional neuronal membranes, thus allowing the associated receptors to respond appropriately to anti-AD agents. Copyright © 2017 Elsevier Inc. All rights reserved.

Aging is associated with altered inflammatory, arachidonic acid cascade and synaptic markers, influenced by epigenetic modifications, in the human frontal cortex

PubMed Central

Keleshian, Vasken L.; Modi, Hiren R.; Rapoport, Stanley I.; Rao, Jagadeesh S.

2013-01-01

Aging is a risk factor for Alzheimer’s disease (AD) and is associated with cognitive decline. However, underlying molecular mechanisms of brain aging are not clear. Recent studies suggest epigenetic influences on gene expression in AD, since DNA methylation levels influence protein and mRNA expression in postmortem AD brain. We hypothesized that some of these changes occur with normal aging. To test this hypothesis, we measured markers of the arachidonic acid (AA) cascade, neuroinflammation, pro- and anti-apoptosis factors, and gene specific epigenetic modifications in postmortem frontal cortex from nine middle-aged (41 ± 1 (SEM) years) and ten aged subjects (70 ± 3 years). The aged compared with middle-aged brain showed elevated levels of neuroinflammatory and AA cascade markers, altered pro and anti-apoptosis factors and loss of synaptophysin. Some of these changes correlated with promoter hypermethylation of BDNF, CREB, and synaptophysin and hypomethylation of BAX. These molecular alterations in aging are different from or more subtle than changes associated with AD pathology. The degree to which they are related to changes in cognition or behavior during normal aging remains to be evaluated. PMID:23336521

The algorithm for Alzheimer risk assessment based on APOE promoter polymorphisms.

PubMed

Limon-Sztencel, Anna; Lipska-Ziętkiewicz, Beata S; Chmara, Magdalena; Wasag, Bartosz; Bidzan, Leszek; Godlewska, Beata R; Limon, Janusz

2016-05-19

Over the past two decades, the APOE gene and its polymorphisms have been among the most studied risk factors of Alzheimer disease (AD) development; yet, there are discrepancies between various studies regarding their impact. For this reason, the evaluation of the APOE genotype has not been included in the current European Federation of Neurological Societies guidelines for AD diagnosis and management. This aim of this study was to add to this discussion by assessing the possible influence of multiple polymorphisms in the promoter region of the APOE gene and genotypes of its allele E on the risk for dementia. We performed a comprehensive analysis of APOE gene polymorphisms, assessed the detected genotypes and correlated molecular findings with serum apolipoprotein E concentrations. The study comprised 110 patients with AD and 110 age-matched healthy individuals from the Polish population. Four polymorphisms of the APOE gene had minor allele frequency exceeding 5% and were included in the analysis: -491A/T (rs449647), -427T/C (rs769446), -219T/G (rs405509) in the promoter region and +113G/C (rs440446) in intron 1. A protective effect of the -219G allele on AD development was observed. Also, the -491T and -219G alleles were found to be underrepresented in the carriers of the APOE E4 variant. On the basis of the genotype and linkage disequilibrium studies, a relative score was attributed to given genotypes with respect to the estimated probability of their protective effects against AD, giving rise to the 'preventive score'. This 'preventive score', based on the total sums of the relative scores, expresses the protective effect deriving from the synergistic action of individual single-nucleotide polymorphisms. The 'preventive score' was identified as an independent predictive factor. We propose a novel, more complex approach to AD risk assessment based on the additive effect of multiple polymorphic loci within the APOE promoter region, which on their own may have too weak an impact to reach the level of significance. This has potentially practical implications, as it may help to improve the informative potential of APOE testing in a clinical setting. Subsequent studies of the proposed system in large, multi-ethnic cohorts are necessary for its validation and to assess its potential practical value for clinical applications.

Traumatic brain injury history is associated with an earlier age of dementia onset in autopsy-confirmed Alzheimer's disease.

PubMed

Schaffert, Jeff; LoBue, Christian; White, Charles L; Chiang, Hsueh-Sheng; Didehbani, Nyaz; Lacritz, Laura; Rossetti, Heidi; Dieppa, Marisara; Hart, John; Cullum, C Munro

2018-05-01

To evaluate whether a history of traumatic brain injury (TBI) with reported loss of consciousness (LOC) is a risk factor for earlier onset of Alzheimer's disease (AD) in an autopsy-confirmed sample. Data from 2,133 participants with autopsy-confirmed AD (i.e., at least Braak neurofibrillary tangle stages III to VI and CERAD neuritic plaque score moderate to frequent) were obtained from the National Alzheimer's Coordinating Center (NACC). Participants were categorized by presence/absence of self-reported remote (i.e., >1 year prior to their first Alzheimer's Disease Center visit) history of TBI with LOC (TBI+ vs. TBI-). Analyses of Covariance (ANCOVA) controlling for sex, education, and race compared groups on clinician-estimated age of symptom onset and age of diagnosis. Average age of onset was 2.34 years earlier (p = .01) for the TBI+ group (n = 194) versus the TBI- group (n = 1900). Dementia was diagnosed on average 2.83 years earlier (p = .002) in the TBI+ group (n = 197) versus the TBI- group (n = 1936). Using more stringent neuropathological criteria (i.e., Braak stages V-VI and CERAD frequent), both age of AD onset and diagnosis were 3.6 years earlier in the TBI+ group (both p's < .001). History of TBI with reported LOC appears to be a risk factor for earlier AD onset. This is the first study to use autopsy-confirmed cases, supporting previous investigations that used clinical criteria for the diagnosis of AD. Further investigation as to possible underlying mechanisms of association is needed. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Food allergy in South African children with atopic dermatitis.

PubMed

Gray, Claudia L; Levin, Michael E; Zar, Heather J; Potter, Paul C; Khumalo, Nonhlanhla P; Volkwyn, Lucia; Fenemore, Bartha; du Toit, George

2014-10-01

The prevalence of food allergy in South Africa is unknown, but previously thought to be rare in black South Africans. This study aimed to determine the prevalence of, and risk factors for, IgE-mediated food allergy in South African children with atopic dermatitis (AD). This was a prospective, observational study in a paediatric university hospital in Cape Town. Children with AD, aged 6 months to 10 yrs, were randomly recruited from the dermatology clinic. They were assessed for sensitization and allergy by questionnaire, skin prick tests, Immuno Solid Phase Allergen Chip (ISAC) test and incremental food challenges. 100 participants (59 black Africans and 41 of mixed race) were enrolled, median age 42 months. There were high overall rates of food sensitization (66%) and food allergy (40%). Egg (25%) and peanut (24%) were the most common allergies. Black participants had comparable sensitization (69% vs. 61%) but lower allergy rates (34% vs. 46%) than mixed race participants. This was especially evident for peanut allergy (15% Blacks vs. 37% mixed race allergic to peanut, p = 0.01). Early-onset AD (<6 months), severe eczema, and young age <2 yrs were significant risk factors for food allergy. The prevalence of food allergy is unexpectedly high in South African children with AD, and comparable with food allergy rates in patients with AD in developed countries. There are ethnic differences, with significantly lower peanut allergy rates in Blacks compared to mixed race patients. These results are not generalizable to an unselected South African population, which requires further study. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Reduction in risk factors for type 2 diabetes mellitus in response to a low-sugar, high-fiber dietary intervention in overweight Latino adolescents.

PubMed

Ventura, Emily; Davis, Jaimie; Byrd-Williams, Courtney; Alexander, Katharine; McClain, Arianna; Lane, Christianne Joy; Spruijt-Metz, Donna; Weigensberg, Marc; Goran, Michael

2009-04-01

To examine if reductions in added sugar intake or increases in fiber intake in response to a 16-week intervention were related to improvements in metabolic outcomes related to type 2 diabetes mellitus risk. Secondary analysis of a randomized control trial. Intervention classes at a lifestyle laboratory and metabolic measures at the General Clinical Research Center. Fifty-four overweight Latino adolescents (mean [SD] age, 15.5 [1] years). Intervention Sixteen-week study with 3 groups: control, nutrition, or nutrition plus strength training. Body composition by dual-energy x-ray absorptiometry; visceral adipose tissue by magnetic resonance imaging; glucose and insulin incremental area under the curve by oral glucose tolerance test; insulin sensitivity, acute insulin response, and disposition index by intravenous glucose tolerance test; and dietary intake by 3-day records. Fifty-five percent of all participants decreased added sugar intake (mean decrease, 47 g/d) and 59% increased fiber intake (mean increase, 5 g/d), and percentages were similar in all intervention groups, including controls. Those who decreased added sugar intake had an improvement in glucose incremental area under the curve (-15% vs +3%; P = .049) and insulin incremental area under the curve (-33% vs -9%; P = .02). Those who increased fiber intake had an improvement in body mass index (-2% vs +2%; P = .01) and visceral adipose tissue (-10% vs no change; P = .03). Individuals who reduced added sugar intake by the equivalent of 1 can of soda per day or increased fiber intake by the equivalent of a cup of beans showed improvements in key risk factors for type 2 diabetes, specifically in insulin secretion and visceral fat. Improvements occurred independent of group assignment and were equally likely to occur in control group participants.

High-sensitive factor I and C-reactive protein based biomarkers for coronary artery disease.

PubMed

Zhao, Qing; Du, Jian-Shi; Han, Dong-Mei; Ma, Ying

2014-01-01

An analysis of high-sensitive factor I and C-reactive proteins as biomarkers for coronary artery disease has been performed from 19 anticipated cohort studies that included 21,567 participants having no information about coronary artery disease. Besides, the clinical implications of statin therapy initiated due to assessment of factor I and C-reactive proteins have also been modeled during studies. The measure of risk discrimination (C-index) was increased (by 0.0101) as per the prognostic model for coronary artery disease with respect to sex, smoking status, age, blood pressure, total cholesterol level along with diabetic history characteristic parameters. The C-index was further raised by 0.0045 and 0.0053 when factor I and C-reactive proteins based information were added, respectively which finally predicted 10-year risk categories as: high (> 20%), medium (10% to < 20%), and low (< 10%) risks. We found 2,254 persons (among 15,000 adults (age ≥ 45 years)) would initially be classified as being at medium risk for coronary artery disease when only conventional risk factors were used as calculated risk. Besides, persons with a predicted risk of more than 20% as well as for persons suffering from other risk factors (i.e. diabetes), statin therapy was initiated (irrespective of their decade old predicted risk). We conclude that under current treatment guidelines assessment of factor I and C-reactive proteins levels (as biomarker) in people at medium risk for coronary artery disease could prevent one additional coronary artery disease risk over a period a decade for every 390-500 people screened.

Alzheimer Disease

PubMed Central

Apostolova, Liana G.

2016-01-01

ABSTRACT Purpose of Review: This article discusses the recent advances in the diagnosis and treatment of Alzheimer disease (AD). Recent Findings: In recent years, significant advances have been made in the fields of genetics, neuroimaging, clinical diagnosis, and staging of AD. One of the most important recent advances in AD is our ability to visualize amyloid pathology in the living human brain. The newly revised criteria for diagnosis of AD dementia embrace the use for biomarkers as supportive evidence for the underlying pathology. Guidelines for the responsible use of amyloid positron emission tomography (PET) have been developed, and the clinical and economic implications of amyloid PET imaging are actively being explored. Summary: Our improved understanding of the clinical onset, progression, neuroimaging, pathologic features, genetics, and other risk factors for AD impacts the approaches to clinical diagnosis and future therapeutic interventions. PMID:27042902

Aortic propagation velocity does not correlate with classical aortic stiffness parameters in healthy individuals.

PubMed

Arı, Hatem; Kahraman, Fatih; Türker, Yasin; Güler, Serdar; Baş, Hasan Aydın; Erdoğan, Doğan

2017-10-30

Aortic stiffness is an important cardiovascular risk marker, which can be determined using different noninvasive techniques. Aortic propagation velocity (APV) has recently been established as a novel echocardiographic parameter of aortic stiffness. This study aimed to investigate the association between APV and the classical echocardiography-derived aortic stiffness parameters, aortic distensibility (AD) and aortic strain (AS), in a group of otherwise healthy individuals. In total, 97 consecutive healthy subjects were recruited in this observational study. APV was measured using color M-mode echocardiography from the suprasternal window in the descending aorta. AS and AD were calculated using clinical blood pressure and the M-mode echocardiography-derived aortic diameters. Correlation analyses were performed between cardiovascular risk factors related to increased aortic stiffness (age, obesity, and blood pressure) and measured stiffness parameters (APV, AS, and AD). Correlation analyses were also performed among the measured stiffness parameters. Good correlation of age, blood pressure, and BMI with AS and AD was observed. One-on-one correlation of age, blood pressure, and BMI with APV was not observed. No correlation was observed between APV and AS (r=-0.05, p=0.6) or between APV and AD (r=-0.17, p=0.8). Although APV has been proposed as a novel and practical echocardiographic parameter of aortic stiffness, especially in patients with coronary artery disease, correlations between classical stiffness parameters (AS and AD) and APV were absent in healthy individuals at low-intermediate risk. The clinical and research applicability of APV should be further evaluated.

Late Radiation and Cardiovascular Adverse Effects After Androgen Deprivation and High-Dose Radiation Therapy in Prostate Cancer: Results From the DART 01/05 Randomized Phase 3 Trial

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zapatero, Almudena, E-mail: almudena.zapatero@salud.madrid.org; Guerrero, Araceli; Maldonado, Xavier

Purpose: To present data on the late toxicity endpoints of a randomized trial (DART 01/05) conducted to determine whether long-term androgen deprivation (LTAD) was superior to short-term AD (STAD) when combined with high-dose radiation therapy (HDRT) in patients with prostate cancer (PCa). Patients and Methods: Between November 2005 and December 2010, 355 eligible men with cT1c-T3aN0M0 PCa and intermediate-risk and high-risk factors (2005 National Comprehensive Cancer Network criteria) were randomized to 4 months of AD combined with HDRT (median dose, 78 Gy) (STAD) or the same treatment followed by 24 months of AD (LTAD). Treatment-related complications were assessed using European Organization for Research andmore » Treatment of Cancer–Radiation Therapy Oncology Group and Common Terminology Criteria for Adverse Events v3.0 scoring schemes. Multivariate analyses for late toxicity were done using the Fine-Gray method. Results: The 5-year incidence of grade ≥2 rectal and urinary toxicity was 11.1% and 8.2% for LTAD and 7.6% and 7.3% for STAD, respectively. Compared with STAD, LTAD was not significantly associated with a higher risk of late grade ≥2 rectal toxicity (hazard ratio [HR] 1.360, 95% confidence interval [CI] 0.660-2.790, P=.410) or urinary toxicity (HR 1.028, 95% CI 0.495-2.130, P=.940). The multivariate analysis showed that a baseline history of intestinal comorbidity (HR 3.510, 95% CI 1.560-7.930, P=.025) and the rectal volume receiving >60 Gy (Vr60) (HR 1.030, 95% CI 1.001-1.060, P=.043) were the only factors significantly correlated with the risk of late grade ≥2 rectal complications. A history of previous surgical prostate manipulations was significantly associated with a higher risk of grade ≥2 urinary complications (HR 2.427, 95% CI 1.051-5.600, P=.038). Long-term AD (HR 2.090; 95% CI 1.170-3.720, P=.012) and a history of myocardial infarction (HR 2.080; 95% CI 1.130-3.810, P=.018) were significantly correlated with a higher probability of cardiovascular events. Conclusion: Long-term AD did not significantly impact urinary or rectal radiation-induced toxicity, although it was associated with a higher risk of cardiovascular events. Longer follow-up is needed to measure the impact of AD on late morbidity and non-PCa mortality.« less

Now you see it. Now you don't: fair balance and adequate provision in advertisements for drugs before and after the switch from prescription to over-the-counter.

PubMed

Faerber, Adrienne E; Kreling, David H

2012-01-01

The objective of this study was to measure differences in fair balance (benefit and risk statements) and adequate provision (toll-free numbers, Internet URLs, print ad references, and medical professional references) in advertising content for drugs that have switched from prescription to over-the-counter (OTC). The Vanderbilt TV News Archive was used to select products to study, to measure the frequency and placement of ads for those products, and to view advertising content for those products. Unique advertisements (n = 108) for loratadine (Claritin), citirizine (Zyrtec), and omeprazole (Prilosec) were analyzed for the presence of adequate provision statements and for the frequency of benefit, risk, and other statements. OTC ads were shorter than prescription ads by 10.6 seconds but contained the same total number of statements. Most prescription ads (n (RX) = 31) contained toll-free numbers (97%), Internet URLs (94%), medical professional references (100%) and print ad references (68%). Few OTC ads (n (OTC) = 77) contained adequate provision statements: 4% contained toll-free numbers and 10% contained Internet URLs. Prescription ads had similar numbers of benefits (1.5) and risks (1.8) per 30 seconds of ad time, and OTC ads had more benefits (6.6) than risks (1.2) per 30 seconds of ad time. Prescription drug ads contained risk statements that listed specific side effects and explicit harms from taking the product, but OTC ads contained nonspecific risk information and statements that implied risk rather than directly identifying risk. Differences in the Food and Drug Administration (FDA) and Federal Trade Commission (FTC) regulation of advertising affected the balance of risk and benefit information that appeared and the specificity of risk information available.

A spatially-dynamic preliminary risk assessment of the American peregrine falcon at the Los Alamos National Laboratory (version 1)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gallegos, A.F.; Gonzales, G.J.; Bennett, K.D.

1997-06-01

The Endangered Species Act and the Record of Decision on the Dual Axis Radiographic Hydrodynamic Test Facility at the Los Alamos National Laboratory require protection of the American peregrine falcon. A preliminary risk assessment of the peregrine was performed using a custom FORTRAN model and a geographical information system. Estimated doses to the falcon were compared against toxicity reference values to generate hazard indices. Hazard index results indicated no unacceptable risk to the falcon from the soil ingestion pathway, including a measure of cumulative effects from multiple contaminants that assumes a linear additive toxicity type. Scaling home ranges on themore » basis of maximizing falcon height for viewing prey decreased estimated risk by 69% in a canyons-based home range and increased estimated risk by 40% in a river-based home range. Improving model realism by weighting simulated falcon foraging based on distance from potential nest sites decreased risk by 93% in one exposure unit and by 82% in a second exposure unit. It was demonstrated that choice of toxicity reference values can have a substantial impact on risk estimates. Adding bioaccumulation factors for several organics increased partial hazard quotients by a factor of 110, but increased the mean hazard index by only 0.02 units. Adding a food consumption exposure pathway in the form of biomagnification factors for 15 contaminants of potential ecological concern increased the mean hazard index to 1.16 ({+-} 1.0), which is above the level of acceptability (1.0). Aroclor-1254, dichlorodiphenyltrichlorethane (DDT) and dichlorodiphenylethelyne (DDE) accounted for 81% of the estimated risk that includes soil ingestion and food consumption Contaminant pathways and a biomagnification component. Information on risk by specific geographical location was generated, which can be used to manage contaminated areas, falcon habitat, facility siting, and/or facility operations. 123 refs., 10 figs., 2 tabs.« less

Multiplex proteomics for prediction of major cardiovascular events in type 2 diabetes.

PubMed

Nowak, Christoph; Carlsson, Axel C; Östgren, Carl Johan; Nyström, Fredrik H; Alam, Moudud; Feldreich, Tobias; Sundström, Johan; Carrero, Juan-Jesus; Leppert, Jerzy; Hedberg, Pär; Henriksen, Egil; Cordeiro, Antonio C; Giedraitis, Vilmantas; Lind, Lars; Ingelsson, Erik; Fall, Tove; Ärnlöv, Johan

2018-05-24

Multiplex proteomics could improve understanding and risk prediction of major adverse cardiovascular events (MACE) in type 2 diabetes. This study assessed 80 cardiovascular and inflammatory proteins for biomarker discovery and prediction of MACE in type 2 diabetes. We combined data from six prospective epidemiological studies of 30-77-year-old individuals with type 2 diabetes in whom 80 circulating proteins were measured by proximity extension assay. Multivariable-adjusted Cox regression was used in a discovery/replication design to identify biomarkers for incident MACE. We used gradient-boosted machine learning and lasso regularised Cox regression in a random 75% training subsample to assess whether adding proteins to risk factors included in the Swedish National Diabetes Register risk model would improve the prediction of MACE in the separate 25% test subsample. Of 1211 adults with type 2 diabetes (32% women), 211 experienced a MACE over a mean (±SD) of 6.4 ± 2.3 years. We replicated associations (<5% false discovery rate) between risk of MACE and eight proteins: matrix metalloproteinase (MMP)-12, IL-27 subunit α (IL-27a), kidney injury molecule (KIM)-1, fibroblast growth factor (FGF)-23, protein S100-A12, TNF receptor (TNFR)-1, TNFR-2 and TNF-related apoptosis-inducing ligand receptor (TRAIL-R)2. Addition of the 80-protein assay to established risk factors improved discrimination in the separate test sample from 0.686 (95% CI 0.682, 0.689) to 0.748 (95% CI 0.746, 0.751). A sparse model of 20 added proteins achieved a C statistic of 0.747 (95% CI 0.653, 0.842) in the test sample. We identified eight protein biomarkers, four of which are novel, for risk of MACE in community residents with type 2 diabetes, and found improved risk prediction by combining multiplex proteomics with an established risk model. Multiprotein arrays could be useful in identifying individuals with type 2 diabetes who are at highest risk of a cardiovascular event.

Neuroprotective Effects of Garlic A Review

PubMed Central

Mathew, BC; Biju, RS

2008-01-01

Garlic has been investigated extensively for health benefits, resulting in more than one thousand publications over the last decade alone. It is considered one of the best disease preventive foods, based on its potent and varied effects. Midlife risk factors for cardiovascular diseases, such as high serum total cholesterol, raised LDL, increased LDL oxidation, increased platelet aggregation, impaired fibrinolysis, hypertension and homocystinemia are important risk factors for dementia in later years. These risk factors play a major role in the genesis of atherosclerosis of vital arteries causing both cardiovascular and cerebrovascular disease. Garlic is best known for its lipid lowering and anti-atherogenic effects. Possible mechanisms of action include inhibition of the hepatic activities of lipogenic and cholesterogenic enzymes that are thought to be the genesis for dyslipidemias, increased excretion of cholesterol and suppression of LDL-oxidation. Oxidative stress caused by increased accumulation of reactive oxygen species (ROS) in cells has been implicated in the pathophysiology of several neurodegenerative diseases including Alzheimer's disease (AD). Several studies have demonstrated the antioxidant properties of garlic and its different preparations including Aged Garlic Extract (AGE). AGE and S-allyl-cysteines (SAC), a bioactive and bioavailable component in garlic preparations have been shown in a number of in vitro studies to protect neuronal cells against beta-amyloid (A) toxicity and apoptosis. Thus the broad range of anti-atherogenic, antioxidant and anti-apoptotic protection afforded by garlic may be extended to its neuroprotective action, helping to reduce the risk of dementia, including vascular dementia and AD. PMID:21499478

Erectile Dysfunction in Male Adults With Atopic Dermatitis and Psoriasis.

PubMed

Egeberg, Alexander; Hansen, Peter R; Gislason, Gunnar H; Skov, Lone; Thyssen, Jacob P

2017-03-01

Patients with psoriasis have increased risk of cardiovascular disease, but data on atopic dermatitis (AD) are less clear-cut. However, it is well-established that erectile dysfunction (ED) can serve as a risk marker for coronary disease. To investigate the incidence, prevalence, and risk of ED in men with psoriasis and AD. The sample included all Danish men at least 30 years old. In patients with AD and psoriasis, we determined disease severity based on use of systemic therapy. We performed a cross-sectional study (January 1, 2008) using logistic regression to estimate the prevalence and odds ratio of ED. Moreover, in a cohort study design, patients were followed from January 1, 2008 through December 31, 2012, and Cox regression models were used to estimate adjusted hazard ratios of new-onset ED. Models were adjusted for potential confounding factors, including age, socioeconomic status, health care consumption, smoking, alcohol abuse, diabetes, and cholesterol-lowering drug use. The outcome was initiation of pharmacotherapy used for treatment of ED. The sample consisted of 1,756,679 Danish men (age range = 30-100 years), of which 2,373 and 26,536 had adult AD (mild = 1,072; severe = 1,301) and psoriasis (mild = 21,775; severe = 4,761), respectively. Mean ages (SDs) were 53.0 (14.6), 46.7 (12.0), and 56.3 (13.8) years for the general population, patients with AD, and patients with psoriasis, respectively. Prevalences of ED were 8.7%, 6.7%, and 12.8% for the general population, patients with AD, and patients with psoriasis, respectively. Adjusted odds ratios (logistic regression) of ED were decreased in patients with AD (0.68; 0.57-0.80) but increased in those with psoriasis (1.15; 1.11-1.20). Adjusted odds ratios for mild and severe AD were 0.63 (0.48-0.82) and 0.72 (0.58-0.88), respectively, and those for psoriasis these were 1.16 (1.11-1.21) and 1.13 (1.03-1.23). Adjusted hazard ratios (Cox regression) were 0.92 (0.76-1.11) for AD and 1.14 (1.08-1.20) for psoriasis. The ED risk was not increased in men with mild AD (0.85; 0.63-1.14) or severe AD (0.97; 0.76-1.24) but was significantly increased in men with mild psoriasis (1.13; 1.09-1.20) and severe psoriasis (1.17; 1.04-1.32). We found an increased prevalence and risk of ED in men with psoriasis, whereas the risk was comparable to (and even slightly lower than) the general population for men with AD. Egeberg A, Hansen PR, Gislason GH, et al. Erectile Dysfunction in Male Adults With Atopic Dermatitis and Psoriasis. J Sex Med 2017;14:380-386. Copyright © 2016 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.

The Influence of Cardiac Risk Factor Burden on Cardiac Stress Test Outcomes.

PubMed

Schrock, Jon W; Li, Morgan; Orazulike, Chidubem; Emerman, Charles L

2011-06-01

Chest pain is the most common admission diagnosis for observation unit patients. These patients often undergo cardiac stress testing to further risk stratify for coronary artery disease (CAD). The decision of whom to stress is currently based on clinical judgment. We sought to determine the influence of cardiac risk factor burden on cardiac stress test outcome for patients tested from an observation unit, inpatient or outpatient setting. We performed a retrospective observational cohort study for all patients undergoing stress testing in our institution from June 2006 through July 2007. Cardiac risk factors were collected at the time of stress testing. Risk factors were evaluated in a summative fashion using multivariate regression adjusting for age and known coronary artery disease. The model was tested for goodness of fit and collinearity and the c statistic was calculated using the receiver operating curve. A total of 4026 subjects were included for analysis of which 22% had known CAD. The rates of positive outcome were 89 (12.0%), 95 (12.6%), and 343 (16.9%) for the OU, outpatients, and hospitalized patients respectively. While the odds of a positive test outcome increased for additional cardiac risk factors, ROC curve analysis indicates that simply adding the number of risk factors does not add significant diagnostic value. Hospitalized patients were more likely to have a positive stress test, OR 1.41 (1.10 - 1.81). Our study does not support basing the decision to perform a stress test on the number of cardiac risk factors.

One-hour glucose value as a long-term predictor of cardiovascular morbidity and mortality: the Malmö Preventive Project.

PubMed

Nielsen, Mette L; Pareek, Manan; Leósdóttir, Margrét; Eriksson, Karl-Fredrik; Nilsson, Peter M; Olsen, Michael H

2018-03-01

To examine the predictive capability of a 1-h vs 2-h postload glucose value for cardiovascular morbidity and mortality. Prospective, population-based cohort study (Malmö Preventive Project) with subject inclusion 1974-1992. 4934 men without known diabetes and cardiovascular disease, who had blood glucose (BG) measured at 0, 20, 40, 60, 90 and 120 min during an OGTT (30 g glucose per m 2 body surface area), were followed for 27 years. Data on cardiovascular events and death were obtained through national and local registries. Predictive capabilities of fasting BG (FBG) and glucose values obtained during OGTT alone and added to a clinical prediction model comprising traditional cardiovascular risk factors were assessed using Harrell's concordance index (C-index) and integrated discrimination improvement (IDI). Median age was 48 (25th-75th percentile: 48-49) years and mean FBG 4.6 ± 0.6 mmol/L. FBG and 2-h postload BG did not independently predict cardiovascular events or death. Conversely, 1-h postload BG predicted cardiovascular morbidity and mortality and remained an independent predictor of cardiovascular death (HR: 1.09, 95% CI: 1.01-1.17, P  = 0.02) and all-cause mortality (HR: 1.10, 95% CI: 1.05-1.16, P  < 0.0001) after adjusting for various traditional risk factors. Clinical risk factors with added 1-h postload BG performed better than clinical risk factors alone, in predicting cardiovascular death (likelihood-ratio test, P  = 0.02) and all-cause mortality (likelihood-ratio test, P  = 0.0001; significant IDI, P  = 0.0003). Among men without known diabetes, addition of 1-h BG, but not FBG or 2-h BG, to clinical risk factors provided incremental prognostic yield for prediction of cardiovascular death and all-cause mortality. © 2018 European Society of Endocrinology.

Creating demand for prescription drugs: a content analysis of television direct-to-consumer advertising.

PubMed

Frosch, Dominick L; Krueger, Patrick M; Hornik, Robert C; Cronholm, Peter F; Barg, Frances K

2007-01-01

American television viewers see as many as 16 hours of prescription drug advertisements (ads) each year, yet no research has examined how television ads attempt to influence consumers. This information is important, because ads may not meet their educational potential, possibly prompting consumers to request prescriptions that are clinically inappropriate or more expensive than equally effective alternatives. We coded ads shown during evening news and prime time hours for factual claims they make about the target condition, how they attempt to appeal to consumers, and how they portray the medication and lifestyle behaviors in the lives of ad characters. Most ads (82%) made some factual claims and made rational arguments (86%) for product use, but few described condition causes (26%), risk factors (26%), or prevalence (25%). Emotional appeals were almost universal (95%). No ads mentioned lifestyle change as an alternative to products, though some (19%) portrayed it as an adjunct to medication. Some ads (18%) portrayed lifestyle changes as insufficient for controlling a condition. The ads often framed medication use in terms of losing (58%) and regaining control (85%) over some aspect of life and as engendering social approval (78%). Products were frequently (58%) portrayed as a medical breakthrough. Despite claims that ads serve an educational purpose, they provide limited information about the causes of a disease or who may be at risk; they show characters that have lost control over their social, emotional, or physical lives without the medication; and they minimize the value of health promotion through lifestyle changes. The ads have limited educational value and may oversell the benefits of drugs in ways that might conflict with promoting population health.

Creating Demand for Prescription Drugs: A Content Analysis of Television Direct-to-Consumer Advertising

PubMed Central

Frosch, Dominick L.; Krueger, Patrick M.; Hornik, Robert C.; Cronholm, Peter F.; Barg, Frances K.

2007-01-01

PURPOSE American television viewers see as many as 16 hours of prescription drug advertisements (ads) each year, yet no research has examined how television ads attempt to influence consumers. This information is important, because ads may not meet their educational potential, possibly prompting consumers to request prescriptions that are clinically inappropriate or more expensive than equally effective alternatives. METHODS We coded ads shown during evening news and prime time hours for factual claims they make about the target condition, how they attempt to appeal to consumers, and how they portray the medication and lifestyle behaviors in the lives of ad characters. RESULTS Most ads (82%) made some factual claims and made rational arguments (86%) for product use, but few described condition causes (26%), risk factors (26%), or prevalence (25%). Emotional appeals were almost universal (95%). No ads mentioned lifestyle change as an alternative to products, though some (19%) portrayed it as an adjunct to medication. Some ads (18%) portrayed lifestyle changes as insufficient for controlling a condition. The ads often framed medication use in terms of losing (58%) and regaining control (85%) over some aspect of life and as engendering social approval (78%). Products were frequently (58%) portrayed as a medical breakthrough. CONCLUSIONS Despite claims that ads serve an educational purpose, they provide limited information about the causes of a disease or who may be at risk; they show characters that have lost control over their social, emotional, or physical lives without the medication; and they minimize the value of health promotion through lifestyle changes. The ads have limited educational value and may oversell the benefits of drugs in ways that might conflict with promoting population health. PMID:17261859

Impact of Cardiac Rehabilitation and Exercise Training on Psychological Risk Factors and Subsequent Prognosis in Patients With Cardiovascular Disease.

PubMed

Lavie, Carl J; Menezes, Arthur R; De Schutter, Alban; Milani, Richard V; Blumenthal, James A

2016-10-01

The role of psychological risk factors has been under-recognized in most subspecialties of medicine, as well as in general medicine practices. However, considerable evidence indicates that psychosocial factors are involved in the pathogenesis and progression of cardiovascular disease (CVD). Emerging data from cardiac rehabilitation (CR) settings and CR exercise training (CRET) programs have demonstrated the value of comprehensive CRET to improve psychological functioning and reduce all-cause mortality. Recent evidence also supports the role of CRET and the added value of stress management training in the secondary prevention of CVD. Copyright © 2016 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

Added sugars and periodontal disease in young adults: an analysis of NHANES III data.

PubMed

Lula, Estevam C O; Ribeiro, Cecilia C C; Hugo, Fernando N; Alves, Cláudia M C; Silva, Antônio A M

2014-10-01

Added sugar consumption seems to trigger a hyperinflammatory state and may result in visceral adiposity, dyslipidemia, and insulin resistance. These conditions are risk factors for periodontal disease. However, the role of sugar intake in the cause of periodontal disease has not been adequately studied. We evaluated the association between the frequency of added sugar consumption and periodontal disease in young adults by using NHANES III data. Data from 2437 young adults (aged 18-25 y) who participated in NHANES III (1988-1994) were analyzed. We estimated the frequency of added sugar consumption by using food-frequency questionnaire responses. We considered periodontal disease to be present in teeth with bleeding on probing and a probing depth ≥3 mm at one or more sites. We evaluated this outcome as a discrete variable in Poisson regression models and as a categorical variable in multinomial logistic regression models adjusted for sex, age, race-ethnicity, education, poverty-income ratio, tobacco exposure, previous diagnosis of diabetes, and body mass index. A high consumption of added sugars was associated with a greater prevalence of periodontal disease in middle [prevalence ratio (PR): 1.39; 95% CI: 1.02, 1.89] and upper (PR: 1.42; 95% CI: 1.08, 1.85) tertiles of consumption in the adjusted Poisson regression model. The upper tertile of added sugar intake was associated with periodontal disease in ≥2 teeth (PR: 1.73; 95% CI: 1.19, 2.52) but not with periodontal disease in only one tooth (PR: 0.85; 95% CI: 0.54, 1.34) in the adjusted multinomial logistic regression model. A high frequency of consumption of added sugars is associated with periodontal disease, independent of traditional risk factors, suggesting that this consumption pattern may contribute to the systemic inflammation observed in periodontal disease and associated noncommunicable diseases. © 2014 American Society for Nutrition.

Age Drives Distortion of Brain Metabolic, Vascular and Cognitive Functions, and the Gut Microbiome

PubMed Central

Hoffman, Jared D.; Parikh, Ishita; Green, Stefan J.; Chlipala, George; Mohney, Robert P.; Keaton, Mignon; Bauer, Bjoern; Hartz, Anika M. S.; Lin, Ai-Ling

2017-01-01

Advancing age is the top risk factor for the development of neurodegenerative disorders, including Alzheimer’s disease (AD). However, the contribution of aging processes to AD etiology remains unclear. Emerging evidence shows that reduced brain metabolic and vascular functions occur decades before the onset of cognitive impairments, and these reductions are highly associated with low-grade, chronic inflammation developed in the brain over time. Interestingly, recent findings suggest that the gut microbiota may also play a critical role in modulating immune responses in the brain via the brain-gut axis. In this study, our goal was to identify associations between deleterious changes in brain metabolism, cerebral blood flow (CBF), gut microbiome and cognition in aging, and potential implications for AD development. We conducted our study with a group of young mice (5–6 months of age) and compared those to old mice (18–20 months of age) by utilizing metabolic profiling, neuroimaging, gut microbiome analysis, behavioral assessments and biochemical assays. We found that compared to young mice, old mice had significantly increased levels of numerous amino acids and fatty acids that are highly associated with inflammation and AD biomarkers. In the gut microbiome analyses, we found that old mice had increased Firmicutes/Bacteroidetes ratio and alpha diversity. We also found impaired blood-brain barrier (BBB) function and reduced CBF as well as compromised learning and memory and increased anxiety, clinical symptoms often seen in AD patients, in old mice. Our study suggests that the aging process involves deleterious changes in brain metabolic, vascular and cognitive functions, and gut microbiome structure and diversity, all which may lead to inflammation and thus increase the risk for AD. Future studies conducting comprehensive and integrative characterization of brain aging, including crosstalk with peripheral systems and factors, will be necessary to define the mechanisms underlying the shift from normal aging to pathological processes in the etiology of AD. PMID:28993728

A short period of breastfeeding in infancy, excessive house cleaning, absence of older sibling, and passive smoking are related to more severe atopic dermatitis in children.

PubMed

Fotopoulou, Maria; Iordanidou, Maria; Vasileiou, Eleni; Trypsianis, Grigorios; Chatzimichael, Athanasios; Paraskakis, Emmanouil

2018-02-01

Atopic dermatitis (AD) is one of the most common, chronic or chronically relapsing inflammatory skin diseases that affect children. Multiple genetic and environmental factors appear to regulate the pathogenesis of AD. Our aim was to investigate the possible association between family, social, dieting, atopic and environmental factors and the severity of AD evaluated by SCORAD scores in children. The study group included 100 children with AD who attended a paediatric dermatology outpatient clinic with a median age of 18.5 months. The diagnosis of AD was established on the basis of the clinical criteria according to the American Dermatology Society, while the SCORAD score was used to evaluate disease severity. Multivariate linear regression analysis disclosed that excessive cleanliness (p<0.001), RAST level greater than 0.7 KU/l (p<0.001), breastfeeding for less than two months (p = 0.001), and the absence of an older sibling (p = 0.049) were statistically significant independent determinants for high SCORAD scores. Multivariate logistic regression analysis showed that excessive cleanliness (p<0.001) was the strongest independent risk factor for severe AD (SCORAD>36) (aOR: 59.4; 95% CI: 10.9-322.6). RAST level greater than 0.7 KU/l (aOR: 7.9; 95% CI: 1.5-41.0; p = 0.014) and severe passive smoking (aOR: 4.6; 95% CI: 1.0-22.1; p = 0.050) also showed a significant independent, but clearly weaker, association with severe AD. A short duration of breastfeeding, absence of older siblings, parental passive smoking, food allergens along with aeroallergens, and excessive cleanliness should be considered as negative prognostic factors, leading to a higher SCORAD score in children with AD.

Risk of Cardiac Events Associated With Antidepressant Therapy in Patients With Long QT Syndrome.

PubMed

Wang, Meng; Szepietowska, Barbara; Polonsky, Bronislava; McNitt, Scott; Moss, Arthur J; Zareba, Wojciech; Auerbach, David S

2018-01-15

Patients with long QT syndrome (LQTS) are at a high risk of cardiac events. Many patients with LQTS are treated with antidepressant drugs (ADs). We investigated the LQTS genotype-specific risk of recurrent cardiac arrhythmic events (CAEs) associated with AD therapy. The study included 59 LQT1 and 72 LQT2 patients from the Rochester-based LQTS Registry with corrected QT (QT c ) prolongation and a history of AD therapy. Using multivariate Anderson-Gill models, we estimated the LQTS genotype-specific risk of recurrent CAEs (ventricular tachyarrhythmias, aborted cardiac arrest, or sudden cardiac death) associated with time-dependent ADs. Specifically, we examined the risk associated with all ADs, selective serotonin reuptake inhibitor (SSRI), and ADs classified on the CredibleMeds list (www.CredibleMeds.org) as "Conditional" or "Known risk of Torsades de pointes (TdP)." After adjusting for baseline QT c duration, sex, and time-dependent beta-blocker usage, there was an increased risk of recurrent CAEs associated with ADs in LQT1 patients (hazard ratio = 3.67, 95% confidence interval 1.98-6.82, p < 0.001) but not in LQT2 patients (hazard ratio = 0.89, 95% confidence interval 0.49-1.64, p = 0.716; LQT1 vs LQT2 interaction, p < 0.001). Similarly, LQT1 patients who were on SSRIs or ADs with "Known risk of TdP" had a higher risk of recurrent CAEs than those patients off all ADs, whereas there was no association in LQT2 patients. ADs with "Conditional risk of TdP" were not associated with the risk of recurrent CAEs in any of the groups. In conclusion, the risk of recurrent CAEs associated with time-dependent ADs is higher in LQT1 patients but not in LQT2 patients. Results suggest a LQTS genotype-specific effect of ADs on the risk of arrhythmic events. Copyright © 2017 Elsevier Inc. All rights reserved.

The Relationship Between the Genetic and Environmental Influences on Common Externalizing Psychopathology and Mental Wellbeing

PubMed Central

Kendler, Kenneth S.; Myers, John M.; Keyes, Corey L. M.

2012-01-01

To determine the relationship between the genetic and environmental risk factors for externalizing psychopathology and mental wellbeing, we examined detailed measures of emotional, social and psychological wellbeing, and a history of alcohol-related problems and smoking behavior in the last year in 1,386 individual twins from same-sex pairs from the MIDUS national US sample assessed in 1995. Cholesky decomposition analyses were performed with the Mx program. The best fit model contained one highly heritable common externalizing psychopathology factor for both substance use/abuse measures, and one strongly heritable common factor for the three wellbeing measures. Genetic and environmental risk factors for externalizing psychopathology were both negatively associated with levels of mental wellbeing and accounted for, respectively, 7% and 21% of its genetic and environmental influences. Adding internalizing psychopathology assessed in the last year to the model, genetic risk factors unique for externalizing psychopathology were now positively related to levels of mental wellbeing, although accounting for only 5% of the genetic variance. Environmental risk factors unique to externalizing psychopathology continued to be negatively associated with mental wellbeing, accounting for 26% of the environmental variance. When both internalizing psychopathology and externalizing psychopathology are associated with mental wellbeing, the strongest risk factors for low mental wellbeing are genetic factors that impact on both internalizing psychopathology and externalizing psychopathology, and environmental factors unique to externalizing psychopathology. In this model, genetic risk factors for externalizing psychopathology predict, albeit weakly, higher levels of mental wellbeing. PMID:22506307

Artificial neural networks identify the predictive values of risk factors on the conversion of amnestic mild cognitive impairment.

PubMed

Tabaton, Massimo; Odetti, Patrizio; Cammarata, Sergio; Borghi, Roberta; Monacelli, Fiammetta; Caltagirone, Carlo; Bossù, Paola; Buscema, Massimo; Grossi, Enzo

2010-01-01

The search for markers that are able to predict the conversion of amnestic mild cognitive impairment (aMCI) to Alzheimer's disease (AD) is crucial for early mechanistic therapies. Using artificial neural networks (ANNs), 22 variables that are known risk factors of AD were analyzed in 80 patients with aMCI, for a period spanning at least 2 years. The cases were chosen from 195 aMCI subjects recruited by four Italian Alzheimer's disease units. The parameters of glucose metabolism disorder, female gender, and apolipoprotein E epsilon3/epsilon4 genotype were found to be the biological variables with high relevance for predicting the conversion of aMCI. The scores of attention and short term memory tests also were predictors. Surprisingly, the plasma concentration of amyloid-beta (42) had a low predictive value. The results support the utility of ANN analysis as a new tool in the interpretation of data from heterogeneous and distinct sources.

Preclinical Alzheimer disease and risk of falls

PubMed Central

Roe, Catherine M.; Grant, Elizabeth A.; Hollingsworth, Holly; Benzinger, Tammie L.; Fagan, Anne M.; Buckles, Virginia D.; Morris, John C.

2013-01-01

Objective: We determined the rate of falls among cognitively normal, community-dwelling older adults, some of whom had presumptive preclinical Alzheimer disease (AD) as detected by in vivo imaging of fibrillar amyloid plaques using Pittsburgh compound B (PiB) and PET and/or by assays of CSF to identify Aβ42, tau, and phosphorylated tau. Methods: We conducted a 12-month prospective cohort study to examine the cumulative incidence of falls. Participants were evaluated clinically and underwent PiB PET imaging and lumbar puncture. Falls were reported monthly using an individualized calendar journal returned by mail. A Cox proportional hazards model was used to test whether time to first fall was associated with each biomarker and the ratio of CSF tau/Aβ42 and CSF phosphorylated tau/Aβ42, after adjustment for common fall risk factors. Results: The sample (n = 125) was predominately female (62.4%) and white (96%) with a mean age of 74.4 years. When controlled for ability to perform activities of daily living, higher levels of PiB retention (hazard ratio = 2.95 [95% confidence interval 1.01–6.45], p = 0.05) and of CSF biomarker ratios (p < 0.001) were associated with a faster time to first fall. Conclusions: Presumptive preclinical AD is a risk factor for falls in older adults. This study suggests that subtle noncognitive changes that predispose older adults to falls are associated with AD and may precede detectable cognitive changes. PMID:23803314

Combining clinical and angiographic variables for estimating risk of target lesion revascularization after drug eluting stent placement.

PubMed

Stolker, Joshua M; Cohen, David J; Kennedy, Kevin F; Pencina, Michael J; Arnold, Suzanne V; Kleiman, Neal S; Spertus, John A

Drug-eluting stents (DES) reduce restenosis but require prolonged antiplatelet therapy, when compared with bare metal stents. Ideally, the patient should be involved in this risk:benefit assessment prior to selecting DES, to maximize the benefits and cost-effectiveness of care, and to improve medication adherence. However, accurate estimation of restenosis risk may require angiographic factors identified at cardiac catheterization. In a large PCI registry, we used logistic regression to identify clinical and angiographic predictors of clinically-driven target lesion revascularization (TLR) over the first year after stent placement. Discrimination c-statistic and integrated discrimination improvement (IDI) were used to calculate the incremental utility of angiographic variables when added to clinical predictors. Of 8501 PCI patients, TLR occurred in 4.5%. After adjusting for DES use, clinical TLR predictors were younger age, female sex, diabetes, prior PCI, and prior bypass surgery (model c-statistic 0.630). Angiographic predictors were vein graft PCI, in-stent restenosis lesion, longer stent length, and smaller stent diameter (c-statistic 0.650). After adding angiographic factors to the clinical model, c-statistic improved to 0.680 and the average separation in TLR risk among patients with and without TLR improved by 1% (IDI=0.010, 95% CI 0.009-0.014), primarily driven by those experiencing TLR (from 5.9% to 6.9% absolute risk). Among unselected PCI patients, the incidence of clinically-indicated TLR is <5% at 1-year, and standard clinical variables only moderately discriminate who will and will not experience TLR. Angiographic variables significantly improve TLR risk assessment, suggesting that stent selection may be best performed after coronary anatomy has been delineated. Although several recent studies have challenged traditional expectations regarding the duration of dual antiplatelet therapy, current guidelines recommend at least 6 to 12months of treatment after implantation of a drug eluting stent, with a shorter course for bare metal stents. Stent selection ideally should involve input from the patient receiving these stents, but multiple studies have suggested that angiographic factors - obtained after the patient has received sedation during the diagnostic catheterization - are important predictors of repeat revascularization. In this analysis from a large registry of patients receiving coronary stents, angiographic characteristics were found to significantly improve risk assessment for target lesion revascularization, when added to clinical variables alone. Copyright © 2016 Elsevier Inc. All rights reserved.

Brain insulin signalling, glucose metabolism and females' reproductive aging: A dangerous triad in Alzheimer's disease.

PubMed

Duarte, A I; Santos, M S; Oliveira, C R; Moreira, P I

2018-02-20

Alzheimer's disease (AD) constitutes a major socioeconomic challenge due to its disabling features and the rise in prevalence (especially among (peri)menopausal women and type 2 diabetes patients). The precise etiopathogenesis of AD remains poorly understood. Importantly, its neurodegenerative perspective has been challenged towards a more "systemic" view. Amyloid-β (Aβ) and hyperphosphorylated Tau protein (P-Tau) (the main AD neuropathological features) affect and are affected by peripheral and brain insulin signalling dysfunction, leading to glucose dysmetabolism, synaptic loss and AD-related cognitive deficits. This may be anticipated and exacerbated by the progressive loss of estrogen (and interactions, e.g., with insulin) during females' aging, increasing their risk for AD, especially during menopause. Under this perspective, we aimed to discuss the recent findings (and controversies) behind the peripheral view of AD, and the role for insulin deficits and brain glucose dysmetabolism in such diseased brain. We also focused on the metabolic shift and the putative effects of gender (especially during midlife/perimenopause) herein. We finally discussed AD as the potential "type 3 diabetes", and the therapeutic potential of restoring brain insulin levels or glucose energy metabolism via administration of intranasal insulin and use of ketogenic diets. In sum, AD appears to lie on an intricate crosstalk between age-related metabolic, hormonal and specific genetic changes that challenge its traditional view. Hence, clarification of AD risk factors (besides aging and gender) and pathophysiological mechanisms will allow to establish accurate preventive strategies, biomarkers and more efficient drugs - all urgent medical needs in our increasingly aged societies. Copyright © 2018 Elsevier Ltd. All rights reserved.

Plasma and blood viscosity in the prediction of cardiovascular disease and mortality in the Scottish Heart Health Extended Cohort Study.

PubMed

Peters, Sanne Ae; Woodward, Mark; Rumley, Ann; Tunstall-Pedoe, Hugh D; Lowe, Gordon DO

2017-01-01

Background There is increasing evidence that blood viscosity and its major determinants (haematocrit and plasma viscosity) are associated with increased risks of cardiovascular disease (CVD) and premature mortality; however, their predictive value for CVD and mortality is not clear. Methods We prospectively assessed the added predictive value of plasma viscosity and whole blood viscosity and haematocrit in 3386 men and women aged 30-74 years participating in the Scottish Heart Health Extended Cohort study. Results Over a median follow-up of 17 years, 819 CVD events and 778 deaths were recorded. Hazard ratios (95% confidence intervals) for a 1 SD increase in plasma viscosity, adjusted for major CVD risk factors, were 1.12 (1.04-1.20) for CVD and 1.20 (1.12-1.29) for mortality. These remained significant after further adjustment for plasma fibrinogen: 1.09 (1.01-1.18) and 1.13 (1.04-1.22). The corresponding results for blood viscosity were 0.99 (0.90, 1.09) for CVD, and 1.11 (1.01, 1.22) for total mortality after adjustment for major CVD risk factors; and 0.97 (0.88, 1.08) and 1.06 (0.96, 1.18) after further adjustment for fibrinogen. Haematocrit showed similar associations to blood viscosity. When added to classical CVD risk factors, plasma viscosity improved the discrimination of CVD and mortality by 2.4% (0.7-4.4%) and 4.1% (2.0-6.5%). Conclusions Although plasma and blood viscosity may have a role in the pathogenesis of CVD and mortality, much of their association with CVD and mortality is due to the mutual effects of major CVD risk factors. However, plasma viscosity adds to the discrimination of CVD and mortality and might be considered for inclusion in multivariable risk scores.

The contribution of an animal model toward uncovering biological risk factors for PTSD.

PubMed

Cohen, Hagit; Matar, Michael A; Richter-Levin, Gal; Zohar, Joseph

2006-07-01

Clinical studies of posttraumatic stress disorder (PTSD) have elicited proposed risk factors for developing PTSD in the aftermath of stress exposure. Generally, these risk factors have arisen from retrospective analysis of premorbid characteristics of study populations. A valid animal model of PTSD can complement clinical studies and help to elucidate issues, such as the contribution of proposed risk factors, in ways which are not practicable in the clinical arena. Important qualities of animal models include the possibility to conduct controlled prospective studies, easy access to postmortem brains, and the availability of genetically manipulated subjects, which can be tailored to specific needs. When these qualities are further complemented by an approach which defines phenomenologic criteria to address the variance in individual response pattern and magnitude, enabling the animal subjects to be classified into definable groups for focused study, the model acquires added validity. This article presents an overview of a series of studies in such an animal model which examine the contribution of two proposed risk factors and the value of two early postexposure pharmacological manipulations on the prevalence rates of subjects displaying an extreme magnitude of behavioral response to a predator stress paradigm.

Association of novel biomarkers of cardiovascular stress with left ventricular hypertrophy and dysfunction: implications for screening.

PubMed

Xanthakis, Vanessa; Larson, Martin G; Wollert, Kai C; Aragam, Jayashri; Cheng, Susan; Ho, Jennifer; Coglianese, Erin; Levy, Daniel; Colucci, Wilson S; Michael Felker, G; Benjamin, Emelia J; Januzzi, James L; Wang, Thomas J; Vasan, Ramachandran S

2013-11-07

Currently available screening tools for left ventricular (LV) hypertrophy (LVH) and systolic dysfunction (LVSD) are either expensive (echocardiography) or perform suboptimally (B-type natriuretic peptide [BNP]). It is unknown whether newer biomarkers are associated with LVH and LVSD and can serve as screening tools. We studied 2460 Framingham Study participants (mean age 58 years, 57% women) with measurements of biomarkers mirroring cardiac biomechanical stress (soluble ST-2 [ST2], growth differentiation factor-15 [GDF-15] and high-sensitivity troponin I [hsTnI]) and BNP. We defined LVH as LV mass/height(2) ≥the sex-specific 80th percentile and LVSD as mild/greater impairment of LV ejection fraction (LVEF) or a fractional shortening <0.29. Adjusting for standard risk factors in logistic models, BNP, GDF-15, and hsTnI were associated with the composite echocardiographic outcome (LVH or LVSD), odds ratios (OR) per SD increment in log-biomarker 1.29, 1.14, and 1.18 (95% CI: 1.15 to 1.44, 1.004 to 1.28, and 1.06 to 1.31), respectively. The C-statistic for the composite outcome increased from 0.765 with risk factors to 0.770 adding BNP, to 0.774 adding novel biomarkers. The continuous Net Reclassification Improvement was 0.212 (95% CI: 0.119 to 0.305, P<0.0001) after adding the novel biomarkers to risk factors plus BNP. BNP was associated with LVH and LVSD in multivariable models, whereas GDF-15 was associated with LVSD (OR 1.41, 95% CI: 1.16 to 1.70), and hsTnI with LVH (OR 1.22, 95% CI: 1.09 to 1.36). ST2 was not significantly associated with any outcome. Our community-based investigation suggests that cardiac stress biomarkers are associated with LVH and LVSD but may have limited clinical utility as screening tools.

Modeling the complex pathology of Alzheimer’s disease in Drosophila

PubMed Central

Fernandez-Funez, Pedro; de Mena, Lorena; Rincon-Limas, Diego E.

2015-01-01

Alzheimer’s disease (AD) is the leading cause of dementia and the most common neurodegenerative disorder. AD is mostly a sporadic disorder and its main risk factor is age, but mutations in three genes that promote the accumulation of the amyloid-β (Aβ42) peptide revealed the critical role of Amyloid precursor protein (APP) processing in AD. Neurofibrillary tangles enriched in tau are the other pathological hallmark of AD, but the lack of causative tau mutations still puzzles researchers. Here, we describe the contribution of a powerful invertebrate model, the fruit fly Drosophila melanogaster, to uncovering the function and pathogenesis of human APP, Aβ42, and tau. APP and tau participate in many complex cellular processes, although their main function is microtubule stabilization and the to-and-fro transport of axonal vesicles. Additionally, expression of secreted Aβ42 induces prominent neuronal death in Drosophila, a critical feature of AD, making this model a popular choice for identifying intrinsic and extrinsic factors mediating Aβ42 neurotoxicity. Overall, Drosophila has made significant contributions to better understand the complex pathology of AD, although additional insight can be expected from combining multiple transgenes, performing genome-wide loss-of-function screens, and testing anti-tau therapies alone or in combination with Aβ42. PMID:26024860

Alzheimer-associated Aβ oligomers impact the central nervous system to induce peripheral metabolic deregulation

PubMed Central

Clarke, Julia R; Lyra e Silva, Natalia M; Figueiredo, Claudia P; Frozza, Rudimar L; Ledo, Jose H; Beckman, Danielle; Katashima, Carlos K; Razolli, Daniela; Carvalho, Bruno M; Frazão, Renata; Silveira, Marina A; Ribeiro, Felipe C; Bomfim, Theresa R; Neves, Fernanda S; Klein, William L; Medeiros, Rodrigo; LaFerla, Frank M; Carvalheira, Jose B; Saad, Mario J; Munoz, Douglas P; Velloso, Licio A; Ferreira, Sergio T; De Felice, Fernanda G

2015-01-01

Alzheimer's disease (AD) is associated with peripheral metabolic disorders. Clinical/epidemiological data indicate increased risk of diabetes in AD patients. Here, we show that intracerebroventricular infusion of AD-associated Aβ oligomers (AβOs) in mice triggered peripheral glucose intolerance, a phenomenon further verified in two transgenic mouse models of AD. Systemically injected AβOs failed to induce glucose intolerance, suggesting AβOs target brain regions involved in peripheral metabolic control. Accordingly, we show that AβOs affected hypothalamic neurons in culture, inducing eukaryotic translation initiation factor 2α phosphorylation (eIF2α-P). AβOs further induced eIF2α-P and activated pro-inflammatory IKKβ/NF-κB signaling in the hypothalamus of mice and macaques. AβOs failed to trigger peripheral glucose intolerance in tumor necrosis factor-α (TNF-α) receptor 1 knockout mice. Pharmacological inhibition of brain inflammation and endoplasmic reticulum stress prevented glucose intolerance in mice, indicating that AβOs act via a central route to affect peripheral glucose homeostasis. While the hypothalamus has been largely ignored in the AD field, our findings indicate that AβOs affect this brain region and reveal novel shared molecular mechanisms between hypothalamic dysfunction in metabolic disorders and AD. PMID:25617315

Combined assessment of DYRK1A, BDNF and homocysteine levels as diagnostic marker for Alzheimer’s disease

PubMed Central

Janel, N; Alexopoulos, P; Badel, A; Lamari, F; Camproux, A C; Lagarde, J; Simon, S; Feraudet-Tarisse, C; Lamourette, P; Arbones, M; Paul, J L; Dubois, B; Potier, M C; Sarazin, M; Delabar, J M

2017-01-01

Early identification of Alzheimer’s disease (AD) risk factors would aid development of interventions to delay the onset of dementia, but current biomarkers are invasive and/or costly to assess. Validated plasma biomarkers would circumvent these challenges. We previously identified the kinase DYRK1A in plasma. To validate DYRK1A as a biomarker for AD diagnosis, we assessed the levels of DYRK1A and the related markers brain-derived neurotrophic factor (BDNF) and homocysteine in two unrelated AD patient cohorts with age-matched controls. Receiver-operating characteristic curves and logistic regression analyses showed that combined assessment of DYRK1A, BDNF and homocysteine has a sensitivity of 0.952, a specificity of 0.889 and an accuracy of 0.933 in testing for AD. The blood levels of these markers provide a diagnosis assessment profile. Combined assessment of these three markers outperforms most of the previous markers and could become a useful substitute to the current panel of AD biomarkers. These results associate a decreased level of DYRK1A with AD and challenge the use of DYRK1A inhibitors in peripheral tissues as treatment. These measures will be useful for diagnosis purposes. PMID:28632203

Health Behavior Changes After Genetic Risk Assessment for Alzheimer Disease: The REVEAL Study

PubMed Central

Chao, Serena; Roberts, J. Scott; Marteau, Theresa M.; Silliman, Rebecca; Cupples, L. Adrienne; Green, Robert C.

2008-01-01

Risk information for Alzheimer disease (AD) may be communicated through susceptibility gene disclosure, even though this is not currently in clinical use. The REVEAL Study is the first randomized clinical trial of risk assessment for AD with apolipoprotein E (APOE) genotype and numerical risk estimate disclosure. We examined whether APOE genotype and numerical risk disclosure to asymptomatic individuals at high risk for AD alters health behaviors. One hundred sixty-two participants were randomized to either intervention (APOE disclosure) or control (no genotype disclosure) groups. Subjects in both groups received numerical lifetime risk estimates of future AD development based on sex and family history of AD. The intervention group received their APOE genotype. Subjects were informed that no proven preventive measures for AD existed and given an information sheet on preventative therapies under investigation. Participants who learned they were ε4 positive were significantly more likely than ε4 negative participants to report AD-specific health behavior change 1 year after disclosure (adjusted odds ratio: 2.73; 95% confidence interval: 1.14, 6.54; P = 0.02). Post hoc analyses revealed similar significant associations between numerical lifetime risk estimates and self-report of AD-specific health behavior change. Despite lack of preventive measures for AD, knowledge of APOE genotype, numerical lifetime risk, or both, influences health behavior. PMID:18317253

Health behavior changes after genetic risk assessment for Alzheimer disease: The REVEAL Study.

PubMed

Chao, Serena; Roberts, J Scott; Marteau, Theresa M; Silliman, Rebecca; Cupples, L Adrienne; Green, Robert C

2008-01-01

Risk information for Alzheimer disease (AD) may be communicated through susceptibility gene disclosure, even though this is not currently in clinical use. The REVEAL Study is the first randomized clinical trial of risk assessment for AD with apolipoprotein E (APOE) genotype and numerical risk estimate disclosure. We examined whether APOE genotype and numerical risk disclosure to asymptomatic individuals at high risk for AD alters health behaviors. One hundred sixty-two participants were randomized to either intervention (APOE disclosure) or control (no genotype disclosure) groups. Subjects in both groups received numerical lifetime risk estimates of future AD development based on sex and family history of AD. The intervention group received their APOE genotype. Subjects were informed that no proven preventive measures for AD existed and given an information sheet on preventative therapies under investigation. Participants who learned they were epsilon 4 positive were significantly more likely than epsilon 4 negative participants to report AD-specific health behavior change 1 year after disclosure (adjusted odds ratio: 2.73; 95% confidence interval: 1.14, 6.54; P=0.02). Post hoc analyses revealed similar significant associations between numerical lifetime risk estimates and self-report of AD-specific health behavior change. Despite lack of preventive measures for AD, knowledge of APOE genotype, numerical lifetime risk, or both, influences health behavior.

Age-dependent effect of Alzheimer’s risk variant of CLU on EEG alpha rhythm in non-demented adults

PubMed Central

Ponomareva, Natalya; Andreeva, Tatiana; Protasova, Maria; Shagam, Lev; Malina, Daria; Goltsov, Andrei; Fokin, Vitaly; Mitrofanov, Andrei; Rogaev, Evgeny

2013-01-01

Polymorphism in the genomic region harboring the CLU gene (rs11136000) has been associated with the risk for Alzheimer’s disease (AD). CLU C allele is assumed to confer risk for AD and the allele T may have a protective effect. We investigated the influence of the AD-associated CLU genotype on a common neurophysiological trait of brain activity (resting-state alpha-rhythm activity) in non-demented adults and elucidated whether this influence is modified over the course of aging. We examined quantitative electroencephalography (EEG) in a cohort of non-demented individuals (age range 20–80) divided into young (age range 20–50) and old (age range 51–80) cohorts and stratified by CLU polymorphism. To rule out the effect of the apolipoprotein E (ApoE) genotype on EEG characteristics, only subjects without the ApoE ε4 allele were included in the study. The homozygous presence of the AD risk variant CLU CC in non-demented subjects was associated with an increase of alpha3 absolute power. Moreover, the influence of CLU genotype on alpha3 was found to be higher in the subjects older than 50 years of age. The study also showed age-dependent alterations of alpha topographic distribution that occur independently of the CLU genotype. The increase of upper alpha power has been associated with hippocampal atrophy in patients with mild cognitive impairment (Moretti etal., 2012a). In our study, the CLU CC-dependent increase in upper alpha rhythm, particularly enhanced in elderly non-demented individuals, may imply that the genotype is related to preclinical dysregulation of hippocampal neurophysiology in aging and that this factor may contribute to the pathogenesis of AD. PMID:24379779

Postural Stability in Older Adults With Alzheimer Disease.

PubMed

Mesbah, Normala; Perry, Meredith; Hill, Keith D; Kaur, Mandeep; Hale, Leigh

2017-03-01

The prevalence of adults with Alzheimer disease (AD) aged >65 years is increasing and estimated to quadruple by 2051. The aim of this study was to investigate postural stability in people with mild to moderate AD and factors contributing to postural instability compared with healthy peers (controls). A computerized systematic search of databases and a hand search of reference lists for articles published from 1984 onward (English-language articles only) were conducted on June 2, 2015, using the main key words "postural stability" and "Alzheimer's disease." Sixty-seven studies were assessed for eligibility (a confirmed diagnosis of AD, comparison of measured postural stability between participants with AD and controls, measured factors potentially contributing to postural instability). Data were extracted, and Downs and Black criteria were applied to evaluate study quality. Eighteen articles were analyzed using qualitative synthesis and reported based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Strength of evidence was guided by the Grading of Recommendations Assessment, Development and Evaluation. Strong evidence was found that: (1) older adults with mild to moderate AD have reduced static and functional postural stability compared with healthy peers (controls) and (2) attentional demand during dual-task activity and loss of visual input were key factors contributing to postural instability. Deta-analysis was not possible due to heterogeneity of the data. Postural stability is impaired in older adults with mild to moderate AD. Decreasing visual input and concentrating on multiple tasks decrease postural stability. To reduce falls risk, more research discerning appropriate strategies for the early identification of impairment of postural stability is needed. Standardization of population description and consensus on outcome measures and the variables used to measure postural -instability and its contributing factors are necessary to ensure meaningful synthesis of data. © 2017 American Physical Therapy Association

An application of the patient rule-induction method for evaluating the contribution of the Apolipoprotein E and Lipoprotein Lipase genes to predicting ischemic heart disease.

PubMed

Dyson, Greg; Frikke-Schmidt, Ruth; Nordestgaard, Børge G; Tybjaerg-Hansen, Anne; Sing, Charles F

2007-09-01

Different combinations of genetic and environmental risk factors are known to contribute to the complex etiology of ischemic heart disease (IHD) in different subsets of individuals. We employed the Patient Rule-Induction Method (PRIM) to select the combination of risk factors and risk factor values that identified each of 16 mutually exclusive partitions of individuals having significantly different levels of risk of IHD. PRIM balances two competing objectives: (1) finding partitions where the risk of IHD is high and (2) maximizing the number of IHD cases explained by the partitions. A sequential PRIM analysis was applied to data on the incidence of IHD collected over 8 years for a sample of 5,455 unrelated individuals from the Copenhagen City Heart Study (CCHS) to assess the added value of variation in two candidate susceptibility genes beyond the traditional, lipid and body mass index risk factors for IHD. An independent sample of 362 unrelated individuals also from the city of Copenhagen was used to test the model obtained for each of the hypothesized partitions. Copyright (c) 2007 Wiley-Liss, Inc.

Motor impairment predicts falls in specialized Alzheimer care units.

PubMed

Camicioli, Richard; Licis, Lisa

2004-01-01

We sought to identify clinical risk factors for falls in people with advanced Alzheimer disease (AD) in a prospective longitudinal observational study set in specialized AD care units. Forty-two patients with probable or possible AD were recruited. Age, sex, Mini-Mental Status Examination, Clinical Dementia Rating Scale, Neuropsychiatric Inventory/Nursing Home, Morse Fall Scale (MFS), modified Unified Parkinson's Rating Scale (mUPDRS), and gait parameters using a GAITRite Gold Walkway System with and without dual-task performance were examined. Time to a first fall was the primary outcome measure, and independent risk factors were identified. Participating subjects were old (non-fallers age, 82.3 +/- 6.7 years; fallers: 83.1 +/- 9.6 years; p = 0.76) and predominantly women (36 female/6 male). Fallers did not differ from non-fallers on any parameter except the MFS (non-fallers: 35.6 +/- 26.1; fallers: 54.4 +/- 29.8; p = 0.04), the UPDRS (non-fallers: 4.75 +/- 3.98; fallers: 7.61 +/- 4.3, p = 0.03) and cadence (steps per minute: non-fallers: 102.3 +/- 12.3; fallers: 91.7 +/- 16, p = 0.02). Fallers and non-fallers were equally affected by dual-task performance. The hazard ratios for MFS, UPDRS, and cadence were not affected by adjusting for age, sex, MMSE, or NPI scores. In conclusion, falls in advanced AD can be predicted using simple clinical measures of motor impairment or cadence. These measures may be useful for targeting interventions.

Atherosclerosis in epilepsy: its causes and implications.

PubMed

Hamed, Sherifa A

2014-12-01

Evidence from epidemiological, longitudinal, prospective, double-blinded clinical trials as well as case reports documents age-accelerated atherosclerosis with increased carotid artery intima media thickness (CA-IMT) in patients with epilepsy. These findings raise concern regarding their implications for age-accelerated cognitive and behavioral changes in midlife and risk of later age-related cognitive disorders including neurodegenerative processes such as Alzheimer's disease (AD). Chronic epilepsy, cerebral atherosclerosis, and age-related cognitive disorders including AD share many clinical manifestations (e.g. characteristic cognitive deficits), risk factors, and structural and pathological brain abnormalities. These shared risk factors include increased CA-IMT, hyperhomocysteinemia (HHcy), lipid abnormalities, weight gain and obesity, insulin resistance (IR), and high levels of inflammatory and oxidative stresses. The resulting brain structural and pathological abnormalities include decreased volume of the hippocampus, increased cortical thinning of the frontal lobe, ventricular expansion and increased white matter ischemic disease, total brain atrophy, and β-amyloid protein deposition in the brain. The knowledge that age-accelerated atherosclerosis may contribute to age-accelerated cognitive and behavioral abnormalities and structural brain pathologies in patients with chronic epilepsy represents an important research path to pursue future clinical and management considerations. Copyright © 2014 Elsevier Inc. All rights reserved.

Insulin Resistance in Alzheimer's Disease

PubMed Central

Dineley, Kelly T; Jahrling, Jordan B; Denner, Larry

2014-01-01

Insulin is a key hormone regulating metabolism. Insulin binding to cell surface insulin receptors engages many signaling intermediates operating in parallel and in series to control glucose, energy, and lipids while also regulating mitogenesis and development. Perturbations in the function of any of these intermediates, which occur in a variety of diseases, cause reduced sensitivity to insulin and insulin resistance with consequent metabolic dysfunction. Chronic inflammation ensues which exacerbates compromised metabolic homeostasis. Since insulin has a key role in learning and memory as well as directly regulating ERK, a kinase required for the type of learning and memory compromised in early Alzheimer's disease (AD), insulin resistance has been identified as a major risk factor for the onset of AD. Animal models of AD or insulin resistance or both demonstrate that AD pathology and impaired insulin signaling form a reciprocal relationship. Of note are human and animal model studies geared toward improving insulin resistance that have led to the identification of the nuclear receptor and transcription factor, peroxisome proliferator-activated receptor gamma (PPARγ) as an intervention tool for early AD. Strategic targeting of alternate nodes within the insulin signaling network has revealed disease-stage therapeutic windows in animal models that coalesce with previous and ongoing clinical trial approaches. Thus, exploiting the connection between insulin resistance and AD provides powerful opportunities to delineate therapeutic interventions that slow or block the pathogenesis of AD. PMID:25237037

Association of insulin resistance with cerebral glucose uptake in late middle-aged adults at risk for Alzheimer’s disease

PubMed Central

Willette, Auriel A.; Bendlin, Barbara B.; Starks, Erika J.; Birdsill, Alex C.; Johnson, Sterling C.; Christian, Bradley T.; Okonkwo, Ozioma C.; La Rue, Asenath; Hermann, Bruce P.; Koscik, Rebecca L.; Jonaitis, Erin M.; Sager, Mark A.; Asthana, Sanjay

2015-01-01

Importance Converging evidence suggests that Alzheimer’s disease (AD) involves insulin signaling impairment. AD patients and people at risk for AD show reduced glucose metabolism, as indexed by F18-fluorodeoxyglucose positron emission tomography ([F18]FDG-PET). Objective To determine if insulin resistance (IR) predicts AD-like global and regional glucose metabolism deficits in late middle-aged participants at risk for AD. A secondary objective was to examine if IR-predicted variation in regional glucose metabolism was associated with worse cognitive performance. Setting A general community sample enriched for AD family history. Participants Population-based, cross-sectional study of 150 cognitively normal, late middle-aged (mean=60.67 years) adults from the Wisconsin Registry for Alzheimer’s Prevention. Design Participants underwent cognitive testing, fasting blood draw, and an [F18]FDG-PET scan at baseline. The Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) was used to assess peripheral insulin resistance. Regression analysis tested the statistical effect of HOMA-IR on global glucose metabolism. A voxel-wise analysis was used to determine if HOMA-IR predicted regional glucose metabolism. Finally, predicted variation in regional glucose metabolism was regressed against cognitive factors. Covariates included age, sex, body mass index, Apolipoprotein E genotype, AD family history status, and a reference region used to normalize regional uptake. Main Outcome Measures Regional glucose uptake determined using [F18]FDG-PET, and neuropsychological factors. Results Higher HOMA-IR was associated with lower global glucose metabolism (β=−0.29, p<.01) and lower regional glucose metabolism across large portions of frontal, lateral parietal, lateral temporal, and medial temporal lobe (MTL; p<.05, family-wise error corrected). The association was especially robust in left MTL (R2=0.178). Lower left MTL glucose metabolism predicted by HOMA-IR was significantly related to worse immediate memory (β=0.317, p<.001) and delayed memory (β=0.305, p<.001) performance. Conclusions Our results show that IR, a prevalent and increasingly common condition in developed countries, is associated with significantly lower regional cerebral glucose metabolism, which in turn may predict worse memory performance. Midlife may be a critical period for initiating treatments to lower peripheral IR in order to maintain neural metabolism and cognitive function. PMID:26214150

Pornography use and sexual aggression: the impact of frequency and type of pornography use on recidivism among sexual offenders.

PubMed

Kingston, Drew A; Fedoroff, Paul; Firestone, Philip; Curry, Susan; Bradford, John M

2008-01-01

In this study, we examined the unique contribution of pornography consumption to the longitudinal prediction of criminal recidivism in a sample of 341 child molesters. We specifically tested the hypothesis, based on predictions informed by the confluence model of sexual aggression that pornography will be a risk factor for recidivism only for those individuals classified as relatively high risk for re-offending. Pornography use (frequency and type) was assessed through self-report and recidivism was measured using data from a national database from the Royal Canadian Mounted Police. Indices of recidivism, which were assessed up to 15 years after release, included an overall criminal recidivism index, as well as subcategories focusing on violent (including sexual) recidivism and sexual recidivism alone. Results for both frequency and type of pornography use were generally consistent with our predictions. Most importantly, after controlling for general and specific risk factors for sexual aggression, pornography added significantly to the prediction of recidivism. Statistical interactions indicated that frequency of pornography use was primarily a risk factor for higher-risk offenders, when compared with lower-risk offenders, and that content of pornography (i.e., pornography containing deviant content) was a risk factor for all groups. The importance of conceptualizing particular risk factors (e.g., pornography), within the context of other individual characteristics is discussed.

Associations between Sleep, Cortisol Regulation, and Diet: Possible Implications for the Risk of Alzheimer Disease.

PubMed

Pistollato, Francesca; Sumalla Cano, Sandra; Elio, Iñaki; Masias Vergara, Manuel; Giampieri, Francesca; Battino, Maurizio

2016-07-01

Accumulation of proteinaceous amyloid β plaques and tau oligomers may occur several years before the onset of Alzheimer disease (AD). Under normal circumstances, misfolded proteins get cleared by proteasome degradation, autophagy, and the recently discovered brain glymphatic system, an astroglial-mediated interstitial fluid bulk flow. It has been shown that the activity of the glymphatic system is higher during sleep and disengaged or low during wakefulness. As a consequence, poor sleep quality, which is associated with dementia, might negatively affect glymphatic system activity, thus contributing to amyloid accumulation. The diet is another important factor to consider in the regulation of this complex network. Diets characterized by high intakes of refined sugars, salt, animal-derived proteins and fats and by low intakes of fruit and vegetables are associated with a higher risk of AD and can perturb the circadian modulation of cortisol secretion, which is associated with poor sleep quality. For this reason, diets and nutritional interventions aimed at restoring cortisol concentrations may ease sleep disorders and may facilitate brain clearance, consequentially reducing the risk of cognitive impairment and dementia. Here, we describe the associations that exist between sleep, cortisol regulation, and diet and their possible implications for the risk of cognitive impairment and AD. © 2016 American Society for Nutrition.

Associations between Sleep, Cortisol Regulation, and Diet: Possible Implications for the Risk of Alzheimer Disease12

PubMed Central

Sumalla Cano, Sandra; Elio, Iñaki; Masias Vergara, Manuel; Giampieri, Francesca; Battino, Maurizio

2016-01-01

Accumulation of proteinaceous amyloid β plaques and tau oligomers may occur several years before the onset of Alzheimer disease (AD). Under normal circumstances, misfolded proteins get cleared by proteasome degradation, autophagy, and the recently discovered brain glymphatic system, an astroglial-mediated interstitial fluid bulk flow. It has been shown that the activity of the glymphatic system is higher during sleep and disengaged or low during wakefulness. As a consequence, poor sleep quality, which is associated with dementia, might negatively affect glymphatic system activity, thus contributing to amyloid accumulation. The diet is another important factor to consider in the regulation of this complex network. Diets characterized by high intakes of refined sugars, salt, animal-derived proteins and fats and by low intakes of fruit and vegetables are associated with a higher risk of AD and can perturb the circadian modulation of cortisol secretion, which is associated with poor sleep quality. For this reason, diets and nutritional interventions aimed at restoring cortisol concentrations may ease sleep disorders and may facilitate brain clearance, consequentially reducing the risk of cognitive impairment and dementia. Here, we describe the associations that exist between sleep, cortisol regulation, and diet and their possible implications for the risk of cognitive impairment and AD. PMID:27422503

12 CFR 1230.2 - Definitions.

Code of Federal Regulations, 2014 CFR

2014-01-01

... money or the provision of any other thing of current or potential value in connection with employment... position; (ii) Compensation factors that indicate added or diminished risks, constraints, or aids in.... 4501 et seq.), as amended by the Housing and Economic Recovery Act of 2008 (HERA), Public Law No. 110...

Improving Synchronization and Functional Connectivity in Autism Spectrum Disorders Through Plasticity-Induced Rehabilitation

DTIC Science & Technology

2013-08-01

Waiter GD, Gilchrist A, Perrett DI, Murray AD, Whiten A. Neural mechanisms of imitation and ‘mirror neuron’ functioning in autistic spectrum...or risk factor associated with the onset of ASD, the inherent heterogeneity of endophenotypical presentation makes clinical management challenging. In

Alzheimer's Disease and Autistic Spectrum Disorder: Is there any Association?

PubMed

Khan, Sarah A; Khan, Shahida A; Narendra, A R; Mushtaq, Gohar; Zahran, Solafa A; Khan, Shahzad; Kamal, Mohammad A

2016-01-01

Autism spectrum disorder (ASD) and Alzheimer's disease (AD) are neurodevelopmental and neurodegenerative disorders respectively, with devastating effects not only on the individual but also the society. Collectively, a number of factors contribute to the expression of ASD and AD. It is of utmost curiosity that these disorders express at different stages of life and there is an involvement of certain susceptible genes. This genetic basis makes the background of common associations like memory deficits, cognition changes, demyelination, oxidative stress and inflammation, an integral part of both disorders. Modern technology resulting in genetically modified crops and increase in gadgets emitting electromagnetic frequencies have resulted in enhanced risks for neurological dysfunctions and disorders like ASD and AD. Subsequent advances in the psychological, pharmacological, biochemical and nutritional aspects of the disorders have resulted in the development of newer therapeutic approaches. The common clinical features like language impairment, executive functions, and motor problems have been discussed along with the patho-physiological changes, role of DNA methylation, myelin development, and heavy metals in the expression of these disorders. Psychopharmacological and nutritional approaches towards the reduction and management of risk factors have gained attention from the researchers in recent years. Current major therapies either target the inflammatory pathways or reduce cellular oxidative stress. This contribution focuses on the commonalities of the two disorders.