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Sample records for adult onset neurodegenerative

  1. Targeting Proteostasis Through the Protein Quality Control Function of the Hsp90/Hsp70-based Chaperone Machinery for Treatment of Adult Onset Neurodegenerative Diseases

    PubMed Central

    Pratt, William B.; Gestwicki, Jason E.; Osawa, Yoichi; Lieberman, Andrew P.

    2015-01-01

    Currently available therapies for adult onset neurodegenerative diseases provide symptomatic relief, but are not disease modifying. We explore here a new neuroprotective approach based on drugs targeting chaperone-directed protein quality control. Critical target proteins that unfold and aggregate in these diseases, such as the polylglutamine androgen receptor (spinal and bulbar muscular atrophy), huntingtin (Huntington’s disease), α-synuclein (Parkinson’s disease) and tau (Alzheimer’s disease) are client proteins of Hsp90, and their turnover is regulated by the protein quality control function of the Hsp90/Hsp70-based chaperone machinery. In protein quality control Hsp90 and Hsp70 have opposing effects on client protein stability; Hsp90 stabilizes the clients and inhibits their ubiquitination, whereas Hsp70 promotes CHIP-dependent ubiquitination and proteasomal degradation. We discuss how drugs that modulate proteostasis by inhibiting Hsp90 function or by promoting Hsp70 function enhance the degradation of the critical aggregating proteins and ameliorate toxic symptoms in cell and animal disease models. PMID:25292434

  2. Adult onset retinoblastoma.

    PubMed

    Sengupta, Sabyasachi; Pan, Utsab; Khetan, Vikas

    2016-07-01

    Retinoblastoma (RB) is the most common primary malignant intraocular tumor of childhood presenting usually before 5 years of age. RB in adults older than 20 years is extremely rare. A literature search using PubMed/PubMed Central, Scopus, Google Scholar, EMBASE, and Cochrane databases revealed only 45 cases till date. Over the past decade, there has been a significant increase in the number of such reports, indicating heightened level of suspicion among ophthalmologists. Compared to its pediatric counterpart, adult onset RB poses unique challenges in diagnosis and treatment. This article summarizes available literature on adult onset RB and its clinical and pathologic profile, genetics, association with retinocytoma, diagnostics, treatment, and outcomes. PMID:27609158

  3. Adult onset retinoblastoma

    PubMed Central

    Sengupta, Sabyasachi; Pan, Utsab; Khetan, Vikas

    2016-01-01

    Retinoblastoma (RB) is the most common primary malignant intraocular tumor of childhood presenting usually before 5 years of age. RB in adults older than 20 years is extremely rare. A literature search using PubMed/PubMed Central, Scopus, Google Scholar, EMBASE, and Cochrane databases revealed only 45 cases till date. Over the past decade, there has been a significant increase in the number of such reports, indicating heightened level of suspicion among ophthalmologists. Compared to its pediatric counterpart, adult onset RB poses unique challenges in diagnosis and treatment. This article summarizes available literature on adult onset RB and its clinical and pathologic profile, genetics, association with retinocytoma, diagnostics, treatment, and outcomes. PMID:27609158

  4. Adult-Onset Hypogonadism.

    PubMed

    Khera, Mohit; Broderick, Gregory A; Carson, Culley C; Dobs, Adrian S; Faraday, Martha M; Goldstein, Irwin; Hakim, Lawrence S; Hellstrom, Wayne J G; Kacker, Ravi; Köhler, Tobias S; Mills, Jesse N; Miner, Martin; Sadeghi-Nejad, Hossein; Seftel, Allen D; Sharlip, Ira D; Winters, Stephen J; Burnett, Arthur L

    2016-07-01

    In August 2015, an expert colloquium commissioned by the Sexual Medicine Society of North America (SMSNA) convened in Washington, DC, to discuss the common clinical scenario of men who present with low testosterone (T) and associated signs and symptoms accompanied by low or normal gonadotropin levels. This syndrome is not classical primary (testicular failure) or secondary (pituitary or hypothalamic failure) hypogonadism because it may have elements of both presentations. The panel designated this syndrome adult-onset hypogonadism (AOH) because it occurs commonly in middle-age and older men. The SMSNA is a not-for-profit society established in 1994 to promote, encourage, and support the highest standards of practice, research, education, and ethics in the study of human sexual function and dysfunction. The panel consisted of 17 experts in men's health, sexual medicine, urology, endocrinology, and methodology. Participants declared potential conflicts of interest and were SMSNA members and nonmembers. The panel deliberated regarding a diagnostic process to document signs and symptoms of AOH, the rationale for T therapy, and a monitoring protocol for T-treated patients. The evaluation and management of hypogonadal syndromes have been addressed in recent publications (ie, the Endocrine Society, the American Urological Association, and the International Society for Sexual Medicine). The primary purpose of this document was to support health care professionals in the development of a deeper understanding of AOH, particularly in how it differs from classical primary and secondary hypogonadism, and to provide a conceptual framework to guide its diagnosis, treatment, and follow-up. PMID:27343020

  5. Adult neurogenesis in the olfactory system and neurodegenerative disease.

    PubMed

    Gallarda, B W; Lledo, P-M

    2012-12-01

    The olfactory system is unique in many respects-two of which include the process of adult neurogenesis which continually supplies it with newborn neurons, and the fact that neurodegenerative diseases are often accompanied by a loss of smell. A link between these two phenomena has been hypothesized, but recent evidence for the lack of robust adult neurogenesis in the human olfactory system calls into question this hypothesis. Nevertheless, model organisms continue to play a critical role in the exploration of neurodegenerative disease. In part one of this review we discuss the most promising recent technological advancements for studying adult neurogenesis in the murine olfactory system. Part two continues by looking at emerging evidence related to adult neurogenesis in neurodegenerative disease studied in model organisms and the differences between animal and human olfactory system adult neurogenesis. Hopefully, the careful application of advanced research methods to the study of neurodegenerative disease in model organisms, while taking into account the recently reported differences between the human and model organism olfactory system, will lead to a better understanding of the reasons for the susceptibility of olfaction to disease.

  6. Adult-onset mitochondrial myopathy.

    PubMed Central

    Fernandez-Sola, J.; Casademont, J.; Grau, J. M.; Graus, F.; Cardellach, F.; Pedrol, E.; Urbano-Marquez, A.

    1992-01-01

    Mitochondrial diseases are polymorphic entities which may affect many organs and systems. Skeletal muscle involvement is frequent in the context of systemic mitochondrial disease, but adult-onset pure mitochondrial myopathy appears to be rare. We report 3 patients with progressive skeletal mitochondrial myopathy starting in adult age. In all cases, the proximal myopathy was the only clinical feature. Mitochondrial pathology was confirmed by evidence of ragged-red fibres in muscle histochemistry, an abnormal mitochondrial morphology in electron microscopy and by exclusion of other underlying diseases. No deletions of mitochondrial DNA were found. We emphasize the need to look for a mitochondrial disorder in some non-specific myopathies starting in adult life. Images Figure 1 Figure 2 PMID:1589382

  7. Prevalence and demographic features of early-onset neurodegenerative dementia in Brescia County, Italy.

    PubMed

    Borroni, Barbara; Alberici, Antonella; Grassi, Mario; Rozzini, Luca; Turla, Marinella; Zanetti, Orazio; Bianchetti, Angelo; Gilberti, Nicola; Bonvicini, Cristian; Volta, Giorgio Dalla; Rozzini, Renzo; Padovani, Alessandro

    2011-01-01

    A few epidemiologic studies are available on the prevalence of early-onset Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD). The aim of this study was to establish in an Italian population, namely in Brescia County, the prevalence of early-onset neurodegenerative dementia, and how it is shared between AD and FTLD. A network among the participating centers has been established for 10 years. A standardized form was sent to be filled in for each patient. The census day was chosen as December 1, 2009. The prevalence of disease was calculated stratifying patients according to sex and diagnosis. On the census day, 175 patients in the whole population aged 45--65 years were enrolled into the study. The resulting overall prevalence of early-onset neurodegenerative dementia was found of 55.1 per 100,000 inhabitants (95%confidence interval, 47.0--63.4). A comparable prevalence between AD and FTLD was reported (25.5 and 29.6 per 100,000 inhabitants, respectively), and no differences in sex distribution were found both in AD and FTLD. The improvement of knowledge on early-onset neurodegenerative dementias allows us to reconsider its epidemiology and to rethink its impact on public polices. This would be crucial for defining the urgency of treatment approaches.

  8. AIMP1 deficiency presents as a cortical neurodegenerative disease with infantile onset.

    PubMed

    Armstrong, L; Biancheri, R; Shyr, C; Rossi, A; Sinclair, G; Ross, C J; Tarailo-Graovac, M; Wasserman, W W; van Karnebeek, C D M

    2014-08-01

    We report the second family with AIMP1 deficiency, due to a homozygous truncating AIMP1 (g.107248613 C > T) mutation. This female showed early-onset developmental arrest, intractable epileptic spasms, microcephaly, and a rapid clinical course leading to premature death, associated with cerebral atrophy and myelin deficiency on brain MRI. Clinical and neuroimaging findings are consistent with a primary neuronal degenerative disorder, rather than with the previously reported Perlizaeus-Merzbacher-like phenotype. Given its critical role in neurofilament assembly 16, impaired myelin formation is due to neuronal/axonal dysfunction. We propose that AIMP1 deficiency be added to the differential diagnosis of infantile onset, progressive neurodegenerative disease.

  9. [Adult-onset rare diseases].

    PubMed

    Pfliegler, György; Kovács, Erzsébet; Kovács, György; Urbán, Krisztián; Nagy, Valéria; Brúgós, Boglárka

    2014-03-01

    The present paper is focusing on rare diseases manifesting in late childhood or adulthood. A part of these syndromes are not of genetic origin, such as relatively or absolutely rare infections, autoimmune diseases, tumours, or diseases due to rare environmental toxic agents. In addition, even a large proportion of genetic disorders may develop in adulthood or may have adult forms as well, affecting are almost each medical specialization. Examples are storage disorders (e.g. adult form of Tay-Sachs disease, Gaucher-disease), enzyme deficiencies (e.g. ornithin-transcarbamylase deficiency of the urea cycle disorders), rare thrombophilias (e.g. homozygous factor V. Leiden mutation, antithrombin deficiency), or some rare monogenic disorders such as Huntington-chorea and many others. It is now generally accepted that at least half of the 6-8000 "rare diseases" belong either to the scope of adult-care (e.g. internal medicine, neurology), or to "age-neutral" specialities such as ophtalmology, dermatology etc.). PMID:24566697

  10. Homozygous mutation of STXBP5L explains an autosomal recessive infantile-onset neurodegenerative disorder.

    PubMed

    Kumar, Raman; Corbett, Mark A; Smith, Nicholas J C; Jolly, Lachlan A; Tan, Chuan; Keating, Damien J; Duffield, Michael D; Utsumi, Toshihiko; Moriya, Koko; Smith, Katherine R; Hoischen, Alexander; Abbott, Kim; Harbord, Michael G; Compton, Alison G; Woenig, Joshua A; Arts, Peer; Kwint, Michael; Wieskamp, Nienke; Gijsen, Sabine; Veltman, Joris A; Bahlo, Melanie; Gleeson, Joseph G; Haan, Eric; Gecz, Jozef

    2015-04-01

    We report siblings of consanguineous parents with an infantile-onset neurodegenerative disorder manifesting a predominant sensorimotor axonal neuropathy, optic atrophy and cognitive deficit. We used homozygosity mapping to identify an ∼12-Mbp interval identical by descent (IBD) between the affected individuals on chromosome 3q13.13-21.1 with an LOD score of 2.31. We combined family-based whole-exome and whole-genome sequencing of parents and affected siblings and, after filtering of likely non-pathogenic variants, identified a unique missense variant in syntaxin-binding protein 5-like (STXBP5L c.3127G>A, p.Val1043Ile [CCDS43137.1]) in the IBD interval. Considering other modes of inheritance, we also found compound heterozygous variants in FMNL3 (c.114G>C, p.Phe38Leu and c.1372T>G, p.Ile458Leu [CCDS44874.1]) located on chromosome 12. STXBP5L (or Tomosyn-2) is expressed in the central and peripheral nervous system and is known to inhibit neurotransmitter release through inhibition of the formation of the SNARE complexes between synaptic vesicles and the plasma membrane. FMNL3 is expressed more widely and is a formin family protein that is involved in the regulation of cell morphology and cytoskeletal organization. The STXBP5L p.Val1043Ile variant enhanced inhibition of exocytosis in comparison with wild-type (WT) STXBP5L. Furthermore, WT STXBP5L, but not variant STXBP5L, promoted axonal outgrowth in manipulated mouse primary hippocampal neurons. However, the FMNL3 p.Phe38Leu and p.Ile458Leu variants showed minimal effects in these cells. Collectively, our clinical, genetic and molecular data suggest that the IBD variant in STXBP5L is the likely cause of the disorder.

  11. Adult onset retinoblastoma: A diagnostic dilemma.

    PubMed

    Raj, Amit; Arya, Sudesh Kumar; Punia, Rajpal Singh; Kohli, Piyush

    2016-01-01

    Retinoblastoma is the most common intraocular tumor of childhood. About 95% of retinoblastoma cases are diagnosed before the age of 5 years. Not more than 30 cases of Adult-onset retinoblastoma have been reported in literature. A 32 year old male presented with a painful blind eye. There was sudden loss of vision accompanied by severe pain and redness in right eye about 1 year ago, for which some surgery was done with neither a gain in vision nor any relief from pain. Then he was put on maximum tolerable medical therapy, later cyclocryotherapy was done. Now he presented to us with complains of extreme pain and bleeding from right eye since 2 days. There is no history of any ocular trauma. Right eye had no perception of light & showed anterior staphyloma with perforation. Right eye evisceration was done & material sent for histopathological examination, which revealed an adult-onset retinoblastoma. CECT scan revealed thickening of optic nerve throughout its entire length with contrast enhancement. He was further taken up for enucleation of residual sclera with maximum optic nerve stump removal to reconfirm the diagnosis. Histopathological examination revealed tumor deposits present in orbital soft tissue, resection margins and optic nerve cut end.Retinoblastoma presenting in adult age creates a diagnostic dilemma because of its low frequency and atypical features. We want to highlight the importance of high clinical suspicion and imaging modalities before taking any patient for evisceration with unexplained vision loss. One should send the eviscerated material for histopathological examination. PMID:26709674

  12. Phenotypes, Risk Factors, and Mechanisms of Adult-Onset Asthma.

    PubMed

    Ilmarinen, Pinja; Tuomisto, Leena E; Kankaanranta, Hannu

    2015-01-01

    Asthma is a heterogeneous disease with many phenotypes, and age at disease onset is an important factor in separating the phenotypes. Genetic factors, atopy, and early respiratory tract infections are well-recognized factors predisposing to childhood-onset asthma. Adult-onset asthma is more often associated with obesity, smoking, depression, or other life-style or environmental factors, even though genetic factors and respiratory tract infections may also play a role in adult-onset disease. Adult-onset asthma is characterized by absence of atopy and is often severe requiring treatment with high dose of inhaled and/or oral steroids. Variety of risk factors and nonatopic nature of adult-onset disease suggest that variety of mechanisms is involved in the disease pathogenesis and that these mechanisms differ from the pathobiology of childhood-onset asthma with prevailing Th2 airway inflammation. Recognition of the mechanisms and mediators that drive the adult-onset disease helps to develop novel strategies for the treatment. The aim of this review was to summarize the current knowledge on the pathogenesis of adult-onset asthma and to concentrate on the mechanisms and mediators involved in establishing adult-onset asthma in response to specific risk factors. We also discuss the involvement of these mechanisms in the currently recognized phenotypes of adult-onset asthma. PMID:26538828

  13. Phenotypes, Risk Factors, and Mechanisms of Adult-Onset Asthma

    PubMed Central

    Ilmarinen, Pinja; Tuomisto, Leena E.; Kankaanranta, Hannu

    2015-01-01

    Asthma is a heterogeneous disease with many phenotypes, and age at disease onset is an important factor in separating the phenotypes. Genetic factors, atopy, and early respiratory tract infections are well-recognized factors predisposing to childhood-onset asthma. Adult-onset asthma is more often associated with obesity, smoking, depression, or other life-style or environmental factors, even though genetic factors and respiratory tract infections may also play a role in adult-onset disease. Adult-onset asthma is characterized by absence of atopy and is often severe requiring treatment with high dose of inhaled and/or oral steroids. Variety of risk factors and nonatopic nature of adult-onset disease suggest that variety of mechanisms is involved in the disease pathogenesis and that these mechanisms differ from the pathobiology of childhood-onset asthma with prevailing Th2 airway inflammation. Recognition of the mechanisms and mediators that drive the adult-onset disease helps to develop novel strategies for the treatment. The aim of this review was to summarize the current knowledge on the pathogenesis of adult-onset asthma and to concentrate on the mechanisms and mediators involved in establishing adult-onset asthma in response to specific risk factors. We also discuss the involvement of these mechanisms in the currently recognized phenotypes of adult-onset asthma. PMID:26538828

  14. Childhood Onset Schizophrenia: Cortical Brain Abnormalities as Young Adults

    ERIC Educational Resources Information Center

    Greenstein, Deanna; Lerch, Jason; Shaw, Philip; Clasen, Liv; Giedd, Jay; Gochman, Peter; Rapoport, Judith; Gogtay, Nitin

    2006-01-01

    Background: Childhood onset schizophrenia (COS) is a rare but severe form of the adult onset disorder. While structural brain imaging studies show robust, widespread, and progressive gray matter loss in COS during adolescence, there have been no longitudinal studies of sufficient duration to examine comparability with the more common adult onset…

  15. Adult bone marrow: which stem cells for cellular therapy protocols in neurodegenerative disorders?

    PubMed

    Wislet-Gendebien, Sabine; Laudet, Emerence; Neirinckx, Virginie; Rogister, Bernard

    2012-01-01

    The generation of neuronal cells from stem cells obtained from adult bone marrow is of significant clinical interest in order to design new cell therapy protocols for several neurological disorders. The recent identification in adult bone marrow of stem cells derived from the neural crests (NCSCs) might explain the neuronal phenotypic plasticity shown by bone marrow cells. However, little information is available about the nature of these cells compared to mesenchymal stem cells (MSCs). In this paper, we will review all information available concerning NCSC from adult tissues and their possible use in regenerative medicine. Moreover, as multiple recent studies showed the beneficial effect of bone marrow stromal cells in neurodegenerative diseases, we will discuss which stem cells isolated from adult bone marrow should be more suitable for cell replacement therapy.

  16. Is Adolescent-Onset First-Episode Psychosis Different from Adult Onset?

    ERIC Educational Resources Information Center

    Ballageer, Trevor; Malla, Ashok; Manchanda, Rahul; Takhar, Jatinder; Haricharan, Raj

    2005-01-01

    Objective: To examine whether first-episode psychosis patients with onset during adolescence (ages 15-18) differ significantly from those with young-adult onset (ages 19-30). Method: Consecutive patients presenting with first-episode psychosis (N = 242) were assessed for demographic and illness characteristics such as duration of untreated…

  17. Clinical Characteristics of Pediatric-Onset and Adult-Onset Multiple Sclerosis in Hispanic Americans.

    PubMed

    Langille, Megan M; Islam, Talat; Burnett, Margaret; Amezcua, Lilyana

    2016-07-01

    Multiple sclerosis can affect pediatric patients. Our aim was to compare characteristics between pediatric-onset multiple sclerosis and adult-onset multiple sclerosis in Hispanic Americans. This was a cross-sectional analysis of 363 Hispanic American multiple scleroses cases; demographic and clinical characteristics were analyzed. A total of 110 Hispanic patients presented with multiple sclerosis before age 18 and 253 as adult multiple sclerosis. The most common presenting symptoms for both was optic neuritis. Polyfocal symptoms, seizures, and cognitive symptoms at presentation were more prevalent in pediatric-onset multiple sclerosis (P ≤ .001). Transverse myelitis was more frequent in adult-onset multiple sclerosis (P ≤ .001). Using multivariable analysis, pediatric-onset multiple sclerosis (adjusted odds ratio, 0.3OR 95% confidence interval 0.16-0.71, P = .004) and being US born (adjusted odds ratio, 0.553, 95% confidence interval 0.3-1.03, P = .006) were less likely to have severe ambulatory disability. Results suggest that pediatric-onset multiple sclerosis and adult-onset multiple sclerosis in Hispanics have differences that could be important for treatment and prognosis.

  18. Associated Markers for Adult-onset Allergic Asthma.

    PubMed

    Bedolla-Barajas, Martín; Morales-Romero, Jaime; Ramses-Bedolla-Pulido, Tonatiuh; Fabiola-García-Padilla, Lourdes; Hernández-Colín, Dante

    2015-10-01

    The clinical behavior of asthma varies with age at onset. This study was undertaken to identify associated markers of adult-onset allergic asthma (age ≥20 years).This cross-sectional study compared two groups: 58 patients with asthma onset at ≥20 years and 66 with onset at ≥20 years. They were compared depending on results of clinical history, and body mass index (BMI), aeroallergen sensitization, total serum IgE, eosinophil count, asthma control test, and asthma severity level.Ages at first asthma episode were 10.0 ± 6.6 and 33.4 ± 10.5 (p<0.001) in the <20 and ≥20 group, respectively. BMI was higher in adult asthmatic subjects (29.8 versus 27.1, P=0.017), but BMI ≥30 kg/m(2) was not associated with asthma onset in ≥20 years (odds ratio [OR] = 1.56, 95% confidence interval [CI] 0.759 to 3.211; p= 0.227). After multivariate analysis, allergic rhinitis and IgE ≥150 IU/mL were negatively correlated with asthma onset in ≥20 years old (OR adjusted [ORa] = 0.255, 95% CI 0.078 to 0.837, P= 0.024, and ORa =0.385, 95% CI 0.175 to 0.849, p= 0.018, respectively).Adult-onset allergic asthma was not different from early-onset asthma. PMID:26742445

  19. Associated Markers for Adult-onset Allergic Asthma.

    PubMed

    Bedolla-Barajas, Martín; Morales-Romero, Jaime; Ramses-Bedolla-Pulido, Tonatiuh; Fabiola-García-Padilla, Lourdes; Hernández-Colín, Dante

    2015-10-01

    The clinical behavior of asthma varies with age at onset. This study was undertaken to identify associated markers of adult-onset allergic asthma (age ≥20 years).This cross-sectional study compared two groups: 58 patients with asthma onset at ≥20 years and 66 with onset at ≥20 years. They were compared depending on results of clinical history, and body mass index (BMI), aeroallergen sensitization, total serum IgE, eosinophil count, asthma control test, and asthma severity level.Ages at first asthma episode were 10.0 ± 6.6 and 33.4 ± 10.5 (p<0.001) in the <20 and ≥20 group, respectively. BMI was higher in adult asthmatic subjects (29.8 versus 27.1, P=0.017), but BMI ≥30 kg/m(2) was not associated with asthma onset in ≥20 years (odds ratio [OR] = 1.56, 95% confidence interval [CI] 0.759 to 3.211; p= 0.227). After multivariate analysis, allergic rhinitis and IgE ≥150 IU/mL were negatively correlated with asthma onset in ≥20 years old (OR adjusted [ORa] = 0.255, 95% CI 0.078 to 0.837, P= 0.024, and ORa =0.385, 95% CI 0.175 to 0.849, p= 0.018, respectively).Adult-onset allergic asthma was not different from early-onset asthma.

  20. Differences Between Early and Late Onset Adult Depression

    PubMed Central

    Bukh, Jens Drachmann; Bock, Camilla; Vinberg, Maj; Gether, Ulrik; Kessing, Lars Vedel

    2011-01-01

    Background: It is unclear, whether age-of-onset identifies subgroups of depression. Aim: To assess the clinical presentation of depression with onset in the early adult age (18-30 years) as compared to depression with later onset (31-70 years). Method: A total number of 301 patients with first episode depression were systematically recruited. Characteristics including psychiatric co-morbidity, personality disorders and traits, stressful life events prior to onset, family history, and treatment outcome were assessed by structured interviews and compared by chi-square tests for categorical data, t-tests for continuous parametric data and Mann-Whitney U-test for continuous nonparametric data. Logistic and multiple regression analyses were used to adjust the analyses for potentially confounding variables. Results: Patients with early onset of depression were characterised by a higher prevalence of co-morbid personality disorders, higher levels of neuroticism, and a lower prevalence of stressful life events preceding onset compared to patients with later age-of-onset. There were no differences in severity of the depressive episode, treatment outcome or family loading of psychiatric illness. Conclusion: Early adult onset of depression is associated with co-morbid personality deviances, whereas late onset is associated with environmental risk factors. PMID:21866230

  1. Fetal programming, epigenetics, and adult onset disease.

    PubMed

    Lane, Robert H

    2014-12-01

    How early life events program adult disease is undergoing a transition from the broad field of maternal malnutrition to the current relevant issues of food deserts and prematurity. Although many adult diseases and morbidities associate with various early life events and programming, the morbidities of insulin resistance, cardiovascular disease, and obesity seem to be common end points of many early life events despite potential confounders.

  2. Adult Hippocampal Neurogenesis, Aging and Neurodegenerative Diseases: Possible Strategies to Prevent Cognitive Impairment.

    PubMed

    Vivar, Carmen

    2015-01-01

    The adult brain of humans and other mammals continuously generates new neurons throughout life. However, this neurogenic capacity is limited to two brain areas, the dentate gyrus (DG of the hippocampus and the subventricular zone (SVZ of the lateral ventricle. Although the DG generates new neurons, its neurogenic capacity declines with age and neurodegenerative diseases such as Alzheimer's disease (AD and Huntington's disease (HD. This review focuses on the role of newly-born neurons in cognitive processes, and discusses some of the strategies proposed in humans and animals to enhance neurogenesis and counteract age-related cognitive deficits, such as physical exercise and intake of natural products like omega-3 fatty acids, curcumin and flavanols. PMID:26059358

  3. In Vivo Profiling Reveals a Competent Heat Shock Response in Adult Neurons: Implications for Neurodegenerative Disorders

    PubMed Central

    Carnemolla, Alisia; Lazell, Hayley; Moussaoui, Saliha; Bates, Gillian P.

    2015-01-01

    The heat shock response (HSR) is the main pathway used by cells to counteract proteotoxicity. The inability of differentiated neurons to induce an HSR has been documented in primary neuronal cultures and has been proposed to play a critical role in ageing and neurodegeneration. However, this accepted dogma has not been demonstrated in vivo. We used BAC transgenic mice generated by the Gene Expression Nervous System Atlas project to investigate the capacity of striatal medium sized spiny neurons to induce an HSR as compared to that of astrocytes and oligodendrocytes. We found that all cell populations were competent to induce an HSR upon HSP90 inhibition. We also show the presence and relative abundance of heat shock-related genes and proteins in these striatal cell populations. The identification of a competent HSR in adult neurons supports the development of therapeutics that target the HSR pathway as treatments for neurodegenerative disorders. PMID:26134141

  4. In Vivo Profiling Reveals a Competent Heat Shock Response in Adult Neurons: Implications for Neurodegenerative Disorders.

    PubMed

    Carnemolla, Alisia; Lazell, Hayley; Moussaoui, Saliha; Bates, Gillian P

    2015-01-01

    The heat shock response (HSR) is the main pathway used by cells to counteract proteotoxicity. The inability of differentiated neurons to induce an HSR has been documented in primary neuronal cultures and has been proposed to play a critical role in ageing and neurodegeneration. However, this accepted dogma has not been demonstrated in vivo. We used BAC transgenic mice generated by the Gene Expression Nervous System Atlas project to investigate the capacity of striatal medium sized spiny neurons to induce an HSR as compared to that of astrocytes and oligodendrocytes. We found that all cell populations were competent to induce an HSR upon HSP90 inhibition. We also show the presence and relative abundance of heat shock-related genes and proteins in these striatal cell populations. The identification of a competent HSR in adult neurons supports the development of therapeutics that target the HSR pathway as treatments for neurodegenerative disorders. PMID:26134141

  5. Alcohol-Induced Developmental Origins of Adult-Onset Diseases.

    PubMed

    Lunde, Emilie R; Washburn, Shannon E; Golding, Michael C; Bake, Shameena; Miranda, Rajesh C; Ramadoss, Jayanth

    2016-07-01

    Fetal alcohol exposure may impair growth, development, and function of multiple organ systems and is encompassed by the term fetal alcohol spectrum disorders (FASD). Research has so far focused on the mechanisms, prevention, and diagnosis of FASD, while the risk for adult-onset chronic diseases in individuals exposed to alcohol in utero is not well explored. David Barker's hypothesis on Developmental Origins of Health and Disease (DOHaD) suggests that insults to the milieu of the developing fetus program it for adult development of chronic diseases. In the 25 years since the introduction of this hypothesis, epidemiological and animal model studies have made significant advancements in identifying in utero developmental origins of chronic adult-onset diseases affecting cardiovascular, endocrine, musculoskeletal, and psychobehavioral systems. Teratogen exposure is an established programming agent for adult diseases, and recent studies suggest that prenatal alcohol exposure correlates with adult onset of neurobehavioral deficits, cardiovascular disease, endocrine dysfunction, and nutrient homeostasis instability, warranting additional investigation of alcohol-induced DOHaD, as well as patient follow-up well into adulthood for affected individuals. In utero epigenetic alterations during critical periods of methylation are a key potential mechanism for programming and susceptibility of adult-onset chronic diseases, with imprinted genes affecting metabolism being critical targets. Additional studies in epidemiology, phenotypic characterization in response to timing, dose, and duration of exposure, as well as elucidation of mechanisms underlying FASD-DOHaD inter relation, are thus needed to clinically define chronic disease associated with prenatal alcohol exposure. These studies are critical to establish interventional strategies that decrease incidence of these adult-onset diseases and promote healthier aging among individuals affected with FASD. PMID:27254466

  6. Alcohol-Induced Developmental Origins of Adult-Onset Diseases.

    PubMed

    Lunde, Emilie R; Washburn, Shannon E; Golding, Michael C; Bake, Shameena; Miranda, Rajesh C; Ramadoss, Jayanth

    2016-07-01

    Fetal alcohol exposure may impair growth, development, and function of multiple organ systems and is encompassed by the term fetal alcohol spectrum disorders (FASD). Research has so far focused on the mechanisms, prevention, and diagnosis of FASD, while the risk for adult-onset chronic diseases in individuals exposed to alcohol in utero is not well explored. David Barker's hypothesis on Developmental Origins of Health and Disease (DOHaD) suggests that insults to the milieu of the developing fetus program it for adult development of chronic diseases. In the 25 years since the introduction of this hypothesis, epidemiological and animal model studies have made significant advancements in identifying in utero developmental origins of chronic adult-onset diseases affecting cardiovascular, endocrine, musculoskeletal, and psychobehavioral systems. Teratogen exposure is an established programming agent for adult diseases, and recent studies suggest that prenatal alcohol exposure correlates with adult onset of neurobehavioral deficits, cardiovascular disease, endocrine dysfunction, and nutrient homeostasis instability, warranting additional investigation of alcohol-induced DOHaD, as well as patient follow-up well into adulthood for affected individuals. In utero epigenetic alterations during critical periods of methylation are a key potential mechanism for programming and susceptibility of adult-onset chronic diseases, with imprinted genes affecting metabolism being critical targets. Additional studies in epidemiology, phenotypic characterization in response to timing, dose, and duration of exposure, as well as elucidation of mechanisms underlying FASD-DOHaD inter relation, are thus needed to clinically define chronic disease associated with prenatal alcohol exposure. These studies are critical to establish interventional strategies that decrease incidence of these adult-onset diseases and promote healthier aging among individuals affected with FASD.

  7. Etiopathogenesis and Therapeutic Approach to Adult Onset Acne

    PubMed Central

    Kaur, Sarabjit; Verma, Poonam; Sangwan, Ankita; Dayal, Surabhi; Jain, Vijay Kumar

    2016-01-01

    Acne vulgaris is usually considered as a skin disorder that primarily affects adolescents reaching a peak at the age of 14–17 years in females and 16–19 years in males. However, recent epidemiologic studies have shown that a significant number of female patients aged >25 years experience acne. As it is regarded as a disease of teenagers, adults are more apprehensive and experience social anxiety. Hence, adult onset acne has become a matter of concern. PMID:27512185

  8. Etiopathogenesis and Therapeutic Approach to Adult Onset Acne.

    PubMed

    Kaur, Sarabjit; Verma, Poonam; Sangwan, Ankita; Dayal, Surabhi; Jain, Vijay Kumar

    2016-01-01

    Acne vulgaris is usually considered as a skin disorder that primarily affects adolescents reaching a peak at the age of 14-17 years in females and 16-19 years in males. However, recent epidemiologic studies have shown that a significant number of female patients aged >25 years experience acne. As it is regarded as a disease of teenagers, adults are more apprehensive and experience social anxiety. Hence, adult onset acne has become a matter of concern. PMID:27512185

  9. Caring for Others: Internet Video-Conferencing Group Intervention for Family Caregivers of Older Adults with Neurodegenerative Disease

    ERIC Educational Resources Information Center

    Marziali, Elsa; Donahue, Peter

    2006-01-01

    Purpose: The aim of this pilot feasibility study was to evaluate the effects of an innovative, Internet-based psychosocial intervention for family caregivers of older adults with neurodegenerative disease. Design and Methods: After receiving signed informed consent from each participant, we randomly assigned 66 caregivers to an Internet-based…

  10. Adult-onset laryngomalacia: case reports and review of management.

    PubMed

    Hey, Shi Ying; Oozeer, Nashreen Banon; Robertson, Stuart; MacKenzie, Kenneth

    2014-12-01

    Laryngomalacia is a dynamic airway condition characterised by inward collapse of flaccid supraglottic structures during inspiration. Although the most common cause of stridor in the paediatric population, adult-onset laryngomalacia remains a rare entity and its management, challenging. Two cases of adult-onset laryngomalacia are reported. A review of the English literature is performed and additional publications identified by hand-searching relevant papers; 13 case reports/series comprising 28 cases of adult-onset laryngomalacia were identified, divided into two main groups: idiopathic (6/28) and acquired (22/28). The aetiology of the acquired form includes neurological, traumatic and iatrogenic. Reported therapeutic measures used are laser supraglottoplasty, epiglottopexy, partial epiglottidectomy, defunctioning tracheostomy and intubation whilst correcting the underlying cause. The majority of patients only required one therapeutic procedure (follow-up of 2-24 months). A strong index of suspicion is required to diagnose adult-onset laryngomalacia aided by in-office laryngoscopy. The rarity of this condition prevents management-based randomised controlled trials. PMID:24615649

  11. Clinical profile of patients with adult-onset eosinophilic asthma

    PubMed Central

    Storm, Huib; Amelink, Marijke; de Nijs, Selma B.; Eichhorn, Edwin; Reitsma, Bennie H.; Bel, Elisabeth H.D.; ten Brinke, Anneke

    2016-01-01

    Adult-onset eosinophilic asthma is increasingly recognised as a severe and difficult-to-treat subtype of asthma. In clinical practice, early recognition of patients with this asthma subtype is important because it may have treatment implications. Therefore, physicians need to know the distinct characteristics of this asthma phenotype. The objective of the present study was to determine the characteristic profile of patients with adult-onset eosinophilic asthma. 130 patients with adult-onset (>18 years of age) asthma and high blood eosinophil counts (≥0.3×109 L−1) were compared with 361 adult-onset asthma patients with low (<0.3×109 L−1) blood eosinophils. Measurements included a series of clinical, functional and imaging parameters. Patients with high blood eosinophils were more often male, had less well controlled asthma and higher exacerbation rates, despite the use of higher doses of inhaled corticosteroids. They had higher levels of total IgE without more sensitisation to common inhaled allergens. In addition, these patients had worse lung function, and more often showed fixed airflow limitation, air trapping, nasal polyposis and abnormalities on sinus computed tomography scanning. Chronic rhinosinusitis, air trapping and male sex were three independent factors associated with blood eosinophilia (adjusted OR 3.8 (95% CI 1.7–8.1), 3.0 (95% CI 1.1–8.1) and 2.4 (95% CI 1.3–4.4), respectively). Patients with adult-onset asthma with elevated blood eosinophils exhibit a distinct profile, which can readily be recognised in clinical practice. PMID:27730197

  12. Predictive Medicine: Recombinant DNA Technology and Adult-Onset Genetic Disorders

    PubMed Central

    Hayden, Michael

    1988-01-01

    Genetic factors are of great importance in common adult-onset disorders such as atherosclerosis, cancer, and neuro-degenerative diseases. Advances in DNA technology now allow identification of persons at high-risk of developing some of these diseases. This advance is leading to predictive medicine. In some genetic disorders, such as those leading to atherosclerosis and cancer, identification of high-risk individuals allows intervention which alters the natural history of the disorder. In other diseases, for which there is no treatment, such as Huntington's disease, the application of this technology provides information that relieves uncertainty and may affect quality of life, but does not alter the course of the illness. General implementation of predictive testing programs awaits the results of pilot projects, which will demonstrate the needs, appropriate levels of support, and guidelines for delivery of such testing. PMID:21253100

  13. [Late-onset Neurodegenerative Diseases Following Traumatic Brain Injury: Chronic Traumatic Encephalopathy (CTE) and Alzheimer's Disease Secondary to TBI (AD-TBI)].

    PubMed

    Takahata, Keisuke; Tabuchi, Hajime; Mimura, Masaru

    2016-07-01

    Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease, which is associated with mild repetitive traumatic brain injury (TBI). This long-term and progressive symptom due to TBI was initially called punch-drunk syndrome or dementia pugilistica, since it was believed to be associated with boxing. However, serial neuropathological studies of mild repetitive TBI in the last decade have revealed that CTE occurs not only in boxers but also in a wider population including American football players, wrestlers, and military personnel. CTE has gained large public interest owing to dramatic cases involving retired professional athletes wherein serious behavioral problems and tragic incidents were reported. Unlike mild repetitive TBI, a single episode of severe TBI can cause another type of late-onset neuropsychiatric disease including Alzheimer's disease (AD). Several epidemiological studies have shown that a single episode of severe TBI is one of the major risk factors of AD. Pathologically, both AD and CTE are characterized by abnormal accumulations of hyperphosphorylated tau proteins. However, recent neuropathological studies revealed that CTE demonstrates a unique pattern of tau pathology in neurons and astrocytes, and accumulation of other misfolded proteins such as TDP-43. Currently, no reliable biomarkers of late-onset neurodegenerative diseases following TBI are available, and a definitive diagnosis can be made only via postmortem neuropathological examination. Development in neuroimaging techniques such as tau and amyloid positron emission tomography imaging might not only enable early diagnosis of CTE, but also contribute to the interventions for prevention of late-onset neurodegenerative diseases following TBI. Further studies are necessary to elucidate the mechanisms of neurodegeneration in the living brain of patients with TBI. PMID:27395469

  14. Adult-onset bulbar ptosis in Joubert syndrome

    PubMed Central

    Burt, Benjamin; Levine, Johanan; Le, Kim

    2012-01-01

    In this case report, we describe a case of adult-onset bulbar ptosis in a patient with Joubert syndrome. Joubert syndrome is a rare neurodevelopmental disorder with malformations in cerebellum and brainstem. Many ocular abnormalities have been noted in Joubert syndrome, but the association of this syndrome with adult-onset ptosis has not been described to date. This 24-year-old Joubert patient developed a cerebrospinal fluid cyst in her midbrain. She had signs of bilateral third nerve palsy and abducens palsy in the left eye. The bilateral central third nerve palsy causing functional blindness secondary to severe bilateral levator palsy was treated successfully with silicone sling frontalis suspension, as the seventh nerve nucleus was not involved. PMID:22291457

  15. Season of Birth and Risk for Adult Onset Glioma

    PubMed Central

    Efird, Jimmy T.

    2010-01-01

    Adult onset glioma is a rare cancer which occurs more frequently in Caucasians than African Americans, and in men than women. The etiology of this disease is largely unknown. Exposure to ionizing radiation is the only well established environmental risk factor, and this factor explains only a small percentage of cases. Several recent studies have reported an association between season of birth and glioma risk. This paper reviews the plausibility of evidence focusing on the seasonal interrelation of farming, allergies, viruses, vitamin D, diet, birth weight, and handedness. To date, a convincing explanation for the occurrence of adult gliomas decades after a seasonal exposure at birth remains elusive. PMID:20623001

  16. Adult-Onset Acquired Partial Lipodystrophy Accompanied by Rheumatoid Arthritis

    PubMed Central

    Muto, Yusuke; Fujimura, Taku; Kakizaki, Aya; Tsuchiyama, Kenichiro; Kusakari, Yoshiyuki; Aiba, Setsuya

    2015-01-01

    Lipodystrophy is a group of metabolic disorders, possibly caused by autoimmune disease. In this report, we describe a case of adult-onset acquired partial lipodystrophy accompanied by rheumatoid arthritis without a family history. Interestingly, immunohistochemical staining revealed dense infiltration of IL-27-producing cells as well as MMP-7-and MMP-28-expressing cells, both of which have been reported to facilitate the development of autoimmune disease. Our present case might suggest possible mechanisms for acquired partial lipodystrophy. PMID:26034476

  17. Adult-onset autosomal recessive ataxia associated with neuronal ceroid lipofuscinosis type 5 gene (CLN5) mutations.

    PubMed

    Mancini, Cecilia; Nassani, Stefano; Guo, Yiran; Chen, Yulan; Giorgio, Elisa; Brussino, Alessandro; Di Gregorio, Eleonora; Cavalieri, Simona; Lo Buono, Nicola; Funaro, Ada; Pizio, Nicola Renato; Nmezi, Bruce; Kyttala, Aija; Santorelli, Filippo Maria; Padiath, Quasar Salem; Hakonarson, Hakon; Zhang, Hao; Brusco, Alfredo

    2015-01-01

    Autosomal recessive inherited ataxias are a growing group of genetic disorders. We report two Italian siblings presenting in their mid-50s with difficulty in walking, dysarthria and progressive cognitive decline. Visual loss, ascribed to glaucoma, manifested a few years before the other symptoms. Brain MRI showed severe cerebellar atrophy, prevalent in the vermis, with marked cortical atrophy of both hemispheres. Exome sequencing identified a novel homozygous mutation (c.935G > A;p.Ser312Asn) in the ceroid neuronal lipofuscinosis type 5 gene (CLN5). Bioinformatics predictions and in vitro studies showed that the mutation was deleterious and likely affects ER-lysosome protein trafficking. Our findings support CLN5 hypomorphic mutations cause autosomal recessive cerebellar ataxia, confirming other reports showing CLN mutations are associated with adult-onset neurodegenerative disorders. We suggest CLN genes should be considered in the molecular analyses of patients presenting with adult-onset autosomal recessive cerebellar ataxia.

  18. Coats’ disease of adult-onset in 48 eyes

    PubMed Central

    Rishi, Ekta; Rishi, Pukhraj; Appukuttan, Bindu; Uparkar, Mahesh; Sharma, Tarun; Gopal, Lingam

    2016-01-01

    Background: Coats’ disease diagnosed in adulthood is an idiopathic, retinal exudative vascular disease without an inciting factor and has retinal features different from the childhood disease. Aim: To describe clinical features, treatment, and outcomes of eyes with Coats’ disease first diagnosed in patients 35 years or older. Materials and Methods: Retrospective chart review of patients first diagnosed with Coats’ disease at the age of 35 years or more at a tertiary eye care center between January 1995 and 2012. Eyes with retinal exudation or Coats’-like response from secondary causes were excluded. Results: Forty-five of 646 patients (7%) diagnosed with Coats’ disease had adult-onset disease. Mean age at presentation was 47 years. Systemic hypertension was the most common (22%) systemic association and decreased vision the predominant presenting feature (83%). Localized (<6 clock h) presentation (74%) was unique to adults as against diffuse involvement (69%) in children (P < 0.001). Eyes were treated with laser photocoagulation 29 (60%), cryotherapy (4%), or both (2%) with surgical intervention in three (6%) eyes. Following treatment eight (35%) eyes improved, 11 (48%) eyes were stable while four (12%) eyes worsened due to complications. Conclusion: Adult-onset Coats’ disease has less extensive involvement, more benign natural course, and a more favorable treatment outcome as against the childhood-onset disease. The bilateral presentation emphasizes the need for regular follow-up to detect possible future involvement of the fellow eye. PMID:27609165

  19. Memory Loss and Frontal Cognitive Dysfunction in a Patient with Adult-onset Neuronal Intranuclear Inclusion Disease.

    PubMed

    Araki, Kunihiko; Sone, Jun; Fujioka, Yusuke; Masuda, Michihito; Ohdake, Reiko; Tanaka, Yasuhiro; Nakamura, Tomohiko; Watanabe, Hirohisa; Sobue, Gen

    2016-01-01

    Neuronal intranuclear inclusion disease (NIID) is an uncommon progressive neurodegenerative disorder. Adult-onset NIID can result in prominent dementia. We herein describe the case of a 74-year-old man who presented with dementia, cerebellar ataxia, neuropathy, and autonomic dysfunction. Diffusion-weighted imaging showed hyperintensity of the corticomedullary junction. Fluid-attenuated inversion recovery images showed frontal-dominant white matter hyperintensity. NIID was diagnosed from the presence of intranuclear inclusions in a skin biopsy sample. Neuropsychological testing revealed memory loss and frontal cognitive dysfunction, especially in relation to language and executive functions. We were therefore able to confirm the association of NIID with cognitive dysfunction. PMID:27523009

  20. Office Work Exposures and Adult-Onset Asthma

    PubMed Central

    Jaakkola, Maritta S.; Jaakkola, Jouni J.K.

    2007-01-01

    Background Office exposures have been linked to symptoms of sick building syndrome, but their relation to the development of asthma has not been studied previously. These exposures have increasing importance because an increasing proportion of the workforce is working in office environments. Objectives The aim of this study was to assess the relations of exposure to carbonless copy paper (CCP), paper dust, and fumes from photocopiers and printers to adult-onset asthma. Methods We conducted a population-based incident case–control study of adults 21–63 years of age living in the Pirkanmaa District in South Finland. All new clinically diagnosed cases (n = 521) of asthma were recruited during a 3-year study period. A random sample of the source population formed the controls (n = 1,016). This part focused on 133 cases and 316 controls who were office workers according to their current occupation classified by the 1988 International Standard Classification of Occupations. All participants answered a questionnaire on health, smoking, occupation, and exposures at work and home. Subjects with previous asthma were excluded. Results Exposures to paper dust [adjusted odds ratio (OR) = 1.97; 95% confidence interval (CI), 1.25–3.10] and CCP (OR = 1.66; 95% CI, 1.03–2.66) were related to significantly increased risk of adult-onset asthma. An exposure–response relation was observed between exposure to paper dust and risk of asthma. Conclusions This study provides new evidence that exposures to paper dust and CCP in office work are related to increased risk of adult-onset asthma. Reduction of these exposures could prevent asthma in office workers. Clinicians seeing asthma patients should be aware of this link to office exposures. PMID:17637914

  1. New onset of idiopathic bilateral ear tics in an adult.

    PubMed

    Agrawal, Amit; Shrestha, Rabin

    2009-04-01

    Tic disorders are commonly considered to be childhood syndromes. Newly presenting tic disorders during adulthood are uncommon and mostly described in relation to an acquired brain lesion or as incidental tics, particularly in context with other neurological or psychiatric diseases. Tic disorder involving the ears is extremely uncommon with only few studies in English literature. In the present case, we describe an adult patient with new-onset idiopathic tics disorder involving both ears, causing social embarrassment. In addition, our patient had recent onset of the tics without any childhood or family history of tic disorders. The single most important component of management is an accurate diagnosis. At the same time, tics should be differentiated from other movement disorders such as chorea, stereotypy, and dystonias.

  2. Adult-Onset Still's Disease: From Pathophysiology to Targeted Therapies

    PubMed Central

    Mavragani, Clio P.; Spyridakis, Evangelos G.; Koutsilieris, Michael

    2012-01-01

    Adult-onset Still's disease (AOSD) is a systemic inflammatory disorder affecting primarily young individuals. The diagnosis is primarily clinical and necessitates the exclusion of a wide range of mimicking disorders. Given the lack of solid data in regard to the underlying pathogenetic mechanisms, treatment of AOSD has been for years largely empirical. Recent advances have revealed a pivotal role of several proinflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8), and interleukin-18 (IL-18) in disease pathogenesis, giving rise to the development of new targeted therapies aiming at optimal disease control. PMID:22792508

  3. Comparing illness presentation, treatment and functioning between patients with adolescent- and adult-onset psychosis.

    PubMed

    Hui, Christy Lai-Ming; Li, Adrienne Wing-Yee; Leung, Chung-Ming; Chang, Wing-Chung; Chan, Sherry Kit-Wa; Lee, Edwin Ho-Ming; Chen, Eric Yu-Hai

    2014-12-30

    Studies have shown that early- and adult-onset schizophrenia patients differ in pre-morbid traits, illness presentation, psychopathology, and prognosis. We aimed to compare adult-onset patients (age range 26-55 years) with an adolescent-onset cohort (15-25 years) in demographics, illness presentation and functioning at baseline. Participants were from two territory-wide early intervention services for adolescent-onset (n=671) and adult-onset psychosis patients (n=360) in Hong Kong. The adolescent-onset cohort had their initial psychotic episode from 2001-2003; retrospective data collection was done through systematic case note review. The adult-onset cohort was recruited for a larger interventional study from 2009-2011; information was collected via face-to-face interviews. Adult-onset psychosis was significantly associated with more females, more smokers, more non-local birth, more full-time employment, better functioning, poorer medication adherence, more psychiatric hospitalization and fewer with schizophrenia than adolescent-onset psychosis (mean age: 20.4). The effect sizes were small, except for medication adherence where a robust effect was found. No group difference in DUP was found. The finding that adult-onset patients had better functioning challenges the view that adolescent- and adult-onset psychoses share a similar prognostic trajectory. Implications for adapting intervention processes for adolescent- and adult-onset psychosis are discussed.

  4. Delta Activity at Sleep Onset and Cognitive Performance in Community-Dwelling Older Adults

    PubMed Central

    Kawai, Makoto; Beaudreau, Sherry A.; Gould, Christine E.; Hantke, Nathan C.; Jordan, Josh T.; O'Hara, Ruth

    2016-01-01

    Study Objectives: Frontal intermittent rhythmic delta activity (FIRDA) has long been considered to be an abnormal variant in the electroencephalogram (EEG) among older adults. Prior work also indicates a predominance of slow wave EEG activity among patients with dementia. However, instability of state control occurring with aging generally and among many neurodegenerative diseases raises the possibility that FIRDA might represent the intrusion of sleep related elements of the EEG into the waking state. We examined delta activity at sleep onset (DASO) in community-dwelling, older adults without dementia, and examined whether this activity is related to poorer cognitive performance. Methods: 153 community-dwelling, older adults without dementia underwent overnight polysomnography and measures of global cognition, delayed verbal memory, information processing speed, attention, inhibition, verbal naming, and visuospatial ability. Delta activity during sleep/wake transitions (scored either as Waking or N1) was analyzed visually. Results: Participants were 83 women and 70 men, mean age 71.3 ± 0.6 y. DASO was present in 30 participants (19.6%). Age, years of education, sex, and body mass index did not differ between DASO (+) and (−) groups. Multiple regression analyses indicated faster reading of the Stroop color words in DASO (+) subjects (P = 0.007). None of the other cognitive domains differed between the two groups. Conclusions: DASO was relatively common in our sample of community-dwelling, older adults without dementia. DASO was not associated with poorer performance on any cognitive domain. Instead, individuals with DASO demonstrated better performance on a simple reading task. Although these findings suggest that an abnormal EEG activity may represent normal variation, our work underscores the importance of distinguishing DASO from FIRDA when examining sleep in older adults. Commentary: A commentary on this article appears in this issue on page 725. Citation

  5. Neurodegenerative evidences during early onset of depression in CMS rats as detected by proton magnetic resonance spectroscopy at 7 T.

    PubMed

    Hemanth Kumar, B S; Mishra, Sushanta Kumar; Rana, Poonam; Singh, Sadhana; Khushu, Subash

    2012-06-15

    Depression is a complex psychiatric disorder characterized by anhedonia and feeling of sadness and chronic mild stress (CMS) seems to be a valuable animal model of depression. CMS animal model was induced and validated using behavioral studies. In the present study we investigated the neuro-metabolite changes occurring in prefrontal cortex and hippocampus during the onset of depression, in CMS rat model using in vivo proton magnetic resonance spectroscopy ((1)H MRS) at field strength of 7 T. Results showed that CMS caused depression-like behavior in rats, as indicated by the decrease in sucrose consumption and locomotor activity. (1)H MRS was performed in both control and CMS rats (n=10, in each group) and the quantitative assessment of the neurometabolites was done using LC model. Relative concentrations of all the metabolites along with the macromolecules were calculated for analysis. The results revealed a significant decrease of glutamate (Glu), glutamine (Gln), NAA+NAAG, Glx and GABA levels in both hippocampus and prefrontal cortex of CMS animals and an elevated level of myo-ionisitol (mI) and taurine (Tau) was observed only in hippocampus. These metabolite fluctuations revealed by proton MRS indicate that there might be change in the neuronal integrity of the glial cells and neurons within prefrontal cortex and hippocampus in CMS model of depression. The present study also suggests that there may be a degenerative process concerning the brain morphology in the CMS rats. The overall finding using (1)H MRS suggests that, there might be a major role of the glia and neuron in the onset of depression. PMID:22449862

  6. Adult Onset Vitiligo: Multivariate Analysis Suggests the Need for a Thyroid Screening

    PubMed Central

    Lazzeri, L.; Cammi, A.; Dragoni, F.

    2016-01-01

    Background. There are limited epidemiological studies evaluating the effect of age at onset on disease features in vitiligo. Objectives. To identify factors associated with adult onset vitiligo in comparison with childhood onset vitiligo. Patients and Methods. We retrospectively collected medical records of 191 patients. Such records included clinical examination, personal and familial medical history, laboratory evaluations, concomitant vitiligo treatment and drug assumption. Results. 123 patients with a disease onset after the age of 40 (adult onset vitiligo) were compared with 68 patients who developed vitiligo before the age of 12 (childhood onset vitiligo). Multivariate analysis revealed that personal history of thyroid diseases (P = 0.04; OR 0.4), stress at onset (P = 0.002; OR = 0.34), personal history of autoimmune thyroid disease (ATD) (P = 0.003; OR = 0.23), and thyroid nodules (P = 0.001; OR 0.90) were independently associated with adult onset vitiligo, whereas family history of dermatological diseases (P = 0.003; OR = 2.87) and Koebner phenomenon (P < 0.001; OR = 4.73) with childhood onset vitiligo. Moreover, in the adult onset group, concomitant thyroid disease preceded vitiligo in a statistically significant number of patients (P = 0.014). Conclusions. Childhood onset and adult onset vitiligo have different clinical features. In particular, ATD and thyroid nodules were significantly associated with adult onset vitiligo, suggesting that a thyroid screening should be recommended in this group of patients. PMID:27747240

  7. Efficacy of Anakinra in Refractory Adult-Onset Still's Disease

    PubMed Central

    Ortiz-Sanjuán, Francisco; Blanco, Ricardo; Riancho-Zarrabeitia, Leyre; Castañeda, Santos; Olivé, Alejandro; Riveros, Anne; Velloso-Feijoo, María.L.; Narváez, Javier; Jiménez-Moleón, Inmaculada; Maiz-Alonso, Olga; Ordóñez, Carmen; Bernal, José A.; Hernández, María V.; Sifuentes-Giraldo, Walter A.; Gómez-Arango, Catalina; Galíndez-Agirregoikoa, Eva; Blanco-Madrigal, Juan; Ortiz-Santamaria, Vera; del Blanco-Barnusell, Jordi; De Dios, Juan R.; Moreno, Mireia; Fiter, Jordi; Riscos, Marina de los; Carreira, Patricia; Rodriguez-Valls, María J.; González-Vela, M. Carmen; Calvo-Río, Vanesa; Loricera, Javier; Palmou-Fontana, Natalia; Pina, Trinitario; Llorca, Javier; González-Gay, Miguel A.

    2015-01-01

    Abstract Adult-onset Still's disease (AOSD) is often refractory to standard therapy. Anakinra (ANK), an interleukin-1 receptor antagonist, has demonstrated efficacy in single cases and small series of AOSD. We assessed the efficacy of ANK in a series of AOSD patients. Multicenter retrospective open-label study. ANK was used due to lack of efficacy to standard synthetic immunosuppressive drugs and in some cases also to at least 1 biologic agent. Forty-one patients (26 women/15 men) were recruited. They had a mean age of 34.4 ± 14 years and a median [interquartile range (IQR)] AOSD duration of 3.5 [2–6] years before ANK onset. At that time the most common clinical features were joint manifestations 87.8%, fever 78%, and cutaneous rash 58.5%. ANK yielded rapid and maintained clinical and laboratory improvement. After 1 year of therapy, the frequency of joint and cutaneous manifestations had decreased to 41.5% and to 7.3% respectively, fever from 78% to 14.6%, anemia from 56.1% to 9.8%, and lymphadenopathy from 26.8% to 4.9%. A dramatic improvement of laboratory parameters was also achieved. The median [IQR] prednisone dose was also reduced from 20 [11.3–47.5] mg/day at ANK onset to 5 [0–10] at 12 months. After a median [IQR] follow-up of 16 [5–50] months, the most important side effects were cutaneous manifestations (n = 8), mild leukopenia (n = 3), myopathy (n = 1), and infections (n = 5). ANK is associated with rapid and maintained clinical and laboratory improvement, even in nonresponders to other biologic agents. However, joint manifestations are more refractory than the systemic manifestations. PMID:26426623

  8. Adult-onset hypothyroidism in a lynx (Lynx canadensis).

    PubMed

    Greer, Leah L; Troutman, Mitchell; McCracken, Malcolm D; Ramsay, Edward C

    2003-09-01

    A 19-yr-old female lynx (Lynx canadensis) presented for an acute onset of anorexia and reluctance to move. Physical examination, radiography, hematology, and serum biochemistry revealed evidence of renal failure, presumptive uremic gastritis, chronic intervertebral disk disease at T13-L1, and markedly low serum levels of total thyroxine (1.54 nmol/L) and total triixodothyronine (0.55 nmol/L). Twenty-five hours after its original presentation, the lynx exhibited horizontal nystagmus, which has been suggested as a clinical sign associated with hypothyroidism in domestic dogs. The lynx was euthanatized because of poor prognosis, and medical management concerns related to its chronic renal failure. Necropsy examination substantiated that the lynx had true hypothyroidism with 60-90% of the thyroid gland replaced with adipose tissue. Although feline adult-onset hypothyroidism may have low incidence, it should still be considered as a cause of nonspecific signs of disease in cats, as well as signs suggestive of hypothyroidism. Routine monitoring of baseline exotic felid thyroid levels throughout life would help to identify normal values and diagnose a potential disease that has obscure clinical signs.

  9. Two sporadic cases of adult-onset progressive mucinous histiocytosis.

    PubMed

    Young, A; Olivere, J; Yoo, S; Martins, C; Barrett, T

    2006-02-01

    Progressive mucinous histiocytosis is a rare, benign, non-Langerhans' cell histiocytosis limited to the skin. Ten cases--all women--in four families and one sporadic case have been described in the literature. The disorder usually begins in childhood and progresses slowly. We report two sporadic cases of adult-onset progressive mucinous histiocytosis in unrelated African-American women, aged 48 and 55 years, respectively, who developed red-brown and flesh-coloured, asymptomatic papules on the face, the arms and the legs without truncal, mucosal or visceral involvement. The lesions showed no spontaneous regression. Both patients lacked associated systemic symptoms, including polyuria, polydipsia or seizures. There was no underlying hyperlipidaemia, paraproteinaemia or lymphoproliferative disease. No family history of similar lesions could be identified. Light microscopy revealed dermal proliferation of spindle-shaped histiocytes with abundant mucin deposition. Electron microscopy demonstrated a high number of myelin figures or zebra bodies in the cytoplasm of histiocytes. On immunohistochemistry, positive staining with macrophage markers--CD68, HAM56 and lysozyme--and factor XIIIa, a transglutaminase present in dermal dendrocytes, and negative staining with Langerhans' cell markers--CD1a and S100--and CD34, a marker present in dermal dendritic cells derived from uncommitted mesenchymal cells, were observed. PMID:16420313

  10. Obesity's Effects on the Onset of Functional Impairment among Older Adults

    ERIC Educational Resources Information Center

    Jenkins, Kristi Rahrig

    2004-01-01

    Purpose: This study has two purposes. First, it determines if there is a relationship between body weight and the onset of functional impairment across time among this sample of older adults. More specifically, it examines if obese older adults are more likely to experience the onset of functional impairment. Second, it explores how health…

  11. Warming up Improves Speech Production in Patients with Adult Onset Myotonic Dystrophy

    ERIC Educational Resources Information Center

    de Swart, B.J.M.; van Engelen, B.G.M.; Maassen, B.A.M.

    2007-01-01

    This investigation was conducted to study whether warming up decreases myotonia (muscle stiffness) during speech production or causes adverse effects due to fatigue or exhaustion caused by intensive speech activity in patients with adult onset myotonic dystrophy. Thirty patients with adult onset myotonic dystrophy (MD) and ten healthy controls…

  12. Successful treatment of adult-onset erythromelalgia with steroid pulse and pregabalin.

    PubMed

    Kakizaki, Aya; Fujimura, Taku; Kambayashi, Yumi; Watabe, Akiko; Aiba, Setsuya

    2012-09-01

    Adult-onset erythromelalgia (EM) is a rare disease characterized by episodic bouts of burning pain and erythema for which the optimal therapy is unclear. In this report, we describe a 68-year-old Japanese woman with adult-onset EM. Intravenous administration of methylprednisolone sodium succinate 1,000 mg/day dramatically improved her pain as evaluated by the visual analog scale. Although the patient's pain gradually developed again, it could be controlled with pregabalin. Our present case might suggest a possible, optimal therapy for adult-onset EM. PMID:23275767

  13. Successful Treatment of Adult-Onset Erythromelalgia with Steroid Pulse and Pregabalin

    PubMed Central

    Kakizaki, Aya; Fujimura, Taku; Kambayashi, Yumi; Watabe, Akiko; Aiba, Setsuya

    2012-01-01

    Adult-onset erythromelalgia (EM) is a rare disease characterized by episodic bouts of burning pain and erythema for which the optimal therapy is unclear. In this report, we describe a 68-year-old Japanese woman with adult-onset EM. Intravenous administration of methylprednisolone sodium succinate 1,000 mg/day dramatically improved her pain as evaluated by the visual analog scale. Although the patient's pain gradually developed again, it could be controlled with pregabalin. Our present case might suggest a possible, optimal therapy for adult-onset EM. PMID:23275767

  14. Young-Onset Dementia

    PubMed Central

    Kuruppu, Dulanji K; Matthews, Brandy R

    2014-01-01

    Young-onset dementia (YOD) is an neurological syndrome that affects behavior and cognition of patients younger than 65 years of age. Although frequently misdiagnosed, a systematic approach, reliant upon attainment of detailed medical history, collateral history from an informant, neuropsychological testing, laboratory studies, and neuroimaging, may facilitate earlier and more accurate diagnosis with subsequent intervention. The differential diagnosis of YOD is extensive and includes early-onset forms of adult neurodegenerative conditions including Alzheimer's disease, vascular dementia, frontotemporal dementia, Lewy body dementias, Huntington's disease, and prion disease. Late-onset forms of childhood neurodegenerative conditions may also present as YOD and include mitochondrial disorders, lysosomal storage disorders, and leukodystrophies. Potentially reversible etiologies including inflammatory disorders, infectious diseases, toxic/metabolic abnormalities, transient epileptic amnesia, obstructive sleep apnea, and normal pressure hydrocephalus also represent important differential diagnostic considerations in YOD. This review will present etiologies, diagnostic strategies, and options for management of YOD with comprehensive summary tables for clinical reference. PMID:24234358

  15. Sleep in Neurodegenerative Diseases.

    PubMed

    Iranzo, Alex

    2016-03-01

    Disorders of sleep are an integral part of neurodegenerative diseases and include insomnia, sleep-wake cycle disruption, excessive daytime sleepiness that may be manifested as persistent somnolence or sudden onset of sleep episodes, obstructive and central sleep apnea, rapid eye movement sleep behavior disorder, and restless legs syndrome. The origin of these sleep disorders is multifactorial including degeneration of the brain areas that modulate sleep, the symptoms of the disease, and the effect of medications. Treatment of sleep disorders in patients with neurodegenerative diseases should be individualized and includes behavioral therapy, sleep hygiene, bright light therapy, melatonin, hypnotics, waking-promoting agents, and continuous positive airway pressure. PMID:26972029

  16. Childhood Psychosocial Stressors and Adult Onset Arthritis: Broad Spectrum Risk Factors and Allostatic Load

    PubMed Central

    Von Korff, Michael; Alonso, Jordi; Ormel, Johan; Angermeyer, Matthais; Bruffaerts, Ronny; Fleiz, Clara; de Girolamo, Giovanni; Kessler, Ronald C.; Kovess-Masfety, Viviane; Posada-Villa, José; Scott, Kate M.; Uda, Hidenori

    2009-01-01

    Neural, endocrine and immune stress mediators are hypothesized to increase risks of diverse chronic diseases, including arthritis. Retrospective data from the World Mental Health Surveys (N=18,309) were employed to assess whether adult onset of arthritis was associated with childhood adversities and early onset psychological disorder. Cox proportional hazard models assessed the association of number of childhood adversities and the presence of early onset psychological disorder with arthritis age of onset. Controlling for age, sex and early onset mental disorder, relative to persons with no childhood adversities, persons with two adversities had increased risk of adult onset arthritis (Hazard ratio=1.27, 95% CI= 1.08, 1.50), while persons with three or more adversities had higher risk (HR=1.44, CI=1.24,1.67). Early onset depressive and/or anxiety disorder was associated with increased risk of adult-onset arthritis after controlling for childhood adversities (HR=1.43, CI=1.28, 1.61). Since psychosocial stressors may be broad spectrum risk factors that increase risks of diverse chronic conditions in later life (e.g., arthritis, heart disease, diabetes, asthma, chronic pain), prospective studies of childhood psychosocial stressors may be most productive if multiple disease outcomes are assessed in the same study. Results from this study provide methodological guidance for future prospective studies of the relationship between childhood psychosocial stressors and subsequent risk of adult onset arthritis. PERSPECTIVE Retrospective reports of early onset mood-anxiety disorder and multiple childhood adversities were independently associated with increased risk of adult onset arthritis. Carrying out prospective studies of these relationships entails significant challenges. Since childhood psychosocial stressors may be broad spectrum risk factors for diverse chronic conditions, multiple disease outcomes should be assessed in prospective studies assessing health consequences

  17. Genetics Home Reference: adult-onset leukoencephalopathy with axonal spheroids and pigmented glia

    MedlinePlus

    ... it causes a severe decline in thinking and reasoning abilities (dementia). Over time, motor skills are affected, ... Schmahmann JD. Adult onset leukodystrophy with neuroaxonal spheroids: clinical, neuroimaging and neuropathologic observations. Brain Pathol. 2009 Jan; ...

  18. [Kimura's disease: an unrecognized cause of adult-onset nephrotic syndrome with minimal change disease].

    PubMed

    Shehwaro, N; Langlois, A-L; Gueutin, V; Debchi, L; Charlotte, F; Rouvier, P; Rottembourg, J; Izzedine, H

    2014-02-01

    Kimura's disease (KD) is an angiolymphoid proliferative disorder of soft tissue with eosinophilia, with a predilection for head and neck regions in young Oriental men. Kidney disease is thought to be rare in KD. About a case of adult-onset nephrotic syndrome with minimal change disease, we comment Kimura's disease and its associated kidney damage. Kimura disease should be suspected and included in the diagnosis of adult-onset nephrotic syndrome with minimal change disease.

  19. [Adult onset Still's disease with the initial symptom of pharyngalgia: a case report].

    PubMed

    Zhou, Enhui; Chen, Xiaoping; Zhang, Jingfei

    2015-09-01

    Adult onset Still's disease is a rare inflammatory disease characterized by spiking fevers, arthritis/ arthralgias, typical salmon-colored bumpy rash, pharyngalgia, myalgia and possible involvement of visceral organs. The diagnosis is exclusively based on clinical symptoms, according to the criteria, after the exclusion of well-known infectious, neoplastic, or other autoimmune/autoinflammatory disorders. This report includes one case of adult onset Still's disease with the initial symptom of pharyngalgia. PMID:26647549

  20. Mutations in DNAJC5, Encoding Cysteine-String Protein Alpha, Cause Autosomal-Dominant Adult-Onset Neuronal Ceroid Lipofuscinosis

    PubMed Central

    Nosková, Lenka; Stránecký, Viktor; Hartmannová, Hana; Přistoupilová, Anna; Barešová, Veronika; Ivánek, Robert; Hůlková, Helena; Jahnová, Helena; van der Zee, Julie; Staropoli, John F.; Sims, Katherine B.; Tyynelä, Jaana; Van Broeckhoven, Christine; Nijssen, Peter C.G.; Mole, Sara E.; Elleder, Milan; Kmoch, Stanislav

    2011-01-01

    Autosomal-dominant adult-onset neuronal ceroid lipofuscinosis (ANCL) is characterized by accumulation of autofluorescent storage material in neural tissues and neurodegeneration and has an age of onset in the third decade of life or later. The genetic and molecular basis of the disease has remained unknown for many years. We carried out linkage mapping, gene-expression analysis, exome sequencing, and candidate-gene sequencing in affected individuals from 20 families and/or individuals with simplex cases; we identified in five individuals one of two disease-causing mutations, c.346_348delCTC and c.344T>G, in DNAJC5 encoding cysteine-string protein alpha (CSPα). These mutations—causing a deletion, p.Leu116del, and an amino acid exchange, p.Leu115Arg, respectively—are located within the cysteine-string domain of the protein and affect both palmitoylation-dependent sorting and the amount of CSPα in neuronal cells. The resulting depletion of functional CSPα might cause in parallel the presynaptic dysfunction and the progressive neurodegeneration observed in affected individuals and lysosomal accumulation of misfolded and proteolysis-resistant proteins in the form of characteristic ceroid deposits in neurons. Our work represents an important step in the genetic dissection of a genetically heterogeneous group of ANCLs. It also confirms a neuroprotective role for CSPα in humans and demonstrates the need for detailed investigation of CSPα in the neuronal ceroid lipofuscinoses and other neurodegenerative diseases presenting with neuronal protein aggregation. PMID:21820099

  1. Adult onset Hallervorden-Spatz disease with psychotic symptoms.

    PubMed

    del Valle-López, Pilar; Pérez-García, Rosa; Sanguino-Andrés, Rosa; González-Pablos, Emilio

    2011-01-01

    Hallervorden-Spatz disease is a rare neurological disorder characterized by pyramidal and extrapyramidal manifestations, dysarthria and dementia. Its onset is usually in childhood and most patients have a fatal outcome in few years. A high percentage of cases are hereditary with a recessive autosomal pattern. In the majority of the patients reported, a mutation of the gene that encodes the pantothenate kinase (PANK2) located in the 20p13-p12.3 chromosome that causes iron storage in the basal ganglia of the brain has been found. Its diagnosis is based on clinical symptoms as well as specific MRI imaging findings. The most common psychiatric features are cognitive impairment as well as depressive symptoms. There are few documented cases with psychotic disorders. We present the case of a patient with late onset Hallervorden-Spatz disease and psychotic symptoms that preceded the development of neurological manifestations. The pathophysiology and the treatment of psychotic symptomatology are presented and discussed. Key words: Psicosis, Hallervorden-Spatz, late onset, Basal ganglia. PMID:21769749

  2. Adult onset Hallervorden-Spatz disease with psychotic symptoms.

    PubMed

    del Valle-López, Pilar; Pérez-García, Rosa; Sanguino-Andrés, Rosa; González-Pablos, Emilio

    2011-01-01

    Hallervorden-Spatz disease is a rare neurological disorder characterized by pyramidal and extrapyramidal manifestations, dysarthria and dementia. Its onset is usually in childhood and most patients have a fatal outcome in few years. A high percentage of cases are hereditary with a recessive autosomal pattern. In the majority of the patients reported, a mutation of the gene that encodes the pantothenate kinase (PANK2) located in the 20p13-p12.3 chromosome that causes iron storage in the basal ganglia of the brain has been found. Its diagnosis is based on clinical symptoms as well as specific MRI imaging findings. The most common psychiatric features are cognitive impairment as well as depressive symptoms. There are few documented cases with psychotic disorders. We present the case of a patient with late onset Hallervorden-Spatz disease and psychotic symptoms that preceded the development of neurological manifestations. The pathophysiology and the treatment of psychotic symptomatology are presented and discussed. Key words: Psicosis, Hallervorden-Spatz, late onset, Basal ganglia.

  3. Sandhoff disease mimicking adult-onset bulbospinal neuronopathy.

    PubMed Central

    Thomas, P K; Young, E; King, R H

    1989-01-01

    A 32 year old male is described with an onset of upper limb postural tremor in adolescence followed by muscle cramps. Progressive proximal amyotrophy and weakness in the limbs developed late in the third decade. Examination disclosed, in addition, bilateral facial weakness and mild dysarthria. Enzyme studies revealed hexosaminidase A and B deficiency, indicating a diagnosis of Sandhoff disease. Intra-axonal membranocytoplasmic bodies were present in a rectal biopsy. The presentation, which resembled that of X-linked bulbospinal neuronopathy, widens the clinical spectrum for disorders related to G(M2) gangliosidosis. Images PMID:2795083

  4. Predictors of Relapse in Adult-Onset Nephrotic Minimal Change Disease

    PubMed Central

    Lee, Hajeong; Yoo, Kyung Don; Oh, Yun Kyu; Kim, Dong Ki; Oh, Kook-Hwan; Joo, Kwon Wook; Kim, Yon Su; Ahn, Curie; Han, Jin Suk; Lim, Chun Soo

    2016-01-01

    Abstract Minimal change disease (MCD) is a well-known benign primary glomerulonephritis because of its distinct rare tendency to progress to end-stage renal disease. However, factors associated with relapse in adults are not well known. We aimed to identify predictors of relapse in adult-onset MCD patients. A retrospective cohort of 195 patients with adult-onset primary MCD with nephritic syndrome and disease onset between 1979 and 2013 was followed up for >12 months. The number of relapses was counted and predictors of relapse were analyzed. A total of 195 patients were included. Median age at diagnosis was 38 years (IQR, 23–53 years) and 113 (57.9%) were men. During 81 months (IQR, 44–153 months) of follow-up, 92% of patients achieved remission after initial treatment. However, only 60 (32.8%) did not experience a relapse and 11 patients failed to remit. Among the remaining 124 patients, 65 experienced a relapse once or twice and 59 experienced a relapse more than twice. Younger onset age, increased severity of nephrotic features such as lower serum albumin levels and higher cholesterol level were associated with relapse. Interestingly, the grade of mesangial proliferation was lower in patients who experienced a relapse. Initial combined treatment with corticosteroids (CS) and cyclophosphamide reduced the number of relapses. In addition, patients with shorter treatment duration tended to experience relapse more often. Multivariate analysis showed that younger onset age, combined mesangial proliferation, initial treatment regimen, and treatment duration were independent risk factors for relapse. Progression to end-stage renal disease was developed in only a patient. In conclusion, more than two-thirds of adult-onset nephrotic MCD patients experienced relapse, although their renal progression was rare. Younger onset age, CS without cyclophosphamide treatment, and shorter treatment duration were independent risk factors for relapse in adult-onset MCD patients

  5. Predictors of Relapse in Adult-Onset Nephrotic Minimal Change Disease.

    PubMed

    Lee, Hajeong; Yoo, Kyung Don; Oh, Yun Kyu; Kim, Dong Ki; Oh, Kook-Hwan; Joo, Kwon Wook; Kim, Yon Su; Ahn, Curie; Han, Jin Suk; Lim, Chun Soo

    2016-03-01

    Minimal change disease (MCD) is a well-known benign primary glomerulonephritis because of its distinct rare tendency to progress to end-stage renal disease. However, factors associated with relapse in adults are not well known. We aimed to identify predictors of relapse in adult-onset MCD patients.A retrospective cohort of 195 patients with adult-onset primary MCD with nephritic syndrome and disease onset between 1979 and 2013 was followed up for >12 months. The number of relapses was counted and predictors of relapse were analyzed.A total of 195 patients were included. Median age at diagnosis was 38 years (IQR, 23-53 years) and 113 (57.9%) were men. During 81 months (IQR, 44-153 months) of follow-up, 92% of patients achieved remission after initial treatment. However, only 60 (32.8%) did not experience a relapse and 11 patients failed to remit. Among the remaining 124 patients, 65 experienced a relapse once or twice and 59 experienced a relapse more than twice. Younger onset age, increased severity of nephrotic features such as lower serum albumin levels and higher cholesterol level were associated with relapse. Interestingly, the grade of mesangial proliferation was lower in patients who experienced a relapse. Initial combined treatment with corticosteroids (CS) and cyclophosphamide reduced the number of relapses. In addition, patients with shorter treatment duration tended to experience relapse more often. Multivariate analysis showed that younger onset age, combined mesangial proliferation, initial treatment regimen, and treatment duration were independent risk factors for relapse. Progression to end-stage renal disease was developed in only a patient.In conclusion, more than two-thirds of adult-onset nephrotic MCD patients experienced relapse, although their renal progression was rare. Younger onset age, CS without cyclophosphamide treatment, and shorter treatment duration were independent risk factors for relapse in adult-onset MCD patients.

  6. Childhood- and adult-onset lupus: an update of similarities and differences.

    PubMed

    Papadimitraki, Eva D; Isenberg, David A

    2009-07-01

    Systemic lupus erythematosus (SLE) is a multifactorial autoimmune rheumatic disease. Although its highest prevalence is among women of childbearing age, the disease is not confined within this population. A total of 15-20% of cases of SLE are diagnosed in children younger than 16 years (childhood-onset lupus). Although there have been few studies directly comparing childhood- to adult-onset lupus, there is substantial evidence to suggest that pediatric lupus patients display some differences in their disease profile compared with adult-onset populations. Overall, an increased male-to-female ratio, a higher prevalence of nephritis and CNS involvement necessitating a more sustained need for steroids and immnosuppressive drugs, and a higher prevalence of progression to end-stage renal disease are distinguishing features of childhood-onset lupus. In contrast, a higher prevalence of pulmonary involvement, arthritis and discoid lupus are reported in adult-onset SLE patients. Furthermore, childhood-onset lupus patients may experience a serious negative impact on their psychosocial and physical development, issues that pose extra challenges to healthcare providers. Growth delay, osteoporosis, the psychological effect of steroid-induced alterations of the physical image, and often poor treatment compliance are the issues that need to be addressed in pediatric lupus populations. In this review, we compare the epidemiological, clinical and laboratory features, and treatment options of childhood- and adult-onset lupus, and comment on the applicability of the instruments that measure activity, severity and cumulative disease damage in childhood-onset disease. In addition, we highlight special issues of concern for pediatric lupus patients, discussing the significance in the transition from pediatric to adult rheumatology care.

  7. Niemann-Pick type C: focus on the adolescent/adult onset form.

    PubMed

    Di Lazzaro, Vincenzo; Marano, Massimo; Florio, Lucia; De Santis, Stefano

    2016-11-01

    Niemann-Pick disease type C (NP-C) is an inherited sphingolipidosis characterized by progressive neurological deterioration and early mortality. The symptomatology and disease progression of NP-C are markedly affected by the age at onset of neurological manifestations, and categorization into early-infantile, late-infantile, juvenile, adolescent/adult neurological onset forms can aid evaluation of disease course and responses to therapy. Here, we review current information on the detection, diagnosis, monitoring and treatment of NP-C, with a focus on the adolescent/adult-onset form. A recent analysis indicated that the combined incidence of NP-C related to NPC1 gene mutations (NPC1) and NP-C related to NPC2 gene mutations (NPC2) is approximately 1 case in every 89 000 live births. In particular, late-onset phenotypes might well provide a greater contribution to the overall incidence than has previously been reported. Some neuropathological features in NP-C are held in common with other advanced age-onset diseases such as Alzheimer's disease. Visceral symptoms such as splenomegaly are frequently asymptomatic in patients with adolescent/adult-onset NP-C, and are only occasionally detected during routine ultrasound assessments. In contrast, most patients with adolescent/adult-onset exhibit some degree of slowly progressive, non-disease-specific movement disorders (e.g. cerebellar ataxia), and/or more pathognomonic neurological signs such as vertical supranuclear gaze palsy. An increasing number of adolescent/adult-onset cases have been reported following initial recognition of cognitive impairment and/or psychiatric signs. The recent development and implementation of new clinical screening tools (e.g. the NP-C suspicion index) and biomarkers (e.g. plasma oxysterols) should help identify patients who warrant further investigation and possible treatment. PMID:26998855

  8. Niemann-Pick type C: focus on the adolescent/adult onset form.

    PubMed

    Di Lazzaro, Vincenzo; Marano, Massimo; Florio, Lucia; De Santis, Stefano

    2016-11-01

    Niemann-Pick disease type C (NP-C) is an inherited sphingolipidosis characterized by progressive neurological deterioration and early mortality. The symptomatology and disease progression of NP-C are markedly affected by the age at onset of neurological manifestations, and categorization into early-infantile, late-infantile, juvenile, adolescent/adult neurological onset forms can aid evaluation of disease course and responses to therapy. Here, we review current information on the detection, diagnosis, monitoring and treatment of NP-C, with a focus on the adolescent/adult-onset form. A recent analysis indicated that the combined incidence of NP-C related to NPC1 gene mutations (NPC1) and NP-C related to NPC2 gene mutations (NPC2) is approximately 1 case in every 89 000 live births. In particular, late-onset phenotypes might well provide a greater contribution to the overall incidence than has previously been reported. Some neuropathological features in NP-C are held in common with other advanced age-onset diseases such as Alzheimer's disease. Visceral symptoms such as splenomegaly are frequently asymptomatic in patients with adolescent/adult-onset NP-C, and are only occasionally detected during routine ultrasound assessments. In contrast, most patients with adolescent/adult-onset exhibit some degree of slowly progressive, non-disease-specific movement disorders (e.g. cerebellar ataxia), and/or more pathognomonic neurological signs such as vertical supranuclear gaze palsy. An increasing number of adolescent/adult-onset cases have been reported following initial recognition of cognitive impairment and/or psychiatric signs. The recent development and implementation of new clinical screening tools (e.g. the NP-C suspicion index) and biomarkers (e.g. plasma oxysterols) should help identify patients who warrant further investigation and possible treatment.

  9. Does age at onset have clinical significance in older adults with bipolar disorder?

    PubMed Central

    Chu, David; Gildengers, Ariel G.; Houck, Patricia R.; Anderson, Stewart J.; Mulsant, Benoit H.; Reynolds, Charles F.; Kupfer, David J.

    2011-01-01

    Objective While age at onset may be useful in explaining some of the heterogeneity of bipolar disorder (BD) in large, mixed age groups, investigations to date have found few meaningful clinical differences between early versus late age at onset in older adults with BD. Methods Data were collected from sixty-one subjects aged 60 years and older, mean (SD) age 67.6 (7.0), with BD I (75%) and II (25%). Subjects were grouped by early (<40 years; n=43) versus late (≥40 years; n=18) age at onset. Early versus late onset groups were compared on psychiatric comorbidity, medical burden, and percentage of days well during study participation. Results Except for family history of major psychiatric illnesses, there were no differences between the groups on demographic or clinical variables. Patients with early and late onset experienced similar percentages of days well; however, those with early onset had slightly more percentage of days depressed than those with late onset (22% versus 13%) Conclusion Distinguishing older adults with BD by early or late age at onset has limited clinical usefulness. PMID:20082348

  10. Mutations in CIZ1 cause adult-onset primary cervical dystonia

    PubMed Central

    Xiao, Jianfeng; Uitti, Ryan J.; Zhao, Yu; Vemula, Satya R.; Perlmutter, Joel S.; Wszolek, Zbigniew K.; Maraganore, Demetrius M.; Auburger, Georg; Leube, Barbara; Lehnhoff, Katja; LeDoux, Mark S.

    2012-01-01

    Objective Primary dystonia is usually of adult onset, can be familial, and frequently involves the cervical musculature. Our goal was to identify the causal mutation in a family with adult-onset, primary cervical dystonia. Methods Linkage and haplotype analyses were combined with solution-based whole-exome capture and massively parallel sequencing in a large Caucasian pedigree with adult-onset, primary cervical dystonia to identify a cosegregating mutation. High-throughput screening and Sanger sequencing were completed in 308 Caucasians with familial or sporadic adult-onset cervical dystonia and matching controls for sequence variants in this mutant gene. Results Exome sequencing led to the identification of an exonic splicing enhancer mutation in Exon 7 of CIZ1 (c.790A>G, p.S264G) which encodes CIZ1, Cip1-interacting zinc finger protein 1. CIZ1 is a p21Cip1/Waf1-interacting zinc finger protein expressed in brain and involved in DNA synthesis and cell-cycle control. Using a minigene assay, we showed that c.790A>G altered CIZ1 splicing patterns. The p.S264G mutation also altered the nuclear localization of CIZ1. Screening in subjects with adult-onset cervical dystonia identified two additional CIZ1 missense mutations (p.P47S and p.R672M). Interpretation Mutations in CIZ1 may cause adult-onset, primary cervical dystonia, possibly by precipitating neurodevelopmental abnormalities that manifest in adults and/or G1/S cell-cycle dysregulation in the mature central nervous system. PMID:22447717

  11. Adult-Onset Esophageal Crohn’s Disease

    PubMed Central

    Kasarala, George; Durrett, Sam

    2016-01-01

    Crohn’s disease (CD) is an idiopathic inflammatory bowel disease that can involve any part of the gastrointestinal tract. Esophageal involvement is rarely seen in adults, especially at the initial diagnosis of CD. Esophageal symptoms as primary manifestations of the disease are extremely rare. We report a case of a CD with esophageal involvement at the time of her initial diagnosis of CD. PMID:27761477

  12. Huntington Disease: A Case Study of Early Onset Presenting as Depression

    ERIC Educational Resources Information Center

    Duesterhus, Pia; Schimmelmann, Benno Graf; Wittkugel, Oliver; Schulte-Markwort, Michael

    2004-01-01

    Huntington disease is a dominantly inherited, neurodegenerative disease characterized by choreiform movement disturbances and dementia, usually with adult onset. The rare juvenile-onset Huntington disease differs from the adult phenotype. A case presenting twice, at age 10 with all the signs of a major depression and age 14 with mutism and…

  13. Recurrent adult onset Henoch-Schonlein Purpura: a case report.

    PubMed

    Gaskill, Neil; Guido, Bruce; Mago, Cynthia

    2016-01-01

    Henoch-Schonlein purpura is an immunoglobulin A (IgA)-immune complex mediated leukocytoclastic vasculitis that classically manifests with palpable purpura, abdominal pain, arthritis, and hematuria or proteinuria. The condition is much more predominant in children (90% of cases) and commonly follows an upper respiratory infection. We present a case of recurrent Henoch-Schonlein purpura (HSP) complicated by nephritis in an adult female initially categorized as IgA nephropathy (IgAN). We review the pathophysiologic basis of HSP nephritis as the variant of HSP accompanied by renal involvement and its pathogenetic commonality with IgA nephropathy. PMID:27617937

  14. Adult-onset phenylketonuria with rapidly progressive dementia and parkinsonism.

    PubMed

    Tufekcioglu, Zeynep; Cakar, Arman; Bilgic, Basar; Hanagasi, Hasmet; Gurvit, Hakan; Emre, Murat

    2016-06-01

    Phenylketonuria (PKU) is an autosomal recessive metabolic disorder due to mutations in the phenylalanine hydroxylase (PAH) gene, which converts phenylalanine (PHE) to tyrosine. Although it is principally a childhood disorder, in rare cases, the first signs of PKU may develop in late adulthood resembling common neurological diseases. Here we report a 59-year-old, previously normal functioning man who was admitted with blurred vision, cognitive problems, and gait difficulty that began 8 months before. He had brisk reflexes and left side dominant parkinsonism. His Mini-Mental State Examination (MMSE) score was 25/30, and neuropsychological evaluation revealed a dysexecutive syndrome with simultanagnosia and constructional apraxia. His Clinical Dementia Rating score (CDR) was 1. Cranial MRI revealed bilateral diffuse hyperintense lesions in parietal and occipital white matter in T2, fluid-attenuated inversion recovery, and diffusion weighted images. Diagnostic workup for rapidly progressive dementias was all normal except PHE level which was found to be highly elevated (1075 μmol/L, normal 39-240 μmol/L) with normal tyrosine level (61.20 μmol/L, normal 35-100 μmol/L). Three months after PHE-restricted diet, his cognitive impairment and signs of parkinsonism significantly improved, with MRI scan unchanged. This case demonstrates that late-onset PKU is a rare, treatable cause of rapidly progressive dementia and parkinsonism with certain constellations such as consanguinity and white matter abnormalities (WMAs) in imaging. PMID:26962957

  15. Adult-Onset Still's Disease and Cardiac Tamponade: A Rare Association

    PubMed Central

    Silva, Doroteia; de Jesus Silva, Maria; André, Rui; Varela, Manuel Gato; Diogo, António Nunes

    2015-01-01

    Adult-onset Still's disease is a rare disorder with potentially severe clinical features, including cardiac involvement. This systemic inflammatory disease of unknown origin should be considered in the differential diagnosis of pericarditis, with or without pericardial effusion. Cardiac tamponade is a very rare sequela that requires an invasive approach, such as percutaneous or surgical pericardial drainage, in addition to the usual conservative therapy. The authors describe a case of adult-onset Still's disease rendered more difficult by pericarditis and cardiac tamponade, and they briefly review the literature on this entity. PMID:26175648

  16. The distinction between juvenile and adult-onset primary open-angle glaucoma

    SciTech Connect

    Wiggs, J.L.; Haines, J.L.; Damji, K.F.

    1996-01-01

    Because of the significant differences between the juvenile and adult forms of open-angle glaucoma, especially with regard to inheritance, prevalence, severity, and age of onset, we read with interest the recent publication by Morissette et al., describing a pedigree with a phenotype that overlaps the distinctive features of juvenile-onset open-angle glaucoma (JOAG) and adult-onset primary open-angle glaucoma (usually abbreviated as POAG or COAG). These authors conclude that a gene mapped to human chromosome 1q21-q31 (GLC1A) can be responsible for both juvenile and adult forms of open-angle glaucoma. The implications of such a result could be extremely important, in light of the high prevalence of the adult form of the disease. However, while the data presented in this report suggest that variable expressivity of the GLC1A gene may lead to a broader range of onset for this form of juvenile glaucoma, these data do not identify the GLC1A gene as an important cause of POAG. To prevent misleading interpretations of this and similar studies, we wish to clarify the distinction between the juvenile and adult forms of open-angle glaucoma. 8 refs.

  17. The need for improved detection and management of adult-onset hearing loss in australia.

    PubMed

    McMahon, Catherine M; Gopinath, Bamini; Schneider, Julie; Reath, Jennifer; Hickson, Louise; Leeder, Stephen R; Mitchell, Paul; Cowan, Robert

    2013-01-01

    Adult-onset hearing loss is insidious and typically diagnosed and managed several years after onset. Often, this is after the loss having led to multiple negative consequences including effects on employment, depressive symptoms, and increased risk of mortality. In contrast, the use of hearing aids is associated with reduced depression, longer life expectancy, and retention in the workplace. Despite this, several studies indicate high levels of unmet need for hearing health services in older adults and poor use of prescribed hearing aids, often leading to their abandonment. In Australia, the largest component of financial cost of hearing loss (excluding the loss of well-being) is due to lost workplace productivity. Nonetheless, the Australian public health system does not have an effective and sustainable hearing screening strategy to tackle the problem of poor detection of adult-onset hearing loss. Given the increasing prevalence and disease burden of hearing impairment in adults, two key areas are not adequately met in the Australian healthcare system: (1) early identification of persons with chronic hearing impairment; (2) appropriate and targeted referral of these patients to hearing health service providers. This paper reviews the current literature, including population-based data from the Blue Mountains Hearing Study, and suggests different models for early detection of adult-onset hearing loss. PMID:23710184

  18. Psychiatric disorders and suicidal behavior in neurotypical young adults with childhood-onset epilepsy

    PubMed Central

    Baldin, Elisa; Hesdorffer, Dale C; Caplan, Rochelle; Berg, Anne T.

    2015-01-01

    OBJECTIVES We examined the association between lifetime, current history of psychiatric disorders, suicidal thoughts and behaviors with childhood-onset epilepsies in a community-based cohort of young adults. METHODS Cases were neurotypical (normal neurological, cognitive, and imaging exams and no evidence of a brain insult responsible for the epilepsy) young adults with childhood-onset epilepsy followed since the onset of their epilepsy approximately 15 years earlier and recruited as part of a community-based study. They were compared to two different control groups, siblings and external controls from the National Comorbidity Survey-Replication (NCS-R). The Diagnostic Interview Survey assessed lifetime and current DSM-IV-TR diagnoses of mood disorders and anxiety disorders. Suicidal thoughts and suicide attempt were assessed using the Diagnostic Interview Survey for Children-IV and the Diagnostic Interview Survey. RESULTS Two hundred fifty-seven cases and 134 sibling controls participated in the DIS portion of the young adult assessment. Comparing cases both to their sibling controls and to the controls drawn from the NCS-R, we did not find any evidence to suggest a higher prevalence of lifetime and current mood or anxiety disorders, suicidal thoughts and suicide attempt in young adults with childhood-onset epilepsies. SIGNIFICANCE Our findings, from a community-based sample of neurotypical young adults, do not suggest a substantial or lasting association between childhood epilepsy and psychiatric disorders and suicidal behavior. PMID:26387857

  19. Adult Onset of Xanthelasmoid Mastocytosis: Report of a Rare Entity.

    PubMed

    Nabavi, Nafiseh Sadat; Nejad, Masumeh Hosseini; Feli, Shahab; Bakhshoodeh, Behnoosh; Layegh, Pouran

    2016-01-01

    Xanthelasmoid or pseudoxanthomatous mastocytosis is an extremely rare variant of diffuse cutaneous mastocytosis. Herein, we describe an adult male with cutaneous mastocytosis showing multiple widespread yellowish ovoid papules like eruptive xanthoma. A 60-year-old male visited our outpatient clinic with a 1-year history of generalized yellowish, ovoid, and skin color papular eruption located on the trunk, groin, extremities, with the modest pruritus. Vital signs were stable, and Darier's sign was negative. No other subjective and objective signs were detected during the examination. No abnormality was detected in his diagnostic laboratory tests. Skin biopsy was taken, and histopathologic examination revealed proliferation of mast cells with ovoid and spindle nuclei with distinct cytoplasm borders around the capillaries, which was compatible with mastocytosis. Antihistamine was prescribed for pruritus control which was successful, but eruptions were persistent, and even 1-year phototherapy was not useful. PMID:27512209

  20. Substance use among ADHD adults: implications of late onset and subthreshold diagnoses.

    PubMed

    Faraone, Stephen V; Wilens, Timothy E; Petty, Carter; Antshel, Kevin; Spencer, Thomas; Biederman, Joseph

    2007-01-01

    Diagnosing ADHD in adults is difficult when the diagnostician cannot establish an onset prior to the DSM-IV criterion of age seven or if the number of symptoms does not achieve the DSM threshold for diagnosis. These diagnostic issues are an even larger concern for clinicians faced with adults with substance use disorders (SUD). The present study compared four groups of adults: full ADHD subjects who met all DSM-IV criteria for childhood onset ADHD, late onset ADHD subjects who met all criteria except the age at onset criterion, subthreshold ADHD subjects who did not meet full symptom criteria, and non-ADHD subjects who did not meet any of the above criteria. Diagnoses were by the Structured Clinical Interview for DSM-IV, and the Drug Use Severity Index (DUSI) was used for self-report of substance use. Cigarette and marijuana use was significantly greater in all ADHD groups relative to non-ADHD controls. Although usage rates of other drugs failed to reach significance, the ADHD groups were more likely to have used each drug (except alcohol) compared with the non-ADHD group. The late onset and full ADHD groups were more likely to have endorsed ever having a problem due to use of cigarettes, alcohol, or marijuana and reported more trouble resisting use of drugs or alcohol. The full ADHD group was more likely than the other groups to have reported "getting high" as their reason for using their preferred drug. Adults with ADHD have elevated rates of substance use and related impairment. Data about late onset ADHD provides further support for the idea that the DSM-IV age at onset criterion is too stringent. In contrast, subthreshold ADHD seems to be a milder form of the disorder, or perhaps a heterogeneous group of true ADHD cases and false positives.

  1. Management of adults with paediatric-onset chronic liver disease: strategic issues for transition care.

    PubMed

    Vajro, Pietro; Ferrante, Lorenza; Lenta, Selvaggia; Mandato, Claudia; Persico, Marcello

    2014-04-01

    Advances in the management of children with chronic liver disease have enabled many to survive into adulthood with or without their native livers, so that the most common of these conditions are becoming increasingly common in adult hepatology practice. Because the aetiologies of chronic liver disease in children may vary significantly from those in adulthood, adults with paediatric-onset chronic liver disease may often present with clinical manifestations unfamiliar to their adulthood physician. Transition of medical care to adult practice requires that the adulthood medical staff (primary physicians and subspecialists) have a comprehensive knowledge of childhood liver disease and their implications, and of the differences in caring for these patients. Pending still unavailable Scientific Society guidelines, this article examines causes, presentation modes, evaluation, management, and complications of the main paediatric-onset chronic liver diseases, and discusses key issues to aid in planning a program of transition from paediatric to adult patients.

  2. What can pluripotent stem cells teach us about neurodegenerative diseases?

    PubMed

    Wichterle, Hynek; Przedborski, Serge

    2010-07-01

    Neurodegenerative diseases represent a growing public health challenge. Current medications treat symptoms, but none halt or retard neurodegeneration. The recent advent of pluripotent cell biology has opened new avenues for neurodegenerative disease research. The greatest potential for induced pluripotent cells derived from affected individuals is likely to be their utility for modeling and understanding the mechanisms underlying neurodegenerative processes, and for searching for new treatments, including cell replacement therapies. However, much work remains to be done before pluripotent cells can be used for preclinical and clinical applications. Here we discuss the challenges of generating specific neural cell subtypes from pluripotent stem cells, the use of pluripotent stem cells to model both cell-autonomous and non-cell-autonomous mechanisms of neurodegeneration, whether adult-onset neurodegeneration can be emulated in short-term cultures and the hurdles of cell replacement therapy. Progress in these four areas will substantially accelerate effective application of pluripotent stem cells.

  3. Adult versus adolescent onset of smoking: how are mood disorders and other risk factors involved?

    PubMed Central

    Ajdacic-Gross, Vladeta; Landolt, Karin; Angst, Jules; Gamma, Alex; Merikangas, Kathleen R.; Gutzwiller, Felix; Rössler, Wulf

    2010-01-01

    Aims To examine the strength of association between smoking and mood disorders and the association between smoking and its traditional risk factors, comparing those who started smoking in adolescence with those who started smoking in early adulthood. Design and participants The analyses relied on prospective data from the Zurich Study. This longitudinal community study started in 1979 with a stratified sample of 591 participants aged 20/21 years, weighted towards those with mental disorders. Follow-up interviews were conducted at ages 23, 28, 30, 35 and 41. Measurements In this analysis the adult versus adolescent onset of smoking was regressed on the cumulative prevalence of mood disorders, personality characteristics measured by the Freiburg Personality Inventory, common risk factors such as parental smoking, conduct and school problems, troubles with the family and basic sociodemographic variables (sex, education). Findings In the Zurich Study cohort we found that 61.6% were former or current smokers, of whom 87% started smoking before the age of 20 and 13% after the age of 20. Adolescent onset of smoking was associated strongly with later major depression, dysthymia or bipolar disorders and, furthermore, with parental smoking, extroverted personality and discipline problems and rebelliousness in youth. However, only depression and dysthymia were associated with adult onset smoking and other risk factors associated with smoking were not so associated in this group. Conclusions Correlates of smoking onset in adolescence are mainly not applicable to the onset of smoking in young adulthood. Smoking onset beyond adolescence is an open research issue. PMID:19624327

  4. Early-Onset Psychoses: Comparison of Clinical Features and Adult Outcome in 3 Diagnostic Groups

    ERIC Educational Resources Information Center

    Ledda, Maria Giuseppina; Fratta, Anna Lisa; Pintor, Manuela; Zuddas, Alessandro; Cianchetti, Carlo

    2009-01-01

    A comparison of clinical features and adult outcome in adolescents with three types of psychotic disorders: schizophrenic (SPh), schizoaffective (SA) and bipolar with psychotic features (BPP). Subjects (n = 41) were finally diagnosed (DSM-IV criteria) with SPh (n = 17), SA (n = 11) or BPP (n = 13). Clinical evaluation took place at onset and at a…

  5. Physical Therapists' Perceptions of Providing Services to Adults with Childhood-Onset Neuromotor Disabilities

    ERIC Educational Resources Information Center

    Compton-Griffith, Kelsi N.; Cicirello, Nancy A.; Turner, Anne

    2011-01-01

    Adults with childhood-onset neuromotor disabilities face problems accessing health care services. There are often challenges finding primary care providers or specialized providers, such as physical therapists, who are knowledgeable about neuromotor disabilities. The purpose of this study was to determine the perceptions of physical therapists…

  6. Adult-Onset Antisocial Behavior Trajectories: Associations with Adolescent Family Processes and Emerging Adulthood Functioning

    ERIC Educational Resources Information Center

    Mata, Andrea D.; van Dulmen, Manfred H. M.

    2012-01-01

    Guided by conceptual and empirical work on emerging adulthood, this study investigated the role of closeness to mother and father and behavioral autonomy during adolescence on the development of adult-onset antisocial behavior. Using data from the National Longitudinal Study of Adolescent Health (Add Health), we identified four aggressive…

  7. Epidemiology and outcome of articular complications in adult onset Still's disease.

    PubMed

    Mahfoudhi, Madiha; Shimi, Rafik; Turki, Sami; Kheder, Adel

    2015-01-01

    The adult onset Still's disease is a rare inflammatory pathology of unknown pathogeny. The clinical features are variable. The diagnosis is difficult since exclusion of infectious, systemic and tumoral pathologies should be done. The articular complications are frequent and can be revelatory of this pathology. The articular prognosis depends on the diagnosis delay and the treatment efficiency. Our study aims to analyze different aspects of articular manifestations complicating adult onset Still disease to define epidemiological, clinical and evolving characteristics of these complications. It was a cross-sectional study concerning 18 cases of adult onset Still disease diagnosed from 1990 to 2014 in the internal medicine A department of Charles Nicolle Hospital in Tunis, meeting Yamaguchi criteria. We identified clinical, radiological, evolving and therapeutic profile of the articular manifestations occurred in these patients. There were 11 women and 7 men. The average age was 27 years. The arthralgias were reported in all cases; while, the arthritis interested thirteen patients. A hand deformation was found in four patients. A wrist ankylosis was noted in one case and a flexion elbow in one patient. The Standard articular radiographs were normal in ten cases. The treatment associated essentially non-steroidal anti-inflammatory and/or corticosteroids and/or methotrexate. Concerning the evolving profile, the monocyclic form was present in 25% of the cases, the intermittent form in 40% and the chronic articular form in 35% of our patients. The adult onset Still's disease is rare and heterogeneous. The articular disturbances are frequent and have various outcomes.

  8. Childhood-Onset Disease Predicts Mortality in an Adult Cohort of Patients with Systemic Lupus Erythematosus

    PubMed Central

    Hersh, Aimee O.; Trupin, Laura; Yazdany, Jinoos; Panopalis, Peter; Julian, Laura; Katz, Patricia; Criswell, Lindsey A.; Yelin, Edward

    2013-01-01

    Objective To examine childhood-onset disease as a predictor of mortality in a cohort of adult patients with systemic lupus erythematosus (SLE). Methods Data were derived from the University of California Lupus Outcomes Study, a longitudinal cohort of 957 adult subjects with SLE that includes 98 subjects with childhood-onset SLE. Baseline and follow-up data were obtained via telephone interviews conducted between 2002-2007. The number of deaths during 5 years of follow-up was determined and standardized mortality ratios (SMRs) for the cohort, and across age groups, were calculated. Kaplan-Meier life table analysis was used to compare mortality rates between childhood (defined as SLE diagnosis <18 years) and adult-onset SLE. Multivariate Cox proportional hazard models were used to determine predictors of mortality. Results During the median follow-up period of 48 months, 72 deaths (7.5% of subjects) occurred, including 9 (12.5%) among those with childhood-onset SLE. The overall SMR was 2.5 (CI 2.0-3.2). In Kaplan-Meier survival analysis, after adjusting for age, childhood-onset subjects were at increased risk for mortality throughout the follow-up period (p<0.0001). In a multivariate model adjusting for age, disease duration and other covariates, childhood-onset SLE was independently associated with an increased mortality risk (hazard ratio [HR]: 3.1; 95% confidence interval [CI]: 1.3-7.3), as was low socioeconomic status measured by education (HR: 1.9; 95% CI 1.1-3.2) and end stage renal disease (HR: 2.1; 95% CI 1.1-4.0). Conclusion Childhood-onset SLE was a strong predictor of mortality in this cohort. Interventions are needed to prevent early mortality in this population. PMID:20235215

  9. A multi-hit endocrine model of intrinsic adult-onset asthma.

    PubMed

    Atwood, Craig S; Bowen, Richard L

    2008-04-01

    Epidemiological studies indicate that adult-onset asthma is initiated by stress (anxiety and depression), obesity and menopause. Ironically, despite our understanding of the various stressors that promote chronic adult-onset asthma, most of which are known to elevate cortisol production via the hypothalamic-pituitary-adrenal (HPA) axis, inhaled and systemic corticosteroids are the mainstay for the treatment of chronic asthma. This implicates other endocrine or cellular changes independent of cortisol synthesis in non-allergic adult-onset asthma. The mechanism by which corticosteroids are thought to modulate bronchial tone in relieving asthma is via corticosteroid-responsive genes that increase PGE(2) and cAMP production which promote muscle relaxation. Therefore, any physiological condition that suppresses intracellular PGE(2) and cAMP production would counter cortisol-induced muscle relaxation and potentially trigger non-allergic adult-onset asthma. Stress, obesity and menopause act on three interrelated endocrine pathways, the serotonergic, leptinergic and hypothalamic pathways, all of which operate through receptors to modulate cAMP and Ca(2+) metabolism in smooth muscle cells (SMCs). We propose that the level of SMC cAMP, as determined by overall signaling through corticosteroid receptors, leptin receptors and the GPCRs of the HPG and serotonergic pathways, will regulate bronchial tone (i.e. the 'Multi-Hit Endocrine Model of Adult-Onset Asthma'). Thus, decreases in HPG (menopause) and serotonergic (depression) signaling and increases in leptinergic (obesity) signaling relative to HPA signaling would decrease cellular SMC cAMP and promote muscle contraction. This model can explain the discrepant epidemiological data associating stress, obesity, depression and menopause with adult-onset asthma and is supported by basic and clinical data. Treatment of depressed or menopausal asthmatics with selective serotonin reuptake inhibitors or hormone replacement therapy

  10. The Evidence-Based Approach to Adult-Onset Idiopathic Nephrotic Syndrome

    PubMed Central

    Canetta, Pietro A. A.; Radhakrishnan, Jai

    2015-01-01

    Adult-onset nephrotic syndrome (NS) differs from its pediatric counterpart in several important ways. Most importantly, NS in adults is more etiologically heterogeneous compared to children, and thus treatment approaches rely heavily on the histological diagnosis provided by renal biopsy. The evidence-based approach to treatment of adult NS has been critically examined by the Kidney Disease Improving Global Outcomes (KDIGO) guidelines in glomerulonephritis, published in 2012. Here, we examine the strengths and limits of those guidelines and review recent work that expands the evidence-based approach. PMID:26442238

  11. The effect of time-dependent macromolecular crowding on the kinetics of protein aggregation: a simple model for the onset of age-related neurodegenerative disease

    NASA Astrophysics Data System (ADS)

    Minton, Allen

    2014-08-01

    A linear increase in the concentration of "inert" macromolecules with time is incorporated into simple excluded volume models for protein condensation or fibrillation. Such models predict a long latent period during which no significant amount of protein aggregates, followed by a steep increase in the total amount of aggregate. The elapsed time at which these models predict half-conversion of model protein to aggregate varies by less than a factor of two when the intrinsic rate constant for condensation or fibril growth of the protein is varied over many orders of magnitude. It is suggested that this concept can explain why the symptoms of neurodegenerative diseases associated with the aggregation of very different proteins and peptides appear at approximately the same advanced age in humans.

  12. Adult-onset Nemaline Myopathy Coexisting With Myasthenia Gravis: A Case Report.

    PubMed

    Cao, Lingling; Wang, Yanling; Liu, Xiaofeng; Hu, Yanxia; Li, Nianchun; Qiu, Guoping; Luo, Yun; Li, Weidong

    2016-01-01

    Myasthenia gravis (MG) is an autoimmune neuromuscular junction disorder which is characterized by fluctuating muscle fatigue. However, the association of MG with nemaline myopathy is rarely reported. Here we report a case of MG coexisting with adult-onset nemaline myopathy. A 55-year-old man endured fluctuating muscle weakness with positive acetylcholine receptor and titin antibodies. After the patient was administrated cholinergic drugs and immunosuppression, the muscle weakness of the patient had mildly been alleviated. Electromyography showed a progressive decrement in the amplitude of muscle action potential at low frequency. Muscle biopsy showed numerous nemalines in the muscle fibers. This is the first reported case of nemalines present in the muscle fibers of adult patient with MG. The pathogenesis of nemaline may be related to titin antibody in adult-onset nemaline myopathy with MG. PMID:26825889

  13. Mapping a gene for adult-onset primary open-angle glaucoma to chromosome 3q

    SciTech Connect

    Wirtz, M.K.; Samples, J.R.; Kramer, P.L.

    1997-02-01

    Glaucoma is the third-leading cause of blindness in the world, affecting >13.5 million people. Adult-on-set primary open-angle glaucoma (POAG) is the most common form of glaucoma in the United States. We present a family in which adult-onset POAG is inherited as an autosomal dominant trait. Twelve affected family members were identified from 44 at-risk individuals. The disease-causing gene was mapped to chromosome 3q21-24, with analysis of recombinant haplotypes suggesting a total inclusion region of 11.1 cM between markers D3S3637 and D3S1744. This is the first report of mapping of an adult-onset POAG gene to chromosome 3q, gene symbol GLC1C. 57 refs., 3 figs., 3 tabs.

  14. Epidemiology of adult-onset hydrocephalus: institutional experience with 2001 patients.

    PubMed

    Bir, Shyamal C; Patra, Devi Prasad; Maiti, Tanmoy K; Sun, Hai; Guthikonda, Bharat; Notarianni, Christina; Nanda, Anil

    2016-09-01

    OBJECTIVE Adult-onset hydrocephalus is not commonly discussed in the literature, especially regarding its demographic distribution. In contrast to pediatric hydrocephalus, which is related to a primary CSF pathway defect, its development in adults is often secondary to other pathologies. In this study, the authors investigated the epidemiology of adult-onset hydrocephalus as it pertains to different etiologies and in reference to age, sex, and race distributions. METHODS The authors retrospectively reviewed the clinical notes of 2001 patients with adult-onset hydrocephalus who presented to Louisiana State University Health Sciences Center within a 25-year span. Significant differences between the groups were analyzed by a chi-square test; p < 0.05 was considered significant. RESULTS The overall mean (± SEM) incidence of adult hydrocephalus in this population was 77 ± 30 per year, with a significant increase in incidence in the past decade (55 ± 3 [1990-2003] vs 102 ± 6 [2004-2015]; p < 0.0001). Hydrocephalus in a majority of the patients had a vascular etiology (45.5%) or was a result of a tumor (30.2%). The incidence of hydrocephalus in different age groups varied according to various pathologies. The incidence was significantly higher in males with normal-pressure hydrocephalus (p = 0.03) or head injury (p = 0.01) and higher in females with pseudotumor cerebri (p < 0.0001). In addition, the overall incidence of hydrocephalus was significantly higher in Caucasian patients (p = 0.0002) than in those of any other race. CONCLUSIONS Knowledge of the demographic variations in adult-onset hydrocephalus is helpful in achieving better risk stratification and better managing the disease in patients. For general applicability, these results should be validated in a large-scale meta-analysis based on a national population database.

  15. Epidemiology of adult-onset hydrocephalus: institutional experience with 2001 patients.

    PubMed

    Bir, Shyamal C; Patra, Devi Prasad; Maiti, Tanmoy K; Sun, Hai; Guthikonda, Bharat; Notarianni, Christina; Nanda, Anil

    2016-09-01

    OBJECTIVE Adult-onset hydrocephalus is not commonly discussed in the literature, especially regarding its demographic distribution. In contrast to pediatric hydrocephalus, which is related to a primary CSF pathway defect, its development in adults is often secondary to other pathologies. In this study, the authors investigated the epidemiology of adult-onset hydrocephalus as it pertains to different etiologies and in reference to age, sex, and race distributions. METHODS The authors retrospectively reviewed the clinical notes of 2001 patients with adult-onset hydrocephalus who presented to Louisiana State University Health Sciences Center within a 25-year span. Significant differences between the groups were analyzed by a chi-square test; p < 0.05 was considered significant. RESULTS The overall mean (± SEM) incidence of adult hydrocephalus in this population was 77 ± 30 per year, with a significant increase in incidence in the past decade (55 ± 3 [1990-2003] vs 102 ± 6 [2004-2015]; p < 0.0001). Hydrocephalus in a majority of the patients had a vascular etiology (45.5%) or was a result of a tumor (30.2%). The incidence of hydrocephalus in different age groups varied according to various pathologies. The incidence was significantly higher in males with normal-pressure hydrocephalus (p = 0.03) or head injury (p = 0.01) and higher in females with pseudotumor cerebri (p < 0.0001). In addition, the overall incidence of hydrocephalus was significantly higher in Caucasian patients (p = 0.0002) than in those of any other race. CONCLUSIONS Knowledge of the demographic variations in adult-onset hydrocephalus is helpful in achieving better risk stratification and better managing the disease in patients. For general applicability, these results should be validated in a large-scale meta-analysis based on a national population database. PMID:27581317

  16. Rapid onset pressor and sympathetic responses to static handgrip in older hypertensive adults.

    PubMed

    Greaney, J L; Edwards, D G; Fadel, P J; Farquhar, W B

    2015-07-01

    Exaggerated pressor and muscle sympathetic nerve activity (MSNA) responses have been reported during static handgrip in hypertensive (HTN) adults. Recent work suggests that such responses may occur much more rapidly in HTN patients; however, this has not been extensively studied. Thus, we examined the blood pressure (BP) and MSNA responses at the immediate onset of muscle contraction and tested the hypothesis that older HTN adults would exhibit rapid onset pressor and sympathetic responses compared with normotensive (NTN) adults. Heart rate (HR), BP (Finometer) and MSNA (peroneal microneurography) were retrospectively analyzed in 15 HTN (62 ± 1 years; resting BP 153 ± 3/91 ± 5 mm Hg) and 23 age-matched NTN (60 ± 1 years; resting BP 112 ± 1/67 ± 2 mm Hg) subjects during the first 30 s of static handgrip at 30 and 40% of maximal voluntary contraction (MVC). HTN adults demonstrated exaggerated increases in mean BP during the first 10 s of both 30% (NTN: Δ1 ± 1 vs HTN: Δ7 ± 2 mm Hg; P < 0.05) and 40% (NTN: Δ2 ± 1 vs HTN: Δ8 ± 2 mm Hg; P < 0.05) intensity handgrip. Likewise, HTN adults exhibited atypical increases in MSNA within 10 s. Increases in HR were also greater in HTN adults at 10 s of 30% MVC handgrip, although not at 40% MVC. There were no group differences in 10 s pressor or sympathetic responses to a cold pressor test, suggesting no differences in generalized sympathetic responsiveness. Thus, static handgrip evokes rapid onset pressor and sympathetic responses in older HTN adults. These findings suggest that older HTN adults likely have greater cardiovascular risk even during short duration activities of daily living that contain an isometric component. PMID:25471615

  17. Rapid onset pressor and sympathetic responses to static handgrip in older hypertensive adults.

    PubMed

    Greaney, J L; Edwards, D G; Fadel, P J; Farquhar, W B

    2015-07-01

    Exaggerated pressor and muscle sympathetic nerve activity (MSNA) responses have been reported during static handgrip in hypertensive (HTN) adults. Recent work suggests that such responses may occur much more rapidly in HTN patients; however, this has not been extensively studied. Thus, we examined the blood pressure (BP) and MSNA responses at the immediate onset of muscle contraction and tested the hypothesis that older HTN adults would exhibit rapid onset pressor and sympathetic responses compared with normotensive (NTN) adults. Heart rate (HR), BP (Finometer) and MSNA (peroneal microneurography) were retrospectively analyzed in 15 HTN (62 ± 1 years; resting BP 153 ± 3/91 ± 5 mm Hg) and 23 age-matched NTN (60 ± 1 years; resting BP 112 ± 1/67 ± 2 mm Hg) subjects during the first 30 s of static handgrip at 30 and 40% of maximal voluntary contraction (MVC). HTN adults demonstrated exaggerated increases in mean BP during the first 10 s of both 30% (NTN: Δ1 ± 1 vs HTN: Δ7 ± 2 mm Hg; P < 0.05) and 40% (NTN: Δ2 ± 1 vs HTN: Δ8 ± 2 mm Hg; P < 0.05) intensity handgrip. Likewise, HTN adults exhibited atypical increases in MSNA within 10 s. Increases in HR were also greater in HTN adults at 10 s of 30% MVC handgrip, although not at 40% MVC. There were no group differences in 10 s pressor or sympathetic responses to a cold pressor test, suggesting no differences in generalized sympathetic responsiveness. Thus, static handgrip evokes rapid onset pressor and sympathetic responses in older HTN adults. These findings suggest that older HTN adults likely have greater cardiovascular risk even during short duration activities of daily living that contain an isometric component.

  18. Nephrin mutations cause childhood- and adult-onset focal segmental glomerulosclerosis.

    PubMed

    Santín, Sheila; García-Maset, Rafael; Ruíz, Patricia; Giménez, Isabel; Zamora, Isabel; Peña, Antonia; Madrid, Alvaro; Camacho, Juan A; Fraga, Gloria; Sánchez-Moreno, Ana; Cobo, Maria Angeles; Bernis, Carmen; Ortiz, Alberto; de Pablos, Augusto Luque; Pintos, Guillem; Justa, Maria Luisa; Hidalgo-Barquero, Emilia; Fernández-Llama, Patricia; Ballarín, José; Ars, Elisabet; Torra, Roser

    2009-12-01

    Mutations in the NPHS1 gene cause congenital nephrotic syndrome of the Finnish type presenting before the first 3 months of life. Recently, NPHS1 mutations have also been identified in childhood-onset steroid-resistant nephrotic syndrome and milder courses of disease, but their role in adults with focal segmental glomerulosclerosis remains unknown. Here we developed an in silico scoring matrix to evaluate the pathogenicity of amino-acid substitutions using the biophysical and biochemical difference between wild-type and mutant amino acid, the evolutionary conservation of the amino-acid residue in orthologs, and defined domains, with the addition of contextual information. Mutation analysis was performed in 97 patients from 89 unrelated families, of which 52 presented with steroid-resistant nephrotic syndrome after 18 years of age. Compound heterozygous or homozygous NPHS1 mutations were identified in five familial and seven sporadic cases, including one patient 27 years old at onset of the disease. Substitutions were classified as 'severe' or 'mild' using this in silico approach. Our results suggest an earlier onset of the disease in patients with two 'severe' mutations compared to patients with at least one 'mild' mutation. The finding of mutations in a patient with adult-onset focal segmental glomerulosclerosis indicates that NPHS1 analysis could be considered in patients with later onset of the disease.

  19. Curcumin and neurodegenerative diseases

    PubMed Central

    Monroy, Adriana; Lithgow, Gordon J.; Alavez, Silvestre

    2013-01-01

    Over the last ten years curcumin has been reported to be effective against a wide variety of diseases and is characterized as having anti-carcinogenic, hepatoprotective, thrombosuppressive, cardioprotective, anti-arthritic, and anti-infectious properties. Recent studies performed in both vertebrate and invertebrate models have been conducted to determine whether curcumin was also neuroprotective. The efficacy of curcumin in several pre-clinical trials for neurodegenerative diseases has created considerable excitement mainly due to its lack of toxicity and low cost. This suggests that curcumin could be a worthy candidate for nutraceutical intervention. Since aging is a common risk factor for neurodegenerative diseases, it is possible that some compounds that target aging mechanisms could also prevent these kinds of diseases. One potential mechanism to explain several of the general health benefits associated with curcumin is that it may prevent aging-associated changes in cellular proteins that lead to protein insolubility and aggregation. This loss in protein homeostasis is associated with several age-related diseases. Recently, curcumin has been found to help maintain protein homeostasis and extend lifespan in the model invertebrate Caenorhabditis elegans. Here, we review the evidence from several animal models that curcumin improves healthspan by preventing or delaying the onset of various neurodegenerative diseases. PMID:23303664

  20. Effects of Age, Gender, Bolus Volume, Bolus Viscosity, and Gustation on Swallowing Apnea Onset Relative to Lingual Bolus Propulsion Onset in Normal Adults

    ERIC Educational Resources Information Center

    Hiss, Susan G.; Strauss, Monica; Treole, Kathleen; Stuart, Andrew; Boutilier, Susan

    2004-01-01

    The purpose of this study was to ascertain the normal relation of swallowing apnea (SA) onset relative to lingual bolus propulsion along with factors that may alter this relation. Forty adults, composed of 10 men and 10 women in each of 2 age groups (i.e., 20-30 and 63-79 years) participated. SA onset was assessed during 5- and 20-ml bolus volumes…

  1. The potential use of adult stem cells for the treatment of multiple sclerosis and other neurodegenerative disorders.

    PubMed

    Slavin, Shimon; Kurkalli, Basan G S; Karussis, Dimitrios

    2008-11-01

    No specific treatment exists for patients with multiple sclerosis (MS) who fail to respond to conventional immunosuppressive and immunomodulating modalities. Furthermore, no method is available for regeneration of existing defect in the central nervous system (CNS). The ultimate goals of MS treatment, similarly to other autoimmune diseases, are twofold: first, to eliminate self-reactive lymphocytes and to prevent de novo development of self-reactivity by induction of self-tolerance. Second, attempting regeneration and repair of existing damage. In the case of MS, there is a need to stop the ongoing process of inflammation against the CNS by self-reactive lymphocytes thus facilitating spontaneous re-myelinization while in parallel attempt to recover existing neurological deficits caused by the autoimmune process resulting in demyelinization. Cell therapy stands out as the most rationale approach for neurological regeneration. In the absence of clinically applicable approaches involving the use of embryonic stem cells, we are investigating the feasibility and efficacy of enriched autologous mesenchymal stromal cells (MSC) injected intrathecally and intravenously to induce in situ immunomodulation and neuroprotection and possibly facilitate repair of the CNS in patients with MS and other neurodegenerative disorders. Our preclinical results suggest that bone marrow cells may provide a source of stem cells with a potential for migration into inflamed CNS and differentiate into cells expressing neuronal and glial cell markers. Based on the preclinical data, we are currently evaluating the safety of a similar therapeutic approach in a small group of patients with MS and other neurodegenerative diseases.

  2. [Pathophysiology, subtypes, and treatments of adult-onset Still's disease: An update].

    PubMed

    Gerfaud-Valentin, M; Sève, P; Hot, A; Broussolle, C; Jamilloux, Y

    2015-05-01

    Adult-onset Still's disease is a rare and difficult to diagnose multisystemic disorder considered as a multigenic autoinflammatory syndrome. Its immunopathogenesis seems to be at the crossroads between inflammasomopathies and hemophagocytic lymphohistiocytosis, the most severe manifestation of the disease. According to recent insights in the pathophysiology and thanks to cohort studies and therapeutic trials, two phenotypes of adult-onset Still's disease may be distinguished: a systemic pattern, initially highly symptomatic and with a higher risk to exhibit life-threatening complications such as reactive hemophagocytic lymphohistiocytosis, where interleukin-1 blockade seems to be very effective, a chronic articular pattern, more indolent with arthritis in the foreground and less severe systemic manifestations, which would threat functional outcome and where interleukin-6 blockade seems to be more effective. This review focuses on these data.

  3. How does dementia onset in parents influence unmarried adult children's wealth.

    PubMed

    Arora, Kanika

    2016-03-01

    There is a growing concern that long-term care (LTC) needs of older adults lead to negative financial consequences for their family members. This paper examines whether the onset of dementia in parents influences wealth change among unmarried adult children regardless of their status as informal caregivers. Longitudinal data from seven waves (1998-2010) of the Health and Retirement Study (1540 person-wave observations) are used to analyze this question. Unconditional quantile regressions demonstrate that as a result of parental dementia diagnosis, unmarried adult children have lower wealth accumulation above the median of the wealth change distribution. These effects are more pronounced for unmarried adult children without siblings. Further, this response is observed to persist in the subsequent period as well. Both losses in labor income and nursing home expenditures may play a role in leading to wealth declines. PMID:26859082

  4. How does dementia onset in parents influence unmarried adult children's wealth.

    PubMed

    Arora, Kanika

    2016-03-01

    There is a growing concern that long-term care (LTC) needs of older adults lead to negative financial consequences for their family members. This paper examines whether the onset of dementia in parents influences wealth change among unmarried adult children regardless of their status as informal caregivers. Longitudinal data from seven waves (1998-2010) of the Health and Retirement Study (1540 person-wave observations) are used to analyze this question. Unconditional quantile regressions demonstrate that as a result of parental dementia diagnosis, unmarried adult children have lower wealth accumulation above the median of the wealth change distribution. These effects are more pronounced for unmarried adult children without siblings. Further, this response is observed to persist in the subsequent period as well. Both losses in labor income and nursing home expenditures may play a role in leading to wealth declines.

  5. Intra-arterial Chemotherapy for Adult Onset Retinoblastoma in a 32-Year-Old Man.

    PubMed

    Magan, Tejal; Khoo, Chloe T L; Jabbour, Pascal M; Fuller, Dwain G; Shields, Carol L

    2016-01-01

    A 32-year-old man with active unilateral group D retinoblastoma that was recurrent following external beam radiotherapy was treated with intra-arterial chemotherapy, leading to tumor regression. Additional plaque radiotherapy and intravitreal chemotherapy were required for complete control. Final visual acuity was 20/40. In selected cases, adult-onset retinoblastoma can be managed with intra-arterial chemotherapy. [J Pediatr Ophthalmol Strabismus. 2016;53:e43-e46.]. PMID:27486894

  6. Urticaria and dermographism in patients with adult-onset Still's disease.

    PubMed

    Criado, Paulo Ricardo; de Carvalho, Jozélio Freire; Ayabe, Liliane Akemi; Brandt, Hebert Roberto Clivati; Romiti, Ricardo; Maruta, Celina W

    2012-08-01

    Adult-onset Still's disease (AOSD) patients typically present with arthralgia, fever, lymphadenopathy and a transient salmon maculopapular rash. Only approximately 25 cases of AOSD with urticaria were described in the literature. In this article, the authors report three additional cases of AOSD with urticarial and dermographic lesions who had a good clinical response to glucocorticoid and antihistamines. A review of the literature concerning this issue is also herein written.

  7. Epidemiology and outcome of articular complications in adult onset still's disease

    PubMed Central

    Mahfoudhi, Madiha; Shimi, Rafik; Turki, Sami; Kheder, Adel

    2015-01-01

    The adult onset Still's disease is a rare inflammatory pathology of unknown pathogeny. The clinical features are variable. The diagnosis is difficult since exclusion of infectious, systemic and tumoral pathologies should be done. The articular complications are frequent and can be revelatory of this pathology. The articular prognosis depends on the diagnosis delay and the treatment efficiency. Our study aims to analyze different aspects of articular manifestations complicating adult onset Still disease to define epidemiological, clinical and evolving characteristics of these complications. It was a cross-sectional study concerning 18 cases of adult onset Still disease diagnosed from 1990 to 2014 in the internal medicine A department of Charles Nicolle Hospital in Tunis, meeting Yamaguchi criteria. We identified clinical, radiological, evolving and therapeutic profile of the articular manifestations occurred in these patients. There were 11 women and 7 men. The average age was 27 years. The arthralgias were reported in all cases; while, the arthritis interested thirteen patients. A hand deformation was found in four patients. A wrist ankylosis was noted in one case and a flexion elbow in one patient. The Standard articular radiographs were normal in ten cases. The treatment associated essentially non-steroidal anti-inflammatory and/or corticosteroids and/or methotrexate. Concerning the evolving profile, the monocyclic form was present in 25% of the cases, the intermittent form in 40% and the chronic articular form in 35% of our patients. The adult onset Still's disease is rare and heterogeneous. The articular disturbances are frequent and have various outcomes. PMID:26834930

  8. An active lifestyle postpones dementia onset by more than one year in very old adults.

    PubMed

    Paillard-Borg, Stéphanie; Fratiglioni, Laura; Xu, Weili; Winblad, Bengt; Wang, Hui-Xin

    2012-01-01

    The purpose of this study was to test the hypothesis that an active lifestyle delays age at dementia onset. This study included 388 incident dementia cases (DSM-III-R criteria) that developed over a 9-year follow-up period among 1,375 baseline dementia-free community dwellers with good cognitive function (MMSE >23) (mean age = 81.2) from the Kungsholmen Project. An active lifestyle was defined as participation in mental, physical, or social activity. We used linear regression models to estimate influence of baseline active lifestyle on age at onset of incident dementia and general linear models to estimate mean age at dementia onset. Age at onset of dementia was significantly older in persons who had higher levels of participation in mental, physical, or social activity (β: 0.18, 0.29 and 0.23 respectively, p < 0.001 for all the activities) independent of education, medical condition, functional status, and other confounders including APOE. When the three types of activities were integrated into an index, we found that the broader the spectrum of participation in the activities, the later the onset of disease (β = 0.93, p = 0.01 for participating in two activities, and β = 1.42, p < 0.001 for three activities). There were 17 months difference in mean age at dementia onset between the inactive group and the most active group. An active lifestyle operates as a protective factor for dementia by delaying the clinical onset of the disease. These findings highlight the relevance of encouraging old adults to have active lifestyles, which could have a great impact on public health. PMID:22751170

  9. Type II (adult onset) citrullinaemia: clinical pictures and the therapeutic effect of liver transplantation

    PubMed Central

    Ikeda, S; Yazaki, M; Takei, Y; Ikegami, T; Hashikura, Y; Kawasaki, S; Iwai, M; Kobayashi, K; Saheki, T

    2001-01-01

    OBJECTIVE—Adult onset type II citrullinemia is an inherited disorder of amino acid metabolism caused by a deficiency of liver specific argininosuccinate synthetase activity. Most of the patients with this disease were reported in Japan and therefore, this disease has not been well recognised outside this country. The detailed clinical pictures of the patients with type II citrullinaemia are reported and their outcomes after liver transplantation referred to.
METHODS—Ten patients with this disease were evaluated. Seven of them underwent liver transplants using a graft obtained from a healthy family member.
RESULTS—There were six men and four women; the age of onset of encephalopathy ranged from 17 to 51 years. The initial symptom in nine patients was sudden onset disturbance of consciousness, and one patient had long been regarded as having a chronic progressive psychotic illness. High concentrations of plasma citrulline and ammonia were commonly seen on admission. Although brain CT or MRI lacked any consistent findings, the EEG was abnormal in all patients, showing diffuse slow waves. Additionally, in five patients chronic pancreatitis preceded the onset of encephalopathy. After liver transplantation the metabolic abnormalities, including abnormal plasma concentrations of citrulline and ammonia, were immediately corrected and all neuropsychic symptoms soon disappeared, except for impaired cognitive function in one patient. Six out of these seven patients returned to their previous social lives, including work.
CONCLUSIONS—The clinical concept of adult onset type II citrullinaemia coincides well with the range of hepatic encephalopathy, and liver transplantation is a very promising therapeutic approach.

 PMID:11606680

  10. Chinese new immigrant mothers' perception about adult-onset non-communicable diseases prevention during childhood.

    PubMed

    Wang, Linda Dong Ling; Lam, Wendy Wing Tak; Wu, Joseph Tsz Kei; Fielding, Richard

    2015-12-01

    Many non-communicable diseases (NCDs) are largely preventable via behaviour change and healthy lifestyle, which may be best established during childhood. This study sought insights into Chinese new immigrant mothers' perceptions about adult-onset NCDs prevention during childhood. Twenty-three semi-structured interviews were carried out with new immigrant mothers from mainland China who had at least one child aged 14 years or younger living in Hong Kong. Interviews were audio taped, transcribed and analysed using a Grounded Theory approach. The present study identified three major themes: perceived causes of adult NCDs, beliefs about NCDs prevention and everyday health information practices. Unhealthy lifestyle, contaminated food and environment pollution were perceived as the primary causes of adult NCDs. Less than half of the participants recognized that parents had responsibility for helping children establish healthy behaviours from an early age to prevent diseases in later life. Most participants expressed helplessness about chronic diseases prevention due to lack of knowledge of prevention, being perceived as beyond individual control. Many participants experienced barriers to seeking health information, the most common sources of health information being interpersonal conversation and television. Participants' everyday information practice was passive and generally lacked awareness regarding early prevention of adult-onset NCDs. Updated understanding of this issue has notable implications for future health promotion interventions.

  11. The social behavior of male rats administered an adult-onset calorie restriction regimen.

    PubMed

    Govic, Antonina; Levay, Elizabeth A; Kent, Stephen; Paolini, Antonio G

    2009-03-23

    The behavioral outcomes of a calorie restricted diet are often neglected in favour of a more physiological examination of the consequences of calorie restriction (CR). This is especially the case with social behavior. A few findings within the maternal CR literature suggest that adult male social behavior is altered by this regimen. Despite the paucity of findings within the maternal CR literature, a systematic investigation of the behavioral phenotype of males administered an adult-onset CR is completely lacking and was the focus of the current study. Adult male hooded Wistar rats were administered a three week CR, with one group receiving a 25% CR and another group receiving a 50% CR before male-to-male social behavior was examined and compared with ad libitium fed males. Various behavioral elements were modulated by CR, both the CR25% and 50% group initiated contact sooner and engaged in greater social activity compared to the ad libitum fed controls. The CR25% group also demonstrated less non-social (self-grooming) behavior and a greater frequency of walkovers compared to all groups, indicating a propensity towards dominance. The CR50% group demonstrated greater environmental assessment/exploration, as measured by the frequency of rearing. As with the maternal CR literature, an adult-onset chronic CR induces a more socially active behavioral phenotype and reduces interest in non-social behavior in the moderately CR group. Taken together, the social behavioral phenotype can be modulated by a CR initiated and maintained during adulthood.

  12. Chinese new immigrant mothers' perception about adult-onset non-communicable diseases prevention during childhood.

    PubMed

    Wang, Linda Dong Ling; Lam, Wendy Wing Tak; Wu, Joseph Tsz Kei; Fielding, Richard

    2015-12-01

    Many non-communicable diseases (NCDs) are largely preventable via behaviour change and healthy lifestyle, which may be best established during childhood. This study sought insights into Chinese new immigrant mothers' perceptions about adult-onset NCDs prevention during childhood. Twenty-three semi-structured interviews were carried out with new immigrant mothers from mainland China who had at least one child aged 14 years or younger living in Hong Kong. Interviews were audio taped, transcribed and analysed using a Grounded Theory approach. The present study identified three major themes: perceived causes of adult NCDs, beliefs about NCDs prevention and everyday health information practices. Unhealthy lifestyle, contaminated food and environment pollution were perceived as the primary causes of adult NCDs. Less than half of the participants recognized that parents had responsibility for helping children establish healthy behaviours from an early age to prevent diseases in later life. Most participants expressed helplessness about chronic diseases prevention due to lack of knowledge of prevention, being perceived as beyond individual control. Many participants experienced barriers to seeking health information, the most common sources of health information being interpersonal conversation and television. Participants' everyday information practice was passive and generally lacked awareness regarding early prevention of adult-onset NCDs. Updated understanding of this issue has notable implications for future health promotion interventions. PMID:24842077

  13. X-linked neurodegenerative syndrome with congenital ataxia, late-onset progressive myoclonic encephalopathy and selective macular degeneration, linked to Xp22.33-pter

    SciTech Connect

    Portes, V. des; Beldjord, C.; Bruels, T.

    1996-07-12

    Linkage analysis was performed in a previously described family segregating for an X-linked progressive neurological disorder. In three generations, the disease was inherited from the mothers in seven affected males. Five had severe congenital hypotonia and died during the first year of life. Two other boys (maternal cousins) were found to have severe congenital ataxia, late-onset progressive myoclonic encephalopathy, and selective macular degeneration; brain CT-scan showed moderate cerebellar vermis hypoplasia. Linkage analysis was carried out in 12 informative relatives using 35 microsatellite markers (Genethon) evenly distributed on the X chromosome. A multipoint analysis showed a significant linkage (Z > 2) between the disease and three markers in the Xp22.33 region: DYS403 (Z = 2.37, {theta} = 0) which maps in the pseudoautosomal region, DXS7099 (Z = 2.45, {theta} = 0), and DXS7100 (Z = 2.48, {theta} = 0). Further linkage analysis with more telomeric markers will refine the location of this severe X-linked encephalopathy. 12 refs., 2 figs., 1 tab.

  14. Tension-type headache in Parma's adult general population: a focus on age of onset.

    PubMed

    Taga, Arens; Russo, Marco; Manzoni, Gian C; Torelli, Paola

    2015-01-01

    In the present paper, we focus on the age of onset for tension-type headache in a population-based sample in the Parma, distinguishing its different subtypes and considering definite and probable diagnoses. Age of headache onset is a useful clinical feature for differential diagnosis between primary headaches and between primary and secondary headache forms. A total of 904 subjects representative of the Parma's adult general population were interviewed face to face by a physician from the Parma Headache Centre, using a validated questionnaire specially designed for the diagnosis of primary headaches according to the ICHD-II criteria. In the majority of subjects diagnosed with definite tension-type headache, age of onset was 39 years or less, while mean age of onset was 29.7 years (SD 16.3 years, range 5-79 years), the median being 25 years. Both infrequent and frequent episodic definite tension-type headache first occurred in the majority of cases in the second, third and fourth decades. Subjects with chronic definite tension-type headache reported a later onset in life (i.e. fourth, fifth and sixth decades). In our study, mean age of onset for probable tension-type headache was 23.7 years (SD 9.2 years, range 10-40 years) and the median was 22 years. In no case did we find significant gender differences. Our study results are similar to most of those reported in the literature. Further research needs to be done in the Italian epidemiological context, given the lack of literature reports on this topic.

  15. Pesticide methoxychlor promotes the epigenetic transgenerational inheritance of adult-onset disease through the female germline.

    PubMed

    Manikkam, Mohan; Haque, M Muksitul; Guerrero-Bosagna, Carlos; Nilsson, Eric E; Skinner, Michael K

    2014-01-01

    Environmental compounds including fungicides, plastics, pesticides, dioxin and hydrocarbons can promote the epigenetic transgenerational inheritance of adult-onset disease in future generation progeny following ancestral exposure during the critical period of fetal gonadal sex determination. This study examined the actions of the pesticide methoxychlor to promote the epigenetic transgenerational inheritance of adult-onset disease and associated differential DNA methylation regions (i.e. epimutations) in sperm. Gestating F0 generation female rats were transiently exposed to methoxychlor during fetal gonadal development (gestation days 8 to 14) and then adult-onset disease was evaluated in adult F1 and F3 (great-grand offspring) generation progeny for control (vehicle exposed) and methoxychlor lineage offspring. There were increases in the incidence of kidney disease, ovary disease, and obesity in the methoxychlor lineage animals. In females and males the incidence of disease increased in both the F1 and the F3 generations and the incidence of multiple disease increased in the F3 generation. There was increased disease incidence in F4 generation reverse outcross (female) offspring indicating disease transmission was primarily transmitted through the female germline. Analysis of the F3 generation sperm epigenome of the methoxychlor lineage males identified differentially DNA methylated regions (DMR) termed epimutations in a genome-wide gene promoters analysis. These epimutations were found to be methoxychlor exposure specific in comparison with other exposure specific sperm epimutation signatures. Observations indicate that the pesticide methoxychlor has the potential to promote the epigenetic transgenerational inheritance of disease and the sperm epimutations appear to provide exposure specific epigenetic biomarkers for transgenerational disease and ancestral environmental exposures.

  16. Pesticide Methoxychlor Promotes the Epigenetic Transgenerational Inheritance of Adult-Onset Disease through the Female Germline

    PubMed Central

    Manikkam, Mohan; Haque, M. Muksitul; Guerrero-Bosagna, Carlos; Nilsson, Eric E.; Skinner, Michael K.

    2014-01-01

    Environmental compounds including fungicides, plastics, pesticides, dioxin and hydrocarbons can promote the epigenetic transgenerational inheritance of adult-onset disease in future generation progeny following ancestral exposure during the critical period of fetal gonadal sex determination. This study examined the actions of the pesticide methoxychlor to promote the epigenetic transgenerational inheritance of adult-onset disease and associated differential DNA methylation regions (i.e. epimutations) in sperm. Gestating F0 generation female rats were transiently exposed to methoxychlor during fetal gonadal development (gestation days 8 to 14) and then adult-onset disease was evaluated in adult F1 and F3 (great-grand offspring) generation progeny for control (vehicle exposed) and methoxychlor lineage offspring. There were increases in the incidence of kidney disease, ovary disease, and obesity in the methoxychlor lineage animals. In females and males the incidence of disease increased in both the F1 and the F3 generations and the incidence of multiple disease increased in the F3 generation. There was increased disease incidence in F4 generation reverse outcross (female) offspring indicating disease transmission was primarily transmitted through the female germline. Analysis of the F3 generation sperm epigenome of the methoxychlor lineage males identified differentially DNA methylated regions (DMR) termed epimutations in a genome-wide gene promoters analysis. These epimutations were found to be methoxychlor exposure specific in comparison with other exposure specific sperm epimutation signatures. Observations indicate that the pesticide methoxychlor has the potential to promote the epigenetic transgenerational inheritance of disease and the sperm epimutations appear to provide exposure specific epigenetic biomarkers for transgenerational disease and ancestral environmental exposures. PMID:25057798

  17. The Onset of Depression During the Great Recession: Foreclosure and Older Adult Mental Health

    PubMed Central

    Cagney, Kathleen A.; Browning, Christopher R.; Iveniuk, James; English, Ned

    2014-01-01

    Objectives. We examined neighborhood-level foreclosure rates and their association with onset of depressive symptoms in older adults. Methods. We linked data from the National Social Life, Health, and Aging Project (2005–2006 and 2010–2011 waves), a longitudinal, nationally representative survey, to data on zip code–level foreclosure rates, and predicted the onset of depressive symptoms using logit-linked regression. Results. Multiple stages of the foreclosure process predicted the onset of depressive symptoms, with adjustment for demographic characteristics and changes in household assets, neighborhood poverty, and visible neighborhood disorder. A large increase in the number of notices of default (odds ratio [OR] = 1.75; 95% confidence interval [CI] = 1.14, 2.67) and properties returning to ownership by the bank (OR = 1.62; 95% CI = 1.06, 2.47) were associated with depressive symptoms. A large increase in properties going to auction was suggestive of such an association (OR = 1.45; 95% CI = 0.96, 2.19). Age, fewer years of education, and functional limitations also were predictive. Conclusions. Increases in neighborhood-level foreclosure represent an important risk factor for depression in older adults. These results accord with previous studies suggesting that the effects of economic crises are typically first experienced through deficits in emotional well-being. PMID:24446830

  18. Intermittent rhabdomyolysis with adult onset associated with a mutation in the ACADVL gene.

    PubMed

    Antunes, Ana Patrícia; Nogueira, Célia; Rocha, Hugo; Vilarinho, Laura; Evangelista, Teresinha

    2013-12-01

    Deficiency of very-long-chain acyl-CoA dehydrogenase (VLCAD) is an autosomal recessive disease. Most common phenotypes occur in the neonatal period or in childhood with cardiomyopathy, hepatomegaly, and hypoketogenic hypoglycemia. Juvenile/adult-onset is characterized by exercise intolerance and recurrent rhabdomyolysis triggered by prolonged exercise or fasting. This article reports a patient with the homozygous mutation c.1097G>A (p.R366H) in the ACADVL gene. In Portugal, VLCAD deficiency became part of the neonatal screening plan in 2004, and as of 2012, 8 early-onset cases have been diagnosed, giving an incidence rate of 1:97.238 per 737.902 newborns. This patient was diagnosed outside of the neonatal screening plan. Beta-oxidation defects pose a diagnostic challenge because of their transient clinical and laboratorial manifestations and the absence of morphological changes in muscle biopsy further complicate matters, especially in the late-onset forms of the disease. The adult phenotype of VLCAD deficiency is highlighted, emphasizing the need for a high suspicion index and the value of tandem mass spectrometry for the diagnosis. PMID:24263034

  19. Mutated CTSF in adult-onset neuronal ceroid lipofuscinosis and FTD

    PubMed Central

    van der Zee, Julie; Mariën, Peter; Crols, Roeland; Van Mossevelde, Sara; Dillen, Lubina; Perrone, Federica; Engelborghs, Sebastiaan; Verhoeven, Jo; D'aes, Tine; Ceuterick-De Groote, Chantal; Sieben, Anne; Versijpt, Jan; Cras, Patrick; Martin, Jean-Jacques

    2016-01-01

    Objective: To investigate the molecular basis of a Belgian family with autosomal recessive adult-onset neuronal ceroid lipofuscinosis (ANCL or Kufs disease [KD]) with pronounced frontal lobe involvement and to expand the findings to a cohort of unrelated Belgian patients with frontotemporal dementia (FTD). Methods: Genetic screening in the ANCL family and FTD cohort (n = 461) was performed using exome sequencing and targeted massive parallel resequencing. Results: We identified a homozygous mutation (p.Ile404Thr) in the Cathepsin F (CTSF) gene cosegregating in the ANCL family. No other mutations were found that could explain the disease in this family. All 4 affected sibs developed motor symptoms and early-onset dementia with prominent frontal features. Two of them evolved to akinetic mutism. Disease presentation showed marked phenotypic variation with the onset ranging from 26 to 50 years. Myoclonic epilepsy in one of the sibs was suggestive for KD type A, while epilepsy was not present in the other sibs who presented with clinical features of KD type B. In a Belgian cohort of unrelated patients with FTD, the same heterozygous p.Arg245His mutation was identified in 2 patients who shared a common haplotype. Conclusions: A homozygous CTSF mutation was identified in a recessive ANCL pedigree. In contrast to the previous associations of CTSF with KD type B, our findings suggest that CTSF genetic testing should also be considered in patients with KD type A as well as in early-onset dementia with prominent frontal lobe and motor symptoms.

  20. Juvenile versus adult-onset ankylosing spondylitis -- clinical, radiographic, and social outcomes. a systematic review.

    PubMed

    Jadon, Deepak R; Ramanan, Athimalaipet V; Sengupta, Raj

    2013-11-01

    Ankylosing spondylitis (AS) has 2 main modes of onset: juvenile-onset AS (JoAS) and adult-onset AS (AoAS). It is not known whether JoAS is a subtype of AS, or AS modulated by early age of onset and longer disease duration. We performed a systematic review of the literature, identifying 12 articles and 1 abstract directly comparing JoAS and AoAS cohorts, with observational study design. Patients with JoAS appear to have more peripheral joint involvement both clinically and radiographically (especially knees and ankles) and more root joint involvement (hips and shoulders); they are more likely to proceed to hip arthroplasty and often initially present with peripheral rather than axial symptoms. Patients with AoAS appear to have more axial symptoms and radiographic disease, particularly in the lumbar spine, and worse axial metrology. In terms of other characteristics, more evidence is needed to confidently state whether JoAS and AoAS are different.

  1. ATP1A3 Mutation in Adult Rapid-Onset Ataxia.

    PubMed

    Sweadner, Kathleen J; Toro, Camilo; Whitlow, Christopher T; Snively, Beverly M; Cook, Jared F; Ozelius, Laurie J; Markello, Thomas C; Brashear, Allison

    2016-01-01

    A 21-year old male presented with ataxia and dysarthria that had appeared over a period of months. Exome sequencing identified a de novo missense variant in ATP1A3, the gene encoding the α3 subunit of Na,K-ATPase. Several lines of evidence suggest that the variant is causative. ATP1A3 mutations can cause rapid-onset dystonia-parkinsonism (RDP) with a similar age and speed of onset, as well as severe diseases of infancy. The patient's ATP1A3 p.Gly316Ser mutation was validated in the laboratory by the impaired ability of the expressed protein to support the growth of cultured cells. In a crystal structure of Na,K-ATPase, the mutated amino acid was directly apposed to a different amino acid mutated in RDP. Clinical evaluation showed that the patient had many characteristics of RDP, however he had minimal fixed dystonia, a defining symptom of RDP. Successive magnetic resonance imaging (MRI) revealed progressive cerebellar atrophy, explaining the ataxia. The absence of dystonia in the presence of other RDP symptoms corroborates other evidence that the cerebellum contributes importantly to dystonia pathophysiology. We discuss the possibility that a second de novo variant, in ubiquilin 4 (UBQLN4), a ubiquitin pathway component, contributed to the cerebellar neurodegenerative phenotype and differentiated the disease from other manifestations of ATP1A3 mutations. We also show that a homozygous variant in GPRIN1 (G protein-regulated inducer of neurite outgrowth 1) deletes a motif with multiple copies and is unlikely to be causative. PMID:26990090

  2. ATP1A3 Mutation in Adult Rapid-Onset Ataxia.

    PubMed

    Sweadner, Kathleen J; Toro, Camilo; Whitlow, Christopher T; Snively, Beverly M; Cook, Jared F; Ozelius, Laurie J; Markello, Thomas C; Brashear, Allison

    2016-01-01

    A 21-year old male presented with ataxia and dysarthria that had appeared over a period of months. Exome sequencing identified a de novo missense variant in ATP1A3, the gene encoding the α3 subunit of Na,K-ATPase. Several lines of evidence suggest that the variant is causative. ATP1A3 mutations can cause rapid-onset dystonia-parkinsonism (RDP) with a similar age and speed of onset, as well as severe diseases of infancy. The patient's ATP1A3 p.Gly316Ser mutation was validated in the laboratory by the impaired ability of the expressed protein to support the growth of cultured cells. In a crystal structure of Na,K-ATPase, the mutated amino acid was directly apposed to a different amino acid mutated in RDP. Clinical evaluation showed that the patient had many characteristics of RDP, however he had minimal fixed dystonia, a defining symptom of RDP. Successive magnetic resonance imaging (MRI) revealed progressive cerebellar atrophy, explaining the ataxia. The absence of dystonia in the presence of other RDP symptoms corroborates other evidence that the cerebellum contributes importantly to dystonia pathophysiology. We discuss the possibility that a second de novo variant, in ubiquilin 4 (UBQLN4), a ubiquitin pathway component, contributed to the cerebellar neurodegenerative phenotype and differentiated the disease from other manifestations of ATP1A3 mutations. We also show that a homozygous variant in GPRIN1 (G protein-regulated inducer of neurite outgrowth 1) deletes a motif with multiple copies and is unlikely to be causative.

  3. ATP1A3 Mutation in Adult Rapid-Onset Ataxia

    PubMed Central

    Sweadner, Kathleen J.; Toro, Camilo; Whitlow, Christopher T.; Snively, Beverly M.; Cook, Jared F.; Ozelius, Laurie J.; Markello, Thomas C.; Brashear, Allison

    2016-01-01

    A 21-year old male presented with ataxia and dysarthria that had appeared over a period of months. Exome sequencing identified a de novo missense variant in ATP1A3, the gene encoding the α3 subunit of Na,K-ATPase. Several lines of evidence suggest that the variant is causative. ATP1A3 mutations can cause rapid-onset dystonia-parkinsonism (RDP) with a similar age and speed of onset, as well as severe diseases of infancy. The patient’s ATP1A3 p.Gly316Ser mutation was validated in the laboratory by the impaired ability of the expressed protein to support the growth of cultured cells. In a crystal structure of Na,K-ATPase, the mutated amino acid was directly apposed to a different amino acid mutated in RDP. Clinical evaluation showed that the patient had many characteristics of RDP, however he had minimal fixed dystonia, a defining symptom of RDP. Successive magnetic resonance imaging (MRI) revealed progressive cerebellar atrophy, explaining the ataxia. The absence of dystonia in the presence of other RDP symptoms corroborates other evidence that the cerebellum contributes importantly to dystonia pathophysiology. We discuss the possibility that a second de novo variant, in ubiquilin 4 (UBQLN4), a ubiquitin pathway component, contributed to the cerebellar neurodegenerative phenotype and differentiated the disease from other manifestations of ATP1A3 mutations. We also show that a homozygous variant in GPRIN1 (G protein-regulated inducer of neurite outgrowth 1) deletes a motif with multiple copies and is unlikely to be causative. PMID:26990090

  4. Ketosis-onset diabetes in Tunisian adults: immunological markers and beta-cell function.

    PubMed

    Harzallah, F; Ben Brahim, A; Laadhar, L; Feki, M; Zitouni, M; Makni, S; Kaabachi, N; Slimane, H

    2010-01-01

    The aim of this study in Tunisia was to classify ketosis-onset diabetes in adult patients. All patients aged > 30 years without known diabetes, presenting with ketosis and admitted to our department were studied. Patients with secondary or gestational diabetes and those on corticoid therapy or with coinciding infection were excluded. The data included clinical characteristics, immunological markers and beta-cell function. Of the 63 patients, islet-cell antibodies were present in 27.0%, glutamic acid decarboxylase antibodies in 25.4% and thyrosin phosphatase antibodies in 19.0%. Beta-cell functional reserve was preserved in 54.0%. Our results confirm that patients with ketosis-onset diabetes mellitus in adulthood are a heterogeneous group. PMID:20214161

  5. Adult-Onset Familial Mediterranean Fever in Northwestern Iran; Clinical Feature and Treatment Outcome

    PubMed Central

    Nobakht, H; Zamani, F; Ajdarkosh, H; Mohamadzadeh, Z; Fereshtehnejad, SM; Nassaji, M

    2011-01-01

    BACKGROUND Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterized by sporadic, paroxysmal attacks of fever and serosal inflammation. Although the disease usually begins before the age of 20 years, we aimed to evaluate the demography, clinical features and treatment outcome of familial Mediterranean fever in Iranian adult patients above 20 years old. METHODS In this cross-sectional study, adult patients (first attack at the age of >20 years) with a diagnosis of FMF who referred to the gastroenterology and rheumatology Clinics of Ardebil University of Medical Science (situated in north west of Iran) over the period of 2004-2009 were enrolled. FMF diagnosis was based on clinical criteria. RESULTS Forty four FMF patients (30 male and 14 female) with the mean [± Standard Deviation (SD)] age of first attack of 29 ± 7.8 years were enrolled. Abdominal pain (95.5%) and fever (91%) were the most common clinical findings. All of the patients had satisfactorily responded to therapy. Response was complete in 76.7% and partial in 23.3% of the patients. There was no clinical or laboratory evidence of amyloidosis at the time of diagnosis or during follow-up. CONCLUSION Our findings demonstrated that adult-onset FMF in Iran has different characteristics (more common in males, lesser prevalence of arthritis and erysipelas-like erythema, less delay in diagnosis) and treatment outcome (favorable response even to low-dose colchicine) in comparison with the previous data on early onset patients. PMID:25197532

  6. Adult-onset familial mediterranean Fever in northwestern iran; clinical feature and treatment outcome.

    PubMed

    Nobakht, H; Zamani, F; Ajdarkosh, H; Mohamadzadeh, Z; Fereshtehnejad, Sm; Nassaji, M

    2011-03-01

    BACKGROUND Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterized by sporadic, paroxysmal attacks of fever and serosal inflammation. Although the disease usually begins before the age of 20 years, we aimed to evaluate the demography, clinical features and treatment outcome of familial Mediterranean fever in Iranian adult patients above 20 years old. METHODS In this cross-sectional study, adult patients (first attack at the age of >20 years) with a diagnosis of FMF who referred to the gastroenterology and rheumatology Clinics of Ardebil University of Medical Science (situated in north west of Iran) over the period of 2004-2009 were enrolled. FMF diagnosis was based on clinical criteria. RESULTS Forty four FMF patients (30 male and 14 female) with the mean [± Standard Deviation (SD)] age of first attack of 29 ± 7.8 years were enrolled. Abdominal pain (95.5%) and fever (91%) were the most common clinical findings. All of the patients had satisfactorily responded to therapy. Response was complete in 76.7% and partial in 23.3% of the patients. There was no clinical or laboratory evidence of amyloidosis at the time of diagnosis or during follow-up. CONCLUSION Our findings demonstrated that adult-onset FMF in Iran has different characteristics (more common in males, lesser prevalence of arthritis and erysipelas-like erythema, less delay in diagnosis) and treatment outcome (favorable response even to low-dose colchicine) in comparison with the previous data on early onset patients.

  7. Generation of a novel mouse model that recapitulates early and adult onset glycogenosis type IV.

    PubMed

    Akman, H Orhan; Sheiko, Tatiana; Tay, Stacey K H; Finegold, Milton J; Dimauro, Salvatore; Craigen, William J

    2011-11-15

    Glycogen storage disease type IV (GSD IV) is a rare autosomal recessive disorder caused by deficiency of the glycogen branching enzyme (GBE). The diagnostic feature of the disease is the accumulation of a poorly branched form of glycogen known as polyglucosan (PG). The disease is clinically heterogeneous, with variable tissue involvement and age of disease onset. Absence of enzyme activity is lethal in utero or in infancy affecting primarily muscle and liver. However, residual enzyme activity (5-20%) leads to juvenile or adult onset of a disorder that primarily affects muscle as well as central and peripheral nervous system. Here, we describe two mouse models of GSD IV that reflect this spectrum of disease. Homologous recombination was used to insert flippase recognition target recombination sites around exon 7 of the Gbe1 gene and a phosphoglycerate kinase-Neomycin cassette within intron 7, leading to a reduced synthesis of GBE. Mice bearing this mutation (Gbe1(neo/neo)) exhibit a phenotype similar to juvenile onset GSD IV, with wide spread accumulation of PG. Meanwhile, FLPe-mediated homozygous deletion of exon 7 completely eliminated GBE activity (Gbe1(-/-)), leading to a phenotype of lethal early onset GSD IV, with significant in utero accumulation of PG. Adult mice with residual GBE exhibit progressive neuromuscular dysfunction and die prematurely. Differently from muscle, PG in liver is a degradable source of glucose and readily depleted by fasting, emphasizing that there are structural and regulatory differences in glycogen metabolism among tissues. Both mouse models recapitulate typical histological and physiological features of two human variants of branching enzyme deficiency. PMID:21856731

  8. Characterisation of a syndrome of autoimmune adult onset focal epilepsy and encephalitis.

    PubMed

    Ramanathan, Sudarshini; Bleasel, Andrew; Parratt, John; Orr, Carolyn; Dale, Russell C; Vincent, Angela; Fung, Victor S C

    2014-07-01

    We report a series of patients with a clinical syndrome characterised by the explosive onset in adulthood of recurrent focal seizures of frontotemporal onset and features suggestive of autoimmune encephalitis. We propose that this presentation of "autoimmune adult onset focal epilepsy and encephalitis" is a recognisable clinical syndrome, and provide evidence it may be associated with heterogeneous immunological targets. Between 2008 and 2011 we encountered six patients with new-onset epilepsy in whom we suspected an autoimmune aetiology. We first characterised the clinical, electroencephalographic, cerebrospinal fluid (CSF), imaging, and pathological findings of this syndrome. We subsequently tested them for antibodies against both intracellular and neuronal cell surface antigens. All patients presented with recurrent seizures with focal frontotemporal onset, refractory to multiple anticonvulsants. Four had focal T2-weighted hyperintensities on MRI. CSF mononuclear cells were variably elevated with positive oligoclonal bands in four. Brain biopsy in one patient demonstrated perivascular lymphocytic infiltration. Two were treated with immunosuppression and went on to achieve complete seizure control and return to baseline cognition. Three of four patients who received only pulsed steroids or no treatment had ongoing frequent seizures, with two dying of sudden unexpected death in epilepsy. Subsequently, three had antibodies identified against neuronal cell surface antigens including N-methyl-D-aspartate receptor and leucine-rich glioma inactivated 1. We suggest that patients with such a presentation should be carefully evaluated for a suspected autoimmune aetiology targeting cell surface antigens and have a therapeutic trial of immunosuppression as this may improve their long-term outcome. PMID:24518268

  9. Bartonella henselae infection presenting with a picture of adult-onset Still's disease.

    PubMed

    Durey, Areum; Kwon, Hea Yoon; Im, Jae-Hyoung; Lee, Sun Myoung; Baek, JiHyeon; Han, Seung Baik; Kang, Jae-Seung; Lee, Jin-Soo

    2016-05-01

    We report a patient with a clinical picture of suggestive for adult-onset Still's Disease (ASOD) due to Bartonella infection. A 42-year-old immunocompetent man was admitted with fever, rash, arthralgia and sore throat. As his clinical picture suggested ASOD except unusual skin manifestation, we treated him on steroid and ibuprofen. His fever and constitutional symptoms responded immediately within 24hrs of commencing therapy, yet rash and leukocytosis remained. Meanwhile, Bartonella infection was proved by culture of bone marrow. Minocyclin treatment started combined with hydroxychloroquine sulfate and the patient discharged with overall improvement. PMID:27000538

  10. Adult Onset Still's Disease: A Review on Diagnostic Workup and Treatment Options.

    PubMed

    Gopalarathinam, Rajesh; Orlowsky, Eric; Kesavalu, Ramesh; Yelaminchili, Sreeteja

    2016-01-01

    Adult onset Still's disease (AOSD) is a rare systemic inflammatory disease of unknown etiology and pathogenesis that presents in 5 to 10% of patients as fever of unknown origin (FUO) accompanied by systemic manifestations. We report an interesting case of a 33-year-old African-American male who presented with one-month duration of FUO along with skin rash, sore throat, and arthralgia. After extensive workup, potential differential diagnoses were ruled out and the patient was diagnosed with AOSD based on the Yamaguchi criteria. The case history, incidence, pathogenesis, clinical manifestations, differential diagnoses, diagnostic workup, treatment modalities, and prognosis of AOSD are discussed in this case report. PMID:27042373

  11. Psychological impact of genetic testing for adult-onset disorders. An update for clinicians.

    PubMed

    Meiser, B; Gleeson, M A; Tucker, K M

    2000-02-01

    Testing for gene mutations that confer susceptibility to adult-onset disorders has potential benefits, but these must be balanced against the psychological harms, if any. We review published findings on the psychological effects of such testing, focusing on Huntington's disease, which has the most available data, and the hereditary cancer syndromes. Most of the evidence suggests that non-carriers and carriers differ significantly in terms of short-term, but not long-term, psychological adjustment to test results. The psychological impact of genetic testing depends more on pretest psychological distress than the test result itself. PMID:10735024

  12. Herpes Zoster Meningitis Complicating Combined Tocilizumab and Cyclosporine Therapy for Adult-Onset Still's Disease

    PubMed Central

    Tsurukawa, Shinichiro; Iwanaga, Nozomi; Izumi, Yasumori; Shirakawa, Atsunori; Kawahara, Chieko; Shukuwa, Tetsuo; Inamoto, Miwako; Kawakami, Atsushi; Migita, Kiyoshi

    2016-01-01

    A 56-year-old female with refractory adult-onset Still's disease presented with ocular herpes zoster infection during TCZ treatment. After three days of acyclovir treatment (5 mg/kg), she developed a severe headache and high fever. Viral DNA isolation and cerebral spinal fluid abnormalities led to a herpes zoster meningitis diagnosis. Her meningitis was cured by high doses of intravenous acyclovir (10 mg/kg for 14 days). To our knowledge, this is the first report of meningeal herpes zoster infection in rheumatic diseases under TCZ treatment. PMID:27092286

  13. Adult Onset Still's Disease: A Review on Diagnostic Workup and Treatment Options

    PubMed Central

    Gopalarathinam, Rajesh; Orlowsky, Eric; Kesavalu, Ramesh; Yelaminchili, Sreeteja

    2016-01-01

    Adult onset Still's disease (AOSD) is a rare systemic inflammatory disease of unknown etiology and pathogenesis that presents in 5 to 10% of patients as fever of unknown origin (FUO) accompanied by systemic manifestations. We report an interesting case of a 33-year-old African-American male who presented with one-month duration of FUO along with skin rash, sore throat, and arthralgia. After extensive workup, potential differential diagnoses were ruled out and the patient was diagnosed with AOSD based on the Yamaguchi criteria. The case history, incidence, pathogenesis, clinical manifestations, differential diagnoses, diagnostic workup, treatment modalities, and prognosis of AOSD are discussed in this case report. PMID:27042373

  14. Cord Blood Transplantation Following Reduced-intensity Conditioning for Adult-onset Inherited Hemophagocytic Lymphohistiocytosis.

    PubMed

    Kuriyama, Takuro; Kato, Koji; Sakamoto, Keiji; Hayashi, Masayasu; Takashima, Shuichiro; Mori, Yasuo; Takenaka, Katsuto; Iwasaki, Hiromi; Teshima, Takanori; Harada, Naoki; Nagafuji, Koji; Miyamoto, Toshihiro; Akashi, Koichi

    2016-01-01

    Inherited hemophagocytic lymphohistiocytosis (HLH) is a genetic anomaly disorder in which abnormally activated cytotoxic T lymphocytes cannot induce the apoptosis of target cells and antigen-presenting cells, leading to hemophagocytosis, pancytopenia, and a variety of symptoms such as a high fever. The present patient with adult-onset HLH developed refractory disease despite receiving immunosuppressive treatments. He underwent a reduced-intensity conditioning (RIC) regimen that comprised antithymocyte globulin (ATG) followed by cord blood transplantation (RIC-CBT). He achieved and maintained a complete donor type. The incorporation of ATG into RIC-CBT may prevent graft failure and control hemophagocytosis, however, further efforts are necessary to reduce infectious complications. PMID:26984088

  15. Herpes Zoster Meningitis Complicating Combined Tocilizumab and Cyclosporine Therapy for Adult-Onset Still's Disease.

    PubMed

    Tsurukawa, Shinichiro; Iwanaga, Nozomi; Izumi, Yasumori; Shirakawa, Atsunori; Kawahara, Chieko; Shukuwa, Tetsuo; Inamoto, Miwako; Kawakami, Atsushi; Migita, Kiyoshi

    2016-01-01

    A 56-year-old female with refractory adult-onset Still's disease presented with ocular herpes zoster infection during TCZ treatment. After three days of acyclovir treatment (5 mg/kg), she developed a severe headache and high fever. Viral DNA isolation and cerebral spinal fluid abnormalities led to a herpes zoster meningitis diagnosis. Her meningitis was cured by high doses of intravenous acyclovir (10 mg/kg for 14 days). To our knowledge, this is the first report of meningeal herpes zoster infection in rheumatic diseases under TCZ treatment. PMID:27092286

  16. Biology of Mitochondria in Neurodegenerative Diseases

    PubMed Central

    Martin, Lee J.

    2012-01-01

    Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) are the most common human adult-onset neurodegenerative diseases. They are characterized by prominent age-related neurodegeneration in selectively vulnerable neural systems. Some forms of AD, PD, and ALS are inherited, and genes causing these diseases have been identified. Nevertheless, the mechanisms of the neuronal degeneration in these familial diseases, and in the more common idiopathic (sporadic) diseases, are unresolved. Genetic, biochemical, and morphological analyses of human AD, PD, and ALS, as well as their cell and animal models, reveal that mitochondria could have roles in this neurodegeneration. The varied functions and properties of mitochondria might render subsets of selectively vulnerable neurons intrinsically susceptible to cellular aging and stress and the overlying genetic variations. In AD, alterations in enzymes involved in oxidative phosphorylation, oxidative damage, and mitochondrial binding of Aβ and amyloid precursor protein have been reported. In PD, mutations in mitochondrial proteins have been identified and mitochondrial DNA mutations have been found in neurons in the substantia nigra. In ALS, changes occur in mitochondrial respiratory chain enzymes and mitochondrial programmed cell death proteins. Transgenic mouse models of human neurodegenerative disease are beginning to reveal possible principles governing the biology of selective neuronal vulnerability that implicate mitochondria and the mitochondrial permeability transition pore. This chapter reviews several aspects of mitochondrial biology and how mitochondrial pathobiology might contribute to the mechanisms of neurodegeneration in AD, PD, and ALS. PMID:22482456

  17. Adult-onset painful axonal polyneuropathy caused by a dominant NAGLU mutation

    PubMed Central

    Tétreault, Martine; Gonzalez, Michael; Dicaire, Marie-Josée; Allard, Pierre; Gehring, Kalle; Leblanc, Diane; Leclerc, Nadine; Schondorf, Ronald; Mathieu, Jean; Zuchner, Stephan

    2015-01-01

    Late-onset painful sensory neuropathies are usually acquired conditions associated with common diseases. Adult presentations of known hereditary forms are often accompanied by other organ involvement. We recruited a large French-Canadian family with a dominantly inherited late-onset painful sensory neuropathy. The main clinical feature is recurrent leg pain that progresses to constant painful paraesthesias in the feet and later the hands. As it evolves, some patients develop a mild sensory ataxia. We selected four affected individuals for whole exome sequencing. Analysis of rare variants shared by all cases led to a list of four candidate variants. Segregation analysis in all 45 recruited individuals has shown that only the p.Ile403Thr variant in the α-N-acetyl-glucosaminidase (NAGLU) gene segregates with the disease. Recessive NAGLU mutations cause the severe childhood lysosomal disease mucopolysacharidosis IIIB. Family members carrying the mutation showed a significant decrease of the enzymatic function (average 45%). The late-onset and variable severity of the symptoms may have precluded the description of such symptoms in parents of mucopolysaccharidosis IIIB cases. The identification of a dominant phenotype associated with a NAGLU mutation supports that some carriers of lysosomal enzyme mutations may develop later in life much milder phenotypes. PMID:25818867

  18. Compound heterozygote mutations in SPG7 in a family with adult-onset primary lateral sclerosis

    PubMed Central

    Yang, Yi; Lynch, David R.; Lukas, Thomas; Ahmeti, Kreshnik; Sleiman, Patrick M.A.; Ryan, Eanna; Schadt, Kimberly A.; Newman, Jordan H.; Deng, Han-Xiang; Siddique, Nailah

    2016-01-01

    Objective: To identify the genetic defect for adult-onset primary lateral sclerosis (PLS) in a family with 5 patients. Methods: Whole-exome sequencing was performed to identify the shared genetic variants in 3 affected members in a PLS family with 5 affected individuals. Sanger sequencing was used for validation of the variants and for cosegregation analysis. Mitochondrial activity for both patients and unaffected siblings was measured using a SeaHorse metabolic analyzer. Results: Whole-exome sequencing and subsequent cosegregation analysis demonstrated that compound heterozygous missense variants L695P and I743T in SPG7 were the only mutations cosegregating with the disease in an autosomal recessive fashion in this family. The parents and siblings are genetically heterozygous and clinically unaffected. Functional studies suggested that the PLS-associated SPG7 mutants affect mitochondrial function when glucose is reduced. Conclusions: Compound heterozygote mutations in SPG7 are associated with adult-onset PLS, extending the spectrum of SPG7-linked neurologic diseases. Patients with the PLS phenotype should have genetic testing for paraplegin, especially when the condition is familial. PMID:27123479

  19. Similarities in speech and white matter characteristics in idiopathic developmental stuttering and adult-onset stuttering

    PubMed Central

    Chang, Soo-Eun; Synnestvedt, Anna; Ostuni, John

    2009-01-01

    Adult-onset stuttering (AS) typically occurs following neurological and/or psychological trauma, considered different from developmental stuttering (DS), which starts during early childhood with few if any new cases reported after adolescence. Here we report four cases of AS, two with apparent psychological trigger and two without, none with evidence of neurological injury, and none conforming to previously reported characteristics of psychogenic stuttering. We asked whether this group of AS would have similar speech and neuroanatomical characteristics to those with DS. We conducted blinded analyses of speech samples in both AS cases and 14 cases of DS on type, frequency, and loci of disfluencies. Diffusion tensor imaging (DTI) was conducted to compare white matter tracts using fractional anisotropy (FA). We found that AS did not differ significantly from DS in any of the speech characteristics measured. On DTI, DS had significantly increased FA relative to controls in the right superior longitudinal tract. AS cases showed a similar trend for increases in these regions when compared to controls. The results of this study suggest that symptoms of idiopathic stuttering can begin during adulthood, and that similar neuroanatomical differences from controls may be associated with both developmental and adult onset idiopathic stuttering. PMID:20640049

  20. Efficacy of Retigabine in Adjunctive Treatment of Partial Onset Seizures in Adults

    PubMed Central

    Splinter, Michele Y.

    2013-01-01

    Objective To evaluate efficacy and tolerability of retigabine (ezogabine, US adopted name) in the adjunctive treatment of partial-onset seizures in adults. Retigabine is the first anticonvulsant in its class, decreasing neuronal excitability by opening voltage-gated potassium channels. Methods MEDLINE and EMBASE were systematically searched using search terms retigabine and ezogabine for randomized controlled trials published from 1980 through August 17, 2013. Additionally, articles relating to pharmacology, pharmacokinetics, tolerability and interactions were examined for inclusion. Published abstracts and websites of the Food and Drug Administration and European Medication Agency were reviewed for additional relevant information. Results One phase IIb and two phase III trials were identified. Retigabine has been reported to have dose dependent efficacy in adjunctive treatment of resistant partial-onset seizures in adults in doses of 600, 900 and 1200 mg/day. Similar to other anticonvulsants, the most common adverse events were central nervous system related. Retigabine has several unique adverse events compared to other anticonvulsants: urinary retention and, with extended use, pigment changes to the skin and retina. Retigabine is metabolized by glucuronidation and acetylation. There are few drug interactions with retigabine. Conclusions Retigabine has been shown to have efficacy when used as adjunctive therapy in partial-onset seizures. It has a novel mechanism of action, activation of voltage-gated potassium channels. It has less drug interactions than many other anticonvulsants because it is not metabolized through the P-450 system. Its place in therapy has yet to be determined, especially with recent reports of pigment discoloration of skin and the retina with extended use. PMID:24250245

  1. Axial mitochondrial myopathy in a patient with rapidly progressive adult-onset scoliosis.

    PubMed

    Hiniker, Annie; Wong, Lee-Jun; Berven, Sigurd; Truong, Cavatina K; Adesina, Adekunle M; Margeta, Marta

    2014-01-01

    Axial myopathy can be the underlying cause of rapidly progressive adult-onset scoliosis; however, the pathogenesis of this disorder remains poorly understood. Here we present a case of a 69-year old woman with a family history of scoliosis affecting both her mother and her son, who over 4 years developed rapidly progressive scoliosis. The patient had a history of stable scoliosis since adolescence that worsened significantly at age 65, leading to low back pain and radiculopathy. Paraspinal muscle biopsy showed morphologic evidence of a mitochondrial myopathy. Diagnostic deficiencies of electron transport chain enzymes were not detected using standard bioassays, but mitochondrial immunofluorescence demonstrated many muscle fibers totally or partially deficient for complexes I, III, IV-I, and IV-IV. Massively parallel sequencing of paraspinal muscle mtDNA detected multiple deletions as well as a 40.9% heteroplasmic novel m.12293G > A (MT-TL2) variant, which changes a G:C pairing to an A:C mispairing in the anticodon stem of tRNA Leu(CUN). Interestingly, these mitochondrial abnormalities were not detected in the blood of either the patient or her son, suggesting that the patient's rapidly progressive late onset scoliosis was due to the acquired paraspinal mitochondrial myopathy; the cause of non-progressive scoliosis in the other two family members currently remains unexplained. Notably, this case illustrates that isolated mitochondrial myopathy can underlie rapidly-progressive adult-onset scoliosis and should be considered in the differential diagnosis of the primary axial myopathy.

  2. Sensorimotor Oscillations Prior to Speech Onset Reflect Altered Motor Networks in Adults Who Stutter

    PubMed Central

    Mersov, Anna-Maria; Jobst, Cecilia; Cheyne, Douglas O.; De Nil, Luc

    2016-01-01

    Adults who stutter (AWS) have demonstrated atypical coordination of motor and sensory regions during speech production. Yet little is known of the speech-motor network in AWS in the brief time window preceding audible speech onset. The purpose of the current study was to characterize neural oscillations in the speech-motor network during preparation for and execution of overt speech production in AWS using magnetoencephalography (MEG). Twelve AWS and 12 age-matched controls were presented with 220 words, each word embedded in a carrier phrase. Controls were presented with the same word list as their matched AWS participant. Neural oscillatory activity was localized using minimum-variance beamforming during two time periods of interest: speech preparation (prior to speech onset) and speech execution (following speech onset). Compared to controls, AWS showed stronger beta (15–25 Hz) suppression in the speech preparation stage, followed by stronger beta synchronization in the bilateral mouth motor cortex. AWS also recruited the right mouth motor cortex significantly earlier in the speech preparation stage compared to controls. Exaggerated motor preparation is discussed in the context of reduced coordination in the speech-motor network of AWS. It is further proposed that exaggerated beta synchronization may reflect a more strongly inhibited motor system that requires a stronger beta suppression to disengage prior to speech initiation. These novel findings highlight critical differences in the speech-motor network of AWS that occur prior to speech onset and emphasize the need to investigate further the speech-motor assembly in the stuttering population.

  3. Sensorimotor Oscillations Prior to Speech Onset Reflect Altered Motor Networks in Adults Who Stutter.

    PubMed

    Mersov, Anna-Maria; Jobst, Cecilia; Cheyne, Douglas O; De Nil, Luc

    2016-01-01

    Adults who stutter (AWS) have demonstrated atypical coordination of motor and sensory regions during speech production. Yet little is known of the speech-motor network in AWS in the brief time window preceding audible speech onset. The purpose of the current study was to characterize neural oscillations in the speech-motor network during preparation for and execution of overt speech production in AWS using magnetoencephalography (MEG). Twelve AWS and 12 age-matched controls were presented with 220 words, each word embedded in a carrier phrase. Controls were presented with the same word list as their matched AWS participant. Neural oscillatory activity was localized using minimum-variance beamforming during two time periods of interest: speech preparation (prior to speech onset) and speech execution (following speech onset). Compared to controls, AWS showed stronger beta (15-25 Hz) suppression in the speech preparation stage, followed by stronger beta synchronization in the bilateral mouth motor cortex. AWS also recruited the right mouth motor cortex significantly earlier in the speech preparation stage compared to controls. Exaggerated motor preparation is discussed in the context of reduced coordination in the speech-motor network of AWS. It is further proposed that exaggerated beta synchronization may reflect a more strongly inhibited motor system that requires a stronger beta suppression to disengage prior to speech initiation. These novel findings highlight critical differences in the speech-motor network of AWS that occur prior to speech onset and emphasize the need to investigate further the speech-motor assembly in the stuttering population. PMID:27642279

  4. Sensorimotor Oscillations Prior to Speech Onset Reflect Altered Motor Networks in Adults Who Stutter

    PubMed Central

    Mersov, Anna-Maria; Jobst, Cecilia; Cheyne, Douglas O.; De Nil, Luc

    2016-01-01

    Adults who stutter (AWS) have demonstrated atypical coordination of motor and sensory regions during speech production. Yet little is known of the speech-motor network in AWS in the brief time window preceding audible speech onset. The purpose of the current study was to characterize neural oscillations in the speech-motor network during preparation for and execution of overt speech production in AWS using magnetoencephalography (MEG). Twelve AWS and 12 age-matched controls were presented with 220 words, each word embedded in a carrier phrase. Controls were presented with the same word list as their matched AWS participant. Neural oscillatory activity was localized using minimum-variance beamforming during two time periods of interest: speech preparation (prior to speech onset) and speech execution (following speech onset). Compared to controls, AWS showed stronger beta (15–25 Hz) suppression in the speech preparation stage, followed by stronger beta synchronization in the bilateral mouth motor cortex. AWS also recruited the right mouth motor cortex significantly earlier in the speech preparation stage compared to controls. Exaggerated motor preparation is discussed in the context of reduced coordination in the speech-motor network of AWS. It is further proposed that exaggerated beta synchronization may reflect a more strongly inhibited motor system that requires a stronger beta suppression to disengage prior to speech initiation. These novel findings highlight critical differences in the speech-motor network of AWS that occur prior to speech onset and emphasize the need to investigate further the speech-motor assembly in the stuttering population. PMID:27642279

  5. Mutated CTSF in adult-onset neuronal ceroid lipofuscinosis and FTD

    PubMed Central

    van der Zee, Julie; Mariën, Peter; Crols, Roeland; Van Mossevelde, Sara; Dillen, Lubina; Perrone, Federica; Engelborghs, Sebastiaan; Verhoeven, Jo; D'aes, Tine; Ceuterick-De Groote, Chantal; Sieben, Anne; Versijpt, Jan; Cras, Patrick; Martin, Jean-Jacques

    2016-01-01

    Objective: To investigate the molecular basis of a Belgian family with autosomal recessive adult-onset neuronal ceroid lipofuscinosis (ANCL or Kufs disease [KD]) with pronounced frontal lobe involvement and to expand the findings to a cohort of unrelated Belgian patients with frontotemporal dementia (FTD). Methods: Genetic screening in the ANCL family and FTD cohort (n = 461) was performed using exome sequencing and targeted massive parallel resequencing. Results: We identified a homozygous mutation (p.Ile404Thr) in the Cathepsin F (CTSF) gene cosegregating in the ANCL family. No other mutations were found that could explain the disease in this family. All 4 affected sibs developed motor symptoms and early-onset dementia with prominent frontal features. Two of them evolved to akinetic mutism. Disease presentation showed marked phenotypic variation with the onset ranging from 26 to 50 years. Myoclonic epilepsy in one of the sibs was suggestive for KD type A, while epilepsy was not present in the other sibs who presented with clinical features of KD type B. In a Belgian cohort of unrelated patients with FTD, the same heterozygous p.Arg245His mutation was identified in 2 patients who shared a common haplotype. Conclusions: A homozygous CTSF mutation was identified in a recessive ANCL pedigree. In contrast to the previous associations of CTSF with KD type B, our findings suggest that CTSF genetic testing should also be considered in patients with KD type A as well as in early-onset dementia with prominent frontal lobe and motor symptoms. PMID:27668283

  6. Pain Characteristics Associated With the Onset of Disability in Older Adults: The MOBILIZE Boston Study

    PubMed Central

    Eggermont, Laura H.P.; Leveille, Suzanne G.; Shi, Ling; Kiely, Dan K.; Shmerling, Robert H.; Jones, Rich N.; Guralnik, Jack M.; Bean, Jonathan F.

    2014-01-01

    Background/Objectives To determine the effects of chronic pain on the development of disability and decline in physical performance over time among older adults. Design Longitudinal cohort study with 18 months follow-up. Setting Urban/suburban communities Participants 634 community-dwelling older adults aged >64 years. Measurements Chronic pain assessment consisted of musculoskeletal pain locations, and pain severity and pain interference by subscales of the Brief Pain Inventory. Disability was self-reported as any difficulty in mobility and basic and instrumental activities of daily living (ADL, IADL). Mobility performance was measured using the Short Physical Performance Battery (SPPB). Relationships between baseline pain and incident disability in 18 months were determined using risk ratios (RRs) from multivariable Poisson regression models. Results Almost 65% of participants reported chronic musculoskeletal pain at baseline. New onset of mobility difficulty at 18-months was strongly associated with baseline pain distribution: 7% (no sites), 18% (1 site), 24% (multisite) and 39% (widespread pain, p-value for trend <0.001). Similar graded effects were found for other disability measures. Elders with multisite or widespread pain had at least a three-fold increased risk for onset of mobility difficulty compared to their peers without pain after adjusting for disability risk factors (multisite pain: RR=2.95, 95%CI, 1.58–5.50; widespread pain: RR=3.57, 95%CI, 1.71–7.48). Widespread pain contributed to decline in mobility performance (1 point decline in SPPB, RR=1.47, 95%CI, 1.08–2.01). Similar associations were found for baseline pain interference predicting subsequent mobility decline and (I)ADL disability. Weaker and less consistent associations were observed with pain severity. Conclusion Older community-dwelling adults living with chronic pain in multiple musculoskeletal locations have a substantial increased risk for developing disability over time and for

  7. Adult onset sinonasal rhabdomyosarcoma - a rare case report with cytohistological features.

    PubMed

    Sood, N; Sehrawat, N

    2016-08-01

    Rhabdomyosarcoma (RMS) is a fast growing, malignant tumour arising from immature mesenchymal cells, committed to skeletal muscle differentiation. It is more often seen in the paediatric population and constitutes less than 1% of all malignancies and less than 3% of all soft tissue tumours. RMS of the paranasal sinuses constitutes 10-15% of adult head and neck RMS, ethmoidal and maxillary sinuses being the most common. We report a 56-year-oldman presenting with left nasal obstruction, epistaxis on and off and left cheek swelling. Nasal endoscopy revealed a reddish friable mass, bleeding on touch, in the left nasal cavity. CECT scan showed a heterogeneous growth in the left maxillary sinus eroding the medial orbital wall and lateral nasal wall. FNAC of the left cheek swelling yielded highly cellular smears showing predominantly singly scattered round to ovoid neoplastic cells with scanty cytoplasm and indistinct nucleoli. Few of the cells had eccentric nuclei with moderate amount of eosinophilic cytoplasm. Attempted pseudorossette formation was seen. An impression of round cell tumour was given. A diagnosis of an adult onset sinonasal rhabdomyosarcoma was made on histopathological examination of the nasal biopsy, supported by immunohistochemistry (IHC) showing strong myogenin positivity, focal positivity for PAX8 and negativity for CK, LCA, S-100 and CD99. Parameningeal RMS is rare in adults especially the elderly. However, it needs to be considered whenever a poorly-differentiated neoplasm is seen in this age and IHC is a useful aid. PMID:27568676

  8. Adult-Onset Hypothyroidism Enhances Fear Memory and Upregulates Mineralocorticoid and Glucocorticoid Receptors in the Amygdala

    PubMed Central

    Montero-Pedrazuela, Ana; Fernández-Lamo, Iván; Alieva, María; Pereda-Pérez, Inmaculada; Venero, César; Guadaño-Ferraz, Ana

    2011-01-01

    Hypothyroidism is the most common hormonal disease in adults, which is frequently accompanied by learning and memory impairments and emotional disorders. However, the deleterious effects of thyroid hormones deficiency on emotional memory are poorly understood and often underestimated. To evaluate the consequences of hypothyroidism on emotional learning and memory, we have performed a classical Pavlovian fear conditioning paradigm in euthyroid and adult-thyroidectomized Wistar rats. In this experimental model, learning acquisition was not impaired, fear memory was enhanced, memory extinction was delayed and spontaneous recovery of fear memory was exacerbated in hypothyroid rats. The potentiation of emotional memory under hypothyroidism was associated with an increase of corticosterone release after fear conditioning and with higher expression of glucocorticoid and mineralocorticoid receptors in the lateral and basolateral nuclei of the amygdala, nuclei that are critically involved in the circuitry of fear memory. Our results demonstrate for the first time that adult-onset hypothyroidism potentiates fear memory and also increases vulnerability to develop emotional memories. Furthermore, our findings suggest that enhanced corticosterone signaling in the amygdala is involved in the pathophysiological mechanisms of fear memory potentiation. Therefore, we recommend evaluating whether inappropriate regulation of fear in patients with post-traumatic stress and other mental disorders is associated with abnormal levels of thyroid hormones, especially those patients refractory to treatment. PMID:22039511

  9. Reverse engineering human neurodegenerative disease using pluripotent stem cell technology.

    PubMed

    Liu, Ying; Deng, Wenbin

    2016-05-01

    With the technology of reprogramming somatic cells by introducing defined transcription factors that enables the generation of "induced pluripotent stem cells (iPSCs)" with pluripotency comparable to that of embryonic stem cells (ESCs), it has become possible to use this technology to produce various cells and tissues that have been difficult to obtain from living bodies. This advancement is bringing forth rapid progress in iPSC-based disease modeling, drug screening, and regenerative medicine. More and more studies have demonstrated that phenotypes of adult-onset neurodegenerative disorders could be rather faithfully recapitulated in iPSC-derived neural cell cultures. Moreover, despite the adult-onset nature of the diseases, pathogenic phenotypes and cellular abnormalities often exist in early developmental stages, providing new "windows of opportunity" for understanding mechanisms underlying neurodegenerative disorders and for discovering new medicines. The cell reprogramming technology enables a reverse engineering approach for modeling the cellular degenerative phenotypes of a wide range of human disorders. An excellent example is the study of the human neurodegenerative disease amyotrophic lateral sclerosis (ALS) using iPSCs. ALS is a progressive neurodegenerative disease characterized by the loss of upper and lower motor neurons (MNs), culminating in muscle wasting and death from respiratory failure. The iPSC approach provides innovative cell culture platforms to serve as ALS patient-derived model systems. Researchers have converted iPSCs derived from ALS patients into MNs and various types of glial cells, all of which are involved in ALS, to study the disease. The iPSC technology could be used to determine the role of specific genetic factors to track down what's wrong in the neurodegenerative disease process in the "disease-in-a-dish" model. Meanwhile, parallel experiments of targeting the same specific genes in human ESCs could also be performed to control

  10. Solitary mastocytoma presenting in an adult: report and literature review of adult-onset solitary cutaneous mastocytoma with recommendations for evaluation and treatment

    PubMed Central

    Cohen, Philip R.

    2016-01-01

    Background: Mastocytosis is either cutaneous (with skin-limited proliferation of mast cells) or systemic (with mast cells in extracutaneous sites). The onset of solitary mastocytoma in an adult is rare. Purpose: A woman with the new onset of solitary mastocytoma is described. The clinical features of patients with adult-onset solitary mastocytoma are summarized. Recommendations for the evaluation and treatment of individuals with adult-onset solitary mastocytoma are proposed. Methods: PubMed was searched with the key words: adult, CD2, CD25, cell, cutaneous, disease, KIT, KIT D816V, mast, mastocytoma, mutation, pigmentosa, solitary, tryptase, and urticarial. The papers generated by the search, and their references, were reviewed. Results: A 38-year-old Taiwanese woman presented with an asymptomatic brown patch, which morphologically mimicked a dysplastic nevus, on her right abdomen; biopsy demonstrated a solitary mastocytoma. Comprehensive evaluation (including serologic and bone marrow examination) excluded systemic mastocytosis and her residual mastocytoma is being monitored. Adult-onset solitary mastocytoma has been described in 16 patients. Lesions were either on the head and neck (5/14), torso (5/14) or extremities (4/14). Urtication following lesion rubbing was noted in 79% (11/14) of patients. Excision of the mastocytoma [75% (9/12)] was the most common treatment. Other management approaches included corticosteroids (topical or intralesional), antihistamines (systemic) or observation. Systemic symptoms were noted in 5 patients: flushing (3 women) and pruritus (3 women); gastrointestinal symptoms and headaches, flushing and/or anaphylaxis were each noted in one woman. None of the patients with adult-onset solitary mastocytoma had systemic mastocytosis; however, only 3 women were evaluated for systemic mastocytosis. Conclusions: Systemic mastocytosis is common in adults with new onset cutaneous mastocytosis. Therefore, a conservative work up for new onset

  11. Solitary mastocytoma presenting in an adult: report and literature review of adult-onset solitary cutaneous mastocytoma with recommendations for evaluation and treatment

    PubMed Central

    Cohen, Philip R.

    2016-01-01

    Background: Mastocytosis is either cutaneous (with skin-limited proliferation of mast cells) or systemic (with mast cells in extracutaneous sites). The onset of solitary mastocytoma in an adult is rare. Purpose: A woman with the new onset of solitary mastocytoma is described. The clinical features of patients with adult-onset solitary mastocytoma are summarized. Recommendations for the evaluation and treatment of individuals with adult-onset solitary mastocytoma are proposed. Methods: PubMed was searched with the key words: adult, CD2, CD25, cell, cutaneous, disease, KIT, KIT D816V, mast, mastocytoma, mutation, pigmentosa, solitary, tryptase, and urticarial. The papers generated by the search, and their references, were reviewed. Results: A 38-year-old Taiwanese woman presented with an asymptomatic brown patch, which morphologically mimicked a dysplastic nevus, on her right abdomen; biopsy demonstrated a solitary mastocytoma. Comprehensive evaluation (including serologic and bone marrow examination) excluded systemic mastocytosis and her residual mastocytoma is being monitored. Adult-onset solitary mastocytoma has been described in 16 patients. Lesions were either on the head and neck (5/14), torso (5/14) or extremities (4/14). Urtication following lesion rubbing was noted in 79% (11/14) of patients. Excision of the mastocytoma [75% (9/12)] was the most common treatment. Other management approaches included corticosteroids (topical or intralesional), antihistamines (systemic) or observation. Systemic symptoms were noted in 5 patients: flushing (3 women) and pruritus (3 women); gastrointestinal symptoms and headaches, flushing and/or anaphylaxis were each noted in one woman. None of the patients with adult-onset solitary mastocytoma had systemic mastocytosis; however, only 3 women were evaluated for systemic mastocytosis. Conclusions: Systemic mastocytosis is common in adults with new onset cutaneous mastocytosis. Therefore, a conservative work up for new onset

  12. Bone Characteristics and Their Determinants in Adolescents and Young Adults with Early-Onset Severe Obesity.

    PubMed

    Viljakainen, H T; Valta, H; Lipsanen-Nyman, M; Saukkonen, T; Kajantie, E; Andersson, S; Mäkitie, O

    2015-10-01

    Childhood obesity is associated with compromised bone health. We studied bone characteristics and their determinants in obese young adults. The study included 68 subjects with early-onset severe obesity and 73 normal-weight controls. Data on physical activity (PA), diet and smoking were collected. Bone characteristics were measured using peripheral QCT. The obese and control subjects were similar in age (mean 19.6 ± 2.6 years) and height but BMIs differed (39.7 and 22.6 kg/m(2)). A clustering of unhealthy lifestyles was marked: Obese subjects reported less supervised PA in childhood, adolescence and currently (p < 0.03) and were more likely to smoke (p = 0.005), and had a lower healthy eating index (HEI) (p = 0.007) but similar alcohol consumption compared with controls. In obese women, all crude bone characteristics were higher than in controls; in men, the differences were smaller. Associations of lifestyle factors with bone characteristics were tested using partial correlations. Independently of BMI, supervised PA in adolescence and alcohol consumption were related positively to bone characteristics in both groups. HEI associated positively with bone characteristics only in controls, while smoking was a positive determinant of bone characteristics only in obese subjects. The multivariate model showed that the contribution of lifestyle factors to bone characteristics was minimal compared with BMI. Early-onset obesity is accompanied by poor dietary quality, sedentary lifestyle, and more frequent smoking, but the overall contribution of these lifestyle factors to bone strength is limited. Bone strength is more likely to be compromised in men and in unloaded bone sites in subjects with early-onset severe obesity. The impact of obesity-related endocrine changes on bone characteristics need to be evaluated in future studies.

  13. Adult-Onset Fatal Neurohepatopathy in a Woman Caused by MPV17 Mutation.

    PubMed

    Mendelsohn, Bryce A; Mehta, Neil; Hameed, Bilal; Pekmezci, Melike; Packman, Seymour; Ralph, Jeffrey

    2014-01-01

    Hepatocerebral mitochondrial DNA depletion syndromes are classically considered diseases of early childhood, typically affecting the liver, peripheral, and central nervous systems with a rapidly progressive course. Evidence is emerging that initial symptom onset can extend into adulthood, though few such cases have been reported. We describe a 25-year-old woman who presented initially with secondary amenorrhea, followed by a megaloblastic anemia, lactic acidosis, leukoencephalopathy, progressive peripheral neuropathy, and liver cirrhosis. An apparently homozygous P98L mutation was identified in MPV17, a gene associated with a lethal infantile neurohepatopathy. Homozygosity for the same allele was recently reported in a man with a similar hepatic and neurologic phenotype. This is the first clinical report of an adult female with this disorder, and the first to describe amenorrhea and megaloblastic anemia as likely associated symptoms. PMID:24190800

  14. Adult onset Still's disease accompanied by acute respiratory distress syndrome: A case report

    PubMed Central

    Xi, Xiao-Tu; Wang, Mao-Jie; Huang, Run-Yue; Ding, Bang-Han

    2016-01-01

    Adult onset Still's disease (AOSD) is a systemic inflammatory disorder characterized by rash, leukocytosis, fever and arthralgia/arthritis. The most common pulmonary manifestations associated with AOSD are pulmonary infiltrates and pleural effusion. The present study describes a 40-year-old male with AOSD who developed fever, sore throat and shortness of breath. Difficulty breathing promptly developed, and the patient was diagnosed with acute respiratory distress syndrome (ARDS). The patient did not respond to antibiotics, including imipenem, vancomycin, fluconazole, moxifloxacin, penicillin, doxycycline and meropenem, but was sensitive to glucocorticoid treatment, including methylprednisolone sodium succinate. ARDS accompanied by AOSD has been rarely reported in the literature. In conclusion, in a patient with ARDS who does not respond to antibiotic treatment, the involvement of AOSD should be considered. PMID:27588099

  15. Adult-onset Still's disease with myocarditis and hemophagocytic lymphohistiocytosis: Rare manifestation with fatal outcome.

    PubMed

    Gupta, Devika; Jagani, Rajat; Mendonca, Satish; Rathi, Khushi Ram

    2016-01-01

    Adult-onset Still's disease (AOSD) is a rare inflammatory disorder of unknown etiology characterized by fever, evanescent pink salmon rash, arthritis, and multiorgan involvement. Here, we report an unusual manifestation of AOSD in a 40-year-old male who presented to our hospital with pyrexia of unknown origin and rash of 3 weeks duration. All his serological investigations and imaging studies were unremarkable. He was fulfilling clinical and laboratory criteria as per Yamaguchi for AOSD and was managed for the same. Our patient did not respond well to the treatment, had a downhill course, and succumbed to his illness. Autopsy confirmed myocarditis and florid bone marrow reactive hemophagocytosis as the cause of his death. PMID:26960645

  16. Case report: An adult-onset type II citrin deficiency patient in the emergency department

    PubMed Central

    TANG, LUJIA; CHEN, LIANG; WANG, HAIRONG; DAI, LIHUA; PAN, SHUMING

    2016-01-01

    Mutations in the solute carrier family 25 (SLC25A13) gene may result in neonatal intrahepatic cholestasis caused by citrin deficiency and/or adult-onset type II citrullinemia. These conditions are inherited in an autosomal recessive manner. The current case report describes a 43-year-old man who presented with sudden delirium and upper limb weakness. Upon admission, the patient was fully conscious and alert but later lost consciousness subsequent to a sudden convulsive seizure. Hyperammonemia was detected and analysis of the SLC25A13 gene identified an 851del4 mutation. Thus, the possibility of genetic disease should be considered as a potential cause of the symptoms of patients with altered states of consciousness, such as delirium and loss of consciousness, in cases where the cause of the disturbance is unknown. PMID:27347070

  17. Adult-onset nemaline myopathy in a dog presenting with persistent atrial standstill and primary hypothyroidism.

    PubMed

    Nakamura, R K; Russell, N J; Shelton, G D

    2012-06-01

    A nine-year-old neutered female mixed breed dog presented for evaluation following a five-day history of lethargy, inappetence, weakness, abdominal distension and generalised muscle atrophy. Persistent vatrial standstill with a junctional rhythm was identified on electrocardiogram. Echocardiogram identified moderate dilation of all cardiac chambers and mild thickening of the mitral and tricuspid valves. Serology was negative for Neospora caninum and Toxoplasma gondii. Permanent pacemaker implantation was performed in addition to endomyocardial and skeletal muscle biopsies. Cryosections from the biceps femoris muscle showed numerous nemaline rod bodies while endomyocardial biopsies were possibly consistent with end-stage myocarditis. Rod bodies have rarely been reported in the veterinary literature. To the authors' knowledge, this is the first report of adult-onset nemaline rod myopathy and hypothyroidism with concurrent cardiac disease in a dog. PMID:22647214

  18. Myotonia and flaccid dysarthria in patients with adult onset myotonic dystrophy

    PubMed Central

    de Swart, B J M; van Engelen, B G M; van de Kerkhof, J P B M; Maassen, B

    2004-01-01

    Objective: To specify and quantify possible defects in speech execution in patients with adult onset myotonic dystrophy. Methods: Studies on speech production were done on 30 mildly affected patients with myotonic dystrophy. Special attention was paid to myotonia. Because muscle activity can result in a decrease of myotonia, speech characteristics were measured before and after warm up. The possibility that warming up causes increased weakness was also assessed. Results: As with other motor skills, a warm up effect was found in speech production, resulting in an increase in repetition rate and a decrease in variability of repetition rate. Signs of fatigue did not occur. Conclusions: Warming up is valuable for patients with myotonic dystrophy in reducing the influence of myotonia on speech production. PMID:15377703

  19. A mouse model of adult-onset anaemia due to erythropoietin deficiency.

    PubMed

    Yamazaki, Shun; Souma, Tomokazu; Hirano, Ikuo; Pan, Xiaoqing; Minegishi, Naoko; Suzuki, Norio; Yamamoto, Masayuki

    2013-01-01

    Erythropoietin regulates erythropoiesis in a hypoxia-inducible manner. Here we generate inherited super-anaemic mice (ISAM) as a mouse model of adult-onset anaemia caused by erythropoietin deficiency. ISAM express erythropoietin in the liver but lack erythropoietin production in the kidney. Around weaning age, when the major erythropoietin-producing organ switches from the liver to the kidney, ISAM develop anaemia due to erythropoietin deficiency, which is curable by administration of recombinant erythropoietin. In ISAM severe chronic anaemia enhances transgenic green fluorescent protein and Cre expression driven by the complete erythropoietin-gene regulatory regions, which facilitates efficient labelling of renal erythropoietin-producing cells. We show that the majority of cortical and outer medullary fibroblasts have the innate potential to produce erythropoietin, and also reveal a new set of erythropoietin target genes. ISAM are a useful tool for the evaluation of erythropoiesis-stimulating agents and to trace the dynamics of erythropoietin-producing cells. PMID:23727690

  20. Prenatal testosterone supplementation alters puberty onset, aggressive behavior, and partner preference in adult male rats.

    PubMed

    Dela Cruz, Cynthia; Pereira, Oduvaldo C M

    2012-03-01

    The objective of this study was to investigate whether prenatal exposure to testosterone (T) could change the body weight (BW), anogenital distance (AGD), anogenital distance index (AGDI), puberty onset, social behavior, fertility, sexual behavior, sexual preference, and T level of male rats in adulthood. To test this hypothesis, pregnant rats received either 1 mg/animal of T propionate diluted in 0.1 ml peanut oil or 0.1 ml peanut oil, as control, on the 17th, 18th and 19th gestational days. No alterations in BW, AGD, AGDI, fertility, and sexual behavior were observed (p > 0.05). Delayed onset of puberty (p < 0.0001), increased aggressive behavior (p > 0.05), altered pattern of sexual preference (p < 0.05), and reduced T plasma level (p < 0.05) were observed for adult male rats exposed prenatally to T. In conclusion, the results showed that prenatal exposure to T was able to alter important aspects of sexual and social behavior although these animals were efficient at producing descendants. In this sense more studies should be carried to evaluated the real impact of this hormonal alteration on critical period of sexual differentiation on humans, because pregnant women exposed to hyperandrogenemia and then potentially exposing their unborn children to elevated androgen levels in the uterus can undergo alteration of normal levels of T during the sexual differentiation period, and, as a consequence, affect the reproductive and behavior patterns of their children in adulthood.

  1. Occasional detection of thymic epithelial tumor 4 years after diagnosis of adult onset Still disease

    PubMed Central

    Lococo, Filippo; Bajocchi, Gianluigi; Caruso, Andrea; Valli, Riccardo; Ricchetti, Tommaso; Sgarbi, Giorgio; Salvarani, Carlo

    2016-01-01

    Abstract Background: Thymoma is a T cell neoplasm arising from the thymic epithelium that due to its immunological role, frequently undercover derangements of immunity such a tumors and autoimmune diseases. Methods: Herein, we report, to the best of our knowledge, the first description of an association between thymoma and adult onset Still disease (AOSD) in a 47-year-old man. The first one was occasionally detected 4 years later the diagnosis of AOSD, and surgically removed via right lateral thoracotomy. Histology confirmed an encapsulated thymic tumor (type AB sec. WHO-classification). Results: The AOSD was particularly resistant to the therapy, requiring a combination of immunosuppressant followed by anti-IL1R, that was the only steroids-sparing treatment capable to induce and maintain the remission. The differential diagnosis was particularly challenging because of the severe myasthenic-like symptoms that, with normal laboratory tests, were initially misinterpreted as fibromyalgia. The pathogenic link of this association could be a thymus escape of autoreactive T lymphocytes causing autoimmunity. Conclusion: Clinicians should be always include the possibility of a thymoma in the differential diagnosis of an unusual new onset of weakness and normal laboratories data, in particular once autoimmune disease is present in the medical history. PMID:27603335

  2. Macrophage Activation Syndrome Associated with Adult-Onset Still's Disease Successfully Treated with Anakinra

    PubMed Central

    Kato, Hiroshi

    2016-01-01

    Macrophage activation syndrome (MAS) is a potentially fatal complication of Adult-Onset Still's disease (Still's disease). Whereas an increasing body of evidence supports interleukin-1 (IL-1) blockade as a promising treatment for Still's disease, whether it is therapeutic for MAS associated with Still's disease remains unclear. We report a 34-year-old Caucasian man with one-decade history of TNF-blockade-responsive seronegative arthritis who presented with abrupt onset of fever, serositis, bicytopenia, splenomegaly, hepatitis, and disseminated intravascular coagulation. Striking hyperferritinemia was noted without evidence of infection, malignancy, or hemophagocytosis on bone marrow biopsy. NK cells were undetectable in the peripheral blood, whereas soluble IL-2 receptor was elevated. His multiorgan disease resolved in association with methylprednisolone pulse therapy, Anakinra, and a tapering course of prednisone. This case reinforces the notion that Still's disease is inherently poised to manifest MAS as one of the clinical phenotypes by shedding light on the role of IL-1 underlying both Still's disease and related MAS.

  3. Meditation and neurodegenerative diseases.

    PubMed

    Newberg, Andrew B; Serruya, Mijail; Wintering, Nancy; Moss, Aleezé Sattar; Reibel, Diane; Monti, Daniel A

    2014-01-01

    Neurodegenerative diseases pose a significant problem for the healthcare system, doctors, and patients. With an aging population, more and more individuals are developing neurodegenerative diseases and there are few treatment options at the present time. Meditation techniques present an interesting potential adjuvant treatment for patients with neurodegenerative diseases and have the advantage of being inexpensive, and easy to teach and perform. There is increasing research evidence to support the application of meditation techniques to help improve cognition and memory in patients with neurodegenerative diseases. This review discusses the current data on meditation, memory, and attention, and the potential applications of meditation techniques in patients with neurodegenerative diseases.

  4. Possible risk factors for primary adult onset dystonia: a case-control investigation by the Italian Movement Disorders Study Group

    PubMed Central

    Defazio, G.; Berardelli, A.; Abbruzzese, G.; Lepore, V.; Coviello, V.; Acquistapace, D.; Capus, L.; Carella, F.; De Berardinis, M. T.; Galardi, G.; Girlanda, P.; Maurri, S.; Albanese, A.; Bertolasi, L.; Liguori, R.; Rossi, A.; Santoro, L.; Tognoni, G.; Livrea, P.

    1998-01-01

    OBJECTIVES—Little is known about the aetiology of idiopathic adult onset dystonia. The Italian Movement Disorders Study Group promoted a case-control study on some hypothetical risk factors including past medical events, life events, life habits, occupational hazards, and family hystory of dystonia, parkinsonism, and tremor.
METHODS—Cases affected by idiopathic adult onset dystonia (age at symptom onset >20 years, duration of disease >one year and adult onset dystonia, whereas hypertension and cigarette smoking exerted a protective effect. The findings also suggested a positive association between local body injury—for example, previous ocular diseases and neck or trunk trauma—and dystonia of the same body part.
CONCLUSIONS—The results support the idea that environmental and genetic factors may both be important in the aetiology of adult onset dystonia, and suggest aetiological clues worthy of further analytical investigation.

 PMID:9436723

  5. Is adult ADHD a childhood-onset neurodevelopmental disorder? Evidence from a 4-decade longitudinal cohort study

    PubMed Central

    Moffitt, Terrie E.; Houts, Renate; Asherson, Philip; Belsky, Daniel W; Corcoran, David L; Hammerle, Maggie; Harrington, Honalee; Hogan, Sean; Meier, Madeline; Polanczyk, Guilherme V.; Poulton, Richie; Ramrakha, Sandhya; Sugden, Karen; Williams, Benjamin; Rohde, Luis Augusto; Caspi, Avshalom

    2015-01-01

    Objective Despite a prevailing assumption that adult ADHD is a childhood-onset neurodevelopmental disorder, no prospective-longitudinal study has described the childhoods of the adult-ADHD population. We report follow-back analyses of ADHD cases diagnosed in adulthood, alongside follow-forward analyses of ADHD cases diagnosed in childhood, in one cohort. Method Participants belonged to a representative birth cohort of 1,037 individuals born in Dunedin, New Zealand in 1972-73 and followed to age 38, with 95% retention. Symptoms of ADHD, associated clinical features, comorbid disorders, neuropsychological deficits, GWAS-derived polygenic risk, and life impairment indicators were assessed. Data sources were participants, parents, teachers, informants, neuropsychological testing, and administrative records. Adult ADHD diagnoses used DSM5 criteria, apart from onset-age and cross-setting corroboration, which were study outcomes. Results As expected, the childhood-ADHD group showed 6% prevalence, male excess, childhood comorbid disorders, neurocognitive deficits, polygenic risk, and, despite having outgrown their ADHD diagnosis, residual adult life impairment. As expected, the adult-ADHD group showed 3% prevalence, gender balance, adult substance dependence, adult life impairment, and treatment contact. Unexpectedly, the childhood-ADHD and adult-ADHD groups comprised virtually non-overlapping sets; 90% of adult-ADHD cases lacked a history of childhood ADHD. Also unexpectedly, the adult-ADHD group did not show tested neuropsychological deficits in childhood or adulthood, nor did they show polygenic risk for childhood ADHD. Conclusion Findings raise the possibility that adults presenting with the ADHD symptom picture may not have a childhood-onset neurodevelopmental disorder. If this finding is replicated, then the disorder's place in the classification system must be reconsidered, and research must investigate the etiology of adult ADHD. PMID:25998281

  6. Effects of Aging and Adult-Onset Hearing Loss on Cortical Auditory Regions

    PubMed Central

    Cardin, Velia

    2016-01-01

    Hearing loss is a common feature in human aging. It has been argued that dysfunctions in central processing are important contributing factors to hearing loss during older age. Aging also has well documented consequences for neural structure and function, but it is not clear how these effects interact with those that arise as a consequence of hearing loss. This paper reviews the effects of aging and adult-onset hearing loss in the structure and function of cortical auditory regions. The evidence reviewed suggests that aging and hearing loss result in atrophy of cortical auditory regions and stronger engagement of networks involved in the detection of salient events, adaptive control and re-allocation of attention. These cortical mechanisms are engaged during listening in effortful conditions in normal hearing individuals. Therefore, as a consequence of aging and hearing loss, all listening becomes effortful and cognitive load is constantly high, reducing the amount of available cognitive resources. This constant effortful listening and reduced cognitive spare capacity could be what accelerates cognitive decline in older adults with hearing loss. PMID:27242405

  7. Evolution of disease phenotype in adult and pediatric onset Crohn’s disease in a population-based cohort

    PubMed Central

    Lovasz, Barbara Dorottya; Lakatos, Laszlo; Horvath, Agnes; Szita, Istvan; Pandur, Tunde; Mandel, Michael; Vegh, Zsuzsanna; Golovics, Petra Anna; Mester, Gabor; Balogh, Mihaly; Molnar, Csaba; Komaromi, Erzsebet; Kiss, Lajos Sandor; Lakatos, Peter Laszlo

    2013-01-01

    AIM: To investigate the evolution of disease phenotype in adult and pediatric onset Crohn’s disease (CD) populations, diagnosed between 1977 and 2008. METHODS: Data of 506 incident CD patients were analyzed (age at diagnosis: 28.5 years, interquartile range: 22-38 years). Both in- and outpatient records were collected prospectively with a complete clinical follow-up and comprehensively reviewed in the population-based Veszprem province database, which included incident patients diagnosed between January 1, 1977 and December 31, 2008 in adult and pediatric onset CD populations. Disease phenotype according to the Montreal classification and long-term disease course was analysed according to the age at onset in time-dependent univariate and multivariate analysis. RESULTS: Among this population-based cohort, seventy-four (12.8%) pediatric-onset CD patients were identified (diagnosed ≤ 17 years of age). There was no significant difference in the distribution of disease behavior between pediatric (B1: 62%, B2: 15%, B3: 23%) and adult-onset CD patients (B1: 56%, B2: 21%, B3: 23%) at diagnosis, or during follow-up. Overall, the probability of developing complicated disease behaviour was 49.7% and 61.3% in the pediatric and 55.1% and 62.4% in the adult onset patients after 5- and 10-years of follow-up. Similarly, time to change in disease behaviour from non stricturing, non penetrating (B1) to complicated, stricturing or penetrating (B2/B3) disease was not significantly different between pediatric and adult onset CD in a Kaplan-Meier analysis. Calendar year of diagnosis (P = 0.04), ileal location (P < 0.001), perianal disease (P < 0.001), smoking (P = 0.038) and need for steroids (P < 0.001) were associated with presence of, or progression to, complicated disease behavior at diagnosis and during follow-up. A change in disease location was observed in 8.9% of patients and it was associated with smoking status (P = 0.01), but not with age at diagnosis. CONCLUSION: Long

  8. Steatogenesis in adult-onset type II citrullinemia is associated with down-regulation of PPARα.

    PubMed

    Komatsu, Michiharu; Kimura, Takefumi; Yazaki, Masahide; Tanaka, Naoki; Yang, Yang; Nakajima, Takero; Horiuchi, Akira; Fang, Zhong-Ze; Joshita, Satoru; Matsumoto, Akihiro; Umemura, Takeji; Tanaka, Eiji; Gonzalez, Frank J; Ikeda, Shu-Ichi; Aoyama, Toshifumi

    2015-03-01

    SLC25A13 (citrin or aspartate-glutamate carrier 2) is located in the mitochondrial membrane in the liver and its genetic deficiency causes adult-onset type II citrullinemia (CTLN2). CTLN2 is one of the urea cycle disorders characterized by sudden-onset hyperammonemia due to reduced argininosuccinate synthase activity. This disorder is frequently accompanied with hepatosteatosis in the absence of obesity and ethanol consumption. However, the precise mechanism of steatogenesis remains unclear. The expression of genes associated with fatty acid (FA) and triglyceride (TG) metabolism was examined using liver samples obtained from 16 CTLN2 patients and compared with 7 healthy individuals. Although expression of hepatic genes associated with lipogenesis and TG hydrolysis was not changed, the mRNAs encoding enzymes/proteins involved in FA oxidation (carnitine palmitoyl-CoA transferase 1α, medium- and very-long-chain acyl-CoA dehydrogenases, and acyl-CoA oxidase 1), very-low-density lipoprotein secretion (microsomal TG transfer protein), and FA transport (CD36 and FA-binding protein 1), were markedly suppressed in CTLN2 patients. Serum concentrations of ketone bodies were also decreased in these patients, suggesting reduced mitochondrial β-oxidation activity. Consistent with these findings, the expression of peroxisome proliferator-activated receptor α (PPARα), a master regulator of hepatic lipid metabolism, was significantly down-regulated. Hepatic PPARα expression was inversely correlated with severity of steatosis and circulating ammonia and citrulline levels. Additionally, phosphorylation of c-Jun-N-terminal kinase was enhanced in CTLN2 livers, which was likely associated with lower hepatic PPARα. Collectively, down-regulation of PPARα is associated with steatogenesis in CTLN2 patients. These findings provide a novel link between urea cycle disorder, lipid metabolism, and PPARα.

  9. White matter hyperintensities in middle-aged adults with childhood-onset type 1 diabetes

    PubMed Central

    Nunley, Karen A.; Ryan, Christopher M.; Orchard, Trevor J.; Aizenstein, Howard J.; Jennings, J. Richard; Ryan, John; Zgibor, Janice C.; Boudreau, Robert M.; Costacou, Tina; Maynard, John D.; Miller, Rachel G.

    2015-01-01

    Objective: Although microvascular complications are common in type 1 diabetes mellitus (T1DM), few studies have quantified the severity, risk factors, and implications of cerebral microvascular damage in these patients. As life expectancy in patients with T1DM increases, patients are exposed to age- and disease-related factors that may contribute to cerebral microvascular disease. Methods: Severity and volume of white matter hyperintensities (WMH) and infarcts were quantified in 97 middle-aged patients with childhood-onset T1DM (mean age and duration: 50 and 41 years, respectively) and 81 non-T1DM adults (mean age: 48 years), concurrent with cognitive and health-related measures. Results: Compared with non-T1DM participants, patients had more severe WMH (Fazekas scores 2 and 3 compared with Fazekas score 1, p < 0.0001) and slower information processing (digit symbol substitution, number correct: 65.7 ± 10.9 and 54.9 ± 13.6; pegboard, seconds: 66.0 ± 9.9 and 88.5 ± 34.2; both p < 0.0001) independent of age, education, or other factors. WMH were associated with slower information processing; adjusting for WMH attenuated the group differences in processing speed (13% for digit symbol, 11% for pegboard, both p ≤ 0.05). Among patients, prevalent neuropathies and smoking tripled the odds of high WMH burden, independent of age or disease duration. Associations between measures of blood pressure or hyperglycemia and WMH were not significant. Conclusions: Clinically relevant WMH are evident earlier among middle-aged patients with childhood-onset T1DM and are related to the slower information processing frequently observed in T1DM. Brain imaging in patients with T1DM who have cognitive difficulties, especially those with neuropathies, may help uncover cerebral microvascular damage. Longitudinal studies are warranted to fully characterize WMH development, risk factors, and long-term effects on cognition. PMID:25904692

  10. Steatogenesis in adult-onset type II citrullinemia is associated with down-regulation of PPARα.

    PubMed

    Komatsu, Michiharu; Kimura, Takefumi; Yazaki, Masahide; Tanaka, Naoki; Yang, Yang; Nakajima, Takero; Horiuchi, Akira; Fang, Zhong-Ze; Joshita, Satoru; Matsumoto, Akihiro; Umemura, Takeji; Tanaka, Eiji; Gonzalez, Frank J; Ikeda, Shu-Ichi; Aoyama, Toshifumi

    2015-03-01

    SLC25A13 (citrin or aspartate-glutamate carrier 2) is located in the mitochondrial membrane in the liver and its genetic deficiency causes adult-onset type II citrullinemia (CTLN2). CTLN2 is one of the urea cycle disorders characterized by sudden-onset hyperammonemia due to reduced argininosuccinate synthase activity. This disorder is frequently accompanied with hepatosteatosis in the absence of obesity and ethanol consumption. However, the precise mechanism of steatogenesis remains unclear. The expression of genes associated with fatty acid (FA) and triglyceride (TG) metabolism was examined using liver samples obtained from 16 CTLN2 patients and compared with 7 healthy individuals. Although expression of hepatic genes associated with lipogenesis and TG hydrolysis was not changed, the mRNAs encoding enzymes/proteins involved in FA oxidation (carnitine palmitoyl-CoA transferase 1α, medium- and very-long-chain acyl-CoA dehydrogenases, and acyl-CoA oxidase 1), very-low-density lipoprotein secretion (microsomal TG transfer protein), and FA transport (CD36 and FA-binding protein 1), were markedly suppressed in CTLN2 patients. Serum concentrations of ketone bodies were also decreased in these patients, suggesting reduced mitochondrial β-oxidation activity. Consistent with these findings, the expression of peroxisome proliferator-activated receptor α (PPARα), a master regulator of hepatic lipid metabolism, was significantly down-regulated. Hepatic PPARα expression was inversely correlated with severity of steatosis and circulating ammonia and citrulline levels. Additionally, phosphorylation of c-Jun-N-terminal kinase was enhanced in CTLN2 livers, which was likely associated with lower hepatic PPARα. Collectively, down-regulation of PPARα is associated with steatogenesis in CTLN2 patients. These findings provide a novel link between urea cycle disorder, lipid metabolism, and PPARα. PMID:25533124

  11. Exclusion of one pedigree affected by adult onset primary open angle glaucoma from linkage to the juvenile glaucoma locus on chromosome 1q21-q31.

    PubMed Central

    Avramopoulos, D; Kitsos, G; Economou-Petersen, E; Grigoriadou, M; Vassilopoulos, D; Papageorgiou, C; Psilas, K; Petersen, M B

    1996-01-01

    A locus for autosomal dominant juvenile onset primary open angle glaucoma (POAG) was recently assigned to chromosome region 1q21-q31. In the present study, a large Greek family with autosomal dominant adult onset POAG was investigated using microsatellite markers. Exclusion of linkage of the adult onset POAG gene to the region D1S194-D1S191 was obtained in this pedigree. Therefore, the data provide evidence that juvenile and adult onset POAG are genetically distinct disease entities. PMID:9004141

  12. Patterns and correlates of multiple risk factors for adult-onset cancer among adolescents

    PubMed Central

    MAYS, DARREN; PESHKIN, BETH N.; WALKER, LESLIE R.; ABRAHAM, ANISHA A.; HAWKINS, KIRSTEN B.; TERCYAK, KENNETH P.

    2012-01-01

    We investigated patterns and correlates of multiple, adult-onset cancer risk factors (MCRFs) among adolescents. Baseline data from an intervention efficacy trial were analyzed to examine patterns of co-occurring MCRFs and sociodemographic and theoretical (e.g., prevention self-efficacy) correlates of MCRFs among adolescents (N = 50) age 13 – 21. The mean total MCRFs was 4.6 (SD = 1.6; range 0–9). The most common risk factors were intentions to use alcohol (n = 40, 80%), < 5 daily servings of fruits/vegetables (n = 40, 80%), and lifetime alcohol use (n = 38, 76%). MCRFs commonly co-occurred, suggesting a clustered risk profile. Greater age (B = 0.19 95% CI 0.01, 0.38) and lower prevention self-efficacy (B = −0.16, 95% CI −0.02, −0.30) were significantly (p < 0.05) associated with MCRFs. Multiple health behavior change interventions are needed to prevent accumulation of risk factors as youth mature. Self-efficacy may be an important target for prevention interventions. PMID:22363044

  13. Health-related quality of life in sporadic adult-onset ataxia.

    PubMed

    Abele, Michael; Klockgether, Thomas

    2007-02-15

    Despite progressive disability in sporadic adult-onset ataxia (SAOA), little is known about patients' assessment of their ataxic disorder and its impact on health-related quality of life (Hr-QoL). This study investigated Hr-QoL by means of the following self-administered scales: Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, Beck Depression Inventory (BDI), and the Medical Outcome Study Short Form (SF-36). Twenty-two unselected ataxia patients were included. Sleep-related complaints were found in 9 (41%) of 22 and symptoms of depression in 6 (38%) of 16 patients. Compared to a large german control group, SAOA patients had lower scores in all SF-36 dimensions except for bodily pain. The greatest impairment was found in the domain physical functioning, followed by the domains social functioning and role limitations (emotional problems). There was a significant negative correlation of all nonmotor SF-36 dimensions with the BDI score. Walking aid dependency was significantly correlated with poorer health status perception in several motor and nonmotor domains. In addition, impaired sleep quality was correlated with an impaired general health perception and with bodily pain. The study demonstrates a great impact of SAOA on Hr-QoL. Adequate treatment of depression, motor disability, and impaired sleep quality is essential to improve Hr-QoL in ataxic patients. PMID:17149704

  14. Effect size of memory deficits in mice with adult-onset P301L tau expression.

    PubMed

    Hunsberger, Holly C; Rudy, Carolyn C; Weitzner, Daniel S; Zhang, Chong; Tosto, David E; Knowlan, Kevin; Xu, Ying; Reed, Miranda N

    2014-10-01

    Transgenic mice expressing mutations in tau have yielded essential discoveries for Alzheimer's disease. One of the most commonly used tau mouse models is the tet-off Tg(tauP301L)4510 model that expresses P301L human tau driven by the calcium-calmodulin kinase IIα (CaMKIIα) promoter system. Tau expression in this model is regulatable, allowing for suppression of mutant tau expression until adulthood and prevention of possible developmental alterations resulting from P301L tau expression during development. Here, we compared the effect and sample sizes needed for three learning and memory tasks in mice with adult-onset P301L tau expression. Our findings indicate that the Incremental Repeated Acquisition (IRA) and trace fear conditioning tasks, neither of which have previously been published with these mice, were highly sensitive to P301L tau expression, whereas the Morris water maze, the most commonly used task with this model, was the least sensitive. Memory deficits were observed at a time when tau pathology was subtle and prior to readily detectable neuronal loss. Thus, we provide essential information (effect and sample sizes needed) for establishing experimental designs at a time point when memory deficits are likely to go undetected if inadequate sample sizes are used. Our work also suggests the tet-off Tg4510 model provides a way to avoid mutant tau expression during the perinatal and early postnatal stages, thereby preventing possible developmental alterations unrelated to Alzheimer's disease.

  15. A search for the primary abnormality in adult-onset type II citrullinemia

    SciTech Connect

    Kobayashi, Keiko; Shaheen, Nazma; Saheki, Takeyori ); Kumashiro, Ryukichi; Tanikawa, Kyuichi ); O'Brien, W.E.; Beaudet, A.L. )

    1993-11-01

    Deficiency of argininosuccinate synthetase (ASS) causes citrullinemia in human beings. Type II citrullinemia is found in most patients with adult-onset citrullinemia in Japan, and ASS deficiency is found specifically in the liver. Previous studies have shown that the decrease of hepatic ASS activity is caused by a decrease in enzyme protein with normal kinetic properties and that there were no apparent abnormalities in the amount, translational activity, and gross structure of hepatic ASS mRNA. In the present work, the authors show by sequencing analysis that there was no mutation in the ASS mRNA from two patients with type II citrullinemia. The authors also report RFLP analysis of a consanguineous family with type II citrullinemia, by using three DNA polymorphisms located within the ASS gene locus. In spite of having consanguineous parents, the patient was not a homozygous haplotype for the ASS gene. The RFLP analysis of 16 affected patients from consanguineous parents showed that 5 of 16 patients had the heterozygous pattern for one of the three DNA probes and that the frequency of the heterozygous haplotype was not different from the control frequency. These results suggest that the primary defect of type II citrullinemia is not within the ASS gene locus. 29 refs., 1 fig., 3 tabs.

  16. Adult-onset liver disease and hepatocellular carcinoma in S-adenosylhomocysteine hydrolase deficiency

    PubMed Central

    Stender, Stefan; Chakrabarti, Rima S.; Xing, Chao; Gotway, Garrett; Cohen, Jonathan C.; Hobbs, Helen H.

    2016-01-01

    Background The etiology of liver disease remains elusive in some adults presenting with severe hepatic dysfunction. Methods and results Here we describe a woman of Pakistani descent who had elevated aminotransferases at age 23. She developed muscle weakness in her mid-20s, and was diagnosed with hepatocellular carcinoma at age 29. She died without a diagnosis at age 32 after having a liver transplant. Exome sequencing revealed that she was homozygous for a missense mutation (R49H) in AHCY, the gene encoding S-adenosylhomocysteine (SAH) hydrolase. SAH hydrolase catalyzes the final step in conversion of methionine to homocysteine and inactivating mutations in this enzyme cause a rare autosomal recessive disorder, SAH hydrolase deficiency, that typically presents in infancy. An asymptomatic 7-year old son of the proband is also homozygous for the AHCY-R49H mutation and has elevated serum aminotransferase levels, as well as markedly elevated serum levels of SAH, S-adenosylmethionine (SAM), and methionine, which are hallmarks of SAH hydrolase deficiency. Conclusion This report reveals several new aspects of SAH hydrolase deficiency. Affected women with SAH hydrolase deficiency can give birth to healthy children. SAH hydrolase deficiency can remain asymptomatic in childhood, and the disorder can be associated with early onset hepatocellular carcinoma. The measurement of serum amino acids should be considered in patients with liver disease or hepatocellular carcinoma of unknown etiology. PMID:26527160

  17. Dysregulation of axonal sodium channel isoforms after adult-onset chronic demyelination.

    PubMed

    Rasband, Matthew N; Kagawa, Tetsushi; Park, Eunice W; Ikenaka, Kazuhiro; Trimmer, James S

    2003-08-15

    Demyelination results in conduction block through changes in passive cable properties of an axon and in the expression and localization of axonal ion channels. We show here that adult-onset chronic demyelination, such as occurs in demyelinating disorders and after nerve injury, alters the complement of axonal voltage-dependent Na+ (Nav) channel isoforms and their localization. As a model, we used heterozygous transgenic mice with two extra copies of the proteolipid protein gene (Plp/-). Retinal ganglion cell axons in these mice myelinate normally, with young Plp/- and wild-type mice expressing Nav1.2 at low levels, whereas Nav1.6 is clustered in high densities at nodes of Ranvier. At 7 months of age, however, Plp/- mice exhibit severe demyelination and oligodendrocyte cell death, leading to a profound reduction in Nav1.6 clusters, loss of the paranodal axoglial apparatus, and a marked increase in Nav1.2. We conclude that myelin is crucial not only for node of Ranvier formation, but also to actively maintain the proper localization and complement of distinct axonal Nav channel isoforms throughout life. The altered Nav channel isoform localization and complement induced by demyelination may contribute to the pathophysiology of demyelinating disorders and nerve injury. PMID:12898531

  18. Neural regulation of acid maltase in an unusual adult onset deficiency.

    PubMed

    Meola, G; Sansone, V; Rotondo, G; Radice, S; Sterlicchio, M; Mauri, M; Bresolin, N; Moggio, M

    1994-01-01

    In a 48-year-old female, the first symptoms apparently manifested themselves 18 years before, with occasional tripping and weakness in both legs. During the next 18 years, weakness progressed and the patient developed a waddling gait; she became unable to rise from a lying or seated position unassisted and the shoulder girdle also became affected. Neurological examination revealed limb and shoulder girdle predominantly involving the lower extremities. We established cell cultures from muscle biopsy specimens obtained from our patient and carried out morphological analysis which, although aspecific, demonstrated clear signs of neurogenic suffering. This was confirmed in EMG studies performed. Biochemical analysis revealed very low acid maltase residual activity. We describe an unusual case of adult-onset acid maltase deficiency (AMD) with neurogenic atrophy and low residual activity. Innervated myofibres prepared by co-culturing the patient's myoblasts, with spinal cord foetal mouse explants were not associated with an abnormal in vitro maturation of the innervated myofibres as expected by the very low residual enzymatic activity found both in the muscle biopsy specimens and in the muscle cultures. There is strong suggestion that factors other than the amount of residual activity must be involved to determine the clinical manifestation of this disease.

  19. Glutathione transferases and neurodegenerative diseases.

    PubMed

    Mazzetti, Anna Paola; Fiorile, Maria Carmela; Primavera, Alessandra; Lo Bello, Mario

    2015-03-01

    There is substantial agreement that the unbalance between oxidant and antioxidant species may affect the onset and/or the course of a number of common diseases including Parkinson's and Alzheimer's diseases. Many studies suggest a crucial role for oxidative stress in the first phase of aging, or in the pathogenesis of various diseases including neurological ones. Particularly, the role exerted by glutathione and glutathione-related enzymes (Glutathione Transferases) in the nervous system appears more relevant, this latter tissue being much more vulnerable to toxins and oxidative stress than other tissues such as liver, kidney or muscle. The present review addresses the question by focusing on the results obtained by specimens from patients or by in vitro studies using cells or animal models related to Parkinson's and Alzheimer's diseases. In general, there is an association between glutathione depletion and Parkinson's or Alzheimer's disease. In addition, a significant decrease of glutathione transferase activity in selected areas of brain and in ventricular cerebrospinal fluid was found. For some glutathione transferase genes there is also a correlation between polymorphisms and onset/outcome of neurodegenerative diseases. Thus, there is a general agreement about the protective effect exerted by glutathione and glutathione transferases but no clear answer about the mechanisms underlying this crucial role in the insurgence of neurodegenerative diseases.

  20. An increased incidence of Hodgkin's lymphoma in patients with adult-onset sarcoma

    PubMed Central

    2012-01-01

    Background Sarcomas are rare, often fatal malignancies of connective tissues that can occur in genetic predisposition syndromes or result from carcinogen exposure. Hodgkin's lymphoma (HL) is not known to contribute to any recognised familial cancer syndrome comprising sarcomas, but is known to be associated with a variety of second cancers, including sarcomas. This study describes the prevalence of HL in families affected by sarcoma. Methods The International Sarcoma Kindred Study (ISKS) is a prospective cohort of 561 families ascertained via a proband with adult-onset sarcoma. Cancer-specific standardised incidence ratios (SIR) for multiple primary malignancies in probands were estimated. Clinical characteristics of individuals reporting both sarcoma and HL were described. Standardised incidence ratios for the occurrence of cancer in ISKS families were also estimated. Results Multiple primary cancers were reported in 16% of probands, significantly higher than in the general population. The risk of HL in probands was increased 15.8-fold (95%CI 7.9-31.6) and increased risks were also seen for breast cancer (SIR 2.9, 95%CI 1.9-4.4) and thyroid cancer (SIR 8.4, 95%CI 4.2-16.8). In 8 probands with both HL and sarcoma, the diagnosis of HL preceded that of sarcoma in 7 cases, and occurred synchronously in one case. Only 3 cases of sarcoma occurred in or close to prior radiotherapy fields. The overall incidence of HL in the ISKS cohort was not significantly increased by comparison with age- and gender-specific population estimates (SIR 1.63, 95%CI 1.05-2.43), suggesting that the association between HL and sarcomas did not extend to other family members. The age of onset of non-sarcoma, non-HL cancers in families affected by both HL and sarcoma was younger than the general population (56.2 y vs 65.6 y, P < 0.0001). Conclusions The basis for the association between HL and sarcomas may include the carcinogenic effects of therapy combined with excellent survival rates for HL

  1. Pesticide use and adult-onset asthma among male farmers in the Agricultural Health Study

    PubMed Central

    Hoppin, Jane A.; Umbach, David M.; London, Stephanie J.; Henneberger, Paul K.; Kullman, Greg J.; Coble, Joseph; Alavanja, Michael C.R.; Beane Freeman, Laura E.; Sandler, Dale P.

    2010-01-01

    Although specific pesticides have been associated with wheeze in farmers, little is known about pesticides and asthma. We used data from 19,704 male farmers in the Agricultural Health Study to evaluate lifetime use of 48 pesticides and prevalent adult-onset asthma, defined as doctor-diagnosed asthma after age 20. We categorized asthma cases as allergic (N=127) and non-allergic (N=314) based on their history of eczema or hayfever. We used polytomous logistic regression controlling for age, state, smoking, and body mass to assess pesticide associations. High pesticide exposure events were associated with a doubling of both allergic and non-allergic asthma. For ever use, 12 individual pesticides were associated with allergic asthma and four with non-allergic asthma. For allergic asthma, coumaphos (odds ratio (OR) =2.34, 95% Confidence Interval (CI) =1.49,3.70), heptachlor (OR=2.01, 95%CI=1.30,3.11), parathion (OR=2.05, 95%CI=1.21,3.46), 80/20 mix (carbon tetrachloride/carbon disulfide) (OR=2.15, 95%CI=1.23,3.76) and ethylene dibromide (OR=2.07, 95%CI=1.02,4.20), all had odds ratios greater than 2.0 and significant exposure-response trends. For non-allergic asthma, DDT had the strongest association (OR=1.41, 95%CI=1.09,1.84) but with little evidence of increasing asthma with increasing use. Current animal handling and farm activities did not confound these results. We saw little evidence that allergy alone was driving these associations. Pesticides may be an overlooked contributor to asthma risk among farmers. PMID:19541724

  2. Parental smoking in pregnancy and the risks of adult-onset hypertension.

    PubMed

    de Jonge, Layla L; Harris, Holly R; Rich-Edwards, Janet W; Willett, Walter C; Forman, Michele R; Jaddoe, Vincent W V; Michels, Karin B

    2013-02-01

    Fetal exposure to parental smoking may lead to developmental adaptations and promote various diseases in later life. This study evaluated the associations of parental smoking during pregnancy with the risk of hypertension in the daughter in adulthood, and assessed whether these associations are explained by birth weight or body weight throughout life. We used data on 33086 participants of the Nurses' Health Study II and the Nurses' Mothers' Cohort. Cox proportional hazards models were used to examine the associations of maternal and paternal smoking during pregnancy with the nurse daughter, with self-reported physician-diagnosed hypertension from 1989 until 2007. Overall, 8575 (25.9%) mothers and 18874 (57.0%) fathers smoked during pregnancy. During follow-up, 7825 incident cases of adult-onset hypertension were reported. Both maternal and paternal smoking of ≥ 15 cigarettes/d during pregnancy were associated with increased risks of hypertension (rate ratio, 1.19; 95% CI, 1.09-1.29; and rate ratio, 1.18; 95% CI, 1.12-1.25, respectively) in the age-adjusted models. Further adjustment for birth weight did not affect the effect estimates appreciably, whereas additional adjustment for body shape and weight until age 18, or current body mass index, attenuated the associations with both maternal and paternal smoking (rate ratio, 1.07; 95% CI, 0.98-1.16; and rate ratio, 1.06; 95% CI, 1.01-1.12, respectively). The associations of parental smoking during pregnancy with the risk of hypertension in the offspring were largely explained by body weight throughout life, suggesting that these associations may not reflect direct intrauterine mechanisms.

  3. PARENTAL SMOKING IN PREGNANCY AND THE RISKS OF ADULT ONSET HYPERTENSION

    PubMed Central

    De Jonge, Layla L.; Harris, Holly R.; Rich-Edwards, Janet W.; Willett, Walter C.; Forman, Michele R.; Jaddoe, Vincent W.V.; Michels, Karin B.

    2013-01-01

    Fetal exposure to parental smoking may lead to developmental adaptations and promote various diseases in later life. This study evaluated the associations of parental smoking during pregnancy with the risk of hypertension in the daughter in adulthood, and assessed whether these associations are explained by birth weight or body weight throughout life. We used data on 33,086 participants of the Nurses’ Health Study II and the Nurses’ Mothers’ Cohort. Cox proportional hazards models were used to examine the associations of maternal and paternal smoking during pregnancy with the nurse daughter, with self-reported physician-diagnosed hypertension from 1989 until 2007. Overall, 8,575 (25.9%) mothers and 18,874 (57.0%) fathers smoked during pregnancy. During follow-up, 7,825 incident cases of adult-onset hypertension were reported. Both maternal and paternal smoking of ≥15 cigarettes/day during pregnancy were associated with increased risks of hypertension (RR 1.19, 95% CI 1.09 to 1.29, and RR 1.18, 95% CI 1.12 to 1.25, respectively) in the age-adjusted models. Further adjustment for birth weight did not affect the effect estimates appreciably, while additional adjustment for body shape and weight until age 18, or current body mass index, attenuated the associations with both maternal and paternal smoking (RR 1.07, 95% CI 0.98 to 1.16, and RR 1.06, 95% CI 1.01 to 1.12, respectively). The associations of parental smoking during pregnancy with the risk of hypertension in the offspring were largely explained by body weight throughout life, suggesting that these associations may not reflect direct intrauterine mechanisms. PMID:23266542

  4. Astrocyte leptin receptor (ObR) and leptin transport in adult-onset obese mice.

    PubMed

    Pan, Weihong; Hsuchou, Hung; He, Yi; Sakharkar, Amul; Cain, Courtney; Yu, Chuanhui; Kastin, Abba J

    2008-06-01

    The agouti viable yellow (A vy) spontaneous mutation generates an unusual mouse phenotype of agouti-colored coat and adult-onset obesity with metabolic syndrome. Persistent production of agouti signaling protein in A vy mice antagonizes melanocortin receptors in the hypothalamus. To determine how this disruption of neuroendocrine circuits affects leptin transport across the blood-brain barrier (BBB), we measured leptin influx in A vy and B6 control mice after the development of obesity, hyperleptinemia, and increased adiposity. After iv bolus injection, (125)I-leptin crossed the BBB significantly faster in young (2 month old) B6 mice than in young A vy mice or in older (8 month old) mice of either strain. This difference was not observed by in situ brain perfusion studies, indicating the cause being circulating factors, such as elevated leptin levels or soluble receptors. Thus, A vy mice showed peripheral leptin resistance. ObRa, the main transporting receptor for leptin at the BBB, showed no change in mRNA expression in the cerebral microvessels between the age-matched (2 month old) A vy and B6 mice. Higher ObRb mRNA was seen in the A vy microvasculature with unknown significance. Immunofluorescent staining unexpectedly revealed that many of the ObR(+) cells were astrocytes and that the A vy mice showed significantly more ObR(+) astrocytes in the hypothalamus than the B6 mice. Although leptin permeation from the circulation was slower in the A vy mice, the increased ObR expression in astrocytes and increased ObRb mRNA in microvessels suggest the possibility of heightened central nervous system sensitivity to circulating leptin.

  5. Muscle MRI Findings in Childhood/Adult Onset Pompe Disease Correlate with Muscle Function

    PubMed Central

    Figueroa-Bonaparte, Sebastián; Segovia, Sonia; Llauger, Jaume; Belmonte, Izaskun; Pedrosa, Irene; Alejaldre, Aída; Mayos, Mercè; Suárez-Cuartín, Guillermo; Gallardo, Eduard; Illa, Isabel; Díaz-Manera, Jordi

    2016-01-01

    Objectives Enzyme replacement therapy has shown to be effective for childhood/adult onset Pompe disease (AOPD). The discovery of biomarkers useful for monitoring disease progression is one of the priority research topics in Pompe disease. Muscle MRI could be one possible test but the correlation between muscle MRI and muscle strength and function has been only partially addressed so far. Methods We studied 34 AOPD patients using functional scales (Manual Research Council scale, hand held myometry, 6 minutes walking test, timed to up and go test, time to climb up and down 4 steps, time to walk 10 meters and Motor Function Measure 20 Scale), respiratory tests (Forced Vital Capacity seated and lying, Maximun Inspiratory Pressure and Maximum Expiratory Pressure), daily live activities scales (Activlim) and quality of life scales (Short Form-36 and Individualized Neuromuscular Quality of Life questionnaire). We performed a whole body muscle MRI using T1w and 3-point Dixon imaging centered on thighs and lower trunk region. Results T1w whole body muscle MRI showed a homogeneous pattern of muscle involvement that could also be found in pre-symptomatic individuals. We found a strong correlation between muscle strength, muscle functional scales and the degree of muscle fatty replacement in muscle MRI analyzed using T1w and 3-point Dixon imaging studies. Moreover, muscle MRI detected mild degree of fatty replacement in paraspinal muscles in pre-symptomatic patients. Conclusion Based on our findings, we consider that muscle MRI correlates with muscle function in patients with AOPD and could be useful for diagnosis and follow-up in pre-symptomatic and symptomatic patients under treatment. Take home message Muscle MRI correlates with muscle function in patients with AOPD and could be useful to follow-up patients in daily clinic. PMID:27711114

  6. Optogenetics for neurodegenerative diseases

    PubMed Central

    Vann, Kiara T; Xiong, Zhi-Gang

    2016-01-01

    Neurodegenerative diseases are devastating conditions that lead to progressive degeneration of neurons. Neurodegeneration may result in ataxia, dementia, and muscle atrophies, etc. Despite enormous research efforts that have been made, there is lack of effective therapeutic interventions for most of these diseases. Optogenetics is a recently developed novel technique that combines optics and genetics to modulate the activity of specific neurons. Optogenetics has been implemented in various studies including neuropsychiatric disorders and neurodegenerative diseases. This review focuses on the recent advance in using this technique for the studies of common neurodegenerative diseases. PMID:27186317

  7. The diagnostic evaluation of patients with potential adult-onset autoinflammatory disorders: our experience and review of the literature.

    PubMed

    Muscari, Isabella; Iacoponi, Francesca; Cantarini, Luca; Lucherini, Orso Maria; Simonini, Gabriele; Brizi, Maria Giuseppina; Vitale, Antonio; Frediani, Bruno; Cimaz, Rolando; Galeazzi, Mauro

    2012-11-01

    Hereditary periodic fever syndromes (HPFSs) are a group of inherited disorders of the innate immune system caused by mutations of genes involved in the regulation or activation of the inflammatory response, which belong to the category of autoinflammatory disorders. Most HPFs typically have an onset in pediatric age, while a limited number of patients experience disease onset during adulthood. The relative rarity and lack of information on adult-onset autoinflammatory diseases make it likely that genetic testing is often inconclusive. Recently, we have identified a set of variables related to the probability of detecting gene mutations in MEFV, responsible for familial Mediterranean fever, and TNFRSF1A, responsible for tumor necrosis factor receptor-associated periodic syndrome. In addition, we have proposed a diagnostic score for identifying those patients at high risk of carrying mutations in these genes. However, before the score can be recommended for application, further evaluation by means of longitudinal studies on different ethnicities and different populations deriving from other geographical areas is needed in order to definitively verify both its sensitivity and its specificity. The present manuscript offers our suggestions on how to establish a differential diagnosis for adult-onset HPFs, as well as a review of the literature, and we also provide a score revision available online.

  8. Diagnosing young onset dementia can be challenging.

    PubMed

    Ahmed, Samrah; Baker, Ian; Butler, Christopher R

    2016-05-01

    Although the risk of developing dementia increases with age, onset can be as early as the third or fourth decade of life. Genetic influences play a more important role in younger than in older people with dementia, so young onset dementia may cluster in families. Diagnosing young onset dementia is challenging. The range of possible presenting features is broad, encompassing behavioural, cognitive, psychiatric and neurological domains, and symptoms are often subtle initially. Frequently the complaints are misattributed to stress or depression, and the patient is falsely reassured that they are too young to have dementia. The most common causes of young onset dementia are early onset forms of adult neurodegenerative conditions and alcohol. Vascular dementia is the second most common cause of young onset dementia after Alzheimer's disease. Conventional vascular risk factors may be absent and diagnosis relies on imaging evidence of cerebrovascular disease. Obtaining a detailed history remains the most important part of the workup and usually requires corroboration by a third party. Undertaking a basic neurological examination is also important. Those with suspected young onset dementia should be referred to a neurology-led cognitive disorders clinic where available as the differenti diagnosis is considerably broader tha in older adults and requires specialist investigation.

  9. Diagnosing young onset dementia can be challenging.

    PubMed

    Ahmed, Samrah; Baker, Ian; Butler, Christopher R

    2016-05-01

    Although the risk of developing dementia increases with age, onset can be as early as the third or fourth decade of life. Genetic influences play a more important role in younger than in older people with dementia, so young onset dementia may cluster in families. Diagnosing young onset dementia is challenging. The range of possible presenting features is broad, encompassing behavioural, cognitive, psychiatric and neurological domains, and symptoms are often subtle initially. Frequently the complaints are misattributed to stress or depression, and the patient is falsely reassured that they are too young to have dementia. The most common causes of young onset dementia are early onset forms of adult neurodegenerative conditions and alcohol. Vascular dementia is the second most common cause of young onset dementia after Alzheimer's disease. Conventional vascular risk factors may be absent and diagnosis relies on imaging evidence of cerebrovascular disease. Obtaining a detailed history remains the most important part of the workup and usually requires corroboration by a third party. Undertaking a basic neurological examination is also important. Those with suspected young onset dementia should be referred to a neurology-led cognitive disorders clinic where available as the differenti diagnosis is considerably broader tha in older adults and requires specialist investigation. PMID:27382914

  10. Driving and neurodegenerative diseases.

    PubMed

    Uc, Ergun Y; Rizzo, Matthew

    2008-09-01

    The proportion of elderly people in the general population is rising, resulting in greater numbers of drivers with neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. These neurodegenerative disorders impair cognition, visual perception, and motor function, leading to reduced driver fitness and greater crash risk. Yet neither medical diagnosis nor age alone is reliable enough to predict driver safety or crashes or to revoke the driving privileges of these individuals. Driving research utilizes tools such as questionnaires about driving habits and history, driving simulators, standardized road tests utilizing instrumented vehicles, and state driving records. Research challenges include outlining the evolution of driving safety, understanding the mechanisms of driving impairment, and developing a reliable and efficient standardized test battery for prediction of driver safety in neurodegenerative disorders. This information will enable healthcare providers to advise their patients with neurodegenerative disorders with more certainty, affect policy, and help develop rehabilitative measures for driving. PMID:18713573

  11. Trans-Palmitoleic Acid, Metabolic Risk Factors, and New-Onset Diabetes in US Adults

    PubMed Central

    Mozaffarian, Dariush; Cao, Haiming; King, Irena B.; Lemaitre, Rozenn N.; Song, Xiaoling; Siscovick, David S.; Hotamisligil, Gökhan S.

    2011-01-01

    Background Palmitoleic acid (cis-16:1n-7), produced by endogenous fat synthesis, has been linked to both beneficial and deleterious metabolic effects, potentially confounded by diverse determinants and tissue sources of endogenous production. Trans-palmitoleate (trans-16:1n-7) represents a distinctly exogenous source of 16:1n-7, unconfounded by endogenous synthesis or its determinants, that may be uniquely informative. Objective We investigated whether circulating trans-palmitoleate was independently related to lower metabolic risk and incident type2 diabetes. Design Prospective cohort study (1992–2006). Setting Four US communities. Patients 3,736 adults in the Cardiovascular Health Study. Measurements Plasma phospholipid fatty acids, anthropometry, blood lipids, inflammatory markers, and glucose-insulin levels were measured at baseline in 1992; and diet, 3 years earlier. In multivariable-adjusted models, we investigated how demographic, clinical, and lifestyle factors independently related to trans-palmitoleate; how trans-palmitoleate related to major metabolic risk factors; and how trans-palmitoleate related to new-onset diabetes (304 incident cases). We validated findings for metabolic risk factors in an independent cohort of 327 women. Results In multivariable-analyses, whole-fat dairy consumption was most strongly associated with higher trans-palmitoleate. Higher trans-palmitoleate was associated with slightly lower adiposity and, independently, higher high-density-lipoprotein(HDL)-cholesterol (across quintiles: +1.9%, P=0.04), lower triglycerides (−19.0%, P<0.001), lower total:HDL-cholesterol (−4.7%, P<0.001), lower C-reactive protein (−13.8%, P=0.05), and lower insulin resistance (−16.7%, P<0.001). Trans-palmitoleate was associated with substantially lower incidence of diabetes, with multivariable-hazard-ratios=0.41 (95%CI=0.27–0.64) and 0.38 (95%CI=0.24–0.62) in quintile-4 and quintile-5, versus quintile-1 (P-trend<0.001). Findings were

  12. 18F-FDG PET/CT in patients with adult-onset Still's disease.

    PubMed

    Dong, Meng-Jie; Wang, Cai-Qin; Zhao, Kui; Wang, Guo-Lin; Sun, Mei-Ling; Liu, Zhen-Feng; Xu, Liqin

    2015-12-01

    (18)F-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) has become useful for the detection and diagnosis of inflammatory conditions, including rheumatic diseases, immunoglobulin (Ig) G4-related disease and giant cell arteritis. However, few articles based on small sample sizes (n = 7) diagnosed as adult-onset Still's disease (AOSD) have been published. The study aim was to observe the reliable characteristics and usefulness of (18)F-FDG PET/CT for the evaluation of consecutive patients with AOSD. Eligible patients were selected from among those who had undergone (18)F-FDG PET/CT between May 2007 and June 2014. Twenty-six consecutive AOSD patients were recruited retrospectively according to criteria set by Yamaguchi et al. All patients underwent evaluation by (18)F-FDG PET/CT. The characteristics and usefulness of (18)F-FDG PET/CT for evaluation of consecutive patients with AOSD were evaluated. All 26 patients had (18)F-FDG-avid lesion(s) related to their particular disease. Diffuse and homogeneous accumulation of (18)F-FDG was seen in the bone marrow (26/26; 100 %; maximum standardized uptake (SUVmax), 2.10-6.73) and spleen (25/26; 96.15 %). The SUVmax of affected lymph nodes was 1.3-9.53 (mean ± SD, 4.12 ± 2.24). The SUVmax and size factors (maximum diameter and areas) of affected lymph nodes were significantly different (P = 0.033 and P = 0.012, respectively). (18)F-FDG PET/CT showed the general distribution of (18)F-FDG accumulation. This factor helped to exclude malignant disease and aided the diagnosis of AOSD (42.3 %) in 11 cases when combined with clinical features and aided decisions regarding appropriate biopsy sites, such as the lymph nodes (n = 9) and bone marrow (n = 13). (18)F-FDG PET/CT is a unique imaging method for the assessment of metabolic activity throughout the body in subjects with AOSD. Characteristics or patterns of AOSD observed on (18)F-FDG PET/CT can be used for the

  13. Is there evidence for neurodegenerative change following traumatic brain injury in children and youth? A scoping review

    PubMed Central

    Keightley, Michelle L.; Sinopoli, Katia J.; Davis, Karen D.; Mikulis, David J.; Wennberg, Richard; Tartaglia, Maria C.; Chen, Jen-Kai; Tator, Charles H.

    2014-01-01

    While generalized cerebral atrophy and neurodegenerative change following traumatic brain injury (TBI) is well recognized in adults, it remains comparatively understudied in the pediatric population, suggesting that research should address the potential for neurodegenerative change in children and youth following TBI. This focused review examines original research findings documenting evidence for neurodegenerative change following TBI of all severities in children and youth. Our relevant inclusion and exclusion criteria identified a total of 16 articles for review. Taken together, the studies reviewed suggest there is evidence for long-term neurodegenerative change following TBI in children and youth. In particular both cross-sectional and longitudinal studies revealed volume loss in selected brain regions including the hippocampus, amygdala, globus pallidus, thalamus, periventricular white matter, cerebellum, and brain stem as well as overall decreased whole brain volume and increased CSF and ventricular space. Diffusion Tensor Imaging (DTI) studies also report evidence for decreased cellular integrity, particularly in the corpus callosum. Sensitivity of the hippocampus and deep limbic structures in pediatric populations are similar to findings in the adult literature and we consider the data supporting these changes as well as the need to investigate the possibility of neurodegenerative onset in childhood associated with mild traumatic brain injury (mTBI). PMID:24678292

  14. Obesity-related abnormalities couple environmental triggers with genetic susceptibility in adult-onset T1D.

    PubMed

    Nguyen, K Hoa; Ande, Sudharsana R; Mishra, Suresh

    2016-01-29

    The incidence of adult-onset T1D in low-risk non-HLA type has increased several folds, whereas the contemporaneous incidence in high-risk HLA-type remains stable. Various factors behind this selective increase in T1D in young adults remain unclear. Obesity and its associated abnormalities appear to be an important determinant; however, the underlying mechanism involved is not understood. Recently, we have developed two novel transgenic obese mice models, Mito-Ob and m-Mito-Ob, by expressing a pleiotropic protein prohibitin (PHB) and a phospho mutant form of PHB (Y114F-PHB or m-PHB) from the aP2 gene promoter, respectively. Both mice models develop obesity in a sex-neutral manner, independent of diet; but obesity associated chronic low-grade inflammation and insulin resistance in a male sex-specific manner. Interestingly, on a high fat diet (HFD) only male m-Mito-Ob mice displayed marked mononuclear cell infiltration in pancreas and developed insulitis that mimic adult-onset T1D. Male Mito-Ob mice that share the metabolic phenotype of male m-Mito-Ob mice, and female m-Mito-Ob that harbor m-PHB similar to male m-Mito-Ob mice, did not develop insulitis. Thus, insulitis development in male m-Mito-Ob in response to HFD requires both, obesity-related abnormalities and m-PHB. Collectively, this data provides a proof-of-concept that obesity-associated abnormalities couple environmental triggers with genetic susceptibility in adult-onset T1D and reveals PHB as a potential susceptibility gene for T1D.

  15. Increased Expression of the Large Conductance, Calcium-Activated K+ (BK) Channel in Adult-Onset Neuronal Ceroid Lipofuscinosis

    PubMed Central

    Donnelier, Julien; Braun, Samuel T.; Dolzhanskaya, Natalia; Ahrendt, Eva; Braun, Andrew P.; Velinov, Milen; Braun, Janice E. A.

    2015-01-01

    Cysteine string protein (CSPα) is a presynaptic J protein co-chaperone that opposes neurodegeneration. Mutations in CSPα (i.e., Leu115 to Arg substitution or deletion (Δ) of Leu116) cause adult neuronal ceroid lipofuscinosis (ANCL), a dominantly inherited neurodegenerative disease. We have previously demonstrated that CSPα limits the expression of large conductance, calcium-activated K+ (BK) channels in neurons, which may impact synaptic excitability and neurotransmission. Here we show by western blot analysis that expression of the pore-forming BKα subunit is elevated ~2.5 fold in the post-mortem cortex of a 36-year-old patient with the Leu116∆ CSPα mutation. Moreover, we find that the increase in BKα subunit level is selective for ANCL and not a general feature of neurodegenerative conditions. While reduced levels of CSPα are found in some postmortem cortex specimens from Alzheimer’s disease patients, we find no concomitant increase in BKα subunit expression in Alzheimer’s specimens. Both CSPα monomer and oligomer expression are reduced in synaptosomes prepared from ANCL cortex compared with control. In a cultured neuronal cell model, CSPα oligomers are short lived. The results of this study indicate that the Leu116∆ mutation leads to elevated BKα subunit levels in human cortex and extend our initial work in rodent models demonstrating the modulation of BKα subunit levels by the same CSPα mutation. While the precise sequence of pathogenic events still remains to be elucidated, our findings suggest that dysregulation of BK channels may contribute to neurodegeneration in ANCL. PMID:25905915

  16. Glutamate and Neurodegenerative Disease

    NASA Astrophysics Data System (ADS)

    Schaeffer, Eric; Duplantier, Allen

    As the main excitatory neurotransmitter in the mammalian central nervous system, glutamate is critically involved in most aspects of CNS function. Given this critical role, it is not surprising that glutamatergic dysfunction is associated with many CNS disorders. In this chapter, we review the literature that links aberrant glutamate neurotransmission with CNS pathology, with a focus on neurodegenerative diseases. The biology and pharmacology of the various glutamate receptor families are discussed, along with data which links these receptors with neurodegenerative conditions. In addition, we review progress that has been made in developing small molecule modulators of glutamate receptors and transporters, and describe how these compounds have helped us understand the complex pharmacology of glutamate in normal CNS function, as well as their potential for the treatment of neurodegenerative diseases.

  17. Sporadic adult-onset neuronal intranuclear inclusion disease with the main presentation of repeated cerebellar ataxia: a case study.

    PubMed

    Sakurai, Takeo; Harada, Seiko; Wakida, Kenji; Yoshida, Mari; Nishida, Hiroshi

    2016-06-22

    A 66-year-old woman suddenly experienced unsteadiness while walking; she had experienced the same symptom before, but it had resolved immediately. Her neurological findings showed cerebellar ataxia, absence of tendon reflex in the extremities, and orthostatic hypotension. MRI with DWI of the brain showed linear high-intensity areas at the white matter just below the cerebral cortex. Therefore, we suspected neuronal intranuclear inclusion disease (NIID). In her cutaneous skin biopsy, intranuclear inclusion bodies, which tested positive for an anti-ubiquitin antibody and anti-p62 antibody, were observed in sweat gland cells and fibroblasts; therefore, we diagnosed her with NIID. As no one in her family had similar symptoms, this was a case of sporadic NIID. Adult-onset NIID with the main presentation of cerebellar ataxia is rare; in our case, this repeated acute-onset symptom was a unique manifestation of the condition. PMID:27181748

  18. Genetic and neurophysiological correlates of the age of onset of alcohol use disorders in adolescents and young adults

    PubMed Central

    Chorlian, David B.; Rangaswamy, Madhavi; Manz, Niklas; Wang, Jen-Chyong; Dick, Danielle; Almasy, Laura; Bauer, Lance; Bucholz, Kathleen; Foroud, Tatiana; Hesselbrock, Victor; Kang, Sun J.; Kramer, John; Kuperman, Sam; Nurnberger, John; Rice, John; Schuckit, Marc; Tischfield, Jay; Edenberg, Howard J.; Goate, Alison; Bierut, Laura; Porjesz, Bernice

    2013-01-01

    Discrete time survival analysis (DTSA) was used to assess the age-specific association of event related oscillations (EROs) and CHRM2 gene variants on the onset of regular alcohol use and alcohol dependence. The subjects were 2938 adolescents and young adults ages 12 to 25. Results showed that the CHRM2 gene variants and ERO risk factors had hazards which varied considerably with age. The bulk of the significant age-specific associations occurred in those whose age of onset was under 16. These associations were concentrated in those subjects who at some time took an illicit drug. These results are consistent with studies which associate greater rates of alcohol dependence among those who begin drinking at an early age. The age specificity of the genetic and neurophysiological factors is consistent with recent studies of adolescent brain development, which locate an interval of heightened vulnerability to substance use disorders in the early to mid teens. PMID:23963516

  19. Genetic and neurophysiological correlates of the age of onset of alcohol use disorders in adolescents and young adults.

    PubMed

    Chorlian, David B; Rangaswamy, Madhavi; Manz, Niklas; Wang, Jen-Chyong; Dick, Danielle; Almasy, Laura; Bauer, Lance; Bucholz, Kathleen; Foroud, Tatiana; Hesselbrock, Victor; Kang, Sun J; Kramer, John; Kuperman, Sam; Nurnberger, John; Rice, John; Schuckit, Marc; Tischfield, Jay; Edenberg, Howard J; Goate, Alison; Bierut, Laura; Porjesz, Bernice

    2013-09-01

    Discrete time survival analysis was used to assess the age-specific association of event-related oscillations (EROs) and CHRM2 gene variants on the onset of regular alcohol use and alcohol dependence. The subjects were 2,938 adolescents and young adults ages 12-25. Results showed that the CHRM2 gene variants and ERO risk factors had hazards which varied considerably with age. The bulk of the significant age-specific associations occurred in those whose age of onset was under 16. These associations were concentrated in those subjects who at some time took an illicit drug. These results are consistent with studies which associate greater rates of alcohol dependence among those who begin drinking at an early age. The age specificity of the genetic and neurophysiological factors is consistent with recent studies of adolescent brain development, which locate an interval of heightened vulnerability to substance use disorders in the early to mid teens.

  20. Delineation of Early and Later Adult Onset Depression by Diffusion Tensor Imaging

    PubMed Central

    Yu, Hongjun; Nie, Binbin; Li, Na; Luo, Chunrong; Li, Haijun; Liu, Fang; Bai, Yan; Shan, Baoci; Xu, Lin; Xu, Xiufeng

    2014-01-01

    Background Due to a lack of evidence, there is no consistent age of onset to define early onset (EO) versus later onset (LO) major depressive disorder (MDD). Fractional anisotropy (FA), derived from diffusion tensor imaging (DTI), has been widely used to study neuropsychiatric disorders by providing information about the brain circuitry, abnormalities of which might facilitate the delineation of EO versus LO MDD. Method In this study, 61 pairs of untreated, non-elderly, first-episode MDD patients and healthy controls (HCs) aged 18–45 years old received DTI scans. The voxel-based analysis method (VBM), classification analysis, using the Statistical Package for the Social Sciences (SPSS), and regression analyses were used to determine abnormal FA clusters and their correlations with age of onset and clinical symptoms. Results Classification analysis suggested in the best model that there were two subgroups of MDD patients, delineated by an age of onset of 30 years old, by which MDD patients could be divided into EO (18–29 years old) and LO (30–45 years old) groups. LO MDD was characterized by decreased FA, especially in the white matter (WM) of the fronto-occipital fasciculus and posterior limb of internal capsule, with a negative correlation with the severity of depressive symptoms; in marked contrast, EO MDD showed increased FA, especially in the WM of the corpus callosum, corticospinal midbrain and inferior fronto-occipital fasciculus, while FA of the WM near the midbrain had a positive correlation with the severity of depressive symptoms. Conclusion Specific abnormalities of the brain circuitry in EO vs. LO MDD were delineated by an age of onset of 30 years old, as demonstrated by distinct abnormal FA clusters with opposite correlations with clinical symptoms. This DTI study supported the evidence of an exact age for the delineation of MDD, which could have broad multidisciplinary importance. Trial Registration ClinicalTrials.gov NCT00703742 PMID:25393297

  1. Effect of adult onset hypothyroidism on behavioral parameters and acetylcholinesterase isoforms activity in specific brain regions of male mice.

    PubMed

    Vasilopoulou, Catherine G; Constantinou, Caterina; Giannakopoulou, Dimitra; Giompres, Panagiotis; Margarity, Marigoula

    2016-10-01

    Thyroid hormones (TH) are essential for normal development and function of mammalian central nervous system (CNS); TH dysregulation has been implicated in several cognitive and behavioral deficits related to dysfunctions of neurotransmitter systems. In the present study, we investigated the effects of adult onset hypothyroidism on the activity of acetylcholinesterase (AChE) and on related behavioral parameters. For this purpose we used adult male Balb/cJ mice that were divided randomly into euthyroid and hypothyroid animal groups. Animals were rendered hypothyroid through administration of 1% w/v KClO4 in their drinking water for 8weeks. At the end of the treatment, learning/memory procedures were examined through step-through passive avoidance task while fear/anxiety was assessed using elevated plus-maze (EPM) and open-field (OF) tests. AChE activity was determined colorimetrically in two different fractions, salt-soluble fraction (SS) (containing mainly the G1 isoform) and detergent-soluble fraction (DS) (containing mainly the G4 isoform) in cerebral cortex, cerebellum, midbrain, hippocampus and striatum. Our results indicate that adult onset hypothyroidism caused significant memory impairment and increased fear/anxiety. Moreover, the activity of both isoforms of AChE was reduced in all brain regions examined in a brain region- and isoform-specific manner. PMID:27317840

  2. Effect of adult onset hypothyroidism on behavioral parameters and acetylcholinesterase isoforms activity in specific brain regions of male mice.

    PubMed

    Vasilopoulou, Catherine G; Constantinou, Caterina; Giannakopoulou, Dimitra; Giompres, Panagiotis; Margarity, Marigoula

    2016-10-01

    Thyroid hormones (TH) are essential for normal development and function of mammalian central nervous system (CNS); TH dysregulation has been implicated in several cognitive and behavioral deficits related to dysfunctions of neurotransmitter systems. In the present study, we investigated the effects of adult onset hypothyroidism on the activity of acetylcholinesterase (AChE) and on related behavioral parameters. For this purpose we used adult male Balb/cJ mice that were divided randomly into euthyroid and hypothyroid animal groups. Animals were rendered hypothyroid through administration of 1% w/v KClO4 in their drinking water for 8weeks. At the end of the treatment, learning/memory procedures were examined through step-through passive avoidance task while fear/anxiety was assessed using elevated plus-maze (EPM) and open-field (OF) tests. AChE activity was determined colorimetrically in two different fractions, salt-soluble fraction (SS) (containing mainly the G1 isoform) and detergent-soluble fraction (DS) (containing mainly the G4 isoform) in cerebral cortex, cerebellum, midbrain, hippocampus and striatum. Our results indicate that adult onset hypothyroidism caused significant memory impairment and increased fear/anxiety. Moreover, the activity of both isoforms of AChE was reduced in all brain regions examined in a brain region- and isoform-specific manner.

  3. Are Sleep Onset/Maintenance Difficulties Associated with Medical or Psychiatric Comorbidities in Nondemented Community-Dwelling Older Adults?

    PubMed Central

    Zimmerman, Molly E.; Bigal, Marcelo E.; Katz, Mindy J.; Derby, Carol A.; Lipton, Richard B.

    2013-01-01

    Study Objectives: Older adults frequently report disruptions in their ability to initiate and maintain sleep. It remains unclear whether these sleep problems are consequent to associated medical comorbidities or if they represent primary sleep disturbances that exist independent of other disorders of senescence. Herein we describe sleep characteristics and associated medical and psychiatric comorbidities among ethnically diverse nondemented older adults. Methods: The cross-sectional sample consisted of 702 participants drawn from the Einstein Aging Study (EAS), a community-based study of aging. Sleep onset/maintenance difficulties (SO/MD) were ascertained using responses from the Medical Outcomes Study Sleep Scale (MOS-SS). Participants also completed assessments of medical history, psychological symptoms, and medication use. Results: Participants were an average of 80 ± 5.5 years of age and had 14 ± 3.4 years of education. Older adults reported sleeping an average of 6.5 ± 1.2 h/night. Mild SO/MD was reported in 43% of participants, while moderate/severe SO/MD was reported in 12% of participants. Sleep problems were associated with measures of obesity and symptoms of depression and anxiety. SO/MD was not associated with history of common medical conditions. Use rates of insomnia medication were low (0% to 3%). Conclusions: The prevalence of SO/MD is high in the elderly community-dwelling population and is associated with common psychiatric disorders. With the exception of obesity, SO/MD is not associated with common medical disorders. Further study is necessary to disentangle the nature of the relationship between sleep disturbance and psychiatric comorbidity among older adults. Citation: Zimmerman ME; Bigal ME; Katz MJ; Derby CA; Lipton RB. Are sleep onset/maintenance difficulties associated with medical or psychiatric comorbidities in nondemented community-dwelling older adults? J Clin Sleep Med 2013;9(4):363-369. PMID:23585752

  4. Validation of DSM-5 age-of-onset criterion of attention deficit/hyperactivity disorder (ADHD) in adults: Comparison of life quality, functional impairment, and family function.

    PubMed

    Lin, Yu-Ju; Lo, Kuan-Wu; Yang, Li-Kuang; Gau, Susan Shur-Fen

    2015-12-01

    The newly published Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) elevates the threshold of the ADHD age-of-onset criterion from 7 to 12 years. This study evaluated the quality of life and functional impairment of adults with ADHD who had symptoms onset by or after 7 years and examined the mediation effect of family function and anxiety/depression symptoms between ADHD diagnosis and quality of life and functional impairment. We assessed 189 adults with ADHD and 153 non-ADHD controls by psychiatric interview and self-administered reports on the Adult ADHD Quality of Life Scale, Weiss Functional Impairment Rating Scale, Family APGAR, and Adult Self Report Inventory-4. The ADHD group was divided into early-onset ADHD (onset <7 years, n=147) and late-onset ADHD (onset between 7 and 12 years, n=42). The mediation analysis was conducted to verify the mediating factors from ADHD to functional impairment and quality of life. The late-onset ADHD had more severe functional impairment at work and poorer family support than early-onset ADHD while they had comparable impairment at other domains. Less perceived family support and current anxiety/depressive symptoms partially mediated the link between ADHD diagnosis and quality of life/functional impairment both in early- and late-onset ADHD. Our data support decreased quality of life and increased functional impairment in adult ADHD, regardless of age of onset, and these adverse outcomes may be mediated by family support and anxiety/depression at adulthood. Our findings also imply that the new DSM-5 ADHD criteria do not over-include individuals without impairment.

  5. Protective Connections and Educational Attainment among Young Adults with Childhood-Onset Chronic Illness

    ERIC Educational Resources Information Center

    Maslow, Gary; Haydon, Abigail A.; McRee, Annie-Laurie; Halpern, Carolyn T.

    2012-01-01

    Background: Youth with childhood-onset chronic illness (COCI) are at risk of poor educational attainment. Specific protective factors that promote college graduation in this population have not been studied previously. In this study, we examine the role protective factors during adolescence play in promoting college graduation among young adults…

  6. The Effects of Fundamental Frequency Level on Voice Onset Time in Normal Adult Male Speakers

    ERIC Educational Resources Information Center

    McCrea, Christopher R.; Morris, Richard J.

    2005-01-01

    The purpose of this study was to examine the effect of fundamental frequency (F[0]) on stop consonant voice onset time (VOT). VOT was measured from the recordings of 56 young men reading phrases containing all 6 English voiced and voiceless stops in word-initial position across high-, medium-, and low-F[0] levels. Separate analyses of variance for…

  7. The History and Timing of Depression Onset as Predictors of Young Adult Self-Esteem

    ERIC Educational Resources Information Center

    Gayman, Mathew D.; Lloyd, Donald A.; Ueno, Koji

    2011-01-01

    Depression often emerges early in the lifecourse and is consistently shown to be associated with poor self-esteem. The 3 main objectives of the current study are to (1) evaluate the association between a history major depression and self-esteem in young adulthood, (2) assess the relationship between timing of depression onset and young adult…

  8. Comparison of new-onset gout in adults prescribed chlorthalidone vs. hydrochlorothiazide for hypertension.

    PubMed

    Wilson, Liza; Nair, Kavita V; Saseen, Joseph J

    2014-12-01

    This study assessed the risk of new-onset gout following prescribing of hydrochlorothiazide (HCTZ) compared with chlorthalidone (CTD). This retrospective cohort analysis used administrative claims from 2000 to 2012 to identify patients aged 18 to 89 years with hypertension who were prescribed CTD or HCTZ. Patients were excluded if they had a prior diagnosis of gout, conditions or prescription claims for medications that alter risk of gout, or if they switched between these two diuretics. A total of 1011 patients prescribed CTD were matched with 2022 patients prescribed HCTZ based on age, sex, and Chronic Condition Indicator. New-onset gout occurred in 17 of 1011 (1.68%) patients in the CTD group and in 26 of 2022 (1.29%) patients in the HCTZ group (P=.27). The number of days to first occurrence of gout was 183.6 days and 152.7 days in the CTD and HCTZ groups, respectively (P=.39). The mean daily dose was 22.7 mg for CTD and 24.3 mg for HCTZ, and the median dose of both CTD and HCTZ was 25 mg at the time of new-onset gout. Patients prescribed CTD for hypertension have a similar risk of developing new-onset gout compared with patients prescribed similar doses of HCTZ.

  9. Ethical and legal dilemmas arising during predictive testing for adult-onset disease: the experience of Huntington disease.

    PubMed Central

    Huggins, M; Bloch, M; Kanani, S; Quarrell, O W; Theilman, J; Hedrick, A; Dickens, B; Lynch, A; Hayden, M

    1990-01-01

    The goal of predictive testing is to modify the risk for currently healthy individuals to develop a genetic disease in the future. Such testing using polymorphic DNA markers has had major application in Huntington disease. The Canadian Collaborative Study of Predictive Testing for Huntington Disease has been guided by major principles of medical ethics, including autonomy, beneficence, confidentiality, and justice. Numerous ethical and legal dilemmas have arisen in this program, challenging these principles and occasionally casting them into conflict. The present report describes these dilemmas and offers our approach to resolving them. These issues will have relevance to predictive-testing programs for other adult-onset disorders. PMID:1971997

  10. Episodic cervical dystonia associated with gastro-oesophageal reflux. A case of adult-onset Sandifer syndrome.

    PubMed

    Shahnawaz, M; van der Westhuizen, L R; Gledhill, R F

    2001-12-01

    Sandifer syndrome is a dystonic movement disorder described in children with severe gastro-oesophageal reflux. We now report a patient who had the features of Sandifer syndrome first developing in adult life. Onset of dystonic episodes followed closely the occurrence of a Bell's palsy, while symptoms of peptic oesophagitis had been present for several months beforehand. Successful symptomatic treatment of gastro-oesophageal reflux was accompanied by cessation of the dystonic episodes. Possible pathophysiological mechanisms of the abnormal movements in Sandifer syndrome are discussed. PMID:11714563

  11. Adult-onset nemaline rods in a patient treated for suspected dermatomyositis: study with two-dimensional electrophoresis

    SciTech Connect

    Danon, M.J.; Giometti, C.S.; Manaligod, J.R.; Perurena, O.H.; Skosey, J.L.

    1981-12-01

    A 65-year-old woman with progressive muscle weakness and a diffuse rash of three years' duration was examined. Muscle tissue was studied with histochemical techniques, phase-contrast microscopy, electron microscopy, and two-dimensional electrophoresis. Histochemical studies showed numerous nemaline rods, with a normal ratio of types I and II fibers. Two-dimensional electrophoresis revealed abnormalities in the myosin light chain and tropomyosin protein patterns when compared with normal and diseased muscle biopsy samples, including those from two patients with adult-onset dermatomyositis.

  12. Mitochondrial and Cell Death Mechanisms in Neurodegenerative Diseases

    PubMed Central

    Martin, Lee J.

    2010-01-01

    Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS) are the most common human adult-onset neurodegenerative diseases. They are characterized by prominent age-related neurodegeneration in selectively vulnerable neural systems. Some forms of AD, PD, and ALS are inherited, and genes causing these diseases have been identified. Nevertheless, the mechanisms of the neuronal cell death are unresolved. Morphological, biochemical, genetic, as well as cell and animal model studies reveal that mitochondria could have roles in this neurodegeneration. The functions and properties of mitochondria might render subsets of selectively vulnerable neurons intrinsically susceptible to cellular aging and stress and overlying genetic variations, triggering neurodegeneration according to a cell death matrix theory. In AD, alterations in enzymes involved in oxidative phosphorylation, oxidative damage, and mitochondrial binding of Aβ and amyloid precursor protein have been reported. In PD, mutations in putative mitochondrial proteins have been identified and mitochondrial DNA mutations have been found in neurons in the substantia nigra. In ALS, changes occur in mitochondrial respiratory chain enzymes and mitochondrial cell death proteins. Transgenic mouse models of human neurodegenerative disease are beginning to reveal possible principles governing the biology of selective neuronal vulnerability that implicate mitochondria and the mitochondrial permeability transition pore. This review summarizes how mitochondrial pathobiology might contribute to neuronal death in AD, PD, and ALS and could serve as a target for drug therapy. PMID:21258649

  13. Neurodegenerative Models in Drosophila: Polyglutamine Disorders, Parkinson Disease, and Amyotrophic Lateral Sclerosis

    PubMed Central

    Ambegaokar, Surendra S.; Roy, Bidisha; Jackson, George R.

    2010-01-01

    Neurodegenerative diseases encompass a large group of neurological disorders. Clinical symptoms can include memory loss, cognitive impairment, loss of movement or loss of control of movement, and loss of sensation. Symptoms are typically adult onset (although severe cases can occur in adolescents) and are reflective of neuronal and glial cell loss in the central nervous system. Neurodegenerative diseases also are considered progressive, with increased severity of symptoms over time, also reflective of increased neuronal cell death. However, various neurodegenerative diseases differentially affect certain brain regions or neuronal or glial cell types. As an example, Alzheimer disease (AD) primarily affects the temporal lobe, whereas neuronal loss in Parkinson disease (PD) is largely (although not exclusively) confined to the nigrostriatal system. Neuronal loss is almost invariably accompanied by abnormal insoluble aggregates, either intra- or extracellular. Thus, neurodegenerative diseases are categorized by (a) the composite of clinical symptoms, (b) the brain regions or types of brain cells primarily affected, and (c) the types of protein aggregates found in the brain. Here we review the methods by which Drosophila melanogaster has been used to model aspects of polyglutamine diseases, Parkinson disease, and amyotrophic lateral sclerosis and key insights into that have been gained from these models; Alzheimer disease and the tauopathies are covered elsewhere in this special issue. PMID:20561920

  14. Ceruloplasmin in neurodegenerative diseases.

    PubMed

    Vassiliev, Vadim; Harris, Zena Leah; Zatta, Paolo

    2005-11-01

    For decades, abnormalities in ceruloplasmin (Cp) synthesis have been associated with neurodegenerative disease. From the early observation that low circulating serum ceruloplasmin levels served as a marker for Wilson's disease to the recent characterization of a neurodegenerative disorder associated with a complete lack of serum ceruloplasmin, the link between Cp and neuropathology has strengthened. The mechanisms associated with these different central nervous system abnormalities are very distinct. In Wilson's disease, a defect in the P-type ATPase results in abnormal hepatic copper accumulation that eventually leaks into the circulation and is abnormally deposited in the brain. In this case, copper deposition results in the neurodegenerative phenotype observed. Patients with autosomal recessive condition, aceruloplasminemia, lack the ferroxidase activity inherent to the multi-copper oxidase ceruloplasmin and develop abnormal iron accumulation within the central nervous system. In the following review ceruloplasmin gene expression, structure and function will be presented and the role of ceruloplasmin in iron metabolism will be discussed. The molecular events underlying the different forms of neurodegeneration observed will be presented. Understanding the role of ceruloplasmin within the central nervous system is fundamental to further our understanding of the pathology observed. Is the ferroxidase function more essential than the antioxidant role? Does Cp help maintain nitrosothiol stores or does it oxidize critical brain substrates? The answers to these questions hold the promise for the treatment of devastating neurodegenerative conditions such as Alzheimer's and Parkinson's diseases. It is essential to further elucidate the mechanism of the neuronal injury associated with these disorders.

  15. Timing of onset of evening activity of adult chinese rose beetles (Coleoptera: Scarabaeidae)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Adult Chinese rose beetles, Adoretus sinicus (Burmeister) (Coleoptera: Scarabaeidae: Adoretini), present in China, Taiwan, Indonesia, Cambodia, Laos, Singapore, Thailand, Vietnam, the Marianas Islands, the Caroline Islands, and the Hawaiian Islands, are nighttime defoliators that feed on a wide vari...

  16. Association between juvenile onset obesity and severe adult obesity in 73, 532 women.

    PubMed Central

    Rimm, I J; Rimm, A A

    1976-01-01

    The association between juvenile obesity and severe adult obesity was examined using a questionnaire completed by 73,532 weight conscious women. Relative obesity as an adult was determined by the ratio Weight/Height. The question, "Were you considered a fat child?" determined childhood weight status. Analysis of the data revealed that severely obese women (regardless of age) were 2.4 times more likely than normal weight women to have been fat children. This association was noted for all parity groups. The data also suggests that the risk of a fat child developing severe obesity is substantially greater than that for a non-fat child. Since adult obesity is associated with a number of adult diseases, this study emphasizes the importance of weight control in childhood. PMID:1275125

  17. Clinical features and long-term outcomes of systemic lupus erythematosus: comparative data of childhood, adult and late-onset disease in a national register.

    PubMed

    Sousa, S; Gonçalves, M J; Inês, L S; Eugénio, G; Jesus, D; Fernandes, S; Terroso, G; Romão, V C; Cerqueira, M; Raposo, A; Couto, M; Nero, P; Sequeira, G; Nóvoa, T; Melo Gomes, J A; da Silva, J Canas; Costa, L; Macieira, C; Silva, C; Silva, J A P; Canhão, H; Santos, M J

    2016-07-01

    Systemic lupus erythematosus (SLE) affects predominantly women at reproductive age but may present at any age. Age at disease onset has a modulating effect on presentation and course of disease, but controversies persist regarding its impact on long-term outcome. Our aims were to characterize clinical features, co-morbidities and cumulative damage in childhood-onset, adult-onset and late-onset SLE. Patients with childhood-onset SLE fulfilling ACR 1997 criteria were identified in a nationwide register-Reuma.pt/SLE (N = 89) and compared with adult-onset and late-onset counterparts matched 1:1:1 for disease duration. 267 SLE patients with mean disease duration of 11.9 ± 9.3 years were analyzed. Skin (62 %), kidney (58 %), neurological (11 %) and hematologic involvement (76 %) were significantly more common in childhood-onset SLE and disease activity was higher in this subset than in adult- and late-onset disease (SLEDAI-2K 3.4 ± 3.8 vs. 2.2 ± 2.7 vs. 1.6 ± 2.8, respectively; p = 0.004). Also, more childhood-onset patients received cyclophosphamide (10 %) and mycophenolate mofetil (34 %). A greater proportion of women (96 %), prevalence of arthritis (89 %) and anti-SSA antibodies (34 %) were noted in the adult-onset group. There was a significant delay in the diagnosis of SLE in older ages. Co-morbidities such as hypertension, diabetes and thyroid disease were significantly more frequent in late-onset SLE, as well as the presence of irreversible damage evaluated by the SLICC/ACR damage index (20 vs. 26 vs. 40 %; p < 0.001). Greater organ involvement as well as the frequent need for immunosuppressants supports the concept of childhood-onset being a more severe disease. In contrast, disease onset is more indolent but co-morbidity burden and irreversible damage are greater in late-onset SLE, which may have implications for patients' management. PMID:26979603

  18. Are early onset aging conditions correlated to daily activity functions in youth and adults with Down syndrome?

    PubMed

    Lin, Jin-Ding; Lin, Lan-Ping; Hsu, Shang-Wei; Chen, Wen-Xiu; Lin, Fu-Gong; Wu, Jia-Ling; Chu, Cordia

    2014-11-13

    This study aims to answer the research question of "Are early onset aging conditions correlated to daily activity functions in youth and adults with Down syndrome (DS)?" A cross-sectional survey was employed to recruit 216 individuals with DS over 15 years of age in the analyses. A structured questionnaire included demographic data, brief self-reported aging conditions, Dementia Screening Questionnaire for Individuals with Intellectual Disabilities (DSQIID) and activity of daily living (ADL) scales were completed by the primary caregivers who were well-suited for providing information on the functioning conditions of the DS individuals. Results showed that the most five frequent aging conditions (sometimes, usually and always) included frailty (20.2%), vision problem (15.8%), loss of language ability (15.3%), sleep problem (14.9%) and memory impairment (14.5%). Other onset aging conditions included more chronic diseases (13.9%), hearing loss (13%), chewing ability and tooth loss (12.5%), incontinence (11.1%), depressive syndrome (7.7%), falls and gait disorder (7.2%), loss of taste and smell (7.2%). The data also showed scores of DSQIID, onset aging conditions and ADL has significant relationships each other in Pearson's correlation tests. Finally, multiple linear regression analyses indicated onset aging conditions (β=-0.735, p<0.001) can significantly predicted the variation in ADL scores after adjusting other factors (R(2)=0.381). This study suggests that the authority should initiate early intervention programs aim to improve healthy aging and ADL functions for people with DS. PMID:25462513

  19. Aquaporins and Neurodegenerative Diseases

    PubMed Central

    Foglio, Eleonora; Rodella, Luigi Fabrizio

    2010-01-01

    Aquaporins (AQPs) are a family of widely distributed membrane-inserted water channel proteins providing a pathway for osmotically-driven water, glycerol, urea or ions transport through cell membranes and mechanisms to control particular aspects of homeostasis. Beside their physiological expression patterns in Central Nervous System (CNS), it is conceivable that AQPs are also abnormally expressed in some pathological conditions interesting CNS (e.g. neurodegenerative diseases) in which preservation of brain homeostasis is at risk. The purpose of this review was to take in consideration those neurodegenerative diseases in whose pathogenetic processes it was possible to hypothesize some alterations in CNS AQPs expression or modulation leading to damages of brain water homeostasis. PMID:21119882

  20. Aquatherapy for neurodegenerative disorders.

    PubMed

    Plecash, Alyson R; Leavitt, Blair R

    2014-01-01

    Aquatherapy is used for rehabilitation and exercise; water provides a challenging, yet safe exercise environment for many special populations. We have reviewed the use of aquatherapy programs in four neurodegenerative disorders: Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and Huntington's disease. Results support the use of aquatherapy in Parkinson's disease and multiple sclerosis, however further evidence is required to make specific recommendations in all of the aforementioned disorders.

  1. Glycoproteomics in Neurodegenerative Diseases

    PubMed Central

    Hwang, Hyejin; Zhang, Jianpeng; Chung, Kathryn A.; Leverenz, James B.; Zabetian, Cyrus P.; Peskind, Elaine R.; Jankovic, Joseph; Su, Zhen; Hancock, Aneeka M.; Pan, Catherine; Montine, Thomas J.; Pan, Sheng; Nutt, John; Albin, Roger; Gearing, Marla; Beyer, Richard P.; Shi, Min; Zhang, Jing

    2009-01-01

    Protein glycosylation regulates protein function and cellular distribution. Additionally, aberrant protein glycosylations have been recognized to play major roles in human disorders, including neurodegenerative diseases. Glycoproteomics, a branch of proteomics that catalogs and quantifies glycoproteins, provides a powerful means to systematically profile the glycopeptides or glycoproteins of a complex mixture that are highly enriched in body fluids, and therefore, carry great potential to be diagnostic and/or prognostic markers. Application of this mass spectrometry-based technology to the study of neurodegenerative disorders (e.g., Alzheimer's disease and Parkinson's disease) is relatively new, and is expected to provide insight into the biochemical pathogenesis of neurodegeneration, as well as biomarker discovery. In this review, we have summarized the current understanding of glycoproteins in biology and neurodegenerative disease, and have discussed existing proteomic technologies that are utilized to characterize glycoproteins. Some of the ongoing studies, where glycoproteins isolated from cerebrospinal fluid and human brain are being characterized in Parkinson's disease at different stages versus controls, are presented, along with future applications of targeted validation of brain specific glycoproteins in body fluids. PMID:19358229

  2. Adult-onset cystic hygroma: A case report of rare entity

    PubMed Central

    Bahl, Sumit; Shah, Vandana; Anchlia, Sonal; Vyas, Siddharth

    2016-01-01

    Cystic hygroma is a benign congenital malformation of the lymphatic system that occurs in infant or children younger than 2 years of age. Although cystic hygroma is well recognized in pediatric practice, it seldom presents de novo in adulthood. These are commonly present in head and neck but can be present anywhere. Cystic hygroma is very rare in adults, but it should be considered in the differential diagnosis of adult neck swellings. Patients presenting with a painless, soft, fluctuant, and enlarging neck mass should have a careful history and physical examination along with radiological imaging to assist with diagnosis. Surgical intervention is the treatment of choice for this rare condition. Here, we are reporting a case of cystic hygroma in a 32-year-old male patient in the neck region. The objectives of this case report are to discuss the clinical presentation, diagnosis, histopathological findings and management of this malformation. PMID:27134456

  3. Adult-onset cystic hygroma: A case report of rare entity.

    PubMed

    Bahl, Sumit; Shah, Vandana; Anchlia, Sonal; Vyas, Siddharth

    2016-01-01

    Cystic hygroma is a benign congenital malformation of the lymphatic system that occurs in infant or children younger than 2 years of age. Although cystic hygroma is well recognized in pediatric practice, it seldom presents de novo in adulthood. These are commonly present in head and neck but can be present anywhere. Cystic hygroma is very rare in adults, but it should be considered in the differential diagnosis of adult neck swellings. Patients presenting with a painless, soft, fluctuant, and enlarging neck mass should have a careful history and physical examination along with radiological imaging to assist with diagnosis. Surgical intervention is the treatment of choice for this rare condition. Here, we are reporting a case of cystic hygroma in a 32-year-old male patient in the neck region. The objectives of this case report are to discuss the clinical presentation, diagnosis, histopathological findings and management of this malformation. PMID:27134456

  4. Invisible Victims: Delayed Onset Depression among Adults with Same-Sex Parents

    PubMed Central

    Sullins, D. Paul

    2016-01-01

    The relationship of elevated depression risk recently discovered among adult persons raised by same-sex parents with possible precipitating conditions in childhood has not previously been acknowledged. This study tests whether such inattention is supportable. Logistic regression based risk ratios were estimated from longitudinal measures of mental health outcomes observed in three waves (at ages 15, 22, and 28) of the US National Survey of Adolescent to Adult Health (n = 15,701). At age 28, the adults raised by same-sex parents were at over twice the risk of depression (CES-D: risk ratio 2.6, 95% CI 1.4–4.6) as persons raised by man-woman parents. These findings should be interpreted with caution. Elevated risk was associated with imbalanced parental closeness and parental child abuse in family of origin; depression, suicidality, and anxiety at age 15; and stigma and obesity. More research and policy attention to potentially problematic conditions for children with same-sex parents appears warranted. PMID:27313882

  5. Invisible Victims: Delayed Onset Depression among Adults with Same-Sex Parents.

    PubMed

    Sullins, D Paul

    2016-01-01

    The relationship of elevated depression risk recently discovered among adult persons raised by same-sex parents with possible precipitating conditions in childhood has not previously been acknowledged. This study tests whether such inattention is supportable. Logistic regression based risk ratios were estimated from longitudinal measures of mental health outcomes observed in three waves (at ages 15, 22, and 28) of the US National Survey of Adolescent to Adult Health (n = 15,701). At age 28, the adults raised by same-sex parents were at over twice the risk of depression (CES-D: risk ratio 2.6, 95% CI 1.4-4.6) as persons raised by man-woman parents. These findings should be interpreted with caution. Elevated risk was associated with imbalanced parental closeness and parental child abuse in family of origin; depression, suicidality, and anxiety at age 15; and stigma and obesity. More research and policy attention to potentially problematic conditions for children with same-sex parents appears warranted. PMID:27313882

  6. Stem cells and neurodegenerative diseases.

    PubMed

    Hou, LingLing; Hong, Tao

    2008-04-01

    Neurodegenerative diseases are characterized by the neurodegenerative changes or apoptosis of neurons involved in networks, which are important to specific physiological functions. With the development of old-aging society, the incidence of neurodegenerative diseases is on the increase. However, it is difficult to diagnose for most of neurodegenerative diseases. At present, there are too few effective therapies. Advances in stem cell biology have raised the hope and possibility for the therapy of neurodegenerative diseases. Recently, stem cells have been widely attempted to treat neurodegenerative diseases of animal model. Here we review the progress and prospects of various stem cells, including embryonic stem cells, mesenchymal stem cell and neural stem cells and so on, for the treatments of neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease, Huntington' disease and Amyotrophic lateral sclerosis/Lou Gehrig's disease.

  7. Congenital and prolonged adult-onset deafness cause distinct degradations in neural ITD coding with bilateral cochlear implants.

    PubMed

    Hancock, Kenneth E; Chung, Yoojin; Delgutte, Bertrand

    2013-06-01

    Bilateral cochlear implant (CI) users perform poorly on tasks involving interaural time differences (ITD), which are critical for sound localization and speech reception in noise by normal-hearing listeners. ITD perception with bilateral CI is influenced by age at onset of deafness and duration of deafness. We previously showed that ITD coding in the auditory midbrain is degraded in congenitally deaf white cats (DWC) compared to acutely deafened cats (ADC) with normal auditory development (Hancock et al., J. Neurosci, 30:14068). To determine the relative importance of early onset of deafness and prolonged duration of deafness for abnormal ITD coding in DWC, we recorded from single units in the inferior colliculus of cats deafened as adults 6 months prior to experimentation (long-term deafened cats, LTDC) and compared neural ITD coding between the three deafness models. The incidence of ITD-sensitive neurons was similar in both groups with normal auditory development (LTDC and ADC), but significantly diminished in DWC. In contrast, both groups that experienced prolonged deafness (LTDC and DWC) had broad distributions of best ITDs around the midline, unlike the more focused distributions biased toward contralateral-leading ITDs present in both ADC and normal-hearing animals. The lack of contralateral bias in LTDC and DWC results in reduced sensitivity to changes in ITD within the natural range. The finding that early onset of deafness more severely degrades neural ITD coding than prolonged duration of deafness argues for the importance of fitting deaf children with sound processors that provide reliable ITD cues at an early age.

  8. Wiki-Based Clinical Practice Guidelines for the Management of Adult Onset Sarcoma: A New Paradigm in Sarcoma Evidence

    PubMed Central

    Neuhaus, S. J.; Thomas, D.; Desai, J.; Vuletich, C.; von Dincklage, J.; Olver, I.

    2015-01-01

    In 2013 Australia introduced Wiki-based Clinical Practice Guidelines for the Management of Adult Onset Sarcoma. These guidelines utilized a customized MediaWiki software application for guideline development and are the first evidence-based guidelines for clinical management of sarcoma. This paper presents our experience with developing and implementing web-based interactive guidelines and reviews some of the challenges and lessons from adopting an evidence-based (rather than consensus-based) approach to clinical sarcoma guidelines. Digital guidelines can be easily updated with new evidence, continuously reviewed and widely disseminated. They provide an accessible method of enabling clinicians and consumers to access evidence-based clinical practice recommendations and, as evidenced by over 2000 views in the first four months after release, with 49% of those visits being from countries outside of Australia. The lessons learned have relevance to other rare cancers in addition to the international sarcoma community. PMID:25784832

  9. Adult Onset of BRAFV600E-Mutated Langerhans Cell Histiocytosis with Cutaneous Involvement Successfully Diagnosed by Immunohistochemical Staining

    PubMed Central

    Tono, Hisayuki; Fujimura, Taku; Kakizaki, Aya; Furudate, Sadanori; Ishibashi, Masaya; Aiba, Setsuya

    2015-01-01

    Langerhans cell histiocytosis (LCH) is characterized by the clonal proliferation of Langerhans cells; it is categorized as a single-system disease with single or multifocal lesions, and as a multi-system disease with or without the risk of organ involvement. Although the skin is not categorized as a risk organ, the precise diagnosis of skin lesions is necessary to determine the protocol for the treatment of LCH. In this report, we describe a 28-year-old Japanese man with adult onset of BRAFV600E-mutated LCH with cutaneous involvement successfully diagnosed by immunohistochemical staining. Our report suggests that immunohistochemical staining for the BRAFV600E gene could be a diagnostic tool to determine the clinical type of LCH. PMID:26500535

  10. An unusual manifestation in a patient with adult-onset Still’s disease: Minimal glomerular lesion

    PubMed Central

    El Mezouar, Imane; Abourazzak, Fatima Zahra; Ghani, Najoua; Harzy, Taoufik

    2014-01-01

    Adult-onset Still’s disease (AOSD) is a multisystem inflammatory disease of unknown etiology. It is characterized by arthritis, hectic fever, transient rash and visceral lesions such as pleuropericarditis, lymphadenopathy and hepato splenomegaly. Although kidney involvement may appear in some cases of AOSD, minimal glomerular lesion (MGL) has not been described. We describe a female patient, who presented with multisystemic manifestations, including high spiking fever, arthralgias, striking hyperferritinemia, and proteinuria. Renal biopsy showed classic MGL. A diagnosis of AOSD was made on the basis of Yamaguchi’s criteria. The patient was treated with steroids, resulting in remission of the rheumatological condition closely paralleled by remission of proteinuria, thereby strongly suggesting a causative link between AOSD and MGL in this patient. Renal involvement in the AOSD was rarely reported in the literature. MGL may be a cause of unexplained proteinuria in AOSD. In this situation, renal biopsy is necessary to establish a definitive diagnosis.

  11. Adult-onset presentation of a hyperornithinemia-hyperammonemia-homocitrullinuria patient without prior history of neurological complications.

    PubMed

    Tezcan, Kamer; Louie, Kristal T; Qu, Yong; Velasquez, Jorge; Zaldivar, Frank; Rioseco-Camacho, Natalia; Camacho, José Angel

    2012-01-01

    The Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH) syndrome is a disorder of the urea cycle and ornithine degradation pathway caused by mutations in the mitochondrial ornithine transporter, ORNT1 (SLC25A15). In general, the majority of patients with HHH syndrome come to medical attention during infancy or early school years with symptoms such as learning disabilities, changes in cognitive development, spasticity, or liver dysfunction. In this report, we describe a 35-year-old male of Indian descent who was diagnosed with HHH syndrome after he presented to the emergency room with gastroenteritis, disorientation, and slurred speech. Molecular analysis revealed that this patient was heterozygous for two ORNT1 mutations, p.[Gly220Arg(+)Arg275X] (c.[658G>A(+)823C>T]) that had been previously reported in homozygous probands who presented during the first year of life. Cellular studies revealed that the ORNT1 p.Gly220Arg mutation was nonfunctional but targeted to the mitochondria. Given that this patient was a successful college graduate on a vegetarian diet without a prior history of learning or neurological impairment, additional factors such as gene redundancy, environmental, and epigenetic factors may have contributed to the delay in onset of presentation and lack of any previous symptoms. To the best of our knowledge, this is the first reported case of an adult-onset HHH syndrome presentation without a prior history of neurological or cognitive deficiency.

  12. Adult-onset presentation of a hyperornithinemia-hyperammonemia-homocitrullinuria patient without prior history of neurological complications.

    PubMed

    Tezcan, Kamer; Louie, Kristal T; Qu, Yong; Velasquez, Jorge; Zaldivar, Frank; Rioseco-Camacho, Natalia; Camacho, José Angel

    2012-01-01

    The Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH) syndrome is a disorder of the urea cycle and ornithine degradation pathway caused by mutations in the mitochondrial ornithine transporter, ORNT1 (SLC25A15). In general, the majority of patients with HHH syndrome come to medical attention during infancy or early school years with symptoms such as learning disabilities, changes in cognitive development, spasticity, or liver dysfunction. In this report, we describe a 35-year-old male of Indian descent who was diagnosed with HHH syndrome after he presented to the emergency room with gastroenteritis, disorientation, and slurred speech. Molecular analysis revealed that this patient was heterozygous for two ORNT1 mutations, p.[Gly220Arg(+)Arg275X] (c.[658G>A(+)823C>T]) that had been previously reported in homozygous probands who presented during the first year of life. Cellular studies revealed that the ORNT1 p.Gly220Arg mutation was nonfunctional but targeted to the mitochondria. Given that this patient was a successful college graduate on a vegetarian diet without a prior history of learning or neurological impairment, additional factors such as gene redundancy, environmental, and epigenetic factors may have contributed to the delay in onset of presentation and lack of any previous symptoms. To the best of our knowledge, this is the first reported case of an adult-onset HHH syndrome presentation without a prior history of neurological or cognitive deficiency. PMID:23430880

  13. Signal transducer and activator of transcription 5 is implicated in disease activity in adult and juvenile onset systemic lupus erythematosus.

    PubMed

    Meshaal, Safa; El Refai, Rasha; El Saie, Ahmed; El Hawary, Rabab

    2016-06-01

    The Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway is one of a handful of pleiotropic cascades used to transduce a multitude of signals for development and homeostasis in humans. It is the principal signaling mechanism for a wide array of cytokines and growth factors. Dysregulated cytokine action on immune cells plays an important role in the initiation and progress of systemic lupus erythematosus (SLE). In this study, we tried to assess the role of STAT5 in systemic lupus erythematosus and correlate its phosphorylation level with the disease activity. The activation of the STAT5 was assessed by measuring the level of expression of phosphorylated STAT5 (pSTAT5) using flow cytometry on the peripheral blood T and B cells in 58 SLE patients (40 adult and 18 juvenile onset) and on 23 healthy age- and sex-matched controls for both groups. Serum prolactin level was also assessed in the patients and control by ELISA. The study revealed that the level of pSTAT5 was higher in adult SLE patients than in healthy control (p = 0.001) and in juvenile-onset SLE patients versus age-matched control (p = 0.031). A positive correlation existed between the pSTAT5 levels and Systemic Lupus Activity Measure (SLAM) score and also with multiple clinical manifestations indicating a potential role of STAT5 signaling in pathogenesis SLE. The pSTAT5 signaling is implicated in the disease activity of SLE and may be a useful target of therapy by correcting the dysregulation of cytokines involved in the disease pathogenesis.

  14. Signal transducer and activator of transcription 5 is implicated in disease activity in adult and juvenile onset systemic lupus erythematosus.

    PubMed

    Meshaal, Safa; El Refai, Rasha; El Saie, Ahmed; El Hawary, Rabab

    2016-06-01

    The Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway is one of a handful of pleiotropic cascades used to transduce a multitude of signals for development and homeostasis in humans. It is the principal signaling mechanism for a wide array of cytokines and growth factors. Dysregulated cytokine action on immune cells plays an important role in the initiation and progress of systemic lupus erythematosus (SLE). In this study, we tried to assess the role of STAT5 in systemic lupus erythematosus and correlate its phosphorylation level with the disease activity. The activation of the STAT5 was assessed by measuring the level of expression of phosphorylated STAT5 (pSTAT5) using flow cytometry on the peripheral blood T and B cells in 58 SLE patients (40 adult and 18 juvenile onset) and on 23 healthy age- and sex-matched controls for both groups. Serum prolactin level was also assessed in the patients and control by ELISA. The study revealed that the level of pSTAT5 was higher in adult SLE patients than in healthy control (p = 0.001) and in juvenile-onset SLE patients versus age-matched control (p = 0.031). A positive correlation existed between the pSTAT5 levels and Systemic Lupus Activity Measure (SLAM) score and also with multiple clinical manifestations indicating a potential role of STAT5 signaling in pathogenesis SLE. The pSTAT5 signaling is implicated in the disease activity of SLE and may be a useful target of therapy by correcting the dysregulation of cytokines involved in the disease pathogenesis. PMID:27041383

  15. Promotion of the Transition of Adult Patients with Childhood-Onset Chronic Diseases among Pediatricians in Japan

    PubMed Central

    Ishizaki, Yuko; Higashino, Hirohiko; Kaneko, Kazunari

    2016-01-01

    The transition of adult patients with childhood-onset chronic diseases (APCCD) from pediatric to adult health-care systems has recently received worldwide attention. However, Japan is lagging behind European countries and North America as this concept of health-care transition was introduced only 10 years ago. In Japan, before the introduction of this concept, APCCD were referred to as “carryover patients,” who were often considered a burden in pediatric practice. In the late 1990s, groups composed of pediatric nephrologists, developmental and behavioral pediatricians, pediatric nurses, and special education teachers researching the quality of life of adult patients with chronic kidney disease began to discuss the physical and psychosocial problems of APCCD. In 2006, a group of pediatricians first introduced the term “transition” in a Japanese journal. By 2010, a group of adolescent nurses had begun a specialized training program aimed at supporting patients during the transitional period. In 2013, the Ministry of Health, Labour and Welfare in Japan convened a research committee, focusing on issues related to social, educational, and medical support for APCCD, and the Japan Pediatric Society established a committee for the health-care transition of APCCD and summarized their statements. Moreover, in 2013, the Tokyo Metropolitan Children’s Medical Center initiated ambulatory services for APCCD managed by specialized nurses. The concept of health-care transition has rapidly spread over these past 10 years. The purpose of this article is to describe how this concept of health-care transition has advanced in Japan, such that APCCD now experience a positive pediatric to adult health-care transition. PMID:27803894

  16. Inflammatory cues acting on the adult intestinal stem cells and the early onset of cancer (Review)

    PubMed Central

    DE LERMA BARBARO, A.; PERLETTI, G.; BONAPACE, I.M.; MONTI, E.

    2014-01-01

    The observation that cancer often arises at sites of chronic inflammation has prompted the idea that carcinogenesis and inflammation are deeply interwoven. In fact, the current literature highlights a role for chronic inflammation in virtually all the steps of carcinogenesis, including tumor initiation, promotion and progression. The aim of the present article is to review the current literature on the involvement of chronic inflammation in the initiation step and in the very early phases of tumorigenesis, in a type of cancer where adult stem cells are assumed to be the cells of origin of neoplasia. Since the gastrointestinal tract is regarded as the best-established model system to address the liaison between chronic inflammation and neoplasia, the focus of this article will be on intestinal cancer. In fact, the anatomy of the intestinal epithelial lining is uniquely suited to study adult stem cells in their niche, and the bowel crypt is an ideal developmental biology system, as proliferation, differentiation and cell migration are all distributed linearly along the long axis of the crypt. Moreover, crypt stem cells are regarded today as the most likely targets of neoplastic transformation in bowel cancer. More specifically, the present review addresses the molecular mechanisms whereby a state of chronic inflammation could trigger the neoplastic process in the intestine, focusing on the generation of inflammatory cues evoking enhanced proliferation in cells not initiated but at risk of neoplastic transformation because of their stemness. Novel experimental approaches, based on triggering an inflammatory stimulus in the neighbourhood of adult intestinal stem cells, are warranted to address some as yet unanswered questions. A possible approach, the targeted transgenesis of Paneth cells, may be aimed at ‘hijacking’ the crypt stem cell niche from a status characterized by the maintenance of homeostasis to local chronic inflammation, with the prospect of initiating

  17. Effects of adult-onset calorie restriction on anxiety-like behavior in rats.

    PubMed

    Levay, Elizabeth A; Govic, Antonina; Penman, Jim; Paolini, Antonio G; Kent, Stephen

    2007-12-01

    Calorie restriction (CR) has consistently been shown to increase lifespan and ameliorate disease outcomes. Its effects on behavior are less clear, although anxiolytic-like effects have been observed. Rats were subjected to 1 of 4 dietary regimens: control, CR25%, CR50% and, an acute episode of CR and tested in 3 tests of anxiety: the open field test, the elevated plus maze, and the modified open field test. In the open field test, the CR25% and CR50% groups made more central zone entries than the control and Acute groups, which was primarily due to differences in the initial 5 min of the test. Moreover, both CR groups engaged in greater exploration of the central zone than the control group in the initial 5 min of the test. The Acute group also exhibited significantly longer latencies to leave the central zone at test onset than the control and CR50% group. In the elevated plus maze, the Acute group also displayed longer latencies to open arm entry as compared to the control and CR50% group and showed a lower ratio of open to total arm entries compared to all other groups. There were no effects of CR on any variable of the modified open field test. Possible neurochemical mechanisms underlying the anxiolytic-like effect of CR are discussed.

  18. Sporadic early adult-onset distal myopathy with rimmed vacuoles: immunohistochemistry and electron microscopy.

    PubMed

    Ceuterick, C; Martin, J J

    1996-08-01

    We report the histoenzymology, immunohistochemistry and electron microscopy of the tibialis anterior muscle of a 50-year-old male patient affected by a sporadic distal myopathy with onset during adolescence. There was no family history of muscle disorder and no clinical signs of cardiomyopathy. Extremely large variations in muscle fibre diameter (the size of some fibres exceeding 200-250 microns), rimmed vacuoles, necrotic fibres invaded by macrophages, atrophic fibres and perimysial fibrosis were observed. Using a wide range of antibodies raised against membrane- and cytoskeletal muscle proteins, granular desmin immunoreactivity was observed in muscle fibre lesions. There were no inflammatory parameters. Of special interest was the occurrence of autophagic vacuoles without 18-20 nm thick sarcoplasmic filaments and the presence of small aggregates of intermediate desmin-like filaments among a great diversity of ultrastructural findings. The morphological differential diagnosis is discussed. Our results stress the importance of combined immunohistochemistry and electron microscopy in the delineation of distal myopathies. DNA defects, however, still have to be identified which would improve the present classifications of distal myopathies.

  19. Distinct Muscle Biopsy Findings in Genetically Defined Adult-Onset Motor Neuron Disorders

    PubMed Central

    Jokela, Manu; Huovinen, Sanna; Raheem, Olayinka; Lindfors, Mikaela; Palmio, Johanna; Penttilä, Sini; Udd, Bjarne

    2016-01-01

    The objective of this study was to characterize and compare muscle histopathological findings in 3 different genetic motor neuron disorders. We retrospectively re-assessed muscle biopsy findings in 23 patients with autosomal dominant lower motor neuron disease caused by p.G66V mutation in CHCHD10 (SMAJ), 10 X-linked spinal and bulbar muscular atrophy (SBMA) and 11 autosomal dominant c9orf72-mutated amyotrophic lateral sclerosis (c9ALS) patients. Distinct large fiber type grouping consisting of non-atrophic type IIA muscle fibers were 100% specific for the late-onset spinal muscular atrophies (SMAJ and SBMA) and were never observed in c9ALS. Common, but less specific findings included small groups of highly atrophic rounded type IIA fibers in SMAJ/SBMA, whereas in c9ALS, small group atrophies consisting of small-caliber angular fibers involving both fiber types were more characteristic. We also show that in the 2 slowly progressive motor neuron disorders (SMAJ and SBMA) the initial neurogenic features are often confused with considerable secondary “myopathic” changes at later disease stages, such as rimmed vacuoles, myofibrillar aggregates and numerous fibers reactive for fetal myosin heavy chain (dMyHC) antibodies. Based on our findings, muscle biopsy may be valuable in the diagnostic work-up of suspected motor neuron disorders in order to avoid a false ALS diagnosis in patients without clear findings of upper motor neuron lesions. PMID:26999347

  20. Systems biology of neurodegenerative diseases.

    PubMed

    Wood, Levi B; Winslow, Ashley R; Strasser, Samantha Dale

    2015-07-01

    Neurodegenerative diseases (NDs) collectively afflict more than 40 million people worldwide. The majority of these diseases lack therapies to slow or stop progression due in large part to the challenge of disentangling the simultaneous presentation of broad, multifaceted pathophysiologic changes. Present technologies and computational capabilities suggest an optimistic future for deconvolving these changes to identify novel mechanisms driving ND onset and progression. In particular, integration of highly multi-dimensional omic analytical techniques (e.g., microarray, mass spectrometry) with computational systems biology approaches provides a systematic methodology to elucidate new mechanisms driving NDs. In this review, we begin by summarizing the complex pathophysiology of NDs associated with protein aggregation, emphasizing the shared complex dysregulation found in all of these diseases, and discuss available experimental ND models. Next, we provide an overview of technological and computational techniques used in systems biology that are applicable to studying NDs. We conclude by reviewing prior studies that have applied these approaches to NDs and comment on the necessity of combining analysis from both human tissues and model systems to identify driving mechanisms. We envision that the integration of computational approaches with multiple omic analyses of human tissues, and mouse and in vitro models, will enable the discovery of new therapeutic strategies for these devastating diseases.

  1. Childhood dyspraxia predicts adult-onset nonaffective-psychosis-spectrum disorder.

    PubMed

    Schiffman, Jason; Mittal, Vijay; Kline, Emily; Mortensen, Erik L; Michelsen, Niels; Ekstrøm, Morten; Millman, Zachary B; Mednick, Sarnoff A; Sørensen, Holger J

    2015-11-01

    Several neurological variables have been investigated as premorbid biomarkers of vulnerability for schizophrenia and other related disorders. The current study examined whether childhood dyspraxia predicted later adult nonaffective-psychosis-spectrum disorders. From a standardized neurological examination performed with children (aged 10-13) at genetic high risk of schizophrenia and controls, several measures of dyspraxia were used to create a scale composed of face/head dyspraxia, oral articulation, ideomotor dyspraxia (clumsiness), and dressing dyspraxia (n = 244). Multinomial logistic regression showed higher scores on the dyspraxia scale predict nonaffective-psychosis-spectrum disorders relative to other psychiatric disorders and no mental illness outcomes, even after controlling for genetic risk, χ2 (4, 244) = 18.61, p < .001. Findings that symptoms of dyspraxia in childhood (reflecting abnormalities spanning functionally distinct brain networks) specifically predict adult nonaffective-psychosis-spectrum disorders are consistent with a theory of abnormal connectivity, and they highlight a marked early-stage vulnerability in the pathophysiology of nonaffective-psychosis-spectrum disorders. PMID:26439077

  2. Prions mediated neurodegenerative disorders.

    PubMed

    Huang, W-J; Chen, W-W; Zhang, X

    2015-11-01

    Prions are unprecedented infectious pathogens that are devoid of nucleic acid and cause a group of rare and invariably fatal neurodegenerative disorders, affecting approximately 1 person per 1 million inhabitants annually worldwide. These disorders include Creutzfeld-Jacob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), kuru, fatal insomnia (FI), and variable protease-sensitive prionopathy (VPSPr), all of which involve a conformational change of the normal cellular prion protein (PrPC) into the abnormal scrapie prion protein (PrPSc) through a posttranslational process during which PrPc acquires high β-sheet content. This structural change is accompanied by profound changes in the physicochemical properties of PrPC, rendering the molecule resistant to proteolysis. The conformational change of PrPC can occur due to either spontaneous conversion, dominant mutations in the prion protein (PRNP) gene encoding PrPC, or infection with pathogenic isoform PrPsc from exogenous sources. There is general agreement that PrPC serves as a substrate for conversion to abnormal PrPSc. This latter multiplies exponentially and aggregates in the brain, forming deposits that are associated with the neurodegenerative changes. Although the understanding of the primary causes of prion-induced neurodegeneration is still limited, propagation of PrPSc and neurotoxic signaling seem to interplay in pathogenic process of prions. Here, we review recent findings that have provided fresh insights into this process, and present an overview of incidence, causes and spectrum of related disorders.

  3. Metabolic impact of adult-onset, isolated, growth hormone deficiency (AOiGHD) due to destruction of pituitary somatotropes.

    PubMed

    Luque, Raul M; Lin, Qing; Córdoba-Chacón, José; Subbaiah, Papasani V; Buch, Thorsten; Waisman, Ari; Vankelecom, Hugo; Kineman, Rhonda D

    2011-01-19

    Growth hormone (GH) inhibits fat accumulation and promotes protein accretion, therefore the fall in GH observed with weight gain and normal aging may contribute to metabolic dysfunction. To directly test this hypothesis a novel mouse model of adult onset-isolated GH deficiency (AOiGHD) was generated by cross breeding rat GH promoter-driven Cre recombinase mice (Cre) with inducible diphtheria toxin receptor mice (iDTR) and treating adult Cre(+/-),iDTR(+/-) offspring with DT to selectively destroy the somatotrope population of the anterior pituitary gland, leading to a reduction in circulating GH and IGF-I levels. DT-treated Cre(-/-),iDTR(+/-) mice were used as GH-intact controls. AOiGHD improved whole body insulin sensitivity in both low-fat and high-fat fed mice. Consistent with improved insulin sensitivity, indirect calorimetry revealed AOiGHD mice preferentially utilized carbohydrates for energy metabolism, as compared to GH-intact controls. In high-fat, but not low-fat fed AOiGHD mice, fat mass increased, hepatic lipids decreased and glucose clearance and insulin output were impaired. These results suggest the age-related decline in GH helps to preserve systemic insulin sensitivity, and in the context of moderate caloric intake, prevents the deterioration in metabolic function. However, in the context of excess caloric intake, low GH leads to impaired insulin output, and thereby could contribute to the development of diabetes.

  4. New onset pancytopenia in adults: a review of underlying pathologies and their associated clinical and laboratory findings.

    PubMed

    Devitt, Katherine A; Lunde, John H; Lewis, Michael R

    2014-05-01

    Abstract Pancytopenia is regularly encountered in hematology practice, yet there exist few published assessments of the frequencies of various etiologies, and these frequencies exhibit substantial geographic variation. We reviewed bone marrow specimens from pancytopenic adults to determine the most common etiologies and to identify associations with clinical and laboratory findings. Of 132 patients with no history of hematolymphoid neoplasia, no prior bone marrow study for pancytopenia and no recent cytotoxic chemotherapy, 64% had clonal hematopoietic disorders. Most common were myeloid processes: 26% of patients had acute myeloid leukemia, and 17% had myelodysplasia. Less common were lymphoid neoplasms such as non-Hodgkin lymphoma (6%), hairy cell leukemia (5%) and precursor B acute lymphoblastic leukemia (4%). Among non-clonal cases, the most common specific diagnoses were aplastic anemia (5%), megaloblastic anemia (2%) and human immunodeficiency virus (HIV)-related changes (2%). Clonal diagnoses were associated with more severe cytopenias than non-clonal cases. Circulating nucleated erythroid precursors, immature granulocytes and blasts were seen more frequently in clonal cases. Nearly two-thirds of cases of new onset pancytopenia in adults in our North American practice setting have a clonal etiology, with myeloid neoplasms being most common. Blood counts and peripheral smear findings can provide insights into the likelihood of a clonal etiology. PMID:23829306

  5. Adult-onset Kawasaki disease (mucocutaneous lymph node syndrome) and concurrent Coxsackievirus A4 infection: a case report

    PubMed Central

    Ueda, Yuki; Kenzaka, Tsuneaki; Noda, Ayako; Yamamoto, Yu; Matsumura, Masami

    2015-01-01

    Introduction Kawasaki disease (KD) most commonly develops in infants, although its specific cause is still unclear. We report here a rare case of adult-onset KD which revealed to be concurrently infected by Coxsackievirus A4. Case presentation The patient was a 37-year-old Japanese man who presented with fever, exanthema, changes in the peripheral extremities, bilateral non-exudative conjunctival injection, and changes in the oropharynx, signs that meet the diagnostic criteria for KD defined by the Centers for Disease Control and Prevention. In this case, the patient had a significantly high antibody titer for Coxsackievirus A4, which led us to presume that the occurrence of KD was concurrent Coxsackievirus A4 infection. Conclusion We reported a very rare case of KD which suggests that the disease can be concurrent Coxsackievirus A4 infection. Although KD is an acute childhood disease, with fever as one of the principal features, KD should also be considered in the differential diagnosis when adult patients present with a fever of unknown cause associated with a rash. PMID:26491373

  6. Induced pluripotent stem cells and neurodegenerative diseases.

    PubMed

    Chen, Chao; Xiao, Shi-Fu

    2011-04-01

    Neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease and Amyotrophic Lateral Sclerosis, are characterized by idiopathic neuron loss in different regions of the central nervous system, which contributes to the relevant dysfunctions in the patients. The application of cell replacement therapy using human embryonic stem (hES) cells, though having attracted much attention, has been hampered by the intrinsic ethical problems. It has been demonstrated that adult somatic cells can be reprogrammed into the embryonic state, called induced pluripotent stem (iPS) cells. It is soon realized that iPS cells may be an alternative source for cell replacement therapy, because it raises no ethical problems and using patient-specific iPS cells for autologous transplantation will not lead to immunological rejection. What's more, certain types of neurons derived from patient-specific iPS cells may display disease-relevant phenotypes. Thus, patient-specific iPS cells can provide a unique opportunity to directly investigate the pathological properties of relevant neural cells in individual patient, and to study the vulnerability of neural cells to pathogenic factors in vitro, which may help reveal the pathogenesis of many neurodegenerative diseases. In this review, the recent development in cellular treatment of neurodegenerative diseases using iPS cells was summarized, and the potential value of iPS cells in the modeling of neurodegenerative disease was discussed.

  7. Familial adult onset hyperinsulinism due to an activating glucokinase mutation: Implications for pharmacological glucokinase activation

    PubMed Central

    Challis, Benjamin G.; Harris, Julie; Sleigh, Alison; Isaac, Iona; Orme, Steve M.; Seevaratnam, Nandini; Dhatariya, Ketan; Simpson, Helen L.; Semple, Robert K.

    2016-01-01

    Context Glucokinase (GCK) phosphorylates and thereby “traps” glucose in cells, thus serving as a gatekeeper for cellular glucose metabolism, particularly in hepatocytes and pancreatic beta cells. In humans, activating GCK mutations cause familial hyperinsulinaemic hypoglycaemia (GCK-HH), leading to keen interest in the potential of small molecule glucokinase activators (GKAs) as treatments for diabetes mellitus. Many such agents have been developed, however observation of side effects including hypertriglyceridaemia and hepatic steatosis have delayed their clinical development. Objective To describe the clinical presentation and metabolic profiles of affected family members in a kindred with familial hyperinsulinism of adult presentation due to a known activating mutation in GCK. Design Clinical, biochemical and metabolic assessment, and GCK sequencing in affected family members. Results In the 60 year-old female proband, hyperinsulinaemic hypoglycaemia (blood glucose 2.1mmol/mol, insulin 18pmol/l) was confirmed following 34 hours of fasting, however abdominal computed tomography (CT), pancreatic MRI, endoscopic ultrasound, octreotide scintigraphy and selective arterial calcium stimulation failed to localise an insulinoma. A prolonged OGTT revealed fasting hypoglycaemia that was exacerbated after glucose challenge, consistent with dysregulated glucose-stimulated insulin release. A heterozygous activating mutation, p.Val389Leu, in the glucokinase gene (GCK) was found in the proband and four other family members. Of these, two had been investigated elsewhere for recurrent hypoglycaemia in adulthood, while the other two adult relatives were asymptomatic despite profound hypoglycaemia. All three of the available family members with the p.Val389Leu mutation had normal serum lipid profiles, normal rates of fasting hepatic de novo lipogenesis and had hepatic triglyceride levels commensurate with their degree of adiposity. Conclusion Activating GCK mutations may

  8. The promises of neurodegenerative disease modeling.

    PubMed

    Lepesant, Jean-Antoine

    2015-01-01

    The rise in the prevalence of neurodegenerative diseases parallels the rapid increase in human lifespan. Despite intensive research, the molecular and cellular mechanisms underlying the onset and progression of these devastating diseases with age are still poorly understood. Many aspects of these diseases have been modelled successfully in experimental animals such as the mouse, the zebrafish Brachydanio rero, the nematode worm Caenorhaditis elegans and the fruit fly Drosophila melanogaster. This review will focus on the advantages offered by the genetic tools available in Drosophila for combining powerful strategies in order to tackle the causative factors of these complex pathologies and help to elaborate efficient drugs to treat them.

  9. An autopsy case of adult-onset hereditary spastic paraplegia type 2 with a novel mutation in exon 7 of the proteolipid protein 1 gene.

    PubMed

    Suzuki, Satoshi O; Iwaki, Toru; Arakawa, Kenji; Furuya, Hirokazu; Fujii, Naoki; Iwaki, Akiko

    2011-12-01

    We report an autopsy case of rare adult-onset spastic paraplegia type 2 (SPG2) with a novel missense mutation in exon 7 of the proteolipid protein 1 gene (PLP1). The patient was a 67-year-old man whose elder brother had died of a similar disease with onset in his 40s. Thirty-three years before death at the age of 35, he noticed difficulty in walking. He gradually became abasic over a period of 6 years. He also developed progressive dementia and eventually became bed-ridden by 28 years after onset. At autopsy, gross inspection revealed diffuse, moderate atrophy of the cerebrum with a dilated ventricular system and softening of the white matter throughout the central nervous system (CNS). Histopathologically, the CNS showed widespread myelin pallor in the white matter. By contrast, the gray matter and peripheral nerves were well preserved. Some white matter tracts, including the corticospinal tracts, were preferentially affected, and severe axonal degeneration was observed in these tracts. Genetic analysis revealed a novel mutation, p.Tyr263Cys, in exon 7 of PLP1. This case represents an adult-onset SPG2 patient with one of the oldest ages of onset reported to date. The late onset and long clinical course suggest that this novel mutation does not affect the maturation of oligodendrocytes, but is related to insufficient maintenance of myelin.

  10. Copper deficiency elicits glial and neuronal response typical of neurodegenerative disorders.

    PubMed

    Zucconi, G G; Cipriani, S; Scattoni, R; Balgkouranidou, I; Hawkins, D P; Ragnarsdottir, K V

    2007-04-01

    Dysregulation of copper homeostasis has been associated with neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis (ALS) and prion diseases. The investigation of the role of abnormal copper level in the development of neuropathological damage is essential for the understanding of pathogenetic mechanisms of these neurodegenerative disorders. Using a mouse model of perinatally induced copper deficiency, the present study analysed the response of neuronal and glial cells to copper deficiency from infancy to young adult age. In mice born and maintained after weaning on copper-deficient diet, copper measurements indicated that at 6-8 weeks the copper levels in the brain were decreased by about 80% with respect to controls. In the brain of copper-deficient mice, microglial and astrocytic activation was observed, mostly in the cerebral cortex and thalamus. In addition, small vacuolated globoid cells confined to the subgranular zone of the dentate gyrus were found in the third postnatal week, and larger vacuolar profiles, identified as neuronal vacuoles, were observed in layer V of the cortex after the fourth week. The spatial distribution and temporal onset of vacuolation appeared to be unrelated to those of activated microglia and astrocytes. Nitrotyrosine-positivity was found to reflect the distribution of vacuoles in the cortex. The specific histopathological features here reported, as well as the severity of neurological deficits observed in this murine model of copper deficiency, strongly suggest that some hallmarks of neurodegenerative disorders could be mediated by multifactorial pathogenetic mechanisms that include copper dysregulation.

  11. Mitochondria as a Therapeutic Target for Aging and Neurodegenerative Diseases

    PubMed Central

    Reddy, P. Hemachandra; Reddy, Tejaswini P.

    2012-01-01

    Mitochondria are cytoplasmic organelles responsible for life and death. Extensive evidence from animal models, postmortem brain studies of and clinical studies of aging and neurodegenerative diseases suggests that mitochondrial function is defective in aging and neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. Several lines of research suggest that mitochondrial abnormalities, including defects in oxidative phosphorylation, increased accumulation of mitochondrial DNA defects, impaired calcium influx, accumulation of mutant proteins in mitochondria, and mitochondrial membrane potential dissipation are important cellular changes in both early and late-onset neurodegenerative diseases. Further, emerging evidence suggests that structural changes in mitochondria, including increased mitochondrial fragmentation and decreased mitochondrial fusion, are critical factors associated with mitochondrial dysfunction and cell death in aging and neurodegenerative diseases. This paper discusses research that elucidates features of mitochondria that are associated with cellular dysfunction in aging and neurodegenerative diseases and discusses mitochondrial structural and functional changes, and abnormal mitochondrial dynamics in neurodegenerative diseases. It also outlines mitochondria-targeted therapeutics in neurodegenerative diseases. PMID:21470101

  12. A common gene for juvenile and adult-onset primary open-angle glaucomas confined on chromosome 1q

    SciTech Connect

    Morissette, J.; Plante, M.; Raymond, V.

    1995-06-01

    Primary open-angle glaucoma (POAG), which causes progressive loss of the visual fields, was subdivided into two groups according to age at onset: (1) chronic open-angle glaucoma (COAG) diagnosed after 40 years and (2) juvenile open-angle glaucoma (JOAG) diagnosed between 3 years of age and early adulthood. A JOAG gene (GLC1A) was recently mapped to chromosome 1q. We studied 142 members of a huge multigenerational French Canadian family affected with autosomal dominant POAG. Either JOAG or COAG was diagnosed with ocular hypertension (OHT), which may lead to POAG. To localize a common disease gene that might be responsible for both glaucoma subsets, we performed linkage analysis considering JOAG and COAG under the same phenotypic category. JOAG/COAG was tightly linked to seven microsatellite markers on chromosome 1q23-q25; a maximum lod score of 6.62 was obtained with AF-M278ye5. To refine the disease locus, we exploited a recombination mapping strategy based on a unique founder effect. The same characteristic haplotype, composed of 14 markers spanning 12 cM between loci D1S196 and D1S212, was recognized in all persons affected by JOAG, COAG, or OHT, but it did not occur in unaffected spouses and in normal family members >35 years of age, except for three obligatory carriers. Key combination events confined the disease region within a 9-cM interval between loci D1S445 and D1S416/D1S480. These observations demonstrate that the GLC1A gene is responsible for both adult-onset and juvenile glaucomas and suggest that the JOAG and COAG categories within this family may be part of a clinical continuum artificially divided at age 40 years. 49 refs., 4 figs., 2 tabs.

  13. Parenchymal lung involvement in adult-onset Still disease: A STROBE-compliant case series and literature review.

    PubMed

    Gerfaud-Valentin, Mathieu; Cottin, Vincent; Jamilloux, Yvan; Hot, Arnaud; Gaillard-Coadon, Agathe; Durieu, Isabelle; Broussolle, Christiane; Iwaz, Jean; Sève, Pascal

    2016-07-01

    Parenchymal lung involvement (PLI) in adult-onset Still's disease (AOSD) has seldom, if ever, been studied. We examine here retrospective cohort AOSD cases and present a review of the literature (1971-2014) on AOSD-related PLI cases.Patients with PLI were identified in 57 AOSD cases. For inclusion, the patients had to fulfill Yamaguchi or Fautrel classification criteria, show respiratory symptoms, and have imaging evidence of pulmonary involvement, and data allowing exclusion of infectious, cardiogenic, toxic, or iatrogenic cause of PLI should be available. This AOSD + PLI group was compared with a control group (non-PLI-complicated AOSD cases from the same cohort).AOSD + PLI was found in 3 out of the 57 patients with AOSD (5.3%) and the literature mentioned 27 patients. Among these 30 AOSD + PLI cases, 12 presented an acute respiratory distress syndrome (ARDS) and the remaining 18 another PLI. In the latter, a nonspecific interstitial pneumonia computed tomography pattern prevailed in the lower lobes, pulmonary function tests showed a restrictive lung function, the alveolar differential cell count was neutrophilic in half of the cases, and the histological findings were consistent with bronchiolitis and nonspecific interstitial pneumonia. Corticosteroids were fully efficient in all but 3 patients. Ten out of 12 ARDS cases occurred during the first year of the disease course. All ARDS-complicated AOSD cases received corticosteroids with favorable outcomes in 10 (2 deceased). Most PLIs occurred during the systemic onset of AOSD.PLI may occur in 5% of AOSDs, of which ARDS is the most severe. Very often, corticosteroids are efficient in controlling this complication. PMID:27472698

  14. Dominant-Negative Effects of Adult-Onset Huntingtin Mutations Alter the Division of Human Embryonic Stem Cells-Derived Neural Cells

    PubMed Central

    Lopes, Carla; Aubert, Sophie; Bourgois-Rocha, Fany; Barnat, Monia; Rego, Ana Cristina; Déglon, Nicole

    2016-01-01

    Mutations of the huntingtin protein (HTT) gene underlie both adult-onset and juvenile forms of Huntington’s disease (HD). HTT modulates mitotic spindle orientation and cell fate in mouse cortical progenitors from the ventricular zone. Using human embryonic stem cells (hESC) characterized as carrying mutations associated with adult-onset disease during pre-implantation genetic diagnosis, we investigated the influence of human HTT and of an adult-onset HD mutation on mitotic spindle orientation in human neural stem cells (NSCs) derived from hESCs. The RNAi-mediated silencing of both HTT alleles in neural stem cells derived from hESCs disrupted spindle orientation and led to the mislocalization of dynein, the p150Glued subunit of dynactin and the large nuclear mitotic apparatus (NuMA) protein. We also investigated the effect of the adult-onset HD mutation on the role of HTT during spindle orientation in NSCs derived from HD-hESCs. By combining SNP-targeting allele-specific silencing and gain-of-function approaches, we showed that a 46-glutamine expansion in human HTT was sufficient for a dominant-negative effect on spindle orientation and changes in the distribution within the spindle pole and the cell cortex of dynein, p150Glued and NuMA in neural cells. Thus, neural derivatives of disease-specific human pluripotent stem cells constitute a relevant biological resource for exploring the impact of adult-onset HD mutations of the HTT gene on the division of neural progenitors, with potential applications in HD drug discovery targeting HTT-dynein-p150Glued complex interactions. PMID:26863614

  15. Dominant-Negative Effects of Adult-Onset Huntingtin Mutations Alter the Division of Human Embryonic Stem Cells-Derived Neural Cells.

    PubMed

    Lopes, Carla; Aubert, Sophie; Bourgois-Rocha, Fany; Barnat, Monia; Rego, Ana Cristina; Déglon, Nicole; Perrier, Anselme L; Humbert, Sandrine

    2016-01-01

    Mutations of the huntingtin protein (HTT) gene underlie both adult-onset and juvenile forms of Huntington's disease (HD). HTT modulates mitotic spindle orientation and cell fate in mouse cortical progenitors from the ventricular zone. Using human embryonic stem cells (hESC) characterized as carrying mutations associated with adult-onset disease during pre-implantation genetic diagnosis, we investigated the influence of human HTT and of an adult-onset HD mutation on mitotic spindle orientation in human neural stem cells (NSCs) derived from hESCs. The RNAi-mediated silencing of both HTT alleles in neural stem cells derived from hESCs disrupted spindle orientation and led to the mislocalization of dynein, the p150Glued subunit of dynactin and the large nuclear mitotic apparatus (NuMA) protein. We also investigated the effect of the adult-onset HD mutation on the role of HTT during spindle orientation in NSCs derived from HD-hESCs. By combining SNP-targeting allele-specific silencing and gain-of-function approaches, we showed that a 46-glutamine expansion in human HTT was sufficient for a dominant-negative effect on spindle orientation and changes in the distribution within the spindle pole and the cell cortex of dynein, p150Glued and NuMA in neural cells. Thus, neural derivatives of disease-specific human pluripotent stem cells constitute a relevant biological resource for exploring the impact of adult-onset HD mutations of the HTT gene on the division of neural progenitors, with potential applications in HD drug discovery targeting HTT-dynein-p150Glued complex interactions.

  16. Cytokine polymorphisms and plasma levels are associated with sleep onset insomnia in adults living with HIV/AIDS.

    PubMed

    Gay, Caryl L; Zak, Rochelle S; Lerdal, Anners; Pullinger, Clive R; Aouizerat, Bradley E; Lee, Kathryn A

    2015-07-01

    Sleep disturbance has been associated with inflammation and cytokine activity, and we previously described genetic associations between cytokine polymorphisms and sleep maintenance and duration among adults with HIV/AIDS. Although sleep onset insomnia (SOI) is also a commonly reported sleep problem, associations between cytokine biomarkers and SOI have not been adequately studied. The purpose of this study was to describe SOI in relation to cytokine plasma concentrations and gene polymorphisms in a convenience sample of 307 adults (212 men, 72 women, and 23 transgender) living with HIV/AIDS. Based on the Pittsburgh Sleep Quality Index item that asks the time it usually took to fall asleep in the past month, participants were categorized as either >30min to fall asleep (n=70, 23%) or 30min or less to fall asleep (n=237). Plasma cytokines were analyzed, and genotyping was conducted for 15 candidate genes involved in cytokine signaling: interferon-gamma (IFNG), IFNG receptor 1 (IFNGR1), interleukins (IL1R2, IL2, IL4, IL6, IL8, IL10, IL13, IL17A), nuclear factor of kappa light polypeptide gene enhancer in B cells (NFKB1 and NFKB2), and tumor necrosis factor alpha (TNFA). Demographic and clinical variables were evaluated as potential covariates. After adjusting for genomic estimates of ancestry, self-reported race/ethnicity and viral load, SOI was associated with higher IL-13 plasma levels and with six single nucleotide polymorphisms (SNPs): IL1B rs1143642 and rs1143623, IL6 rs4719714, IL13 rs1295686, NFKB1 rs4648110, and TNFA rs2857602. In addition, the IL1B rs1143642 polymorphism was associated with plasma levels of IL-1β in adjusted analyses. This study strengthens the evidence for an association between inflammation and sleep disturbance, particularly self-report of habitual SOI. In this chronic illness population, the cytokine polymorphisms associated with SOI provide direction for future personalized medicine intervention research.

  17. Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia linked CSF1R mutation: Report of four Korean cases.

    PubMed

    Kim, Eun-Joo; Shin, Jin-Hong; Lee, Jeong Hee; Kim, Jong Hun; Na, Duk L; Suh, Yeon-Lim; Hwang, Sun Jae; Lee, Jae-Hyeok; Lee, Young Min; Shin, Myung-Jun; Lee, Myung Jun; Kim, Seong-Jang; Yoon, Uicheul; Park, Do Youn; Jung, Dae Soo; Ahn, Jae Woo; Sung, Suk; Huh, Gi Yeong

    2015-02-15

    We describe detailed clinical, biochemical, neuroimaging and neuropathological features in adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), encompassing hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) and pigmentary orthochromatic leukodystrophy (POLD), linked to colony-stimulating factor 1 receptor (CSF1R) mutations in four Korean cases. Clinical, biochemical, neuroimaging and neuropathological findings were obtained by direct evaluation and from previous medical records. The genetic analysis of the CSF1R gene was done in two autopsy-confirmed ALSP cases and two cases where ALSP was suspected based on the clinical and neuroimaging characteristics. We identified two known mutations: c.2342C>T (p.A781V) in one autopsy-proven HDLS and clinically ALSP-suspected case and c.2345G>A (p.R782H) in another autopsy-proven POLD case. We also found a novel mutation (c.2296A>G; p.M766V) in a patient presenting with hand tremor, stuttering and hesitant speech, and abnormal behavior whose father died from a possible diagnosis of spinocerebellar ataxia. To the best of our knowledge, this is the first documented ALSP-linked CSF1R mutation in Korea and supports the suggestion that HDLS and POLD, with pathological characteristics that are somewhat different but which are caused by CSF1R mutations, are the same spectrum of disease, ALSP.

  18. Adult-onset multiple acyl CoA dehydrogenation deficiency associated with an abnormal isoenzyme pattern of serum lactate dehydrogenase.

    PubMed

    Sugai, Fuminobu; Baba, Kousuke; Toyooka, Keiko; Liang, Wen-Chen; Nishino, Ichizo; Yamadera, Misaki; Sumi, Hisae; Fujimura, Harutoshi; Nishikawa, Yoshiro

    2012-02-01

    We report a case of a 37 year-old male with multiple acyl-CoA dehydrogenation deficiency (MADD). The patient had suffered from exercise intolerance in his hip and thigh muscles for one year. Then, restriction of carbohydrates for a diet made his symptoms rapidly deteriorate. Blood test revealed compound heterozygosity for two novel missense mutations in the electron transfer flavoprotein dehydrogenase gene (ETFDH), and an abnormal LDH isoenzyme pattern: LDH-1 (60.0%) and LDH-2 (26.0%) predominated with abnormally elevated LDH-1/LDH-2 ratio (2.3), compared with muscle-derived LDH-5 (4.0%). Oral riboflavin treatment significantly improved his exercise intolerance and the LDH profile: LDH-1 (34.4%), LDH-2 (34.9%), LDH-5 (6.9%) and LDH-1/LDH-2 ratio (1.0). The abnormal LDH isoenzyme pattern may be one feature of adult-onset MADD selectively affecting type I muscle fibers with relatively high LDH-1 content. PMID:21907580

  19. Successful Tocilizumab Therapy for Macrophage Activation Syndrome Associated with Adult-Onset Still's Disease: A Case-Based Review.

    PubMed

    Watanabe, Eri; Sugawara, Hitoshi; Yamashita, Takeshi; Ishii, Akira; Oda, Aya; Terai, Chihiro

    2016-01-01

    We report the case of a 71-year-old Japanese woman with adult-onset Still's disease (AOSD) in whom macrophage activation syndrome (MAS) developed despite therapy with oral high-dose prednisolone and intravenous methylprednisolone pulse therapy twice. She was successfully treated with tocilizumab (TCZ). Soon afterward, her fever ceased and high levels of both ferritin and C-reactive protein levels decreased. Her course was complicated by disseminated intravascular coagulation, cytomegalovirus infection, and Pneumocystis jirovecii pneumonia. After these were resolved, AOSD-associated MAS was well controlled. She was discharged on hospital day 87. Although biologics such as TCZ are becoming established for the treatment of AOSD, there is no recommended therapy for AOSD-associated MAS. Several biologics have been tried for this complication, but their efficacy and safety remain controversial. We reviewed reported cases of AOSD-associated MAS successfully treated with various biologics. TCZ initiation after adequate nonselective immunosuppressive therapy, such as methylprednisolone pulse therapy or a prednisolone-based combination of immunosuppressants, can be an effective treatment for AOSD-associated MAS. On the other hand, biologics given after insufficient immunosuppressive therapy may cause MAS. A strategy combining adequate immunosuppression and a biologic could be safe if special attention is given to adverse events such as opportunistic infections or biologic-associated MAS. PMID:27688774

  20. Successful Tocilizumab Therapy for Macrophage Activation Syndrome Associated with Adult-Onset Still's Disease: A Case-Based Review

    PubMed Central

    Watanabe, Eri; Yamashita, Takeshi; Ishii, Akira; Oda, Aya; Terai, Chihiro

    2016-01-01

    We report the case of a 71-year-old Japanese woman with adult-onset Still's disease (AOSD) in whom macrophage activation syndrome (MAS) developed despite therapy with oral high-dose prednisolone and intravenous methylprednisolone pulse therapy twice. She was successfully treated with tocilizumab (TCZ). Soon afterward, her fever ceased and high levels of both ferritin and C-reactive protein levels decreased. Her course was complicated by disseminated intravascular coagulation, cytomegalovirus infection, and Pneumocystis jirovecii pneumonia. After these were resolved, AOSD-associated MAS was well controlled. She was discharged on hospital day 87. Although biologics such as TCZ are becoming established for the treatment of AOSD, there is no recommended therapy for AOSD-associated MAS. Several biologics have been tried for this complication, but their efficacy and safety remain controversial. We reviewed reported cases of AOSD-associated MAS successfully treated with various biologics. TCZ initiation after adequate nonselective immunosuppressive therapy, such as methylprednisolone pulse therapy or a prednisolone-based combination of immunosuppressants, can be an effective treatment for AOSD-associated MAS. On the other hand, biologics given after insufficient immunosuppressive therapy may cause MAS. A strategy combining adequate immunosuppression and a biologic could be safe if special attention is given to adverse events such as opportunistic infections or biologic-associated MAS. PMID:27688774

  1. The Phospholipase D2 Knock Out Mouse Has Ectopic Purkinje Cells and Suffers from Early Adult-Onset Anosmia

    PubMed Central

    Zhang, Qifeng; Smethurst, Elizabeth; Segonds-Pichon, Anne; Schrewe, Heinrich; Wakelam, Michael J. O.

    2016-01-01

    Phospholipase D2 (PLD2) is an enzyme that produces phosphatidic acid (PA), a lipid messenger molecule involved in a number of cellular events including, through its membrane curvature properties, endocytosis. The PLD2 knock out (PLD2KO) mouse has been previously reported to be protected from insult in a model of Alzheimer's disease. We have further analysed a PLD2KO mouse using mass spectrophotometry of its lipids and found significant differences in PA species throughout its brain. We have examined the expression pattern of PLD2 which allowed us to define which region of the brain to analyse for defect, notably PLD2 was not detected in glial-rich regions. The expression pattern lead us to specifically examine the mitral cells of olfactory bulbs, the Cornus Amonis (CA) regions of the hippocampus and the Purkinje cells of the cerebellum. We find that the change to longer PA species correlates with subtle architectural defect in the cerebellum, exemplified by ectopic Purkinje cells and an adult-onset deficit of olfaction. These observations draw parallels to defects in the reelin heterozygote as well as the effect of high fat diet on olfaction. PMID:27658289

  2. Successful Tocilizumab Therapy for Macrophage Activation Syndrome Associated with Adult-Onset Still's Disease: A Case-Based Review

    PubMed Central

    Watanabe, Eri; Yamashita, Takeshi; Ishii, Akira; Oda, Aya; Terai, Chihiro

    2016-01-01

    We report the case of a 71-year-old Japanese woman with adult-onset Still's disease (AOSD) in whom macrophage activation syndrome (MAS) developed despite therapy with oral high-dose prednisolone and intravenous methylprednisolone pulse therapy twice. She was successfully treated with tocilizumab (TCZ). Soon afterward, her fever ceased and high levels of both ferritin and C-reactive protein levels decreased. Her course was complicated by disseminated intravascular coagulation, cytomegalovirus infection, and Pneumocystis jirovecii pneumonia. After these were resolved, AOSD-associated MAS was well controlled. She was discharged on hospital day 87. Although biologics such as TCZ are becoming established for the treatment of AOSD, there is no recommended therapy for AOSD-associated MAS. Several biologics have been tried for this complication, but their efficacy and safety remain controversial. We reviewed reported cases of AOSD-associated MAS successfully treated with various biologics. TCZ initiation after adequate nonselective immunosuppressive therapy, such as methylprednisolone pulse therapy or a prednisolone-based combination of immunosuppressants, can be an effective treatment for AOSD-associated MAS. On the other hand, biologics given after insufficient immunosuppressive therapy may cause MAS. A strategy combining adequate immunosuppression and a biologic could be safe if special attention is given to adverse events such as opportunistic infections or biologic-associated MAS.

  3. Relationship between neuropsychological impairment and grey and white matter changes in adult-onset myotonic dystrophy type 1.

    PubMed

    Baldanzi, Sigrid; Cecchi, Paolo; Fabbri, Serena; Pesaresi, Ilaria; Simoncini, Costanza; Angelini, Corrado; Bonuccelli, Ubaldo; Cosottini, Mirco; Siciliano, Gabriele

    2016-01-01

    Myotonic dystrophy type 1 (DM1) has a wide phenotypic spectrum and potentially may affect central nervous system with mild to severe involvement. Our aim was to investigate grey matter (GM) and white matter (WM) structural alterations in a sample of adult-onset DM1 patients and to evaluate relationship with clinical and cognitive variables. Thirty DM1 patients underwent neuropsychological investigation and 3T-MRI protocol. GM and WM changes were evaluated calculating brain parenchymal fraction (BPF), voxel-based morphometry (VBM), white matter lesion load (LL% and Fazekas scale) and tract based spatial statistical (TBSS). Patients showed main impairment in tests exploring executive and mnesic domains with visuo-spatial involvement, significantly related to BPF. VBM revealed clusters of widespread GM reduction and TBSS revealed areas of decreased fractional anisotropy (FA) and increased radial diffusivity (RD), mean diffusivity (MD) and axial diffusivity (AD) in patients compared to a group of matched healthy controls. Multiple regression analyses showed areas of significant negative relationship between left temporal atrophy and verbal memory, between RD and mnesic and visuo-spatial cognitive domains, and between AD and verbal memory. TBSS results indicate that the involvement of normal appearance WM, beyond the signal changes detected with conventional MR imaging (Fazekas scale and LL%), was associated with neuropsychological deficit. These data suggest that disrupted complex neuronal networks can underlie cognitive-behavioural dysfunctions in DM1. PMID:27437180

  4. Adult-Onset Obesity Reveals Prenatal Programming of Glucose-Insulin Sensitivity in Male Sheep Nutrient Restricted during Late Gestation

    PubMed Central

    Rhodes, Philip; Craigon, Jim; Gray, Clint; Rhind, Stuart M.; Loughna, Paul T.; Gardner, David S.

    2009-01-01

    Background Obesity invokes a range of metabolic disturbances, but the transition from a poor to excessive nutritional environment may exacerbate adult metabolic dysfunction. The current study investigated global maternal nutrient restriction during early or late gestation on glucose tolerance and insulin sensitivity in the adult offspring when lean and obese. Methods/Principal Findings Pregnant sheep received adequate (1.0M; CE, n = 6) or energy restricted (0.7M) diet during early (1–65 days; LEE, n = 6) or late (65–128 days; LEL, n = 7) gestation (term ∼147 days). Subsequent offspring remained on pasture until 1.5 years when all received glucose and insulin tolerance tests (GTT & ITT) and body composition determination by dual energy x-ray absorptiometry (DXA). All animals were then exposed to an obesogenic environment for 6–7 months and all protocols repeated. Prenatal dietary treatment had no effect on birth weight or on metabolic endpoints when animals were ‘lean’ (1.5 years). Obesity revealed generalised metabolic ‘inflexibility’ and insulin resistance; characterised by blunted excursions of plasma NEFA and increased insulinAUC (from 133 to 341 [s.e.d. 26] ng.ml−1.120 mins) during a GTT, respectively. For LEL vs. CE, the peak in plasma insulin when obese was greater (7.8 vs. 4.7 [s.e.d. 1.1] ng.ml−1) and was exacerbated by offspring sex (i.e. 9.8 vs. 4.4 [s.e.d. 1.16] ng.ml−1; LEL male vs. CE male, respectively). Acquisition of obesity also significantly influenced the plasma lipid and protein profile to suggest, overall, greater net lipogenesis and reduced protein metabolism. Conclusions This study indicates generalised metabolic dysfunction with adult-onset obesity which also exacerbates and ‘reveals’ programming of glucose-insulin sensitivity in male offspring prenatally exposed to maternal undernutrition during late gestation. Taken together, the data suggest that metabolic function appears little compromised in young

  5. DNA damage in neurodegenerative diseases.

    PubMed

    Coppedè, Fabio; Migliore, Lucia

    2015-06-01

    Following the observation of increased oxidative DNA damage in nuclear and mitochondrial DNA extracted from post-mortem brain regions of patients affected by neurodegenerative diseases, the last years of the previous century and the first decade of the present one have been largely dedicated to the search of markers of DNA damage in neuronal samples and peripheral tissues of patients in early, intermediate or late stages of neurodegeneration. Those studies allowed to demonstrate that oxidative DNA damage is one of the earliest detectable events in neurodegeneration, but also revealed cytogenetic damage in neurodegenerative conditions, such as for example a tendency towards chromosome 21 malsegregation in Alzheimer's disease. As it happens for many neurodegenerative risk factors the question of whether DNA damage is cause or consequence of the neurodegenerative process is still open, and probably both is true. The research interest in markers of oxidative stress was shifted, in recent years, towards the search of epigenetic biomarkers of neurodegenerative disorders, following the accumulating evidence of a substantial contribution of epigenetic mechanisms to learning, memory processes, behavioural disorders and neurodegeneration. Increasing evidence is however linking DNA damage and repair with epigenetic phenomena, thereby opening the way to a very attractive and timely research topic in neurodegenerative diseases. We will address those issues in the context of Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis, which represent three of the most common neurodegenerative pathologies in humans. PMID:26255941

  6. Rearranged Anaplastic Lymphoma Kinase (ALK) Gene in Adult-Onset Papillary Thyroid Cancer Amongst Atomic Bomb Survivors

    PubMed Central

    Mukai, Mayumi; Takahashi, Keiko; Hayashi, Yuzo; Nakachi, Kei; Kusunoki, Yoichiro

    2012-01-01

    rearrangements, being observed in 6 of 10 PTC cases with ALK rearrangements versus 2 of 15 cases with no ALK rearrangements. The six radiation-exposed cases of PTC harboring both ALK rearrangements and solid/trabecular-like architecture were associated with higher radiation doses and younger ages at the time of the A-bombing and at diagnosis compared to the other 19 PTC with no detectable gene alterations. Conclusion Our findings suggest that ALK rearrangements are involved in the development of radiation-induced adult-onset PTC. PMID:23050789

  7. Liver transplantation versus conservative treatment for adult-onset type II citrullinemia: our experience and a review of the literature.

    PubMed

    Kimura, N; Kubo, N; Narumi, S; Toyoki, Y; Ishido, K; Kudo, D; Umehara, M; Yakoshi, Y; Hakamada, K

    2013-11-01

    Adult-onset type II citrullinemia (CTLN2), an autosomal recessive disorder caused by a mutation in the SLC25A13 gene, is characterized by increased serum citrulline and ammonia levels. Patients with CTLN2 also display various neuropsychiatric symptoms. Many individuals with CTLN2 are fond of protein-rich and/or lipid-rich foods with an aversion to carbohydrate-rich foods. We herein report two cases of CTLN2 treated with living donor liver transplantation (LDLT) and provide a review of the pertinent literature. Case 1 was a 43-year-old man admitted to our hospital for repetitive episodes of consciousness disturbance. Case 2 was a 37-year-old man admitted to our hospital because of abnormal behavior associated with hyperammonemia. A definitive diagnosis of CTLN2 was accomplished by DNA analysis in both patients, who successfully underwent LDLT using liver segments from donor siblings with confirmed heterozygous gene expression. Case 2 also underwent conservative therapy with arginine and a high-fat, carbohydrate-restricted diet prior to LDLT. Postoperative recovery was uneventful and food was unrestricted in both patients. We also identified 77 cases of CTLN2 in the literature and reviewed them in terms of outcome of both liver transplantation and conservative therapy. The survival rate in patients treated by liver transplantation was 100%, whereas that in patients treated by conservative treatment showed improvement from 39.5% to 76.5% over the years. Liver transplantation is a practical treatment that fundamentally improves patient quality of life after transplantation. However, recent studies have suggested that arginine and sodium pyruvate administration combined with intensive nutritional support is also an effective therapy for CTLN2. Further development of conservative therapy may provide a safer, more affordable alternative to liver transplantation in the near future.

  8. Prolonged remission state of refractory adult onset Still's disease following CD34-selected autologous peripheral blood stem cell transplantation.

    PubMed

    Lanza, F; Dominici, M; Govoni, M; Moretti, S; Campioni, D; Corte, R L; Latorraca, A; Tieghi, A; Castagnari, B; Trotta, F; Castoldi, G

    2000-06-01

    We report a 38-year-old patient affected by refractory adult onset Still's disease who achieved a prolonged remission following CD34-selected ABMT. The conditioning regimen was based on the use of CY and anti-thymocyte globulin. A 3.0 and 2.0 log reduction of T (CD3+) and B (CD19+) lymphocytes, respectively, was obtained using a Ceprate device to select CD34+ cells from PBSC. In the pre-transplant period (1994-1998) the patient had a chronic persistent disease course with frequent and recurrent systemic articular flares and loss of some functional abilities, despite daily prednisone, pulses of CY and immunosuppressive therapy (CYA or MTX). At the time of ABMT the patient had become non-ambulatory. Within 3 weeks of ABMT the patient showed a marked decrease in joint swelling, and morning stiffness. Joint pain and systemic symptoms disappeared, the patient was able to walk and run and gained general well being. ESR, C-reactive protein and WBC count were significantly decreased, while Hb level increased. This partial remission persisted for at least 1 year after ABMT, although at 15 months of follow-up a reappearance of moderate synovitis in the knees and wrists was noted. Our data further showed that both patient BM microenvironment and stem-progenitor cell function (as assessed by LTC-IC assay) were damaged even 1 year after CD34-selected ABMT, suggesting that the persistence of these alterations could have facilitated the favorable outcome of the disease following ABMT. Bone Marrow Transplantation (2000) 25, 1307-1310. PMID:10871738

  9. Comparison of Glomerular Transcriptome Profiles of Adult-Onset Steroid Sensitive Focal Segmental Glomerulosclerosis and Minimal Change Disease

    PubMed Central

    Ren, Hong; Liu, Jian; Zhang, Weijia; Wei, Chengguo; Xu, Jing; Zhang, Wen; Li, Xiao; Wang, Weiming; Lv, Danfeng; He, John Cijiang; Chen, Nan

    2015-01-01

    Objective To search for biomarkers to differentiate primary focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD). Methods We isolated glomeruli from kidney biopsies of 6 patients with adult-onset steroid sensitiveFSGS and 5 patients with MCD, and compared the profiles of glomerular transcriptomes between the two groups of patients using microarray analysis. Results Analysis of differential expressed genes (DEGs) revealed that up-regulated DEGs in FSGS patients compared with MCD patients were primarily involved in spermatogenesis, gamete generation, regulation of muscle contraction, response to unfolded protein, cell proliferation and skeletal system development. The down-regulated DEGs were primarily related to metabolic process, intracellular transport, oxidation/reduction andestablishment of intracellular localization. We validated the expression of the top 6 up-regulated and top 6 down-regulated DEGs using real-time PCR. Membrane metallo-endopeptidase (MME) is a down-regulated gene that was previously identified as a key gene for kidney development. Immunostaining confirmed that the protein expression of MME decreased significantly in FSGS kidneys compared with MCD kidneys. Conclusions This report was the first study to examine transcriptomes in Chinese patients with various glomerular diseases. Expressions of MME both in RNA and protein level decreased significantly in glomeruli of FSGS kidneys compared with MCD kidneys. Our data suggested that MME might play a role in the normal physiological function of podocytes and a decrease in MME expression might be related to podocyte injury. We also identified genes and pathways specific for FSGS versus MCD, and our data could help identify potential new biomarkers for the differential diagnosis between these two diseases. PMID:26536600

  10. The synaptic maintenance problem: membrane recycling, Ca2+ homeostasis and late onset degeneration

    PubMed Central

    2013-01-01

    Most neurons are born with the potential to live for the entire lifespan of the organism. In addition, neurons are highly polarized cells with often long axons, extensively branched dendritic trees and many synaptic contacts. Longevity together with morphological complexity results in a formidable challenge to maintain synapses healthy and functional. This challenge is often evoked to explain adult-onset degeneration in numerous neurodegenerative disorders that result from otherwise divergent causes. However, comparably little is known about the basic cell biological mechanisms that keep normal synapses alive and functional in the first place. How the basic maintenance mechanisms are related to slow adult-onset degeneration in different diseasesis largely unclear. In this review we focus on two basic and interconnected cell biological mechanisms that are required for synaptic maintenance: endomembrane recycling and calcium (Ca2+) homeostasis. We propose that subtle defects in these homeostatic processes can lead to late onset synaptic degeneration. Moreover, the same basic mechanisms are hijacked, impaired or overstimulated in numerous neurodegenerative disorders. Understanding the pathogenesis of these disorders requires an understanding of both the initial cause of the disease and the on-going changes in basic maintenance mechanisms. Here we discuss the mechanisms that keep synapses functional over long periods of time with the emphasis on their role in slow adult-onset neurodegeneration. PMID:23829673

  11. Rare complication of ventriculoperitoneal shunt. Early onset of distal catheter migration into scrotum in an adult male: Case report and literature review

    PubMed Central

    Lee, Bryan S.; Vadera, Sumeet; Gonzalez-Martinez, Jorge A.

    2014-01-01

    Introduction The role of shunt placement is to divert cerebrospinal fluid from within the ventricles to an alternative location in the setting of hydrocephalus. One of the rare shunt complications is distal catheter migration, and various body sites have been reported, including the scrotum. Although cases of scrotal migration of distal catheter have been reported in pediatric patients, cases in adult patients are rare due to obliterated processus vaginalis. Furthermore, there has not been a case reported for scrotal migration in an adult at an early onset. Presentation of case 65-year-old male underwent shunt placement for normal-pressure hydrocephalus-like symptoms. On post-operative day seven patient developed right testicular edema, for which ultrasound was performed, revealing hydrocele along with the presence of distal catheter in the scrotum. On post-operative day nine patient underwent distal catheter trimming via laparoscopic approach with general surgery, with post-operative imaging showing satisfactory location of distal catheter in the peritoneal cavity. Discussion/Conclusion Early onset of distal catheter migration into scrotum in an adult male is a unique case, as most cases are reported in pediatric patients, and it is the first case reported in the English literature to have occurrence at an early onset during the peri-operative period. As our case demonstrates, early occurrence and detection of scrotal migration of the distal catheter prevent shunt malfunction. Prompt surgical management of catheter repositioning is therefore recommended to avoid the risk of further complications. PMID:25553524

  12. Adult onset asymmetric upper limb tremor misdiagnosed as Parkinson’s disease: A clinical and electrophysiological study

    PubMed Central

    Schwingenschuh, Petra; Ruge, Diane; Edwards, Mark J; Terranova, Carmen; Katschnig, Petra; Carrillo, Fatima; Silveira-Moriyama, Laura; Schneider, Susanne A; Kägi, Georg; Dickson, John; Lees, Andrew J; Quinn, Niall; Mir, Pablo; Rothwell, John C; Bhatia, Kailash P

    2010-01-01

    different from controls. Taken together, these results may help differentiate these SWEDDs patients from PD and support our hypothesis that adult-onset dystonia is the underlying diagnosis in this sub-group of patients with SWEDDs. PMID:20131394

  13. Quantitative interaction proteomics of neurodegenerative disease proteins.

    PubMed

    Hosp, Fabian; Vossfeldt, Hannes; Heinig, Matthias; Vasiljevic, Djordje; Arumughan, Anup; Wyler, Emanuel; Landthaler, Markus; Hubner, Norbert; Wanker, Erich E; Lannfelt, Lars; Ingelsson, Martin; Lalowski, Maciej; Voigt, Aaron; Selbach, Matthias

    2015-05-19

    Several proteins have been linked to neurodegenerative disorders (NDDs), but their molecular function is not completely understood. Here, we used quantitative interaction proteomics to identify binding partners of Amyloid beta precursor protein (APP) and Presenilin-1 (PSEN1) for Alzheimer's disease (AD), Huntingtin (HTT) for Huntington's disease, Parkin (PARK2) for Parkinson's disease, and Ataxin-1 (ATXN1) for spinocerebellar ataxia type 1. Our network reveals common signatures of protein degradation and misfolding and recapitulates known biology. Toxicity modifier screens and comparison to genome-wide association studies show that interaction partners are significantly linked to disease phenotypes in vivo. Direct comparison of wild-type proteins and disease-associated variants identified binders involved in pathogenesis, highlighting the value of differential interactome mapping. Finally, we show that the mitochondrial protein LRPPRC interacts preferentially with an early-onset AD variant of APP. This interaction appears to induce mitochondrial dysfunction, which is an early phenotype of AD.

  14. Depressive symptoms in neurodegenerative diseases

    PubMed Central

    Baquero, Miquel; Martín, Nuria

    2015-01-01

    Depressive symptoms are very common in chronic conditions. This is true so for neurodegenerative diseases. A number of patients with cognitive decline and dementia due to Alzheimer’s disease and related conditions like Parkinson’s disease, Lewy body disease, vascular dementia, frontotemporal degeneration amongst other entities, experience depressive symptoms in greater or lesser grade at some point during the course of the illness. Depressive symptoms have a particular significance in neurological disorders, specially in neurodegenerative diseases, because brain, mind, behavior and mood relationship. A number of patients may develop depressive symptoms in early stages of the neurologic disease, occurring without clear presence of cognitive decline with only mild cognitive deterioration. Classically, depression constitutes a reliable diagnostic challenge in this setting. However, actually we can recognize and evaluate depressive, cognitive or motor symptoms of neurodegenerative disease in order to establish their clinical significance and to plan some therapeutic strategies. Depressive symptoms can appear also lately, when the neurodegenerative disease is fully developed. The presence of depression and other neuropsychiatric symptoms have a negative impact on the quality-of-life of patients and caregivers. Besides, patients with depressive symptoms also tend to further decrease function and reduce cognitive abilities and also uses to present more affected clinical status, compared with patients without depression. Depressive symptoms are treatable. Early detection of depressive symptoms is very important in patients with neurodegenerative disorders, in order to initiate the most adequate treatment. We review in this paper the main neurodegenerative diseases, focusing in depressive symptoms of each other entities and current recommendations of management and treatment. PMID:26301229

  15. Mitochondrial Dysfunction in Neurodegenerative Diseases

    PubMed Central

    Johri, Ashu

    2012-01-01

    Neurodegenerative diseases are a large group of disabling disorders of the nervous system, characterized by the relative selective death of neuronal subtypes. In most cases, there is overwhelming evidence of impaired mitochondrial function as a causative factor in these diseases. More recently, evidence has emerged for impaired mitochondrial dynamics (shape, size, fission-fusion, distribution, movement etc.) in neurodegenerative diseases such as Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and Alzheimer's disease. Here, we provide a concise overview of the major findings in recent years highlighting the importance of healthy mitochondria for a healthy neuron. PMID:22700435

  16. Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia Caused by a Novel R782G Mutation in CSF1R.

    PubMed

    Foulds, Nicola; Pengelly, Reuben J; Hammans, Simon R; Nicoll, James A R; Ellison, David W; Ditchfield, Adam; Beck, Sarah; Ennis, Sarah

    2015-05-15

    We report a new family with autosomal dominant inheritance of a late onset rapidly progressive leukodystrophy in which exome sequencing has revealed a novel mutation p.R782G in the Colony-Stimulating Factor 1 Receptor gene (CSF1R). Neuropathology of two affected family members showed cerebral white matter degeneration with axonal swellings and pigmented macrophages. The few recently reported families with CSF1R mutations had been previously labelled "hereditary diffuse leukencephalopathy with axonal spheroids" (HDLS) and "pigmentary orthochromatic leukodystrophy" (POLD), disorders which now appear to form a disease continuum. The term "adult-onset leukoencephalopathy with axonal spheroids and pigmented glia" (ALSP) has been proposed to encompass this spectrum. As CSF1R regulates microglia this mutation implies that dysregulation of microglia is the primary cause of the disease.

  17. Nocturnal hydration--an effective modality to reduce recurrent abdominal pain and recurrent pancreatitis in patients with adult-onset cystic fibrosis.

    PubMed

    Obideen, Kamil; Wehbi, Mohammad; Hoteit, Maarouf; Cai, Qiang

    2006-10-01

    Recurrent abdominal pain and recurrent pancreatitis are common problems associated with some patients with cystic fibrosis (CF). There is no known effective method to prevent recurrent abdominal pain and recurrent pancreatitis in such patients. The objective of this study was to determine whether nocturnal hydration (NH) prevents recurrent abdominal pain and recurrent acute pancreatitis in patients with adult-onset CF. Adult CF patients who were referred to our Pancreatic Diseases Clinic for recurrent abdominal pain and pancreatitis were enrolled in the study. Each patient was encouraged to drink plenty of water during the night and established a 6-month diary (3 months before and 3 months after NH was initiated), recording the frequency and severity of their abdominal pain, the amount of pain medication taken, and the volume of their water intake. We also reviewed the number of doctor's clinic visits, emergency room visits, and hospitalizations for about 1 year before and 1 year after the initiation of the NH. The frequency and the severity of abdominal pain in this group of patients were significantly reduced. The amount of pain medication and the number of emergency room visits and hospitalizations for abdominal pain and acute pancreatitis were reduced. NH is a simple and cost-effective method to prevent recurrent abdominal pain and pancreatitis in patients with adult-onset CF.

  18. Adversities in childhood and adult psychopathology in the South Africa Stress and Health Study: associations with first-onset DSM-IV disorders.

    PubMed

    Slopen, Natalie; Williams, David R; Seedat, Soraya; Moomal, Hashim; Herman, Allen; Stein, Dan J

    2010-11-01

    Extensive epidemiologic research from the United States demonstrates that childhood adversities (CAs) are predictive of several psychiatric outcomes, including depression, anxiety, substance abuse, and externalizing disorders. To date, this has not been explored in a national sample of adults in South Africa. The present study examined the joint predictive effects of 11 retrospectively reported CAs on the first onset of DSM-IV disorders in the South Africa Stress and Health Study (SASH), a nationally representative sample of adults. We utilized substantively plausible regression models of joint CA effects that account for the comorbidity between individual CAs; outcomes included DSM-IV anxiety disorders, mood disorders, substance use disorders, and externalizing disorders measured with the WHO Composite International Diagnostic Interview. The results indicated that experiences of CA varied by race, and many CAs were correlated with one another. The best-fitting model for first onset of any disorder included separate indicators for each type of CA, in addition to indicator variables for the number of other CAs reported. Results disaggregated by class of disorder showed that the majority of CAs with significant odds ratios only predicted anxiety disorder. Results disaggregated by life course stage of first onset showed that significant effects of CAs can be observed at each stage of the life course. This study contributes to a growing body of research on the social determinants of mental health in South Africa. Our findings illustrate the importance of utilizing a model that accounts for the clustering and accumulation of CAs, and suggest that a variety of CAs predict onset of mental disorders, particularly anxiety disorders, at several stages of the life course. PMID:20870332

  19. Disturbed sleep as risk factor for the subsequent onset of bipolar disorder--Data from a 10-year prospective-longitudinal study among adolescents and young adults.

    PubMed

    Ritter, Philipp S; Höfler, Michael; Wittchen, Hans-Ulrich; Lieb, Roselind; Bauer, Michael; Pfennig, Andrea; Beesdo-Baum, Katja

    2015-09-01

    There is ample data suggesting that individuals with bipolar disorder more frequently suffer from disturbed sleep even when euthymic. Since sleep is a process that is crucial for affective homeostasis, disturbed sleep in healthy individuals may be a risk factor for the subsequent onset of bipolar disorder. Utilizing data from a large cohort of adolescents and young adults, this study tests the hypothesis that disturbed sleep constitutes a risk factor for the later onset of bipolar disorder. A representative community sample of N = 3021 adolescents and young adults (baseline age 14-24) was assessed using the standardized Composite International Diagnostic Interview and followed-up prospectively up to 3 times over up to 10 years. Disturbed sleep at baseline was quantified utilizing the corresponding items from the self-report inventory SCL-90-R. The compound value (insomnia-score) as an ordinal parameter for the severity of sleep disturbances was used to assess associations with the incidence of bipolar disorder among participants free of major mental disorder at baseline (N = 1943) using odds ratios (OR) from logistic regressions. Analyses were adjusted for age, gender, parental mood disorder and lifetime alcohol or cannabis dependence. Poor sleep quality significantly increased the risk for the subsequent development of bipolar disorder (OR = 1.75; p = 0.001). Regarding individual sleep items, trouble falling asleep and early morning awakening were predictive for the subsequent onset of bipolar disorder. Disturbed sleep in persons otherwise free of major mental disorders appears to confer an increased risk for the subsequent onset of bipolar disorder. PMID:26228404

  20. Disturbed sleep as risk factor for the subsequent onset of bipolar disorder--Data from a 10-year prospective-longitudinal study among adolescents and young adults.

    PubMed

    Ritter, Philipp S; Höfler, Michael; Wittchen, Hans-Ulrich; Lieb, Roselind; Bauer, Michael; Pfennig, Andrea; Beesdo-Baum, Katja

    2015-09-01

    There is ample data suggesting that individuals with bipolar disorder more frequently suffer from disturbed sleep even when euthymic. Since sleep is a process that is crucial for affective homeostasis, disturbed sleep in healthy individuals may be a risk factor for the subsequent onset of bipolar disorder. Utilizing data from a large cohort of adolescents and young adults, this study tests the hypothesis that disturbed sleep constitutes a risk factor for the later onset of bipolar disorder. A representative community sample of N = 3021 adolescents and young adults (baseline age 14-24) was assessed using the standardized Composite International Diagnostic Interview and followed-up prospectively up to 3 times over up to 10 years. Disturbed sleep at baseline was quantified utilizing the corresponding items from the self-report inventory SCL-90-R. The compound value (insomnia-score) as an ordinal parameter for the severity of sleep disturbances was used to assess associations with the incidence of bipolar disorder among participants free of major mental disorder at baseline (N = 1943) using odds ratios (OR) from logistic regressions. Analyses were adjusted for age, gender, parental mood disorder and lifetime alcohol or cannabis dependence. Poor sleep quality significantly increased the risk for the subsequent development of bipolar disorder (OR = 1.75; p = 0.001). Regarding individual sleep items, trouble falling asleep and early morning awakening were predictive for the subsequent onset of bipolar disorder. Disturbed sleep in persons otherwise free of major mental disorders appears to confer an increased risk for the subsequent onset of bipolar disorder.

  1. Mitochondrial Biogenesis: A Therapeutic Target for Neurodevelopmental Disorders and Neurodegenerative Diseases

    PubMed Central

    Uittenbogaard, Martine; Chiaramello, Anne

    2014-01-01

    In the developing and mature brain, mitochondria act as central hubs for distinct but interwined pathways, necessary for neural development, survival, activity, connectivity and plasticity. In neurons, mitochondria assume diverse functions, such as energy production in the form of ATP, calcium buffering and generation of reactive oxygen species. Mitochondrial dysfunction contributes to a range of neurodevelopmental and neurodegenerative diseases, making mitochondria a potential target for pharmacological-based therapies. Pathogenesis associated with these diseases is accompanied by an increase in mitochondrial mass, a quantitative increase to overcome a qualitative deficiency due to mutated mitochondrial proteins that are either nuclear- or mitochondrial-encoded. This compensatory biological response is maladaptive, as it fails to sufficiently augment the bioenergetically functional mitochondrial mass and correct for the ATP deficit. Since regulation of neuronal mitochondrial biogenesis has been scantily investigated, our current understanding on the network of transcriptional regulators, co-activators and signaling regulators mainly derives from other cellular systems. The purpose of this review is to present the current state of our knowledge and understanding of the transcriptional and signaling cascades controlling neuronal mitochondrial biogenesis and the various therapeutic approaches to enhance the functional mitochondrial mass in the context of neurodevelopmental disorders and adult-onset neurodegenerative diseases. PMID:24606804

  2. Pulmonary arterial hypertension secondary to adult-onset Still's disease: Response to cyclosporine and sildenafil over 15 years of follow-up.

    PubMed

    Weatherald, Jason; Lategan, Johan; Helmersen, Doug

    2016-01-01

    Adult onset Still's disease (AOSD) is an autoimmune disease characterized by systemic inflammation and is a rarely reported cause of pulmonary arterial hypertension (PAH). We describe the clinical course of a 40-year-old woman who presented with PAH 19 months after a diagnosis of AOSD. Sildenafil and immunosuppressive therapy with cyclosporine resulted in clinical and hemodynamic improvement with long-term survival 15 years after her initial presentation of AOSD. We review the literature for published cases of PAH due to AOSD and discuss the potential mechanisms relating inflammatory diseases and PAH. PMID:27408785

  3. Uncoupling neuronal death and dysfunction in Drosophila models of neurodegenerative disease.

    PubMed

    Chouhan, Amit K; Guo, Caiwei; Hsieh, Yi-Chen; Ye, Hui; Senturk, Mumine; Zuo, Zhongyuan; Li, Yarong; Chatterjee, Shreyasi; Botas, Juan; Jackson, George R; Bellen, Hugo J; Shulman, Joshua M

    2016-01-01

    Common neurodegenerative proteinopathies, such as Alzheimer's disease (AD) and Parkinson's disease (PD), are characterized by the misfolding and aggregation of toxic protein species, including the amyloid beta (Aß) peptide, microtubule-associated protein Tau (Tau), and alpha-synuclein (αSyn) protein. These factors also show toxicity in Drosophila; however, potential limitations of prior studies include poor discrimination between effects on the adult versus developing nervous system and neuronal versus glial cell types. In addition, variable expression paradigms and outcomes hinder systematic comparison of toxicity profiles. Using standardized conditions and medium-throughput assays, we express human Tau, Aß or αSyn selectively in neurons of the adult Drosophila retina and monitor age-dependent changes in both structure and function, based on tissue histology and recordings of the electroretinogram (ERG), respectively. We find that each protein causes a unique profile of neurodegenerative pathology, demonstrating distinct and separable impacts on neuronal death and dysfunction. Strikingly, expression of Tau leads to progressive loss of ERG responses whereas retinal architecture and neuronal numbers are largely preserved. By contrast, Aß induces modest, age-dependent neuronal loss without degrading the retinal ERG. αSyn expression, using a codon-optimized transgene, is characterized by marked retinal vacuolar change, progressive photoreceptor cell death, and delayed-onset but modest ERG changes. Lastly, to address potential mechanisms, we perform transmission electron microscopy (TEM) to reveal potential degenerative changes at the ultrastructural level. Surprisingly, Tau and αSyn each cause prominent but distinct synaptotoxic profiles, including disorganization or enlargement of photoreceptor terminals, respectively. Our findings highlight variable and dynamic properties of neurodegeneration triggered by these disease-relevant proteins in vivo, and suggest

  4. Stem cell-based models and therapies for neurodegenerative diseases.

    PubMed

    Iyer, Shilpa; Alsayegh, Khaled; Abraham, Sheena; Rao, Raj R

    2009-01-01

    Multiple neurodegenerative disorders typically result from irrevocable damage and improper functioning of specialized neuronal cells or populations of neuronal cells. These disorders have the potential to contribute to an already overburdened health care system unless the progression of neurodegeneration can be altered. Progress in understanding neurodegenerative cell biology has been hampered by a lack of predictive and, some would claim, relevant cellular models. Additionally, the research needed to develop new drugs and determine methods for repair or replacement of damaged neurons is severely hampered by the lack of an adequate in vitro human neuron cell-based model. In this context, pluripotent stem cells and neural progenitors and their properties including unlimited proliferation, plasticity to generate other cell types, and a readily available source of cells--pose an excellent alternative to ex vivo primary cultures or established immortalized cell lines in contributing to our understanding of neurodegenerative cell biology and our ability to analyze the therapeutic or cytotoxic effects of chemicals, drugs, and xenobiotics. Many questions that define the underlying "genesis" of the neuronal death in these disorders also remain unanswered, with evidence suggesting a key role for mitochondrial dysfunction. The assessment of stem cells, neural progenitors, and engineered adult cells can provide useful insights into neuronal development and neurodegenerative processes. Finally, the potential for a combination of cell- and gene-based therapeutics for neurodegenerative disorders is also discussed.

  5. Omental transplantation for neurodegenerative diseases

    PubMed Central

    Rafael, Hernando

    2014-01-01

    Up to date, almost all researchers consider that there is still no effective therapy for neurodegenerative diseases (NDDs) and therefore, these diseases are incurable. However, since May 1998, we know that a progressive ischemia in the medial temporal lobes and subcommissural regions can cause Alzheimer’s disease; because, in contrast to this, its revascularization by means of omental tissue can cure or improve this disease. Likewise we observed that the aging process, Huntington’s disease, Parkinson’s disease, and Amyotrophic lateral sclerosis; all of them are of ischemic origin caused by cerebral atherosclerosis, associated with vascular anomalies and/or environmental chemicals. On the contrary, an omental transplantation on the affected zone can stop and improve these diseases. For these reasons, I believe that NDDs, are wrongly classified as neurodegenerative disorders. PMID:25232510

  6. Molecular diagnostics of neurodegenerative disorders

    PubMed Central

    Agrawal, Megha; Biswas, Abhijit

    2015-01-01

    Molecular diagnostics provide a powerful method to detect and diagnose various neurological diseases such as Alzheimer's and Parkinson's disease. The confirmation of such diagnosis allows early detection and subsequent medical counseling that help specific patients to undergo clinically important drug trials. This provides a medical pathway to have better insight of neurogenesis and eventual cure of the neurodegenerative diseases. In this short review, we present recent advances in molecular diagnostics especially biomarkers and imaging spectroscopy for neurological diseases. We describe advances made in Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD), and finally present a perspective on the future directions to provide a framework for further developments and refinements of molecular diagnostics to combat neurodegenerative disorders. PMID:26442283

  7. Drosophila Models of Neurodegenerative Diseases

    PubMed Central

    Lu, Bingwei; Vogel, Hannes

    2011-01-01

    Neurodegenerative diseases are progressive disorders of the nervous system that affect specific cellular populations in the central and peripheral nervous systems. Although most cases are sporadic, genes associated with familial cases have been identified, thus enabling the development of animal models. Invertebrates such as Drosophila have recently emerged as model systems for studying mechanisms of neurodegeneration in several major neurodegenerative diseases. These models are also excellent in vivo systems for the testing of therapeutic compounds. Genetic studies using these animal models have provided novel insights into the disease process. We anticipate that further exploration of the animal models will further our understanding of mechanisms of neurodegeneration as well as facilitate the development of rational treatments for debilitating degenerative diseases. PMID:18842101

  8. Congenital encephalomyopathy and adult-onset myopathy and diabetes mellitus: Different phenotypic associations of a new heteroplasmic mtDNA tRNA glutamic acid mutation

    SciTech Connect

    Hanna, M.G.; Nelson, I.; Sweeney, M.G.; Cooper, J.M.; Watkins, P.J.; Morgan-Hughes, J.A.; Harding, A.E.

    1995-05-01

    We report the clinical, biochemical, and molecular genetic findings in a family with an unusual mitochondrial disease phenotype harboring a novel mtDNA tRNA glutamic acid mutation at position 14709. The proband and his sister presented with congenital myopathy and mental retardation and subsequently developed cerebellar ataxia. Other family members had either adult-onset diabetes mellitus with muscle weakness or adult-onset diabetes mellitus alone. Ragged-red and cytochrome c oxidase (COX)-negative fibers were present in muscle biopsies. Biochemical studies of muscle mitochondria showed reduced complex I and IV activities. The mtDNA mutation was heteroplasmic in blood and muscle in all matrilineal relatives analyzed. Primary myoblast, but not fibroblast, cultures containing high proportions of mutant mtDNA exhibited impaired mitochondrial translation. These observations indicate that mtDNA tRNA point mutations should be considered in the differential diagnosis of congenital myopathy. In addition they illustrate the diversity of phenotypes associated with this mutation in the same family and further highlight the association between mtDNA mutations and diabetes mellitus. 43 refs., 4 figs., 1 tab.

  9. Longitudinal changes in cerebellar and subcortical volumes in adult-onset Niemann-Pick disease type C patients treated with miglustat.

    PubMed

    Bowman, Elizabeth A; Walterfang, Mark; Abel, Larry; Desmond, Patricia; Fahey, Michael; Velakoulis, Dennis

    2015-09-01

    Niemann-Pick disease type C (NPC) is a rare neurovisceral disorder resulting in impaired intracellular lipid trafficking. The only disease-modifying treatment available to date is miglustat, an iminosugar inhibiting the accumulation of lipid by-products in neurons. This study explored how changes in cerebellar grey and white matter volumes, and in subcortical volumes, related to patient treatment status and disability and ataxia ratings. Nine adult-onset NPC patients and 17 matched controls underwent T1-weighted MRI. One patient was not receiving miglustat, and pre-treatment data were available for a further patient. Semi-automated cerebellar and subcortical segmentation was undertaken, and the rates of change in putamen, hippocampal, thalamic and caudal volumes, and grey and white matter cerebellar volumes, were compared to rates of change in Iturriaga disability score, Brief Ataxia Rating Scale (BARS), and horizontal saccadic gain. Untreated NPC patients appeared to lose cerebellar grey and white matter, bilateral thalamic volume, and right caudate volume faster than treated patients. Cerebellar grey matter volume loss and volume loss in the left thalamus were significantly correlated with Iturriaga disability scale changes. Change in both cerebellar grey and white matter was correlated with decrease in horizontal saccadic gain, but not with change in BARS. This is the first study to examine longitudinal treatment effects of miglustat on cerebellar and subcortical volumes in patients with adult-onset NPC, and is evidence that miglustat may have a protective effect on cerebellar and subcortical structure and function. PMID:26092521

  10. Limbic encephalitis associated with anti-voltage-gated potassium channel complex antibodies as a cause of adult-onset mesial temporal lobe epilepsy.

    PubMed

    Toyota, Tomoko; Akamatsu, Naoki; Tsuji, Sadatoshi; Nishizawa, Shigeru

    2014-06-01

    Recently, some reports have indicated that limbic encephalitis associated with anti-voltage-gated potassium channel complex antibodies (VGKC-Ab) is a cause of adult-onset mesial temporal lobe epilepsy (MTLE). We report a 53-year-old woman who had her first epileptic seizure at the age of 50 years old. Examination by 3-Tesla brain MRI revealed left hippocampal high signal intensity and swelling on fluid-attenuated inversion recovery (FLAIR) and T2-weighted imaging at 2 months after her first seizure. The patient received intravenous methylprednisolone and carbamazepine 300 mg/day. One month later, MRI revealed improvement of her left hippocampal abnormalities. Thereafter, she had no seizures, however, three years after her first seizure, EEG revealed a seizure pattern in the left temporal region. Brain MRI revealed left hippocampal high signal intensity and brain fluorodeoxyglucose positron emission tomography revealed hypermetabolism. Her serum VGKC-Ab levels were 118 pM(normal < 100 pM). Intravenous methylprednisolone therapy was reinitiated. Two months later, her hippocampal abnormalities had improved and 3 months later her VGKC-Ab levels decreased to 4.4 pM. Remission of the epileptic seizures was also observed. This MTLE in the middle age was considered as limbic encephalitis associated with anti- VGKC-Ab. In cases of unexplained adult-onset MTLE, limbic encephalitis associated with anti-VGKC-Ab, which responds well to immunotherapy, should be considered in the differential diagnosis.

  11. Coping efforts and resilience among adult children who grew up with a parent with young-onset dementia: a qualitative follow-up study

    PubMed Central

    Johannessen, Aud; Engedal, Knut; Thorsen, Kirsten

    2016-01-01

    Background It is estimated that one in four persons with young-onset dementia (YOD) (<65 years old) has children younger than 18 years old at the onset of the dementia. These children experience a childhood different from what is expected. Adult children of parents with YOD are seldom addressed in research, and the impact of the dementia on the children's development over time has rarely been studied. Aim The goal of this study was to explore how adult children experienced the influence of their parents’ dementia on their own development during adolescence; what coping efforts, strategies, and resources they employed; and how they evaluated the most recent changes in their life situation. Method A follow-up, grounded theory approach in two phases was used. Qualitative interviews with 14 informants (18–30 years of age) were conducted in 2014 and one year later, in 2015. Findings Nearly all the informants expressed that their emotional well-being and their life situation were better at the second interview compared to the time of dementia onset in their parents. To overcome the difficulties of being a child of a parent with YOD, they used different instrumental, cognitive, and emotional coping strategies, subsumed analytically under the concept detachment. This category covers three subcategories of coping strategies: moving apart, greater personal distance, and calmer emotional reactions. Another category, resilience, designates combinations of the coping strategies. Vital for the development of coping resources and resilience was the need the informants had for social support—for people they saw who listened to them and responded to their needs. Conclusion Most of the informants reported that they experienced a better life situation and less emotional stress over time as their parent's dementia progressed. They developed better coping capacities and greater resilience. Vital for the development of coping resources and resilience was the need the informants

  12. Metal imaging in neurodegenerative diseases

    PubMed Central

    Bourassa, Megan W.

    2014-01-01

    Metal ions are known to play an important role in many neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and prion diseases. In these diseases, aberrant metal binding or improper regulation of redox active metal ions can induce oxidative stress by producing cytotoxic reactive oxygen species (ROS). Altered metal homeostasis is also frequently seen in the diseased state. As a result, the imaging of metals in intact biological cells and tissues has been very important for understanding the role of metals in neurodegenerative diseases. A wide range of imaging techniques have been utilized, including X-ray fluorescence microscopy (XFM), particle induced X-ray emission (PIXE), energy dispersive X-ray spectroscopy (EDS), laser ablation inductively coupled mass spectrometry (LA-ICP-MS), and secondary ion mass spectrometry (SIMS), all of which allow for the imaging of metals in biological specimens with high spatial resolution and detection sensitivity. These techniques represent unique tools for advancing the understanding of the disease mechanisms and for identifying possible targets for developing treatments. In this review, we will highlight the advances in neurodegenerative disease research facilitated by metal imaging techniques. PMID:22797194

  13. Two-year seizure reduction in adults with medically intractable partial onset epilepsy treated with responsive neurostimulation: Final results of the RNS System Pivotal trial

    PubMed Central

    Heck, Christianne N; King-Stephens, David; Massey, Andrew D; Nair, Dileep R; Jobst, Barbara C; Barkley, Gregory L; Salanova, Vicenta; Cole, Andrew J; Smith, Michael C; Gwinn, Ryder P; Skidmore, Christopher; Van Ness, Paul C; Bergey, Gregory K; Park, Yong D; Miller, Ian; Geller, Eric; Rutecki, Paul A; Zimmerman, Richard; Spencer, David C; Goldman, Alica; Edwards, Jonathan C; Leiphart, James W; Wharen, Robert E; Fessler, James; Fountain, Nathan B; Worrell, Gregory A; Gross, Robert E; Eisenschenk, Stephan; Duckrow, Robert B; Hirsch, Lawrence J; Bazil, Carl; O'Donovan, Cormac A; Sun, Felice T; Courtney, Tracy A; Seale, Cairn G; Morrell, Martha J

    2014-01-01

    Objective To demonstrate the safety and effectiveness of responsive stimulation at the seizure focus as an adjunctive therapy to reduce the frequency of seizures in adults with medically intractable partial onset seizures arising from one or two seizure foci. Methods Randomized multicenter double-blinded controlled trial of responsive focal cortical stimulation (RNS System). Subjects with medically intractable partial onset seizures from one or two foci were implanted, and 1 month postimplant were randomized 1:1 to active or sham stimulation. After the fifth postimplant month, all subjects received responsive stimulation in an open label period (OLP) to complete 2 years of postimplant follow-up. Results All 191 subjects were randomized. The percent change in seizures at the end of the blinded period was −37.9% in the active and −17.3% in the sham stimulation group (p = 0.012, Generalized Estimating Equations). The median percent reduction in seizures in the OLP was 44% at 1 year and 53% at 2 years, which represents a progressive and significant improvement with time (p < 0.0001). The serious adverse event rate was not different between subjects receiving active and sham stimulation. Adverse events were consistent with the known risks of an implanted medical device, seizures, and of other epilepsy treatments. There were no adverse effects on neuropsychological function or mood. Significance Responsive stimulation to the seizure focus reduced the frequency of partial-onset seizures acutely, showed improving seizure reduction over time, was well tolerated, and was acceptably safe. The RNS System provides an additional treatment option for patients with medically intractable partial-onset seizures. PMID:24621228

  14. Deletion of RBP-J in adult mice leads to the onset of aortic valve degenerative diseases.

    PubMed

    Li, Zhi; Feng, Lei; Wang, Chun-Mei; Zheng, Qi-Jun; Zhao, Bi-Jun; Yi, Wei; Zhang, Jin-Zhou; Wang, Yue-Min; Guo, Hai-Tao; Yi, Ding-Hua; Han, Hua

    2012-04-01

    Transcription factor RBP-J-mediated Notch signaling has been implicated in several inherited cardiovascular diseases including aortic valve diseases (AVD). But whether Notch signal plays a role in AVD in adults has been unclear. This study aims to test whether the deletion of RBP-J in adult mice would lead to AVD and to investigate the underlying mechanisms. Cre-LoxP-mediated gene deletion was employed to disrupt Notch signal in adult mice. Immunofluorescence and electron microscope observations showed that deletion of RBP-J in adult mice led to early morphological changes of AVD. The size of aortic valve was enlarged. The endothelial homeostasis was perturbed, probably due to the up-regulation of VEGFR2. The endothelial cells exhibited increased proliferation and loose endothelial junctions. The valvular mesenchyme displayed significant fibrosis, consistent with the up-regulation of TGF-β1 and activation of endothelial-mesenchymal transition. We observed melanin-producing cells in aortic valves. The number of melanin-producing cells increased significantly, and their location changed from the mesenchyme to subendothelial layer of valve cusps in RBP-J deficient mice. These results suggest that RBP-J-mediated Notch signaling in aortic valves may be critically involved in valve homeostasis and valve diseases as well. These findings will be helpful for the understanding of the molecular mechanisms of AVD in adults.

  15. Similar L-dopa-stimulated motor activity in mice with adult-onset 6-hydroxydopamine-induced symmetric dopamine denervation and in transcription factor Pitx3 null mice with perinatal-onset symmetric dopamine denervation.

    PubMed

    Li, Li; Sagot, Ben; Zhou, Fu-Ming

    2015-07-30

    The transcription factor Pitx3 null mutant (Pitx3Null) mice have a constitutive perinatal-onset and symmetric bilateral dopamine (DA) loss in the striatum. In these mice l-3,4-dihydroxyphenylalanine (l-dopa) induces apparently normal horizontal movements (walking) but also upward movements consisting of the vertical body trunk and waving paws that are absent in normal animals and in animals with the classic unilateral 6-hydroxydopamine (6-OHDA) lesion-induced DA denervation. Thus, a concern is that the perinatal timing of the DA loss and potential developmental abnormalities in Pitx3Null mice may underlie these upward movements, thus reducing the usefulness as a DA denervation model. Here we show that in normal wild-type (Pitx3WT) mice with adult-onset symmetric, bilateral 6-OHDA-induced DA lesion in the dorsal striatum, l-dopa induces normal horizontal movements and upward movements that are qualitatively identical to those in Pitx3Null mice. Furthermore, after unilateral 6-OHDA lesion of the residual DA innervation in the striatum in Pitx3Null mice, l-dopa induces contraversive rotation that is similar to that in Pitx3WT mice with the classic unilateral 6-OHDA lesion. These results indicate that in Pitx3Null mice, the bilateral symmetric DA denervation in the dorsal striatum is sufficient for expressing the l-dopa-induced motor phenotype and the perinatal timing of their DA loss is not a determining factor, providing further evidence that Pitx3Null mice are a convenient and suitable mouse model to study the consequences of DA loss and dopaminergic replacement therapy in Parkinson's disease.

  16. Torpor expression in juvenile and adult Djungarian hamsters (Phodopus sungorus) differs in frequency, duration and onset in response to a daily cycle in ambient temperature.

    PubMed

    Diedrich, Victoria; Bank, Jonathan H; Scherbarth, Frank; Steinlechner, Stephan

    2015-10-01

    In addition to morphological and physiological traits of short-day acclimatisation, Djungarian hamsters (Phodopus sungorus) from Central Asia exhibit spontaneous daily torpor to decrease energy demands during winter. Environmental factors such as food scarcity and low temperatures have been shown to facilitate the use of this temporal reduction in metabolism and body temperature. We investigated the effect of a daily cycle in ambient temperature on short-day acclimation and torpor expression in juvenile and adult Djungarian hamsters. The animals were exposed to a cold dark phase (6°C) and a warmer light phase (18°C) and were compared with control hamsters kept at a constant ambient temperature of 18°C. Under constant conditions, torpor expression did not differ between adult and juvenile hamsters. Although the daily temperature cycle evoked an increased metabolic rate in adult and juvenile hamsters during the dark phase and strengthened the synchronization between torpor entrance and the beginning of the light phase, it did not induce the expected torpor facilitation. In adult hamsters, torpor expression profiles did not differ from those under constant conditions at all. In contrast, juvenile hamsters showed a delayed onset of torpor season, a decreased torpor frequency, depth and duration, as well as an increased number of early torpor terminations coinciding with the rise in ambient temperature after the beginning of the light phase. While the temperature challenge appeared to be of minor importance for energy balance and torpor expression in adult hamsters, it profoundly influenced the overall energy saving strategy of juvenile hamsters, promoting torpor-alleviating active foragers over torpor-prone energy-savers. In addition, our data suggest a more efficient acclimation in juvenile hamsters under additional energy challenges, which reduces the need for torpor expression.

  17. Oxidative stress in neurodegenerative diseases.

    PubMed

    Chen, Xueping; Guo, Chunyan; Kong, Jiming

    2012-02-15

    Reactive oxygen species are constantly produced in aerobic organisms as by-products of normal oxygen metabolism and include free radicals such as superoxide anion (O2 (-)) and hydroxyl radical (OH(-)), and non-radical hydrogen peroxide (H2O2). The mitochondrial respiratory chain and enzymatic reactions by various enzymes are endogenous sources of reactive oxygen species. Exogenous reactive oxygen species -inducing stressors include ionizing radiation, ultraviolet light, and divergent oxidizing chemicals. At low concentrations, reactive oxygen species serve as an important second messenger in cell signaling; however, at higher concentrations and long-term exposure, reactive oxygen species can damage cellular macromolecules such as DNA, proteins, and lipids, which leads to necrotic and apoptotic cell death. Oxidative stress is a condition of imbalance between reactive oxygen species formation and cellular antioxidant capacity due to enhanced ROS generation and/or dysfunction of the antioxidant system. Biochemical alterations in these macromolecular components can lead to various pathological conditions and human diseases, especially neurodegenerative diseases. Neurodegenerative diseases are morphologically featured by progressive cell loss in specific vulnerable neuronal cells, often associated with cytoskeletal protein aggregates forming inclusions in neurons and/or glial cells. Deposition of abnormal aggregated proteins and disruption of metal ions homeostasis are highly associated with oxidative stress. The main aim of this review is to present as much detailed information as possible that is available on various neurodegenerative disorders and their connection with oxidative stress. A variety of therapeutic strategies designed to address these pathological processes are also described. For the future therapeutic direction, one specific pathway that involves the transcription factor nuclear factor erythroid 2-related factor 2 is receiving considerable attention.

  18. Nutraceuticals and amyloid neurodegenerative diseases: a focus on natural phenols.

    PubMed

    Rigacci, Stefania; Stefani, Massimo

    2015-01-01

    A common molecular feature of amyloid neurodegenerative diseases is the unfolding/misfolding of specific proteins/peptides which consequently become prone to aggregate into toxic assemblies and deposits that are the key histopathological trait of these pathologies. Apart from the rare early-onset familiar forms, these neurodegenerative diseases are age-associated disorders whose symptoms appear in aged people after long incubation periods. This makes the therapeutic approach particularly compelling and boosts the search for both early diagnostic tools and preventive approaches. In this last respect, natural compounds commonly present in foods and beverages are considered promising molecules, at least on the bench side. The so-called 'nutraceutical approach' suggests life-long healthy diets, particularly focusing on food molecules that are candidates to enter clinical trials as such or following a targeted molecular engineering. Natural phenols abundant in 'healthy' foods such as extra virgin olive oil, red wine, green tea, red berries and spices, appear particularly promising. PMID:25418871

  19. [Are we underestimating occupational risks for neurodegenerative diseases?].

    PubMed

    Oddone, Enrico; Imbriani, Marcello

    2015-01-01

    In recent years a great number of studies suggests that occupational exposures could play a role in the onset of some neurodegenerative diseases. The literature data are more numerous for Parkinson's disease, Multiple Sclerosis and Amyotrophic Lateral Sclerosis, although to date no specific occupational exposure was proved to be a definite causal factor. This lack of information is attributable both to the complex patogenesis of these diseases and to a delay regarding this field of research with respect to others pathologies. Nevertheless, available evidence oblige researchers to deepen the studies of occupational exposures as risk factors of neurodegenerative diseases, in order to provide a solid basis possible preventive measures for a class of pathologies with high social impact, both in terms of therapies and in terms of disability.

  20. Extracting regional brain patterns for classification of neurodegenerative diseases

    NASA Astrophysics Data System (ADS)

    Pulido, Andrea; Rueda, Andrea; Romero, Eduardo

    2013-11-01

    In structural Magnetic Resonance Imaging (MRI), neurodegenerative diseases generally present complex brain patterns that can be correlated with di erent clinical onsets of this pathologies. An objective method that aims to determine both global and local changes is not usually available in clinical practice, thus the interpretation of these images is strongly dependent on the radiologist's skills. In this paper, we propose a strategy which interprets the brain structure using a framework that highlights discriminant brain patterns for neurodegenerative diseases. This is accomplished by combining a probabilistic learning technique, which identi es and groups regions with similar visual features, with a visual saliency method that exposes relevant information within each region. The association of such patterns with a speci c disease is herein evaluated in a classi cation task, using a dataset including 80 Alzheimer's disease (AD) patients and 76 healthy subjects (NC). Preliminary results show that the proposed method reaches a maximum classi cation accuracy of 81.39%.

  1. Prions and prion-like pathogens in neurodegenerative disorders.

    PubMed

    Peggion, Caterina; Sorgato, Maria Catia; Bertoli, Alessandro

    2014-02-18

    Prions are unique elements in biology, being able to transmit biological information from one organism to another in the absence of nucleic acids. They have been identified as self-replicating proteinaceous agents responsible for the onset of rare and fatal neurodegenerative disorders-known as transmissible spongiform encephalopathies, or prion diseases-which affect humans and other animal species. More recently, it has been proposed that other proteins associated with common neurodegenerative disorders, such as Alzheimer's and Parkinson's disease, can self-replicate like prions, thus sustaining the spread of neurotoxic entities throughout the nervous system. Here, we review findings that have contributed to expand the prion concept, and discuss if the involved toxic species can be considered bona fide prions, including the capacity to infect other organisms, or whether these pathogenic aggregates share with prions only the capability to self-replicate.

  2. Autophagy, inflammation and neurodegenerative disease

    PubMed Central

    Alirezaei, Mehrdad; Kemball, Christopher C.; Whitton, J. Lindsay

    2010-01-01

    Autophagy is emerging as a central regulator of cellular health and disease and, in the central nervous system (CNS), this homeostatic process appears to influence synaptic growth and plasticity. Herein, we review the evidence that dysregulation of autophagy may contribute to several neurodegenerative diseases of the CNS. Up-regulation of autophagy may prevent, delay or ameliorate at least some of these disorders, and – based on recent findings from our laboratory – we speculate that this goal may be achieved using a safe, simple, and inexpensive approach. PMID:21138487

  3. Adult-onset dysphagia lusoria secondary to a dissecting aberrant right subclavian artery associated with type B acute aortic dissection

    PubMed Central

    Singh, Sarabjeet; Grewal, Puneet Dhillon; Symons, John; Ahmed, Aziz; Khosla, Sandeep; Arora, Rohit

    2008-01-01

    The case of a 78-year-old African American woman who presented at the Mount Sinai Medical Center (Chicago, USA) with excruciating backache is presented. Computed tomography of the chest at the time of admission showed dissection of the aortic arch, descending aorta and dissection of an aberrant right subclavian artery. She was managed medically for Stanford type B acute aortic dissection. The patient was asymptomatic at presentation, but started complaining of new-onset dysphagia during her stay in the hospital. An esophagogram was performed and suggested posterior impingement of the esophagus, a classic sign of an aberrant right subclavian artery. Because the patient had multiple underlying comorbidities and the dysphagia was mild and intermittent, surgery was deferred. The patient was discharged home after complete stabilization and was scheduled for a follow-up appointment. PMID:18209773

  4. The Role of Copper in Neurodegenerative Disease

    NASA Astrophysics Data System (ADS)

    Rose, Francis M.

    My research concerns the fundamental atomistic mechanisms of neurodegenerative diseases and the methodologies by which they may be discerned. This thesis consists of three primary parts. The introductory material is the raison d'etre for this work and a critical overview of the specific physics, mathematics and algorithms used in this research. The methods are presented along with specific details in order to facilitate future replication and enhancement. With the groundwork of mechanisms and methods out of the way, we then explore a nouveau atomistic mechanism describing the onset of Parkinson's disease, a disease that has been closely linked to misfolded metalloproteins. Further exploration of neurodegeneration takes place in the following chapter, where a remedial approach to Alzheimer's disease via a simulated chelation of a metalloprotein is undertaken. Altogether, the methods and techniques applied here allow for simulated exploration of both the atomistic mechanisms of neurodegeneration and their potential remediation strategies. The beginning portion of the research efforts explore protein misfolding dynamics in the presence a copper ion. Misfolding of the human alpha-synuclein (aS) protein has been implicated as a central constituent in neurodegenerative disease. In Parkinson's disease (PD) in particular, aS is thought to be the causative participant when found concentrated into neuritic plaques. Here we propose a scenario involving the metal ion Cu2+ as the protein misfolding initiator of fibrillized aS, the chief component of neuritic plaques. From experimental results we know these misfolded proteins have a rich beta--sheet signature, a marker that we reproduce with our simulated model. This model identifies a process of structural modifications to a natively unfolded alpha-synuclein resulting in a partially folded intermediate with a well defined nucleation site. It serves as a precursor to the fully misfolded protein. Understanding the nucleation

  5. Localization of a locus (GLC1B) for adult-onset primary open angle glaucoma to the 2cen-q13 region

    SciTech Connect

    Stoilova, D.; Trifan, O.C.; Sarfarazi, M.

    1996-08-15

    Primary open angle glaucoma (GLC1) is a common ocular disorder with a characteristic degeneration of the optic nerve and visual field defects that is often associated with an elevated intraocular pressure. The severe but rare juvenile-onset type has previously been mapped to 1q21-q31, and its genetic heterogeneity has been established. Herein, we present a new locus (GLC1B) for one form of GLC1 on chromosome 2cen-q13 with a clinical presentation of low to moderate intraocular pressure, onset in late 40s, and a good response to medical treatment. Two-point and haplotype analyses of affected and unaffected meioses in six families provided maximum linkage information with D2S417, GATA112EO3, D2S113, D2S373, and D2S274 (lod scores ranging from 3.11 to 6.48) within a region of 8.5 cM that is flanked by D2S2161 and D2S2264. Analysis of affected meioses alone revealed no recombination with an additional two markers (D2S2264 and D2S135) in a region of 11.2 cM that is flanked by D2S2161 and D2S176. Analysis of unaffected meioses identified only one healthy 86-year-old male who has inherited the entire affected haplotype and, hence, is a gene carrier for this condition. Eight additional families with similar and/or different clinical presentation did not show any linkage to this region and, therefore, provided evidence for genetic heterogeneity of adult-onset primary open angle glaucoma. 63 refs., 2 figs., 2 tabs.

  6. A previously undiagnosed case of Gerstmann-Sträussler-Scheinker disease revealed by PRNP gene analysis in patients with adult-onset ataxia.

    PubMed

    Cagnoli, Claudia; Brussino, Alessandro; Sbaiz, Luca; Di Gregorio, Eleonora; Atzori, Cristiana; Caroppo, Paola; Orsi, Laura; Migone, Nicola; Buffa, Carlo; Imperiale, Daniele; Brusco, Alfredo

    2008-07-30

    Ataxia is a frequently reported symptom in prion diseases (PD) and it is characteristic of Gerstmann-Sträussler-Scheinker syndrome (GSS), a genetic PD mainly related to the P102L mutation in the PRNP gene. Our aim was to screen for the P102L and other six known PRNP gene mutations (P105L, A117V, Y145X, E200K, D202N, and V210I) a group of 206 consecutive patients diagnosed with adult-onset cerebellar ataxia of unknown origin. The patients, negative for the most common acquired and genetic forms, were analyzed using a combination of restriction endonuclease digestion and pyrosequencing; eight, affected by ataxia and cognitive dysfunction, were also sequenced for the PRNP gene. One patient resulted to be heterozygous for the P102L mutation. Retrospectively, the clinical picture was consistent with a "classical" GSS phenotype. In conclusion, the screening for the P102L mutation, or even the sequencing of the PRNP gene should be taken in consideration in patients with late-onset ataxia (>50 years).

  7. Spinocerebellar ataxia type 1 and Machado-Joseph disease: Incidence of CAG expansions among adult-onset ataxia patients from 311 families with dominant, recessive, or sporadic ataxia

    SciTech Connect

    Ranum, L.P.W.; Gomez, C.; Orr, H.T.

    1995-09-01

    The ataxias are a complex group of diseases with both environmental and genetic causes. Among the autosomal dominant forms of ataxia the genes for two, spinocerebellar ataxia type 1 (SCA1) and Machado-Joseph disease (MJD), have been isolated. In both of these disorders the molecular basis of disease is the expansion of an unstable CAG trinucleotide repeat. To assess the frequency of the SCA1 and MJD trinucleotide repeat expansions among individuals diagnosed with ataxia, we have collected DNA from individuals representing 311 families with adult-onset ataxia of unknown etiology and screened these samples for trinucleotide repeat expansions within the SCA1 and MJD genes. Within this group there are 149 families with dominantly inherited ataxia. Of these, 3% have SCA1 trinucleotide repeat expansions, whereas 21% were positive for the MJD trinucleotide expansion. Thus, together SCA1 and MJD represent 24% of the autosomal dominant ataxias in our group, and the frequency of MJD is substantially greater than that of SCA1. For the 57 patients with MJD trinucleotide repeat expansions, a strong inverse correlation between CAG repeat size and age at onset was observed (r = -.838). Among the MJD patients, the normal and affected ranges of CAG repeat size are 14-40 and 68-82 repeats, respectively. For SCA1 the normal and affected ranges are much closer, containing 19-38 and 40-81 CAG repeats, respectively. 30 refs., 1 fig., 3 tabs.

  8. Oxidative Stress and Neurodegenerative Disorders

    PubMed Central

    Li, Jie; O, Wuliji; Li, Wei; Jiang, Zhi-Gang; Ghanbari, Hossein A.

    2013-01-01

    Living cells continually generate reactive oxygen species (ROS) through the respiratory chain during energetic metabolism. ROS at low or moderate concentration can play important physiological roles. However, an excessive amount of ROS under oxidative stress would be extremely deleterious. The central nervous system (CNS) is particularly vulnerable to oxidative stress due to its high oxygen consumption, weakly antioxidative systems and the terminal-differentiation characteristic of neurons. Thus, oxidative stress elicits various neurodegenerative diseases. In addition, chemotherapy could result in severe side effects on the CNS and peripheral nervous system (PNS) of cancer patients, and a growing body of evidence demonstrates the involvement of ROS in drug-induced neurotoxicities as well. Therefore, development of antioxidants as neuroprotective drugs is a potentially beneficial strategy for clinical therapy. In this review, we summarize the source, balance maintenance and physiologic functions of ROS, oxidative stress and its toxic mechanisms underlying a number of neurodegenerative diseases, and the possible involvement of ROS in chemotherapy-induced toxicity to the CNS and PNS. We ultimately assess the value for antioxidants as neuroprotective drugs and provide our comments on the unmet needs. PMID:24351827

  9. Parkin Regulation and Neurodegenerative Disorders

    PubMed Central

    Zhang, Cheng-Wu; Hang, Liting; Yao, Tso-Pang; Lim, Kah-Leong

    2016-01-01

    Parkin is a unique, multifunctional ubiquitin ligase whose various roles in the cell, particularly in neurons, are widely thought to be protective. The pivotal role that Parkin plays in maintaining neuronal survival is underscored by our current recognition that Parkin dysfunction represents not only a predominant cause of familial parkinsonism but also a formal risk factor for the more common, sporadic form of Parkinson’s disease (PD). Accordingly, keen research on Parkin over the past decade has led to an explosion of knowledge regarding its physiological roles and its relevance to PD. However, our understanding of Parkin is far from being complete. Indeed, surprises emerge from time to time that compel us to constantly update the paradigm of Parkin function. For example, we now know that Parkin’s function is not confined to mere housekeeping protein quality control (QC) roles but also includes mitochondrial homeostasis and stress-related signaling. Furthermore, emerging evidence also suggest a role for Parkin in several other major neurodegenerative diseases including Alzheimer’s disease (AD) and Amyotrophic Lateral Sclerosis (ALS). Yet, it remains truly amazing to note that a single enzyme could serve such multitude of functions and cellular roles. Clearly, its activity has to be tightly regulated. In this review, we shall discuss this and how dysregulated Parkin function may precipitate neuronal demise in various neurodegenerative disorders. PMID:26793099

  10. Tsallis statistics and neurodegenerative disorders

    NASA Astrophysics Data System (ADS)

    Iliopoulos, Aggelos C.; Tsolaki, Magdalini; Aifantis, Elias C.

    2016-08-01

    In this paper, we perform statistical analysis of time series deriving from four neurodegenerative disorders, namely epilepsy, amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), Huntington's disease (HD). The time series are concerned with electroencephalograms (EEGs) of healthy and epileptic states, as well as gait dynamics (in particular stride intervals) of the ALS, PD and HDs. We study data concerning one subject for each neurodegenerative disorder and one healthy control. The analysis is based on Tsallis non-extensive statistical mechanics and in particular on the estimation of Tsallis q-triplet, namely {qstat, qsen, qrel}. The deviation of Tsallis q-triplet from unity indicates non-Gaussian statistics and long-range dependencies for all time series considered. In addition, the results reveal the efficiency of Tsallis statistics in capturing differences in brain dynamics between healthy and epileptic states, as well as differences between ALS, PD, HDs from healthy control subjects. The results indicate that estimations of Tsallis q-indices could be used as possible biomarkers, along with others, for improving classification and prediction of epileptic seizures, as well as for studying the gait complex dynamics of various diseases providing new insights into severity, medications and fall risk, improving therapeutic interventions.

  11. Adult-onset hyperthyroidism impairs spatial learning: possible involvement of mitogen-activated protein kinase signaling pathways.

    PubMed

    Bitiktaş, Soner; Kandemir, Başak; Tan, Burak; Kavraal, Şehrazat; Liman, Narin; Dursun, Nurcan; Dönmez-Altuntaş, Hamiyet; Aksan-Kurnaz, Işil; Suer, Cem

    2016-08-01

    Given evidence that mitogen-activated protein kinase (MAPK) activation is part of the nongenomic actions of thyroid hormones, we investigated the possible consequences of hyperthyroidism for the cognitive functioning of adult rats. Young adult rats were treated with L-thyroxine or saline. Twenty rats in each group were exposed to Morris water maze testing, measuring their performance in a hidden-platform spatial task. In a separate set of rats not exposed to Morris water maze testing (untrained rats), the expression and phosphorylated levels of p38-MAPK and of its two downstream effectors, Elk-1 and cAMP response element-binding protein, were evaluated using quantitative reverse transcriptase-PCR and western blotting. Rats with hyperthyroidism showed delayed acquisition of learning compared with their wild-type counterparts, as shown by increased escape latencies and distance moved on the last two trials of daily training in the water maze. The hyperthyroid rats, however, showed no difference during probe trials. Western blot analyses of the hippocampus showed that hyperthyroidism increased phosphorylated p38-MAPK levels in untrained rats. Although our study is correlative in nature and does not exclude the contribution of other molecular targets, our findings suggest that the observed impairments in acquisition during actual learning in rats with hyperthyroidism may result from the increased phosphorylation of p38-MAPK. PMID:27258653

  12. Quantitative analysis on electrooculography (EOG) for neurodegenerative disease

    NASA Astrophysics Data System (ADS)

    Liu, Chang-Chia; Chaovalitwongse, W. Art; Pardalos, Panos M.; Seref, Onur; Xanthopoulos, Petros; Sackellares, J. C.; Skidmore, Frank M.

    2007-11-01

    Many studies have documented abnormal horizontal and vertical eye movements in human neurodegenerative disease as well as during altered states of consciousness (including drowsiness and intoxication) in healthy adults. Eye movement measurement may play an important role measuring the progress of neurodegenerative diseases and state of alertness in healthy individuals. There are several techniques for measuring eye movement, Infrared detection technique (IR). Video-oculography (VOG), Scleral eye coil and EOG. Among those available recording techniques, EOG is a major source for monitoring the abnormal eye movement. In this real-time quantitative analysis study, the methods which can capture the characteristic of the eye movement were proposed to accurately categorize the state of neurodegenerative subjects. The EOG recordings were taken while 5 tested subjects were watching a short (>120 s) animation clip. In response to the animated clip the participants executed a number of eye movements, including vertical smooth pursued (SVP), horizontal smooth pursued (HVP) and random saccades (RS). Detection of abnormalities in ocular movement may improve our diagnosis and understanding a neurodegenerative disease and altered states of consciousness. A standard real-time quantitative analysis will improve detection and provide a better understanding of pathology in these disorders.

  13. Tau mis-splicing in the pathogenesis of neurodegenerative disorders.

    PubMed

    Park, Sun Ah; Ahn, Sang Il; Gallo, Jean-Marc

    2016-08-01

    Tau proteins, which stabilize the structure and regulate the dynamics of microtubules, also play important roles in axonal transport and signal transduction. Tau proteins are missorted, aggregated, and found as tau inclusions under many pathological conditions associated with neurodegenerative disorders, which are collectively known as tauopathies. In the adult human brain, tau protein can be expressed in six isoforms due to alternative splicing. The aberrant splicing of tau pre-mRNA has been consistently identified in a variety of tauopathies but is not restricted to these types of disorders as it is also present in patients with non-tau proteinopathies and RNAopathies. Tau mis-splicing results in isoform-specific impairments in normal physiological function and enhanced recruitment of excessive tau isoforms into the pathological process. A variety of factors are involved in the complex set of mechanisms underlying tau mis-splicing, but variation in the cis-element, methylation of the MAPT gene, genetic polymorphisms, the quantity and activity of spliceosomal proteins, and the patency of other RNA-binding proteins, are related to aberrant splicing. Currently, there is a lack of appropriate therapeutic strategies aimed at correcting the tau mis-splicing process in patients with neurodegenerative disorders. Thus, a more comprehensive understanding of the relationship between tau mis-splicing and neurodegenerative disorders will aid in the development of efficient therapeutic strategies for patients with a tauopathy or other, related neurodegenerative disorders. [BMB Reports 2016; 49(8): 405-413]. PMID:27222125

  14. Adult children of parents with young-onset dementia narrate the experiences of their youth through metaphors

    PubMed Central

    Johannessen, Aud; Engedal, Knut; Thorsen, Kirsten

    2015-01-01

    Background Limited research exists on the development and needs of children of parents with young-onset dementia (YOD) (<65 years old). There is scarce knowledge of how these children experience the situation of growing up with a parent with dementia. This study investigates the stories of children of persons with YOD and interprets their metaphorical expressions of their experiences as a source of understanding their situation and needs during the development and course of their parent’s dementia. Methods Qualitative interviews with 14 informants (aged 18–30 years; nine daughters, five sons) were conducted in 2014 and subsequently analyzed by the informants’ use of metaphors. Steger’s three-step method for analyzing metaphors was applied. Results The analysis identified four themes in the metaphors: the informants’ relations to the disease, to the self, to the parent, and to others. From these themes, four core metaphors were abstracted: “my parent is sliding away”; “emotional chaos”; “becoming a parent to my parent”; and “a battle”. Conclusion The study revealed that growing up with a parent with dementia has a great impact on the children’s situation and their experiences of their personal development. Children of a parent with YOD are a group with unmet needs for support. A formalized system where the children can get into contact with service providers to receive tailored information and individual follow-up needs to be established. The service providers must listen to the children’s stories, perceive how metaphors convey their experiences, and recognize their need for support for their own development. PMID:26060403

  15. Alzheimer's disease and CADASIL are heritable, adult-onset dementias that both involve damaged small blood vessels.

    PubMed

    Marchesi, Vincent T

    2014-03-01

    This essay explores an alternative pathway to Alzheimer's dementia that focuses on damage to small blood vessels rather than late-stage toxic amyloid deposits as the primary pathogenic mechanism that leads to irreversible dementia. While the end-stage pathology of AD is well known, the pathogenic processes that lead to disease are often assumed to be due to toxic amyloid peptides that act on neurons, leading to neuronal dysfunction and eventually neuronal cell death. Speculations as to what initiates the pathogenic cascade have included toxic abeta peptide aggregates, oxidative damage, and inflammation, but none explain why neurons die. Recent high-resolution NMR studies of living patients show that lesions in white matter regions of the brain precede the appearance of amyloid deposits and are correlated with damaged small blood vessels. To appreciate the pathogenic potential of damaged small blood vessels in the brain, it is useful to consider the clinical course and the pathogenesis of CADASIL, a heritable arteriopathy that leads to damaged small blood vessels and irreversible dementia. CADASIL is strikingly similar to early onset AD in that it is caused by germ line mutations in NOTCH 3 that generate toxic protein aggregates similar to those attributed to mutant forms of the amyloid precursor protein and presenilin genes. Since NOTCH 3 mutants clearly damage small blood vessels of white matter regions of the brain that lead to dementia, we speculate that both forms of dementia may have a similar pathogenesis, which is to cause ischemic damage by blocking blood flow or by impeding the removal of toxic protein aggregates by retrograde vascular clearance mechanisms.

  16. [Progress in induced pluripotent stem cell research for age-related neurodegenerative diseases].

    PubMed

    Ito, Daisuke; Yagi, Takuya; Suzuki, Norihiro

    2013-03-01

    In 2006, Takahashi et al. established a method for reprogramming somatic cells by introducing definite transcription factors, which enabled the generation of induced pluripotent stem cells (iPSCs) with pluripotency comparable to that of embryonic stem cells. In turn, it has become possible to use these iPSCs for producing various tissues needed for the treatment of neurodegenerative disorders, which have been difficult to obtain from living bodies. This advancement is expected to bring forth rapid progress in the clarification of mechanisms underlying the diseases and discovery of new innovative drugs and lead to rapid progress in regenerative medicine. In recent years, recapitulation and analysis of disease conditions using iPSCs derived from the patients themselves have been reported, and remarkable advances have been made, even for late-onset neurodegenerative disorders. These findings show that the phenotypes of late-onset neurodegenerative disorders can be recapitulated in iPSC-derived neuronal cells, which are reflected the early developmental stages, indicating cellular abnormalities exist from the prenatal period, despite the late onset diseases. In this review, we summarize the state of iPSCs research in the context of neurodegenerative disorders, discuss the possible ways for understanding the mechanisms underlying neurodegenerative disorders and discovering new drugs, and describe some other aspects of regenerative medicine.

  17. Neurodegenerative disorders and metabolic disease.

    PubMed

    Pierre, Germaine

    2013-08-01

    Most genetic causes of neurodegenerative disorders in childhood are due to neurometabolic disease. There are over 200 disorders, including aminoacidopathies, creatine disorders, mitochondrial cytopathies, peroxisomal disorders and lysosomal storage disorders. However, diagnosis can pose a challenge to the clinician when patients present with non-specific problems like epilepsy, developmental delay, autism, dystonia and ataxia. The variety of specialist tests involved can also be daunting. This review aims to give a practical approach to the investigation and diagnosis of neurometabolic disease from the neonatal period to late childhood while prioritising disorders where there are therapeutic options. In particular, patients who have a complex clinical picture of several neurological and non-neurological features should be investigated.

  18. Cell-to-cell transmission of pathogenic proteins in neurodegenerative diseases

    PubMed Central

    Guo, Jing L; Lee, Virginia M Y

    2014-01-01

    A common feature of many neurodegenerative diseases is the deposition of β-sheet-rich amyloid aggregates formed by proteins specific to these diseases. These protein aggregates are thought to cause neuronal dysfunction, directly or indirectly. Recent studies have strongly implicated cell-to-cell transmission of misfolded proteins as a common mechanism for the onset and progression of various neurodegenerative disorders. Emerging evidence also suggests the presence of conformationally diverse ‘strains’ of each type of disease protein, which may be another shared feature of amyloid aggregates, accounting for the tremendous heterogeneity within each type of neurodegenerative disease. Although there are many more questions to be answered, these studies have opened up new avenues for therapeutic interventions in neurodegenerative disorders. PMID:24504409

  19. Relations of plasma total and high-molecular-weight adiponectin to new-onset heart failure in adults ≥65 years of age (from the Cardiovascular Health study).

    PubMed

    Karas, Maria G; Benkeser, David; Arnold, Alice M; Bartz, Traci M; Djousse, Luc; Mukamal, Kenneth J; Ix, Joachim H; Zieman, Susan J; Siscovick, David S; Tracy, Russell P; Mantzoros, Christos S; Gottdiener, John S; deFilippi, Christopher R; Kizer, Jorge R

    2014-01-15

    Adiponectin exhibits cardioprotective properties in experimental studies, but elevated levels have been linked to increased mortality in older adults and patients with chronic heart failure (HF). The adipokine's association with new-onset HF remains less well defined. The aim of this study was to investigate the associations of total and high-molecular weight (HMW) adiponectin with incident HF (n = 780) and, in a subset, echocardiographic parameters in a community-based cohort of adults aged ≥65 years. Total and HMW adiponectin were measured in 3,228 subjects without prevalent HF, atrial fibrillation or CVD. The relations of total and HMW adiponectin with HF were nonlinear, with significant associations observed only for concentrations greater than the median (12.4 and 6.2 mg/L, respectively). After adjustment for potential confounders, the hazard ratios per SD increment in total adiponectin were 0.93 (95% confidence interval 0.72 to 1.21) for concentrations less than the median and 1.25 (95% confidence interval 1.14 to 1.38) higher than the median. There was a suggestion of effect modification by body mass index, whereby the association appeared strongest in participants with lower body mass indexes. Consistent with the HF findings, higher adiponectin tended to be associated with left ventricular systolic dysfunction and left atrial enlargement. Results were similar for HMW adiponectin. In conclusion, total and HMW adiponectin showed comparable relations with incident HF in this older cohort, with a threshold effect of increasing risk occurring at their median concentrations. High levels of adiponectin may mark or mediate age-related processes that lead to HF in older adults.

  20. Observational clinical study of 22 adult-onset Pompe disease patients undergoing enzyme replacement therapy over 5years.

    PubMed

    Stepien, Karolina M; Hendriksz, Christian J; Roberts, Mark; Sharma, Reena

    2016-04-01

    Pompe disease is an autosomal recessive disease resulting from deficiency of the acid alpha-glucosidase (GAA). The late-onset Pompe Disease (LOPD) patients develop muscular and respiratory complications later in life. We describe a retrospective observational cohort study including 22 patients with LOPD. The cohort was assessed at baseline before Enzyme Replacement Therapy (ERT) with alglucosidase alpha (20mg/kg biweekly) was commenced and subsequently relevant information was collected at 2, 4 and 5years later. The median age of the patients at study entry was 44years (16-64years), with median disease duration of 11.5years (4-31years). At baseline, 10 patients (45%) could walk without support, 12 (55%) could walk with unilateral or bilateral support including 3/12 were wheelchair bound. Mean predicted FVC % was 55.7 (95% CI 45-66) of predicted normal at baseline and showed no significant change after 5years (54.6 (95% CI 43-66)), (all p=0.9815). Mean FVC % supine was 41.8 (95% CI 33.8-49) of predicted normal at baseline and remained significantly unchanged at 5years (48.4 (95% CI 37-59.6)), (all p=0.8680). The overnight non-invasive ventilator dependence increased by 18.2% as compared with baseline and requirement of mobility aids increased during this period by 5.2% as compared with the baseline. Mean walking distance at 6min walk test was 411.5 (95% CI 338-485) at baseline, 266.5 (95% CI 187-346) m at 2years, 238.6 (95% CI 162-315) m at 4years and 286.8 (95% CI 203-370) m at 5years (p=0.1981; ANOVA was completed only for 14 patients). A gradual decline in FVC% predicted was noted only in four cases and a decline in FVC% supine in two other. Only one patient showed a decline in both pulmonary function tests. In all remaining cases (17/22) respiratory function remains stable. In conclusion overall pulmonary function tests and mobility remained stable for 5years in majority of patients on ERT. However, in some patients they continued to decline in spite of ERT

  1. Caspase-8 Deficiency Presenting as Late-Onset Multi-Organ Lymphocytic Infiltration with Granulomas in two Adult Siblings.

    PubMed

    Niemela, Julie; Kuehn, Hye Sun; Kelly, Corin; Zhang, Mingchang; Davies, Joie; Melendez, Jose; Dreiling, Jennifer; Kleiner, David; Calvo, Katherine; Oliveira, João B; Rosenzweig, Sergio D

    2015-05-01

    Caspase-8 deficiency (CED) was originally described in 2002 in two pediatric patients presenting with clinical manifestations resembling autoimmune lymphoproliferative syndrome (ALPS) accompanied by infections, and T, B and NK cell defects. Since then, no new CED patients were published. Here we report two adult siblings (Pt1 and Pt2) presenting in their late thirties with pulmonary hypertension leading to lung transplant (Pt1), and a complex neurological disease leading to multiple cranial nerves palsies (Pt2) as their main manifestations. A thorough clinical and immunological evaluation was performed at the Primary Immunodeficiency Clinic at NIH, followed by whole exome sequencing. The patients had multiorgan lymphocytic infiltration and granulomas, as well as clinical signs of immune deficiency/ immune dysregulation. Both siblings carried homozygous mutations in CASP8, c.1096C > T, p.248R > W. This was the same mutation described on the previously published CED patients, to whom these new patients were likely distantly related. We report two new CED patients presenting during adulthood with life-threatening end-organ lymphocyte infiltrates affecting the lungs, liver, spleen, bone marrow and central nervous system. This phenotype broadens the clinical spectrum of manifestations associated with this disease and warrants the search of CASP8 mutations in other cohorts of patients. PMID:25814141

  2. Semen quality and onset of sterility following administration of a 4.7-mg deslorelin implant in adult male dogs.

    PubMed

    Romagnoli, S; Siminica, A; Sontas, B H; Milani, C; Mollo, A; Stelletta, C

    2012-12-01

    The purpose of this study was to define (i) the interval between treatment and sterility, and (ii) semen quality in male dogs administered a 4.7-mg deslorelin implant. Six healthy, adult dogs of various breeds and body weights were implanted with deslorelin (Suprelorin, Virbac) and followed every 2 weeks with semen and blood collections. Semen quality remained stable or even improved during the first month following treatment and then showed a progressive decline until the end of the study, except for sperm morphology, which was unaffected by the treatment. Complete sterility was achieved on post-treatment days 70, 84, 60, 23, 51 and 40 for dogs 1 to 6, respectively. The 4.7 mg deslorelin implant caused a significant (p < 0.05) decrease in serum testosterone as well as sperm motility. Our results (i) confirm the efficacy of deslorelin in causing reversible sterility in male dogs, (ii) confirm and provide details about endocrine and seminal parameters involved in this process and (iii) contribute to define the interval between treatment and achievement of complete sterility. Practitioners should be aware that such interval may be longer than 2 months in some cases, and that fertility may actually be increased during the first 2-4 weeks post-treatment.

  3. Alterations in male sexual behaviour, attractiveness and testosterone levels induced by an adult-onset calorie restriction regimen.

    PubMed

    Govic, Antonina; Levay, Elizabeth A; Hazi, Agnes; Penman, Jim; Kent, Stephen; Paolini, Antonio G

    2008-06-26

    Despite an abundance of research on calorie restriction (CR) altering gonadal and appetite regulating hormones, the sexual behavioural consequences of CR remain to be examined systematically. This study compared the sexual behaviour, partner preference, serum testosterone and leptin levels of male adult Hooded Wistar rats administered a CR (continuous 25%, 50% CR or a temporary restriction) with ad libitum fed controls. The temporary restriction (Previous CR) failed to alter sexual behaviour, partner preference and levels of testosterone and leptin. The moderately 25% CR males did not demonstrate an impairment in sexual behaviour but did demonstrate a reduced level of attractiveness to females in one measure of partner preference. Sexual performance was affected by a substantial CR, as the CR 50% group exhibited a longer latency to the first intromission, indicating alteration in sexual arousal. Females also consistently demonstrated a clear preference for the control group compared to the CR 50% group. These findings indicate a possible reduction in the overall reproductive potential of the substantially CR animals. Testosterone levels were equally suppressed by both the 25% and 50% CR, while leptin levels were only reduced in the CR 50% group. Leptin, rather than testosterone, may have influenced the impairment in sexual behaviour only demonstrated by the substantially CR animals. Testosterone, may, however, play a role in modulating the preference of control over CR males, as attractiveness was totally reduced by a substantial CR, and partially reduced by a moderate restricted regimen.

  4. Multimodality imaging of Alzheimer disease and other neurodegenerative dementias.

    PubMed

    Nasrallah, Ilya M; Wolk, David A

    2014-12-01

    Neurodegenerative diseases, such as Alzheimer disease, result in cognitive decline and dementia and are a leading cause of mortality in the growing elderly population. These progressive diseases typically have an insidious onset, with overlapping clinical features early in the disease course that make diagnosis challenging. The neurodegenerative diseases are associated with characteristic, although not completely understood, changes in the brain: abnormal protein deposition, synaptic dysfunction, neuronal injury, and neuronal death. Neuroimaging biomarkers-principally regional atrophy on structural MR imaging, patterns of hypometabolism on (18)F-FDG PET, and detection of cerebral amyloid plaque on amyloid PET--are able to evaluate the patterns of these abnormalities in the brain to improve early diagnosis and help predict the disease course. These techniques have unique strengths and synergies in multimodality evaluation of the patient with cognitive decline or dementia. This review discusses the key imaging biomarkers from MR imaging, (18)F-FDG PET, and amyloid PET; the imaging features of the most common neurodegenerative dementias; the role of various neuroimaging studies in differential diagnosis and prognosis; and some promising imaging techniques under development.

  5. ETHICAL AND GENETIC ASPECTS REGARDING PRESYMPTOMATIC TESTING FOR NEURODEGENERATIVE DISEASES.

    PubMed

    Cozaru, Georgeta Camelial; Aşchie, Mariana; Mitroi, Anca Florentina; Poinăreanu, I; Gorduza, E V

    2016-01-01

    Neurodegenerative diseases, such as Alzheimer's dementia, Huntington's chorea, Parkinson's disease or spinocerebellar ataxia, manifests into adulthood with an insidious onset, slowly of progressive symptoms. All of these diseases are characterized by presimptomatic stages that preceded with many years of clinical debut. In Parkinson's disease, more than half of the dopaminergic neurons of the black substance are lost before the advent of motor characteristic manifestations. In Huntington's chorea, the progressive neurodegenerative disease could be diagnose prenatal and presymptomatic by analyse of the number of CAG repeats in exon 1 of the huntingtin gene. A similar mechanism represented by expansion of trinucleotide repeats during hereditary transmission from parents to children was identified in fragile X syndrome, spinocerebellar ataxia, spinal muscular and bulbar atrophy, or myotonic dystrophy. Presymptomatic diagnosis in all these progressive diseases raise many ethical issues, due to the psychological impact that can cause the prediction of a disease for which there is currently no curative treatment. Therefore, a positive result can produce serious psychological trauma and major changes in the lifestyle of the individual, instead, a negative result can bring joy and tranquillity. But the problem arises if presymptomatic testing in these neurodegenerative diseases brings greater benefits compared to the possible psychological damage, which can add the risk of stigmatization or discrimination. PMID:27125067

  6. Genetic association study of NF-κB genes in UK Caucasian adult and juvenile onset idiopathic inflammatory myopathy

    PubMed Central

    Chinoy, Hector; Li, Charles K.-C.; Platt, Hazel; Fertig, Noreen; Varsani, Hemlata; Gunawardena, Harsha; Betteridge, Zoe; Oddis, Chester V.; McHugh, Neil J.; Wedderburn, Lucy R.; Ollier, William E. R.

    2012-01-01

    Objective. Treatment-resistant muscle wasting is an increasingly recognized problem in idiopathic inflammatory myopathy (IIM). TNF-α is thought to induce muscle catabolism via activation of nuclear factor-kappa B (NF-κB). Several genes share homology with the NF-κB family of proteins. This study investigated the role of NF-κB-related genes in disease susceptibility in UK Caucasian IIM. Methods. Data from 362 IIM cases [274 adults, 49 (±14.0) years, 72% female; 88 juveniles, 6 (±3.6) years, 73% female) were compared with 307 randomly selected Caucasian controls. DNA was genotyped for 63 single nucleotide polymorphisms (SNPs) from NF-κB-related genes. Data were stratified by IIM subgroup/serotype. Results. A significant allele association was observed in the overall IIM group vs controls for the IKBL-62T allele (rs2071592, odds ratio 1.5, 95% CI 1.21, 1.89, corrected P = 0.0086), which strengthened after stratification by anti-Jo-1 or -PM-Scl antibodies. Genotype analysis revealed an increase for the AT genotype in cases under a dominant model. No other SNP was associated in the overall IIM group. Strong pairwise linkage disequilibrium was noted between IKBL-62T, TNF-308A and HLA-B*08 (D′ = 1). Using multivariate regression, the IKBL-62T IIM association was lost after adjustment for TNF-308A or HLA-B*08. Conclusion. An association was noted between IKBL-62T and IIM, with increased risk noted in anti-Jo-1- and -PM-Scl antibody-positive patients. However, the IKBL-62T association is dependent on TNF-308A and HLA-B*08, due to strong shared linkage disequilibrium between these alleles. After adjustment of the 8.1 HLA haplotype, NF-κB genes therefore do not independently confer susceptibility in IIM. PMID:22210660

  7. Melatonin rhythm onset in the adult siberian hamster: influence of photoperiod but not 60-Hz magnetic field exposure on melatonin content in the pineal gland and in circulation.

    PubMed

    Yellon, S M; Truong, H N

    1998-02-01

    To determine the relationship between pineal melatonin production and its appearance in circulation, the rising phase of the pineal and serum melatonin rhythm was studied in the adult Siberian hamster. Melatonin concentrations increased in the pineal gland and in serum at 1.50 and 1.75 h, respectively, relative to lights off in long days (16 h of light/day) and at 2.00 and 2.75 h, respectively, in short days (10 h of light/day). Thus, a photoperiod-dependent melatonin rise in circulation lagged production by the pineal gland by 0.50 h--a delay of 0.75 h in short-day hamsters versus 0.25 h in long-day hamsters. Following initiation of this rise, concentrations that were typical of the nighttime peak were achieved within 2 h of melatonin rhythm onset, regardless of photoperiod. To determine whether clock control of the rising phase of the melatonin rhythm, in the absence of photoperiod cues, may be disrupted by perturbations in the ambient magnetic field, hamsters in constant darkness were acutely exposed to a 1-Gauss, 60-Hz magnetic field for 15 min or were daily exposed to this treatment for 14 or 21 days. Neither the melatonin rise in pineal content or circulation during subjective night was affected by acute or chronic magnetic field exposures; testes regression similarly occurred in sham and daily magnetic field-exposed hamsters in constant darkness. These findings indicate that magnetic field exposures are unlikely to serve as a zeitgeber for the circadian mechanism that controls onset of the melatonin rhythm; rather, photoperiod is a predominant cue that may differentially regulate the rising phase of melatonin production in the pineal gland and concentration in circulation.

  8. Adrenoleukodystrophy: new approaches to a neurodegenerative disease.

    PubMed

    Moser, Hugo W; Raymond, Gerald V; Dubey, Prachi

    2005-12-28

    X-linked adrenoleukodystrophy (X-ALD), which was first described in 1923, was viewed until 1976 as a rare and inexorably fatal neurodegenerative disorder that affected boys. The genetic defect and biochemical abnormalities have now been defined. Ongoing research has resulted in new findings: (1) there is a wide range of phenotypic expression. At least half of patients with X-ALD are adults with somewhat milder manifestations, and women who are carriers may become symptomatic. X-ALD is often misdiagnosed as attention-deficit/hyperactivity disorder in boys and as multiple sclerosis in men and women, and is not an uncommon cause of Addison disease; (2) the incidence of X-ALD, estimated to be 1:17,000 in all ethnic groups, approximates that of phenylketonuria; (3) noninvasive and presymptomatic diagnosis and prenatal diagnosis are available; family screening and genetic counseling are key to disease prevention; and (4) new therapies, applied early, show promise. Neonatal screening is likely to become available, and a wider awareness of X-ALD and its various modes of presentation permit new proactive approaches to this distressing disorder.

  9. Stem cell technology for neurodegenerative diseases.

    PubMed

    Lunn, J Simon; Sakowski, Stacey A; Hur, Junguk; Feldman, Eva L

    2011-09-01

    Over the past 20 years, stem cell technologies have become an increasingly attractive option to investigate and treat neurodegenerative diseases. In the current review, we discuss the process of extending basic stem cell research into translational therapies for patients suffering from neurodegenerative diseases. We begin with a discussion of the burden of these diseases on society, emphasizing the need for increased attention toward advancing stem cell therapies. We then explain the various types of stem cells utilized in neurodegenerative disease research, and outline important issues to consider in the transition of stem cell therapy from bench to bedside. Finally, we detail the current progress regarding the applications of stem cell therapies to specific neurodegenerative diseases, focusing on Parkinson disease, Huntington disease, Alzheimer disease, amyotrophic lateral sclerosis, and spinal muscular atrophy. With a greater understanding of the capacity of stem cell technologies, there is growing public hope that stem cell therapies will continue to progress into realistic and efficacious treatments for neurodegenerative diseases.

  10. Amyloidosis in Retinal Neurodegenerative Diseases.

    PubMed

    Masuzzo, Ambra; Dinet, Virginie; Cavanagh, Chelsea; Mascarelli, Frederic; Krantic, Slavica

    2016-01-01

    As a part of the central nervous system, the retina may reflect both physiological processes and abnormalities related to pathologies that affect the brain. Amyloidosis due to the accumulation of amyloid-beta (Aβ) was initially regarded as a specific and exclusive characteristic of neurodegenerative alterations seen in the brain of Alzheimer's disease (AD) patients. More recently, it was discovered that amyloidosis-related alterations, similar to those seen in the brain of Alzheimer's patients, also occur in the retina. Remarkably, these alterations were identified not only in primary retinal pathologies, such as age-related macular degeneration (AMD) and glaucoma, but also in the retinas of Alzheimer's patients. In this review, we first briefly discuss the biogenesis of Aβ, a peptide involved in amyloidosis. We then discuss some pathological aspects (synaptic dysfunction, mitochondrial failure, glial activation, and vascular abnormalities) related to the neurotoxic effects of Aβ. We finally highlight common features shared by AD, AMD, and glaucoma in the context of Aβ amyloidosis and further discuss why the retina, due to the transparency of the eye, can be considered as a "window" to the brain. PMID:27551275

  11. Peptide aggregation in neurodegenerative disease.

    PubMed

    Murphy, Regina M

    2002-01-01

    In the not-so-distant past, insoluble aggregated protein was considered as uninteresting and bothersome as yesterday's trash. More recently, protein aggregates have enjoyed considerable scientific interest, as it has become clear that these aggregates play key roles in many diseases. In this review, we focus attention on three polypeptides: beta-amyloid, prion, and huntingtin, which are linked to three feared neurodegenerative diseases: Alzheimer's, "mad cow," and Huntington's disease, respectively. These proteins lack any significant primary sequence homology, yet their aggregates possess very similar features, specifically, high beta-sheet content, fibrillar morphology, relative insolubility, and protease resistance. Because the aggregates are noncrystalline, secrets of their structure at nanometer resolution are only slowly yielding to X-ray diffraction, solid-state NMR, and other techniques. Besides structure, the aggregates may possess similar pathways of assembly. Two alternative assembly pathways have been proposed: the nucleation-elongation and the template-assisted mode. These two modes may be complementary, not mutually exclusive. Strategies for interfering with aggregation, which may provide novel therapeutic approaches, are under development. The structural similarities between protein aggregates of dissimilar origin suggest that therapeutic strategies successful against one disease may have broad utility in others. PMID:12117755

  12. Amyloidosis in Retinal Neurodegenerative Diseases

    PubMed Central

    Masuzzo, Ambra; Dinet, Virginie; Cavanagh, Chelsea; Mascarelli, Frederic; Krantic, Slavica

    2016-01-01

    As a part of the central nervous system, the retina may reflect both physiological processes and abnormalities related to pathologies that affect the brain. Amyloidosis due to the accumulation of amyloid-beta (Aβ) was initially regarded as a specific and exclusive characteristic of neurodegenerative alterations seen in the brain of Alzheimer’s disease (AD) patients. More recently, it was discovered that amyloidosis-related alterations, similar to those seen in the brain of Alzheimer’s patients, also occur in the retina. Remarkably, these alterations were identified not only in primary retinal pathologies, such as age-related macular degeneration (AMD) and glaucoma, but also in the retinas of Alzheimer’s patients. In this review, we first briefly discuss the biogenesis of Aβ, a peptide involved in amyloidosis. We then discuss some pathological aspects (synaptic dysfunction, mitochondrial failure, glial activation, and vascular abnormalities) related to the neurotoxic effects of Aβ. We finally highlight common features shared by AD, AMD, and glaucoma in the context of Aβ amyloidosis and further discuss why the retina, due to the transparency of the eye, can be considered as a “window” to the brain. PMID:27551275

  13. FE65 and FE65L1 amyloid precursor protein–binding protein compound null mice display adult-onset cataract and muscle weakness

    PubMed Central

    Suh, Jaehong; Moncaster, Juliet A.; Wang, Lirong; Hafeez, Imran; Herz, Joachim; Tanzi, Rudolph E.; Goldstein, Lee E.; Guénette, Suzanne Y.

    2015-01-01

    FE65 and FE65L1 are cytoplasmic adaptor proteins that bind a variety of proteins, including the amyloid precursor protein, and that mediate the assembly of multimolecular complexes. We previously reported that FE65/FE65L1 double knockout (DKO) mice display disorganized laminin in meningeal fibroblasts and a cobblestone lissencephaly-like phenotype in the developing cortex. Here, we examined whether loss of FE65 and FE65L1 causes ocular and muscular deficits, 2 phenotypes that frequently accompany cobblestone lissencephaly. Eyes of FE65/FE65L1 DKO mice develop normally, but lens degeneration becomes apparent in young adult mice. Abnormal lens epithelial cell migration, widespread small vacuole formation, and increased laminin expression underneath lens capsules suggest impaired interaction between epithelial cells and capsular extracellular matrix in DKO lenses. Cortical cataracts develop in FE65L1 knockout (KO) mice aged 16 months or more but are absent in wild-type or FE65 KO mice. FE65 family KO mice show attenuated grip strength, and the nuclei of DKO muscle cells frequently locate in the middle of muscle fibers. These findings reveal that FE65 and FE65L1 are essential for the maintenance of lens transparency, and their loss produce phenotypes in brain, eye, and muscle that are comparable to the clinical features of congenital muscular dystrophies in humans.—Suh, J., Moncaster, J. A., Wang, L., Hafeez, I., Herz, J., Tanzi, R. E., Goldstein, L. E., Guénette, S. Y. FE65 and FE65L1 amyloid precursor protein–binding protein compound null mice display adult-onset cataract and muscle weakness. PMID:25757569

  14. ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43.

    PubMed

    Arnold, Eveline S; Ling, Shuo-Chien; Huelga, Stephanie C; Lagier-Tourenne, Clotilde; Polymenidou, Magdalini; Ditsworth, Dara; Kordasiewicz, Holly B; McAlonis-Downes, Melissa; Platoshyn, Oleksandr; Parone, Philippe A; Da Cruz, Sandrine; Clutario, Kevin M; Swing, Debbie; Tessarollo, Lino; Marsala, Martin; Shaw, Christopher E; Yeo, Gene W; Cleveland, Don W

    2013-02-19

    Transactivating response region DNA binding protein (TDP-43) is the major protein component of ubiquitinated inclusions found in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with ubiquitinated inclusions. Two ALS-causing mutants (TDP-43(Q331K) and TDP-43(M337V)), but not wild-type human TDP-43, are shown here to provoke age-dependent, mutant-dependent, progressive motor axon degeneration and motor neuron death when expressed in mice at levels and in a cell type-selective pattern similar to endogenous TDP-43. Mutant TDP-43-dependent degeneration of lower motor neurons occurs without: (i) loss of TDP-43 from the corresponding nuclei, (ii) accumulation of TDP-43 aggregates, and (iii) accumulation of insoluble TDP-43. Computational analysis using splicing-sensitive microarrays demonstrates alterations of endogenous TDP-43-dependent alternative splicing events conferred by both human wild-type and mutant TDP-43(Q331K), but with high levels of mutant TDP-43 preferentially enhancing exon exclusion of some target pre-mRNAs affecting genes involved in neurological transmission and function. Comparison with splicing alterations following TDP-43 depletion demonstrates that TDP-43(Q331K) enhances normal TDP-43 splicing function for some RNA targets but loss-of-function for others. Thus, adult-onset motor neuron disease does not require aggregation or loss of nuclear TDP-43, with ALS-linked mutants producing loss and gain of splicing function of selected RNA targets at an early disease stage.

  15. Feasibility of teaching motivational interviewing to parents of young adults with recent-onset schizophrenia and co-occurring cannabis use.

    PubMed

    Smeerdijk, Maarten; Keet, René; de Haan, Lieuwe; Barrowclough, Christine; Linszen, Don; Schippers, Gerard

    2014-03-01

    This study examined the feasibility of providing motivational interviewing (MI) training to parents of young adults with recent-onset schizophrenia and co-occurring cannabis use. The training was offered in a mental health care setting as part of a family motivational intervention (FMI). Ninety-seven parents were randomly assigned to either FMI or routine family support (RFS). To obtain a measure of parent's MI skills at baseline and 3 months after they completed FMI, their role-play interactions with an actor portraying their child were coded. The coding method had satisfactory inter-rater reliability and internal consistency. At follow-up, parents in FMI showed significantly greater adherence to (p=.03) and competence in (p=.04) MI than parents in RFS. Parents in FMI also demonstrated significantly greater increases in expressing empathy (p=.01). These results demonstrate that FMI is a feasible method for increasing MI skills in parents. Additional research is needed to better understand the unique application of MI to parent-child interactions.

  16. A large genomic deletion leads to enhancer adoption by the lamin B1 gene: a second path to autosomal dominant adult-onset demyelinating leukodystrophy (ADLD)

    SciTech Connect

    Giorgio, E.; Robyr, D.; Spielmann, M.; Ferrero, E.; Di Gregorio, E.; Imperiale, D.; Vaula, G.; Stamoulis, G.; Santoni, F.; Atzori, C.; Gasparini, L.; Ferrera, D.; Canale, C.; Guipponi, M.; Pennacchio, L. A.; Antonarakis, S. E.; Brussino, A.; Brusco, A.

    2015-02-20

    Chromosomal rearrangements with duplication of the lamin B1 (LMNB1) gene underlie autosomal dominant adult-onset demyelinating leukodystrophy (ADLD), a rare neurological disorder in which overexpression of LMNB1 causes progressive central nervous system demyelination. However, we previously reported an ADLD family (ADLD-1-TO) without evidence of duplication or other mutation in LMNB1 despite linkage to the LMNB1 locus and lamin B1 overexpression. By custom array-CGH, we further investigated this family and report here that patients carry a large (~660 kb) heterozygous deletion that begins 66 kb upstream of the LMNB1 promoter. Lamin B1 overexpression was confirmed in further ADLD-1-TO tissues and in a postmortem brain sample, where lamin B1 was increased in the frontal lobe. Through parallel studies, we investigated both loss of genetic material and chromosomal rearrangement as possible causes of LMNB1 overexpression, and found that ADLD-1-TO plausibly results from an enhancer adoption mechanism. The deletion eliminates a genome topological domain boundary, allowing normally forbidden interactions between at least three forebrain-directed enhancers and the LMNB1 promoter, in line with the observed mainly cerebral localization of lamin B1 overexpression and myelin degeneration. Finally, this second route to LMNB1 overexpression and ADLD is a new example of the relevance of regulatory landscape modifications in determining Mendelian phenotypes.

  17. A large genomic deletion leads to enhancer adoption by the lamin B1 gene: a second path to autosomal dominant adult-onset demyelinating leukodystrophy (ADLD)

    DOE PAGES

    Giorgio, E.; Robyr, D.; Spielmann, M.; Ferrero, E.; Di Gregorio, E.; Imperiale, D.; Vaula, G.; Stamoulis, G.; Santoni, F.; Atzori, C.; et al

    2015-02-20

    Chromosomal rearrangements with duplication of the lamin B1 (LMNB1) gene underlie autosomal dominant adult-onset demyelinating leukodystrophy (ADLD), a rare neurological disorder in which overexpression of LMNB1 causes progressive central nervous system demyelination. However, we previously reported an ADLD family (ADLD-1-TO) without evidence of duplication or other mutation in LMNB1 despite linkage to the LMNB1 locus and lamin B1 overexpression. By custom array-CGH, we further investigated this family and report here that patients carry a large (~660 kb) heterozygous deletion that begins 66 kb upstream of the LMNB1 promoter. Lamin B1 overexpression was confirmed in further ADLD-1-TO tissues and in amore » postmortem brain sample, where lamin B1 was increased in the frontal lobe. Through parallel studies, we investigated both loss of genetic material and chromosomal rearrangement as possible causes of LMNB1 overexpression, and found that ADLD-1-TO plausibly results from an enhancer adoption mechanism. The deletion eliminates a genome topological domain boundary, allowing normally forbidden interactions between at least three forebrain-directed enhancers and the LMNB1 promoter, in line with the observed mainly cerebral localization of lamin B1 overexpression and myelin degeneration. Finally, this second route to LMNB1 overexpression and ADLD is a new example of the relevance of regulatory landscape modifications in determining Mendelian phenotypes.« less

  18. A large genomic deletion leads to enhancer adoption by the lamin B1 gene: a second path to autosomal dominant adult-onset demyelinating leukodystrophy (ADLD)

    PubMed Central

    Giorgio, Elisa; Robyr, Daniel; Spielmann, Malte; Ferrero, Enza; Di Gregorio, Eleonora; Imperiale, Daniele; Vaula, Giovanna; Stamoulis, Georgios; Santoni, Federico; Atzori, Cristiana; Gasparini, Laura; Ferrera, Denise; Canale, Claudio; Guipponi, Michel; Pennacchio, Len A.; Antonarakis, Stylianos E.; Brussino, Alessandro; Brusco, Alfredo

    2015-01-01

    Chromosomal rearrangements with duplication of the lamin B1 (LMNB1) gene underlie autosomal dominant adult-onset demyelinating leukodystrophy (ADLD), a rare neurological disorder in which overexpression of LMNB1 causes progressive central nervous system demyelination. However, we previously reported an ADLD family (ADLD-1-TO) without evidence of duplication or other mutation in LMNB1 despite linkage to the LMNB1 locus and lamin B1 overexpression. By custom array-CGH, we further investigated this family and report here that patients carry a large (∼660 kb) heterozygous deletion that begins 66 kb upstream of the LMNB1 promoter. Lamin B1 overexpression was confirmed in further ADLD-1-TO tissues and in a postmortem brain sample, where lamin B1 was increased in the frontal lobe. Through parallel studies, we investigated both loss of genetic material and chromosomal rearrangement as possible causes of LMNB1 overexpression, and found that ADLD-1-TO plausibly results from an enhancer adoption mechanism. The deletion eliminates a genome topological domain boundary, allowing normally forbidden interactions between at least three forebrain-directed enhancers and the LMNB1 promoter, in line with the observed mainly cerebral localization of lamin B1 overexpression and myelin degeneration. This second route to LMNB1 overexpression and ADLD is a new example of the relevance of regulatory landscape modifications in determining Mendelian phenotypes. PMID:25701871

  19. Successful Use of Higher-Dose Etanercept for Multirefractory Systemic Flare of Adult-Onset Still's Disease with Liver Failure with No Response to Tocilizumab Therapy

    PubMed Central

    Tamechika, Shinya; Iwagaitsu, Shiho; Maeda, Shinji; Togawa, Hiroyuki

    2013-01-01

    A 21-year-old woman with refractory systemic flare of adult-onset Still's disease with liver failure despite high-dose corticosteroids, cyclosporine, tacrolimus, and tocilizumab, was successfully treated with additional use of etanercept. Etanercept at a dose of 50 mg weekly was partially effective but could not reduce the dose of concomitant betamethasone from 5 mg/day. Etanercept at a dose of 75 mg weekly could lead her to clinical remission and enabled successful tapering off the corticosteroids and discontinuation of etanercept. Normalization of serum C-reactive protein and interleukin 6 and persistent elevation of serum tumor necrosis factor α under the treatment with high-dose corticosteroids and immunosuppressants suggest that tumor necrosis factor α was more deeply involved than at least interleukin 6 in the pathogenesis of refractoriness of the disease in this patient, and these findings might be indicative of potential efficacy for adjunctive use of a tumor necrosis factor inhibitor rather than an interleukin 6 inhibitor. PMID:24455384

  20. Sound Naming in Neurodegenerative Disease

    PubMed Central

    Chow, Maggie L; Brambati, Simona M; Gorno-Tempini, Maria Luisa; Miller, Bruce L; Johnson, Julene K

    2010-01-01

    Modern cognitive neuroscientific theories and empirical evidence suggest that brain structures involved in movement may be related to action-related semantic knowledge. To test this hypothesis, we examined the naming of environmental sounds in patients with corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), two neurodegenerative diseases associated with cognitive and motor deficits. Subjects were presented with 56 environmental sounds: 28 of objects that required manipulation when producing the sound, and 28 that required no manipulation. Subjects were asked to provide the name of the object that produced the sound and also complete a sound-picture matching condition. Subjects included 33 individuals from four groups: CBD/PSP, Alzheimer disease, frontotemporal dementia, and normal controls. We hypothesized that CBD/PSP patients would exhibit impaired naming performance compared with controls, but the impairment would be most apparent when naming sounds associated with actions. We also explored neural correlates of naming environmental sounds using voxel-based morphometry (VBM) of brain MRI. As expected, CBD/PSP patients scored lower on environmental sounds naming (p<0.007) compared with the controls. In particular, the CBD/PSP patients scored the lowest when naming sounds of manipulable objects (p<0.05), but did not show deficits in naming sounds of non-manipulable objects. VBM analysis across all groups showed that performance in naming sounds of manipulable objects correlated with atrophy in the left premotor region, extending from area 6 to the middle and superior frontal gyrus. These results indicate an association between impairment in the retrieval of action-related names and the motor system, and suggest that difficulty in naming manipulable sounds may be related to atrophy in the premotor cortex. Our results support the hypothesis that retrieval of action-related semantic knowledge involves motor regions in the brain. PMID:20089342

  1. Age of onset of amyotrophic lateral sclerosis is modulated by a locus on 1p34.1

    PubMed Central

    2013-01-01

    Amyotrophic lateral sclerosis (ALS) is the third most common adult-onset neurodegenerative disease. Individuals with ALS rapidly progress to paralysis and die from respiratory failure within 3 to 5 years after symptom onset. Epidemiological factors explain only a modest amount of the risk for ALS. However, there is growing evidence of a strong genetic component to both familial and sporadic ALS risk. The International Consortium on Amyotrophic Lateral Sclerosis Genetics was established to bring together existing genome-wide association cohorts and identify sporadic ALS susceptibility and age at symptom onset loci. Here, we report the results of a meta-analysis of the International Consortium on Amyotrophic Lateral Sclerosis Genetics genome-wide association samples, consisting of 4243 ALS cases and 5112 controls from 13 European ancestry cohorts from across the United States and Europe. Eight genomic regions provided evidence of association with ALS, including 9p21.2 (rs3849942, odds ratio [R] = 1.21; p = 4.41 × 10−7), 17p11.2 (rs7477, OR = 1.30; p = 2.89 × 10−7), and 19p13 (rs12608932, OR = 1.37, p = 1.29 × 10−7). Six genomic regions were associated with age at onset of ALS. The strongest evidence for an age of onset locus was observed at 1p34.1, with comparable evidence at rs3011225 (R2partial = 0.0061; p = 6.59 × 10−8) and rs803675 (R2partial = 0.0060; p = 6.96 × 10−8). These associations were consistent across all 13 cohorts. For rs3011225, individuals with at least 1 copy of the minor allele had an earlier average age of onset of over 2 years. Identifying the underlying pathways influencing susceptibility to and age at onset of ALS may provide insight into the pathogenic mechanisms and motivate new pharmacologic targets for this fatal neurodegenerative disease. PMID:22959728

  2. New-onset refractory status epilepticus in an adult with an atypical presentation of cat-scratch disease: successful treatment with high-dose corticosteroids.

    PubMed

    Laswell, Emily M; Chambers, Kasandra D; Whitsel, Danielle R; Poudel, Kiran

    2015-06-01

    New-onset refractory status epilepticus (NORSE) is defined as a sudden onset of refractory status epilepticus in patients who do not have a history of epilepsy. It is a neurologic emergency, and determining the underlying etiology is an important factor for effectively managing and predicting the prognosis of NORSE. We describe the case of a 28-year-old woman who was hospitalized with NORSE secondary to an unknown etiology. She did not respond to traditional anticonvulsant therapy, including benzodiazepines, fosphenytoin, propofol, and levetiracetam. The patient was placed on continuous electroencephalography (EEG) monitoring and was treated further with multiple antiepileptics, which were titrated aggressively based on EEG readings and therapeutic drug levels; despite this treatment, EEG monitoring revealed continued seizures. Thus, high-dose corticosteroids were started for seizure control. Her workup included computed tomography and magnetic resonance imaging of the head, a lumbar puncture, toxicology screening, and extensive testing for multiple infectious and inflammatory etiologies. The patient's history revealed recent exposure to a new cat. Serologic results were positive for Bartonella henselae, and she was diagnosed with cat-scratch disease (CSD). She did not have the typical presentation of symptoms of lymphadenopathy, however, which is common in CSD. Doxycycline 100 mg and rifampin 300 mg twice daily were added to the patient's anticonvulsant and corticosteroid therapy. She was hospitalized for a total of 26 days and discharged with only minor neurologic impairment (short-term memory deficits and minor cognitive problems). The patient was discharged receiving antiepileptics, antibiotics, and a corticosteroid taper. To our knowledge, this is the first clinically known case of NORSE secondary to CSD without typical CSD symptoms in the adult population. The patient failed to respond to traditional anticonvulsant therapy alone. With the addition of high

  3. SETX mutations are a frequent genetic cause of juvenile and adult onset cerebellar ataxia with neuropathy and elevated serum alpha-fetoprotein

    PubMed Central

    2013-01-01

    Objectives/background Ataxia with oculomotor apraxia defines a group of genetically distinct recessive ataxias including ataxia-telangectasia (A-T, ATM gene), ataxia with oculomotor apraxia type 1 (AOA1, APTX gene) and type 2 (AOA2, SETX gene). Although, a few unique clinical features differentiate each of these forms, the patients also share common clinical signs, such as the presence of cerebellar atrophy, sensorimotor axonal neuropathy, and elevated alpha-fetoprotein (AFP) serum level. Materials and methods We selected 22 Italian patients from 21 families, presenting progressive cerebellar ataxia, axonal neuropathy, and elevated serum AFP. We screened the coding regions of ATM, APTX and SETX genes for point mutations by direct sequencing or DHPLC, and searched genomic rearrangements in SETX by MLPA analysis. In selected cases, quantification of ATM and senataxin proteins was performed by Western blot. Clinical, neurophysiological, and neuroimaging data were collected. Results Thirteen patients (12 families) carried SETX mutations (AOA2, 57%), two were mutated in ATM (A-T), and three in APTX (AOA1). In three remaining patients, we could not find pathogenic mutations, and in one case we found, in homozygosis, the SETX p.K992R polymorphism (population frequency 1-2%). In AOA2 cases, we identified 14 novel and three reported SETX mutations. Signs at onset were gait ataxia and facial dyskinesia, and the age ranged between 11 and 18 years. None had obvious oculomotor apraxia at the latest examination (age 14–45 years). The patient carrying the p.K992R SETX polymorphism had a phenotype similar to that of the diagnosed AOA2 patients, while the other three undiagnosed subjects had a very late onset and a few distinguishing clinical features. Discussion and conclusions We describe a large series of 13 AOA2 Italian patients. The phenotype was consistent with previous descriptions of AOA2, except for a higher frequency of strabism, and for the absence of oculomotor

  4. Proteomic analysis for early neurodegenerative biomarker detection in an animal model.

    PubMed

    Vincenzetti, Silvia; Nasuti, Cinzia; Fedeli, Donatella; Ricciutelli, Massimo; Pucciarelli, Stefania; Gabbianelli, Rosita

    2016-02-01

    The exposure to xenobiotics in the early stages of life represents the most important component in the etiology of many neurodegenerative disorders. Proteomic analysis of plasma and brain samples from early life treated animal model was performed in order to identify early biomarkers of neurodegeneration. Two-dimensional gel electrophoresis followed by liquid chromatography-tandem mass spectrometry identified four proteins in the plasma of adolescent rats that deviated from the control group. Low expression levels of transthyretin and plasma transferrin, and the absence of long-chain fatty acid transport 1 were measured. On the other hand, the same proteomic approach was done on striatum of an adult rat model of neurodegeneration. Mitochondrial aspartate aminotransferase and voltage-dependent anion channel were under expressed, while mitochondrial malate dehydrogenase, myelin basic protein and ubiquitin-60S ribosomal protein L40 were absent in striatum of animal model compared to control group. Data show that early biomarkers for the diagnosis of neurodegeneration can be obtained by proteomic analysis, starting from adolescent age and the results highlight the time frame for the onset of neurodegeneration due to early exposure to xenobiotics. PMID:26631339

  5. [Microglial Phagocytosis in the Neurodegenerative Diseases].

    PubMed

    Cao, Sheng-nan; Bao, Xiu-qi; Sun, Hua; Zhang, Dan

    2016-04-01

    Microglia are the resident innate immune cells in the brain. Under endogenous or exogenous stimulates, they become activated and play an important role in the neurodegenerative diseases. Microglial phagocytosis is a process of receptor-mediated engulfment and degradation of apoptotic cells. In addition, microglia can phagocyte brain-specific cargo, such as myelin debris and abnormal protein aggregation. However, recent studies have shown that microglia can also phagocyte stressed-but-viable neurons, causing loss of neurons in the brain. Thus, whether microglial phagocytosis is beneficial or not in neurodegenerative disease remains controversial. This article reviews microglial phagocytosis related mechanisms and its potential roles in neurodegenerative diseases, with an attempt to provide new insights in the treatment of neurodegenerative diseases. PMID:27181903

  6. [Microglial Phagocytosis in the Neurodegenerative Diseases].

    PubMed

    Cao, Sheng-nan; Bao, Xiu-qi; Sun, Hua; Zhang, Dan

    2016-04-01

    Microglia are the resident innate immune cells in the brain. Under endogenous or exogenous stimulates, they become activated and play an important role in the neurodegenerative diseases. Microglial phagocytosis is a process of receptor-mediated engulfment and degradation of apoptotic cells. In addition, microglia can phagocyte brain-specific cargo, such as myelin debris and abnormal protein aggregation. However, recent studies have shown that microglia can also phagocyte stressed-but-viable neurons, causing loss of neurons in the brain. Thus, whether microglial phagocytosis is beneficial or not in neurodegenerative disease remains controversial. This article reviews microglial phagocytosis related mechanisms and its potential roles in neurodegenerative diseases, with an attempt to provide new insights in the treatment of neurodegenerative diseases.

  7. Intrauterine protein restriction combined with early postnatal overfeeding was not associated with adult-onset obesity but produced glucose intolerance by pancreatic dysfunction

    PubMed Central

    2013-01-01

    We investigated if whether intrauterine protein restriction in combination with overfeeding during lactation would cause adult-onset obesity and metabolic disorders. After birth, litters from dams fed with control (17% protein) and low protein (6% protein) diets were adjusted to a size of four (CO and LO groups, respectively) or eight (CC and LC groups, respectively) pups. All of the offspring were fed a diet containing 12% protein from the time of weaning until they were 90 d old. Compared to the CC and LC groups, the CO and LO groups had higher relative and absolute food intakes, oxygen consumption and carbon dioxide production; lower brown adipose tissue weight and lipid content and greater weight gain and absolute and relative white adipose tissue weight and absolute lipid content. Compared with the CO and CC rats, the LC and LO rats exhibited higher relative food intake, brown adipose tissue weight and lipid content, reduced oxygen consumption, carbon dioxide production and spontaneous activity, increased relative retroperitoneal adipose tissue weight and unaltered absolute white adipose tissue weight and lipid content. The fasting serum glucose was similar among the groups. The area under the glucose curve was higher in the LO and CO rats than in the LC and CC rats. The basal insulinemia and homeostasis model assessment of insulin resistance (HOMA-IR) were lower in the LO group than in the other groups. The total area under the insulin curve for the LO rats was similar to the CC rats, and both were lower than the CO and LC rats. Kitt was higher in the LO, LC and CO groups than in the CC group. Thus, intrauterine protein restriction followed by overfeeding during lactation did not induce obesity, but produced glucose intolerance by impairing pancreatic function in adulthood. PMID:23305533

  8. Intrauterine protein restriction combined with early postnatal overfeeding was not associated with adult-onset obesity but produced glucose intolerance by pancreatic dysfunction.

    PubMed

    Coutinho, Grazielle Vitória Ponti; Coutinho, Felipe Rodrigues; Faiad, Jaline Zandonato; Taki, Marina Satie; de Lima Reis, Silvia Regina; Ignácio-Souza, Letícia Martins; Paiva, Adriene Alexandra; Latorraca, Márcia Queiroz; Gomes-da-Silva, Maria Helena Gaíva; Martins, Maria Salete Ferreira

    2013-01-01

    We investigated if whether intrauterine protein restriction in combination with overfeeding during lactation would cause adult-onset obesity and metabolic disorders. After birth, litters from dams fed with control (17% protein) and low protein (6% protein) diets were adjusted to a size of four (CO and LO groups, respectively) or eight (CC and LC groups, respectively) pups. All of the offspring were fed a diet containing 12% protein from the time of weaning until they were 90 d old. Compared to the CC and LC groups, the CO and LO groups had higher relative and absolute food intakes, oxygen consumption and carbon dioxide production; lower brown adipose tissue weight and lipid content and greater weight gain and absolute and relative white adipose tissue weight and absolute lipid content. Compared with the CO and CC rats, the LC and LO rats exhibited higher relative food intake, brown adipose tissue weight and lipid content, reduced oxygen consumption, carbon dioxide production and spontaneous activity, increased relative retroperitoneal adipose tissue weight and unaltered absolute white adipose tissue weight and lipid content. The fasting serum glucose was similar among the groups. The area under the glucose curve was higher in the LO and CO rats than in the LC and CC rats. The basal insulinemia and homeostasis model assessment of insulin resistance (HOMA-IR) were lower in the LO group than in the other groups. The total area under the insulin curve for the LO rats was similar to the CC rats, and both were lower than the CO and LC rats. Kitt was higher in the LO, LC and CO groups than in the CC group. Thus, intrauterine protein restriction followed by overfeeding during lactation did not induce obesity, but produced glucose intolerance by impairing pancreatic function in adulthood. PMID:23305533

  9. Functional and Structural Analyses of CYP1B1 Variants Linked to Congenital and Adult-Onset Glaucoma to Investigate the Molecular Basis of These Diseases.

    PubMed

    Banerjee, Antara; Chakraborty, Subhadip; Chakraborty, Abhijit; Chakrabarti, Saikat; Ray, Kunal

    2016-01-01

    Glaucoma, the leading cause of irreversible blindness, appears in various forms. Mutations in CYP1B1 result in primary congenital glaucoma (PCG) by an autosomal recessive mode of inheritance while it acts as a modifier locus for primary open angle glaucoma (POAG). We investigated the molecular basis of the variable phenotypes resulting from the defects in CYP1B1 by using subclones of 23 CYP1B1 mutants reported in glaucoma patients, in a cell based system by measuring the dual activity of the enzyme to metabolize both retinol and 17β-estradiol. Most variants linked to POAG showed low steroid metabolism while null or very high retinol metabolism was observed in variants identified in PCG. We examined the translational turnover rates of mutant proteins after the addition of cycloheximide and observed that the levels of enzyme activity mostly corroborated the translational turnover rate. We performed extensive normal mode analysis and molecular-dynamics-simulations-based structural analyses and observed significant variation of fluctuation in certain segmental parts of the mutant proteins, especially at the B-C and F-G loops, which were previously shown to affect the dynamic behavior and ligand entry/exit properties of the cytochrome P450 family of proteins. Our molecular study corroborates the structural analysis, and suggests that the pathologic state of the carrier of CYP1B1 mutations is determined by the allelic state of the gene. To our knowledge, this is the first attempt to dissect biological activities of CYP1B1 for correlation with congenital and adult onset glaucomas. PMID:27243976

  10. Functional and Structural Analyses of CYP1B1 Variants Linked to Congenital and Adult-Onset Glaucoma to Investigate the Molecular Basis of These Diseases

    PubMed Central

    Chakrabarti, Saikat; Ray, Kunal

    2016-01-01

    Glaucoma, the leading cause of irreversible blindness, appears in various forms. Mutations in CYP1B1 result in primary congenital glaucoma (PCG) by an autosomal recessive mode of inheritance while it acts as a modifier locus for primary open angle glaucoma (POAG). We investigated the molecular basis of the variable phenotypes resulting from the defects in CYP1B1 by using subclones of 23 CYP1B1 mutants reported in glaucoma patients, in a cell based system by measuring the dual activity of the enzyme to metabolize both retinol and 17β-estradiol. Most variants linked to POAG showed low steroid metabolism while null or very high retinol metabolism was observed in variants identified in PCG. We examined the translational turnover rates of mutant proteins after the addition of cycloheximide and observed that the levels of enzyme activity mostly corroborated the translational turnover rate. We performed extensive normal mode analysis and molecular-dynamics-simulations-based structural analyses and observed significant variation of fluctuation in certain segmental parts of the mutant proteins, especially at the B-C and F-G loops, which were previously shown to affect the dynamic behavior and ligand entry/exit properties of the cytochrome P450 family of proteins. Our molecular study corroborates the structural analysis, and suggests that the pathologic state of the carrier of CYP1B1 mutations is determined by the allelic state of the gene. To our knowledge, this is the first attempt to dissect biological activities of CYP1B1 for correlation with congenital and adult onset glaucomas. PMID:27243976

  11. TLR4 Endogenous Ligand S100A8/A9 Levels in Adult-Onset Still’s Disease and Their Association with Disease Activity and Clinical Manifestations

    PubMed Central

    Kim, Hyoun-Ah; Han, Jae Ho; Kim, Woo-Jung; Noh, Hyun Jin; An, Jeong-Mi; Yim, Hyunee; Jung, Ju-Yang; Kim, You-Sun; Suh, Chang-Hee

    2016-01-01

    S100A8/A9 has been suggested as a marker of disease activity in patients with adult-onset Still’s disease (AOSD). We evaluated the clinical significance of S100A8/A9 as a biomarker and its pathogenic role in AOSD. Blood samples were collected prospectively from 20 AOSD patients and 20 healthy controls (HCs). Furthermore, skin and lymph node biopsy specimens of AOSD patients were investigated for S100A8/A9 expression levels via immunohistochemistry. Peripheral blood mononuclear cells (PBMCs) of active AOSD patients and HCs were investigated for S100A8/A9 cell signals. S100A8/A9, interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) levels in active AOSD patients were higher than those of HCs. S100A8/A9 levels correlated positively with IL-1β, TNF-α and C-reactive protein. The inflammatory cells expressing S100A8/A9 were graded from one to three in skin and lymph node biopsies of AOSD patients. The grading for S100A8/A9 was more intense in the skin lesions with karyorrhexis, mucin deposition, and neutrophil infiltration. Like lipopolysaccharide (LPS), S100A8/A9 induced phosphorylation of p38 and c-Jun amino-terminal kinase (JNK) in PBMCs, suggesting that S100A8/A9 activates Toll-like receptor 4 signaling pathways. These findings suggest that S100A8/A9 may be involved in the inflammatory response with induction of proinflammatory cytokines and may serve as a clinicopathological marker for disease activity in AOSD. PMID:27537874

  12. Localization of the fourth locus (GLC1E) for adult-onset primary open-angle glaucoma to the 10p15-p14 region.

    PubMed

    Sarfarazi, M; Child, A; Stoilova, D; Brice, G; Desai, T; Trifan, O C; Poinoosawmy, D; Crick, R P

    1998-03-01

    One of the major causes of blindness is primary open-angle glaucoma, which affects millions of elderly people worldwide. Genetic studies have so far mapped three loci for the adult-onset form of this condition to the 2cen-q13, 3q21-q24, and 8q23 regions. Herein, we report the localization of a fourth locus, to the 10p15-p14 region, in one large British family with a classical form of normal-tension open-angle glaucoma. Of the 42 meioses genotyped in this pedigree, 39 subjects (16 affected) inherited a haplotype compatible with their prior clinical designation, whereas the remaining 3 were classified as unknown. Although a maximum LOD score of 10.00 at a recombination fraction of straight theta=.00 was obtained with D10S1216, 21 other markers provided significant values, varying between 3.77 and 9.70. When only the affected meioses of this kindred were analyzed, LOD scores remained statistically significant, ranging from 3.16 (D10S527) to 3.57 (D10S506). Two critical recombinational events in the affected subjects positioned this new locus to a region of approximately 21 cM, flanked by D10S1729 and D10S1664. However, an additional recombination in a 59-year-old unaffected female suggests that this locus resides between D10S585 (or D10S1172) and D10S1664, within a genetic distance of 5-11 cM. However, the latter minimum region must be taken cautiously, because the incomplete penetrance has previously been documented for this group of eye conditions. A partial list of genes that positionally are considered as candidates includes NET1, PRKCT, ITIH2, IL2RA, IL15RA, IT1H2, hGATA3, the mRNA for open reading frame KIAA0019, and the gene for D123 protein.

  13. Neurobiology of Childhood-Onset Schizophrenia

    ERIC Educational Resources Information Center

    Biswas, Parthasarathy

    2008-01-01

    In the last decade there has been an exponential increase in studies on neurobiological measures in childhood-onset schizophrenia (COS). There seems to be a consensus that structural changes in COS are more marked than in adolescence-onset (AdOS) or adult-onset schizophrenia (AOS). Atrophy of total brain volume is progressive throughout the course…

  14. Genetically modified pig models for neurodegenerative disorders.

    PubMed

    Holm, Ida E; Alstrup, Aage Kristian Olsen; Luo, Yonglun

    2016-01-01

    Increasing incidence of neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease has become one of the most challenging health issues in ageing humans. One approach to combat this is to generate genetically modified animal models of neurodegenerative disorders for studying pathogenesis, prognosis, diagnosis, treatment, and prevention. Owing to the genetic, anatomic, physiologic, pathologic, and neurologic similarities between pigs and humans, genetically modified pig models of neurodegenerative disorders have been attractive large animal models to bridge the gap of preclinical investigations between rodents and humans. In this review, we provide a neuroanatomical overview in pigs and summarize and discuss the generation of genetically modified pig models of neurodegenerative disorders including Alzheimer's diseases, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, spinal muscular atrophy, and ataxia-telangiectasia. We also highlight how non-invasive bioimaging technologies such as positron emission tomography (PET), computer tomography (CT), and magnetic resonance imaging (MRI), and behavioural testing have been applied to characterize neurodegenerative pig models. We further propose a multiplex genome editing and preterm recloning (MAP) approach by using the rapid growth of the ground-breaking precision genome editing technology CRISPR/Cas9 and somatic cell nuclear transfer (SCNT). With this approach, we hope to shorten the temporal requirement in generating multiple transgenic pigs, increase the survival rate of founder pigs, and generate genetically modified pigs that will more closely resemble the disease-causing mutations and recapitulate pathological features of human conditions. PMID:26446984

  15. [Periodontitis determining the onset and progression of Huntington's disease: review of the literature].

    PubMed

    Rodríguez Coyago, María Lourdes; Sánchez Temiño, Victoria Emilia

    2015-10-27

    Huntington's disease is a neurodegenerative disorder caused by the expansion of a CAG triplet in the huntingtin gene. It presents with physical, cognitive and psychiatric impairment at different ages in the adult, and has a fatal prognosis. Other than the number of triplet repetitions, there seem to be other factors that explain the onset of this disease at an earlier age. It is well known that neuroinflammation has a key role in neurodegenerative disorders; Huntington's disease is not an exception to that rule. Neuroinflammation exacerbates neuronal damage produced by mutation, by initiating aberrant activation of microglia cell, as well as astrocyte and dendritic cell dysfunction; also compromising the blood-brain barrier and activating the complement cascade. The latter as a direct and indirect effect of the mutation and other stimuli such as chronic infections. In this study, periodontitis is presented as a model of chronic oral infection and a systemic inflammation source. We hypothesize the potential role of periodontitis in Huntington's disease, and the mechanisms by which it contributes to the early onset and progress of the disease. We considered experimental studies, systematic reviews, meta-analyses, published in both Spanish and English, obtained from the PubMed and SciELO databases. There are various mechanisms that generate brain inflammation in these patients; mechanisms of innate immunity being especially prominent. Chronic oral-dental infections, such as periodontal disease, may be an exacerbating factor that adds to the neuroinflammation of Huntington'’s disease.

  16. Induced Pluripotent Stem Cells for Disease Modeling and Drug Discovery in Neurodegenerative Diseases.

    PubMed

    Cao, Lei; Tan, Lan; Jiang, Teng; Zhu, Xi-Chen; Yu, Jin-Tai

    2015-08-01

    Although most neurodegenerative diseases have been closely related to aberrant accumulation of aggregation-prone proteins in neurons, understanding their pathogenesis remains incomplete, and there is no treatment to delay the onset or slow the progression of many neurodegenerative diseases. The availability of induced pluripotent stem cells (iPSCs) in recapitulating the phenotypes of several late-onset neurodegenerative diseases marks the new era in in vitro modeling. The iPSC collection represents a unique and well-characterized resource to elucidate disease mechanisms in these diseases and provides a novel human stem cell platform for screening new candidate therapeutics. Modeling human diseases using iPSCs has created novel opportunities for both mechanistic studies as well as for the discovery of new disease therapies. In this review, we introduce iPSC-based disease modeling in neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. In addition, we discuss the implementation of iPSCs in drug discovery associated with some new techniques.

  17. Phenotypic characterization of a Csf1r haploinsufficient mouse model of adult-onset leukodystrophy with axonal spheroids and pigmented glia (ALSP).

    PubMed

    Chitu, Violeta; Gokhan, Solen; Gulinello, Maria; Branch, Craig A; Patil, Madhuvati; Basu, Ranu; Stoddart, Corrina; Mehler, Mark F; Stanley, E Richard

    2015-02-01

    Mutations in the colony stimulating factor-1 receptor (CSF1R) that abrogate the expression of the affected allele or lead to the expression of mutant receptor chains devoid of kinase activity have been identified in both familial and sporadic cases of ALSP. To determine the validity of the Csf1r heterozygous mouse as a model of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) we performed behavioral, radiologic, histopathologic, ultrastructural and cytokine expression studies of young and old Csf1r+/- and control Csf1r+/+ mice. Six to 8-month old Csf1r+/- mice exhibit cognitive deficits, and by 9-11 months develop sensorimotor deficits and in male mice, depression and anxiety-like behavior. MRIs of one year-old Csf1r+/- mice reveal lateral ventricle enlargement and thinning of the corpus callosum. Ultrastructural analysis of the corpus callosum uncovers dysmyelinated axons as well as neurodegeneration, evidenced by the presence of axonal spheroids. Histopathological examination of 11-week-old mice reveals increased axonal and myelin staining in the cortex, increase of neuronal cell density in layer V and increase of microglial cell densities throughout the brain, suggesting that early developmental changes contribute to disease. By 10-months of age, the neuronal cell density normalizes, oligodendrocyte precursor cells increase in layers II-III and V and microglial densities remain elevated without an increase in astrocytes. Also, the age-dependent increase in CSF-1R+ neurons in cortical layer V is reduced. Moreover, the expression of Csf2, Csf3, Il27 and Il6 family cytokines is increased, consistent with microglia-mediated inflammation. These results demonstrate that the inactivation of one Csf1r allele is sufficient to cause an ALSP-like disease in mice. The Csf1r+/- mouse is a model of ALSP that will allow the critical events for disease development to be determined and permit rapid evaluation of therapeutic approaches. Furthermore

  18. Childhood onset schizophrenia and early onset schizophrenia spectrum disorders.

    PubMed

    Driver, David I; Gogtay, Nitin; Rapoport, Judith L

    2013-10-01

    The clinical severity, impact on development, and poor prognosis of childhood onset schizophrenia may represent a more homogeneous group. Positive symptoms in children are necessary for the diagnosis and hallucinations are more often multimodal. In healthy children and children with a variety of other psychiatric illnesses, hallucinations are not uncommon and diagnosis should not be based on these alone. Childhood onset schizophrenia is an extraordinarily rare illness that is poorly understood but seems continuous with the adult onset disorder. Once a diagnosis is affirmed, aggressive medication treatment combined with family education and individual counseling may defer further deterioration.

  19. Metal attenuating therapies in neurodegenerative disease.

    PubMed

    Mot, Alexandra I; Wedd, Anthony G; Sinclair, Layla; Brown, David R; Collins, Steven J; Brazier, Marcus W

    2011-12-01

    The clinical and pathological spectrum of neurodegenerative diseases is diverse, although common to many of these disorders is the accumulation of misfolded proteins, with oxidative stress thought to be an important contributing mechanism to neuronal damage. As a corollary, transition metal ion dyshomeostasis appears to play a key pathogenic role in a number of these maladies, including the most common of neurodegenerative diseases. In this review, studies spanning a wide variety of neurodegenerative disorders are presented with their involvement of transition metals compared and contrasted, including more detailed treatise in relation to Alzheimer's disease, Parkinson's disease and prion diseases. For each of these diseases, a discussion of the evolving scientific rationale for the development of therapies aimed at ameliorating the detrimental effects of transition metal dysregulation, including results from various human trials, is then provided.

  20. Mercury toxicity and neurodegenerative effects.

    PubMed

    Carocci, Alessia; Rovito, Nicola; Sinicropi, Maria Stefania; Genchi, Giuseppe

    2014-01-01

    Mercury is among the most toxic heavy metals and has no known physiological role in humans. Three forms of mercury exist: elemental, inorganic and organic. Mercury has been used by man since ancient times. Among the earliest were the Chinese and Romans, who employed cinnabar (mercury sulfide) as a red dye in ink (Clarkson et al. 2007). Mercury has also been used to purify gold and silver minerals by forming amalgams. This is a hazardous practice, but is still widespread in Brazil's Amazon basin, in Laos and in Venezuela, where tens of thousands of miners are engaged in local mining activities to find and purify gold or silver. Mercury compounds were long used to treat syphilis and the element is still used as an antiseptic,as a medicinal preservative and as a fungicide. Dental amalgams, which contain about 50% mercury, have been used to repair dental caries in the U.S. since 1856.Mercury still exists in many common household products around the world.Examples are: thermometers, barometers, batteries, and light bulbs (Swain et al.2007). In small amounts, some organo mercury-compounds (e.g., ethylmercury tiosalicylate(thimerosal) and phenylmercury nitrate) are used as preservatives in some medicines and vaccines (Ballet al. 2001).Each mercury form has its own toxicity profile. Exposure to Hg0 vapor and MeHg produce symptoms in CNS, whereas, the kidney is the target organ when exposures to the mono- and di-valent salts of mercury (Hg+ and Hg++, respectively)occur. Chronic exposure to inorganic mercury produces stomatitis, erethism and tremors. Chronic MeHg exposure induced symptoms similar to those observed in ALS, such as the early onset of hind limb weakness (Johnson and Atchison 2009).Among the organic mercury compounds, MeHg is the most biologically available and toxic (Scheuhammer et a!. 2007). MeHg is neurotoxic, reaching high levels of accumulation in the CNS; it can impair physiological function by disrupting endocrine glands (Tan et a!. 2009).The most

  1. Mercury toxicity and neurodegenerative effects.

    PubMed

    Carocci, Alessia; Rovito, Nicola; Sinicropi, Maria Stefania; Genchi, Giuseppe

    2014-01-01

    Mercury is among the most toxic heavy metals and has no known physiological role in humans. Three forms of mercury exist: elemental, inorganic and organic. Mercury has been used by man since ancient times. Among the earliest were the Chinese and Romans, who employed cinnabar (mercury sulfide) as a red dye in ink (Clarkson et al. 2007). Mercury has also been used to purify gold and silver minerals by forming amalgams. This is a hazardous practice, but is still widespread in Brazil's Amazon basin, in Laos and in Venezuela, where tens of thousands of miners are engaged in local mining activities to find and purify gold or silver. Mercury compounds were long used to treat syphilis and the element is still used as an antiseptic,as a medicinal preservative and as a fungicide. Dental amalgams, which contain about 50% mercury, have been used to repair dental caries in the U.S. since 1856.Mercury still exists in many common household products around the world.Examples are: thermometers, barometers, batteries, and light bulbs (Swain et al.2007). In small amounts, some organo mercury-compounds (e.g., ethylmercury tiosalicylate(thimerosal) and phenylmercury nitrate) are used as preservatives in some medicines and vaccines (Ballet al. 2001).Each mercury form has its own toxicity profile. Exposure to Hg0 vapor and MeHg produce symptoms in CNS, whereas, the kidney is the target organ when exposures to the mono- and di-valent salts of mercury (Hg+ and Hg++, respectively)occur. Chronic exposure to inorganic mercury produces stomatitis, erethism and tremors. Chronic MeHg exposure induced symptoms similar to those observed in ALS, such as the early onset of hind limb weakness (Johnson and Atchison 2009).Among the organic mercury compounds, MeHg is the most biologically available and toxic (Scheuhammer et a!. 2007). MeHg is neurotoxic, reaching high levels of accumulation in the CNS; it can impair physiological function by disrupting endocrine glands (Tan et a!. 2009).The most

  2. Beyond Krabbe's disease: The potential contribution of galactosylceramidase deficiency to neuronal vulnerability in late-onset synucleinopathies.

    PubMed

    Marshall, Michael S; Bongarzone, Ernesto R

    2016-11-01

    New insights into the pathophysiological mechanisms behind late-onset neurodegenerative diseases have come from unexpected sources in recent years. Specifically, the group of inherited metabolic disorders known as lysosomal storage diseases that most commonly affect infants has been found to have surprising similarities with adult neurodegenerative disorders. Most notable has been the identification of Gaucher's disease as a comorbidity for Parkinson's disease. Prompted by the recent identification of neuronal aggregates of α-synuclein in another lysosomal storage disease, Krabbe's disease, we propose the idea that a similar connection exists between adult synucleinopathies and Krabbe's. Similarities between the two diseases, including the pattern of α-synuclein aggregation in the brain of the twitcher mouse (the authentic murine model of Krabbe's disease), changes to lipid membrane dynamics, and possible dysfunction in synaptic function and macroautophagy, underscore a link between Krabbe's disease and late-onset synucleinopathies. Silent GALC mutations may even constitute a risk factor for the development of Parkinson's in certain patients. More research is required to identify definitively any link and the validity of this hypothesis, but such a connection would prove invaluable for developing novel therapeutic targets for Parkinson's based on our current understanding of Krabbe's disease and for establishing new biomarkers for the identification of at-risk patients. © 2016 Wiley Periodicals, Inc. PMID:27638614

  3. Oligonucleotide-based therapy for neurodegenerative diseases.

    PubMed

    Magen, Iddo; Hornstein, Eran

    2014-10-10

    Molecular genetics insight into the pathogenesis of several neurodegenerative diseases, such as Alzheimer׳s disease, Parkinson׳s disease, Huntington׳s disease and amyotrophic lateral sclerosis, encourages direct interference with the activity of neurotoxic genes or the molecular activation of neuroprotective pathways. Oligonucleotide-based therapies are recently emerging as an efficient strategy for drug development and these can be employed as new treatments of neurodegenerative states. Here we review advances in this field in recent years which suggest an encouraging assessment that oligonucleotide technologies for targeting of RNAs will enable the development of new therapies and will contribute to preservation of brain integrity.

  4. Mitochondrial drug targets in neurodegenerative diseases.

    PubMed

    Lee, Jiyoun

    2016-02-01

    Growing evidence suggests that mitochondrial dysfunction is the main culprit in neurodegenerative diseases. Given the fact that mitochondria participate in diverse cellular processes, including energetics, metabolism, and death, the consequences of mitochondrial dysfunction in neuronal cells are inevitable. In fact, new strategies targeting mitochondrial dysfunction are emerging as potential alternatives to current treatment options for neurodegenerative diseases. In this review, we focus on mitochondrial proteins that are directly associated with mitochondrial dysfunction. We also examine recently identified small molecule modulators of these mitochondrial targets and assess their potential in research and therapeutic applications.

  5. Managing anxiety associated with neurodegenerative disorders

    PubMed Central

    Kumar, Anand

    2015-01-01

    Anxiety is a common symptom among patients with cognitive impairment. The presence of anxiety is correlated with poorer outcomes; despite this, there is limited research on anxiety related to neurodegenerative disorder. In this article, we discuss the prevalence of anxiety and factors involved in the etiology of anxiety in patients with diagnosed neurodegenerative disorders and related states of cognitive impairment as well as the evidence for currently available methods of evaluating and treating these symptoms. Specific treatments are highlighted in light of current evidence, followed by a discussion of the difficulties inherent in the study and treatment of anxiety in this population. PMID:25705388

  6. Circulating microRNAs in Neurodegenerative Diseases.

    PubMed

    Grasso, Margherita; Piscopo, Paola; Crestini, Alessio; Confaloni, Annamaria; Denti, Michela A

    2015-01-01

    Neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS), are caused by a combination of events that impair normal neuronal function. Although they are considered different disorders, there are overlapping features among them from the clinical, pathological, and genetic points of view. Synaptic dysfunction and loss, neurite retraction, and the appearance of other abnormalities such as axonal transport defects normally precede the neuronal loss that is a relatively late event. The diagnosis of many neurodegenerative diseases is mainly based on patient's cognitive function analysis, and the development of diagnostic methods is complicated by the brain's capacity to compensate for neuronal loss over a long period of time. This results in the late clinical manifestation of symptoms, a time when successful treatment is no longer feasible. Thus, a noninvasive diagnostic method based on early events detection is particularly important. In the last years, some biomarkers expressed in human body fluids have been proposed. microRNAs (miRNAs), with their high stability, tissue- or cell type-specific expression, lower cost, and shorter time in the assay development, could constitute a good tool to obtain an early disease diagnosis for a wide number of human pathologies, including neurodegenerative diseases. The possibilities and challenges of using these small RNA molecules as a signature for neurodegenerative disorders is a highly promising approach for developing minimally invasive screening tests and to identify new therapeutic targets.

  7. Neuronal Network Oscillations in Neurodegenerative Diseases.

    PubMed

    Nimmrich, Volker; Draguhn, Andreas; Axmacher, Nikolai

    2015-09-01

    Cognitive and behavioral acts go along with highly coordinated spatiotemporal activity patterns in neuronal networks. Most of these patterns are synchronized by coherent membrane potential oscillations within and between local networks. By entraining multiple neurons into a common time regime, such network oscillations form a critical interface between cellular activity and large-scale systemic functions. Synaptic integrity is altered in neurodegenerative diseases, and it is likely that this goes along with characteristic changes of coordinated network activity. This notion is supported by EEG recordings from human patients and from different animal models of such disorders. However, our knowledge about the pathophysiology of network oscillations in neurodegenerative diseases is surprisingly incomplete, and increased research efforts are urgently needed. One complicating factor is the pronounced diversity of network oscillations between different brain regions and functional states. Pathological changes must, therefore, be analyzed separately in each condition and affected area. However, cumulative evidence from different diseases may result, in the future, in more unifying "oscillopathy" concepts of neurodegenerative diseases. In this review, we report present evidence for pathological changes of network oscillations in Alzheimer's disease (AD), one of the most prominent and challenging neurodegenerative disorders. The heterogeneous findings from AD are contrasted to Parkinson's disease, where motor-related changes in specific frequency bands do already fulfill criteria of a valid biomarker. PMID:25920466

  8. Role of neuroinflammation in neurodegenerative diseases (Review)

    PubMed Central

    CHEN, WEI-WEI; ZHANG, XIA; HUANG, WEN-JUAN

    2016-01-01

    Neurodegeneration is a phenomenon that occurs in the central nervous system through the hallmarks associating the loss of neuronal structure and function. Neurodegeneration is observed after viral insult and mostly in various so-called 'neurodegenerative diseases', generally observed in the elderly, such as Alzheimer's disease, multiple sclerosis, Parkinson's disease and amyotrophic lateral sclerosis that negatively affect mental and physical functioning. Causative agents of neurodegeneration have yet to be identified. However, recent data have identified the inflammatory process as being closely linked with multiple neurodegenerative pathways, which are associated with depression, a consequence of neurodegenerative disease. Accordingly, pro-inflammatory cytokines are important in the pathophysiology of depression and dementia. These data suggest that the role of neuroinflammation in neurodegeneration must be fully elucidated, since pro-inflammatory agents, which are the causative effects of neuroinflammation, occur widely, particularly in the elderly in whom inflammatory mechanisms are linked to the pathogenesis of functional and mental impairments. In this review, we investigated the role played by the inflammatory process in neurodegenerative diseases. PMID:26935478

  9. Prism Management in Patients with Neurodegenerative Disease.

    PubMed

    Gilligan, Rikki

    2015-01-01

    Patients with motility problems due to neurodegenerative disease such as Parkinson's and its variations often present challenging cases for the orthoptist. A few "tricks of the trade" will be presented on how to make a Parkinson's patient's daily life a little easier.

  10. Dysregulation of Glutathione Homeostasis in Neurodegenerative Diseases

    PubMed Central

    Johnson, William M.; Wilson-Delfosse, Amy L.; Mieyal, John. J.

    2012-01-01

    Dysregulation of glutathione homeostasis and alterations in glutathione-dependent enzyme activities are increasingly implicated in the induction and progression of neurodegenerative diseases, including Alzheimer’s, Parkinson’s and Huntington’s diseases, amyotrophic lateral sclerosis, and Friedreich’s ataxia. In this review background is provided on the steady-state synthesis, regulation, and transport of glutathione, with primary focus on the brain. A brief overview is presented on the distinct but vital roles of glutathione in cellular maintenance and survival, and on the functions of key glutathione-dependent enzymes. Major contributors to initiation and progression of neurodegenerative diseases are considered, including oxidative stress, protein misfolding, and protein aggregation. In each case examples of key regulatory mechanisms are identified that are sensitive to changes in glutathione redox status and/or in the activities of glutathione-dependent enzymes. Mechanisms of dysregulation of glutathione and/or glutathione-dependent enzymes are discussed that are implicated in pathogenesis of each neurodegenerative disease. Limitations in information or interpretation are identified, and possible avenues for further research are described with an aim to elucidating novel targets for therapeutic interventions. The pros and cons of administration of N-acetylcysteine or glutathione as therapeutic agents for neurodegenerative diseases, as well as the potential utility of serum glutathione as a biomarker, are critically evaluated. PMID:23201762

  11. Catalpol: a potential therapeutic for neurodegenerative diseases.

    PubMed

    Jiang, B; Shen, R F; Bi, J; Tian, X S; Hinchliffe, T; Xia, Y

    2015-01-01

    Neurodegenerative disorders, e.g., Alzheimer's disease (AD) and Parkinson's disease (PD) are characterized by the progressive loss of neurons and subsequent cognitive decline. They are mainly found in older populations. Due to increasing life expectancies, the toll inflicted upon society by these disorders continues to become heavier and more prominent. Despite extensive research, however, the exact etiology of these disorders is still unknown, though the pathophysiological mechanisms have been attributed to oxidative, inflammatory and apoptotic injury in the brain. Moreover, there is currently no promising therapeutic agent against these neurodegenerative changes. Catalpol, an iridoid glucoside contained richly in the roots of the small flowering plant species Rehmannia glutinosa Libosch, has been shown to have antioxidation, anti-inflammation, anti-apoptosis and other neuroprotective properties and plays a role in neuroprotection against hypoxic/ischemic injury, AD and PD in both in vivo and in vitro models. It may therefore represent a potential therapeutical agent for the treatment of hypoxic/ischemic injury and neurodegenerative diseases. Based on our studies and those of others in the literature, here we comprehensively review the role of Catalpol in neuroprotection against pathological conditions, especially in neurodegenerative states and the potential mechanisms involved.

  12. DNA methylation, a hand behind neurodegenerative diseases

    PubMed Central

    Lu, Haoyang; Liu, Xinzhou; Deng, Yulin; Qing, Hong

    2013-01-01

    Epigenetic alterations represent a sort of functional modifications related to the genome that are not responsible for changes in the nucleotide sequence. DNA methylation is one of such epigenetic modifications that have been studied intensively for the past several decades. The transfer of a methyl group to the 5 position of a cytosine is the key feature of DNA methylation. A simple change as such can be caused by a variety of factors, which can be the cause of many serious diseases including several neurodegenerative diseases. In this review, we have reviewed and summarized recent progress regarding DNA methylation in four major neurodegenerative diseases: Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). The studies of these four major neurodegenerative diseases conclude the strong suggestion of the important role DNA methylation plays in these diseases. However, each of these diseases has not yet been understood completely as details in some areas remain unclear, and will be investigated in future studies. We hope this review can provide new insights into the understanding of neurodegenerative diseases from the epigenetic perspective. PMID:24367332

  13. A Sex-Linked Gene Controlling the Onset of Sexual Maturity in Female and Male Platyfish (XIPHOPHORUS MACULATUS), Fecundity in Females and Adult Size in Males

    PubMed Central

    Kallman, Klaus D.; Borkoski, Valerie

    1978-01-01

    A sex-linked gene, P, controls the onset of sexual maturity in the platyfish, Xiphophorus maculatus. The activity of this gene is correlated with the age and size at which the gonadotropic zone of the adenohypophysis differentiates and becomes physiologically active. Immature fish of all genotypes grow at the same rate; however, as adults, males with "early" genotypes are significantly smaller than males of "late" genotypes, since growth rate declines strongly under the influence of androgenic hormone. Five alleles, P1... P5, have been identified from natural populations that under controlled conditions cause gonad maturation between eight and 73 weeks. P1P1 males become mature at eight weeks and 21 mm, P2P2 and P3P3 males between eleven and 13.5 weeks and 25 to 29 mm, and P4P4 males at 25 weeks and 37 mm. Since P5 is X-linked, no males homozygous for P5 could be produced. The difference between P2 and P3 is largely based upon their interaction with P5. P3P5 males mature at 17.5 weeks and 33.5 mm and P2P5 males at 28 weeks and 38 mm. The rate of transformation of the unmodified anal fin into a gonopodium, which is under androgenic control, is directly related to the age at initiation of sexual maturity, ranging from 3.2 weeks in P1P1 males to seven weeks in P2P 5 males. These differences may reflect different levels of circulating gonadotropic and androgenic hormones.—In two genotypes of females, initiation of vitellogenesis was closely correlated with size and this critical size was independent of age (e.g., 21 mm for P1P1 ). In a third genotype (P1P5) the minimum size for vitellogenesis decreased with increasing age, so that females would mature as early as eleven weeks, provided they had attained at least 29 mm, but at 25 weeks even females as small as 23 mm possessed ripe gonads. For P5P5 females, which become mature between 34 and 73 weeks of age, there is no correlation between size and initiation of vitellogenesis. In all four genotypes of females examined

  14. Neural basis of interpersonal traits in neurodegenerative diseases.

    PubMed

    Sollberger, Marc; Stanley, Christine M; Wilson, Stephen M; Gyurak, Anett; Beckman, Victoria; Growdon, Matthew; Jang, Jung; Weiner, Michael W; Miller, Bruce L; Rankin, Katherine P

    2009-11-01

    Several functional and structural imaging studies have investigated the neural basis of personality in healthy adults, but human lesions studies are scarce. Personality changes are a common symptom in patients with neurodegenerative diseases like frontotemporal dementia (FTD) and semantic dementia (SD), allowing a unique window into the neural basis of personality. In this study, we used the Interpersonal Adjective Scales to investigate the structural basis of eight interpersonal traits (dominance, arrogance, coldness, introversion, submissiveness, ingenuousness, warmth, and extraversion) in 257 subjects: 214 patients with neurodegenerative diseases such as FTD, SD, progressive nonfluent aphasia, Alzheimer's disease, amnestic mild cognitive impairment, corticobasal degeneration, and progressive supranuclear palsy and 43 healthy elderly people. Measures of interpersonal traits were correlated with regional atrophy pattern using voxel-based morphometry (VBM) analysis of structural MR images. Interpersonal traits mapped onto distinct brain regions depending on the degree to which they involved agency and affiliation. Interpersonal traits high in agency related to left dorsolateral prefrontal and left lateral frontopolar regions, whereas interpersonal traits high in affiliation related to right ventromedial prefrontal and right anteromedial temporal regions. Consistent with the existing literature on neural networks underlying social cognition, these results indicate that brain regions related to externally focused, executive control-related processes underlie agentic interpersonal traits such as dominance, whereas brain regions related to internally focused, emotion- and reward-related processes underlie affiliative interpersonal traits such as warmth. In addition, these findings indicate that interpersonal traits are subserved by complex neural networks rather than discrete anatomic areas.

  15. The role of the Wnt canonical signaling in neurodegenerative diseases.

    PubMed

    Libro, Rosaliana; Bramanti, Placido; Mazzon, Emanuela

    2016-08-01

    The Wnt/β-catenin or Wnt canonical pathway controls multiple biological processes throughout development and adult life. Growing evidences have suggested that deregulation of the Wnt canonical pathway could be involved in the pathogenesis of neurodegenerative diseases. The Wnt canonical signaling is a pathway tightly regulated, which activation results in the inhibition of the Glycogen Synthase Kinase 3β (GSK-3β) function and in increased β-catenin activity, that migrates into the nucleus, activating the transcription of the Wnt target genes. Conversely, when the Wnt canonical pathway is turned off, increased levels of GSK-3β promote β-catenin degradation. Hence, GSK-3β could be considered as a key regulator of the Wnt canonical pathway. Of note, GSK-3β has also been involved in the modulation of inflammation and apoptosis, determining the delicate balance between immune tolerance/inflammation and neuronal survival/neurodegeneration. In this review, we have summarized the current acknowledgements about the role of the Wnt canonical pathway in the pathogenesis of some neurodegenerative diseases including Alzheimer's disease, cerebral ischemia, Parkinson's disease, Huntington's disease, multiple sclerosis and amyotrophic lateral sclerosis, with particular regard to the main in vitro and in vivo studies in this field, by reviewing 85 research articles about. PMID:27370940

  16. The role of the Wnt canonical signaling in neurodegenerative diseases.

    PubMed

    Libro, Rosaliana; Bramanti, Placido; Mazzon, Emanuela

    2016-08-01

    The Wnt/β-catenin or Wnt canonical pathway controls multiple biological processes throughout development and adult life. Growing evidences have suggested that deregulation of the Wnt canonical pathway could be involved in the pathogenesis of neurodegenerative diseases. The Wnt canonical signaling is a pathway tightly regulated, which activation results in the inhibition of the Glycogen Synthase Kinase 3β (GSK-3β) function and in increased β-catenin activity, that migrates into the nucleus, activating the transcription of the Wnt target genes. Conversely, when the Wnt canonical pathway is turned off, increased levels of GSK-3β promote β-catenin degradation. Hence, GSK-3β could be considered as a key regulator of the Wnt canonical pathway. Of note, GSK-3β has also been involved in the modulation of inflammation and apoptosis, determining the delicate balance between immune tolerance/inflammation and neuronal survival/neurodegeneration. In this review, we have summarized the current acknowledgements about the role of the Wnt canonical pathway in the pathogenesis of some neurodegenerative diseases including Alzheimer's disease, cerebral ischemia, Parkinson's disease, Huntington's disease, multiple sclerosis and amyotrophic lateral sclerosis, with particular regard to the main in vitro and in vivo studies in this field, by reviewing 85 research articles about.

  17. Interferon Gamma: Influence on Neural Stem Cell Function in Neurodegenerative and Neuroinflammatory Disease

    PubMed Central

    Kulkarni, Apurva; Ganesan, Priya; O’Donnell, Lauren A.

    2016-01-01

    Interferon-gamma (IFNγ), a pleiotropic cytokine, is expressed in diverse neurodegenerative and neuroinflammatory conditions. Its protective mechanisms are well documented during viral infections in the brain, where IFNγ mediates non-cytolytic viral control in infected neurons. However, IFNγ also plays both protective and pathological roles in other central nervous system (CNS) diseases. Of the many neural cells that respond to IFNγ, neural stem/progenitor cells (NSPCs), the only pluripotent cells in the developing and adult brain, are often altered during CNS insults. Recent studies highlight the complex effects of IFNγ on NSPC activity in neurodegenerative diseases. However, the mechanisms that mediate these effects, and the eventual outcomes for the host, are still being explored. Here, we review the effects of IFNγ on NSPC activity during different pathological insults. An improved understanding of the role of IFNγ would provide insight into the impact of immune responses on the progression and resolution of neurodegenerative diseases. PMID:27774000

  18. Untangling the brain's neuroinflammatory and neurodegenerative transcriptional responses

    PubMed Central

    Srinivasan, Karpagam; Friedman, Brad A.; Larson, Jessica L.; Lauffer, Benjamin E.; Goldstein, Leonard D.; Appling, Laurie L.; Borneo, Jovencio; Poon, Chungkee; Ho, Terence; Cai, Fang; Steiner, Pascal; van der Brug, Marcel P.; Modrusan, Zora; Kaminker, Joshua S.; Hansen, David V.

    2016-01-01

    A common approach to understanding neurodegenerative disease is comparing gene expression in diseased versus healthy tissues. We illustrate that expression profiles derived from whole tissue RNA highly reflect the degenerating tissues' altered cellular composition, not necessarily transcriptional regulation. To accurately understand transcriptional changes that accompany neuropathology, we acutely purify neurons, astrocytes and microglia from single adult mouse brains and analyse their transcriptomes by RNA sequencing. Using peripheral endotoxemia to establish the method, we reveal highly specific transcriptional responses and altered RNA processing in each cell type, with Tnfr1 required for the astrocytic response. Extending the method to an Alzheimer's disease model, we confirm that transcriptomic changes observed in whole tissue are driven primarily by cell type composition, not transcriptional regulation, and identify hundreds of cell type-specific changes undetected in whole tissue RNA. Applying similar methods to additional models and patient tissues will transform our understanding of aberrant gene expression in neurological disease. PMID:27097852

  19. Untangling the brain's neuroinflammatory and neurodegenerative transcriptional responses.

    PubMed

    Srinivasan, Karpagam; Friedman, Brad A; Larson, Jessica L; Lauffer, Benjamin E; Goldstein, Leonard D; Appling, Laurie L; Borneo, Jovencio; Poon, Chungkee; Ho, Terence; Cai, Fang; Steiner, Pascal; van der Brug, Marcel P; Modrusan, Zora; Kaminker, Joshua S; Hansen, David V

    2016-01-01

    A common approach to understanding neurodegenerative disease is comparing gene expression in diseased versus healthy tissues. We illustrate that expression profiles derived from whole tissue RNA highly reflect the degenerating tissues' altered cellular composition, not necessarily transcriptional regulation. To accurately understand transcriptional changes that accompany neuropathology, we acutely purify neurons, astrocytes and microglia from single adult mouse brains and analyse their transcriptomes by RNA sequencing. Using peripheral endotoxemia to establish the method, we reveal highly specific transcriptional responses and altered RNA processing in each cell type, with Tnfr1 required for the astrocytic response. Extending the method to an Alzheimer's disease model, we confirm that transcriptomic changes observed in whole tissue are driven primarily by cell type composition, not transcriptional regulation, and identify hundreds of cell type-specific changes undetected in whole tissue RNA. Applying similar methods to additional models and patient tissues will transform our understanding of aberrant gene expression in neurological disease. PMID:27097852

  20. Dysregulated microRNAs in neurodegenerative disorders.

    PubMed

    Lau, Pierre; de Strooper, Bart

    2010-09-01

    The complexity of the nervous system arises in part, from the large diversity of neural cell types that support the architecture of neuronal circuits. Recent studies have highlighted microRNAs as important players in regulating gene expression at the post-transcriptional level and therefore the phenotype of neural cells. A link between microRNAs and neurodegenerative diseases such as Alzheimer's disease, Huntington's disease and Parkinson's disease is becoming increasingly evident. Here, we discuss microRNAs in neurodegeneration, from the fruit fly and mouse utilized as experimental models to dysregulated microRNAs in human neurodegenerative disorders. We propose that studying microRNAs and their mRNA targets in the context of neurodegeneration will significantly contribute to the identification of proteins important for neuronal function and might reveal underlying molecular networks that drive these diseases.

  1. Brain drug delivery systems for neurodegenerative disorders.

    PubMed

    Garbayo, E; Ansorena, E; Blanco-Prieto, M J

    2012-09-01

    Neurodegenerative disorders (NDs) are rapidly increasing as population ages. However, successful treatments for NDs have so far been limited and drug delivery to the brain remains one of the major challenges to overcome. There has recently been growing interest in the development of drug delivery systems (DDS) for local or systemic brain administration. DDS are able to improve the pharmacological and therapeutic properties of conventional drugs and reduce their side effects. The present review provides a concise overview of the recent advances made in the field of brain drug delivery for treating neurodegenerative disorders. Examples include polymeric micro and nanoparticles, lipidic nanoparticles, pegylated liposomes, microemulsions and nanogels that have been tested in experimental models of Parkinson's, Alzheimer's and Huntington's disease. Overall, the results reviewed here show that DDS have great potential for NDs treatment. PMID:23016644

  2. Endocytic membrane trafficking and neurodegenerative disease.

    PubMed

    Schreij, Andrea M A; Fon, Edward A; McPherson, Peter S

    2016-04-01

    Neurodegenerative diseases are amongst the most devastating of human disorders. New technologies have led to a rapid increase in the identification of disease-related genes with an enhanced appreciation of the key roles played by genetics in the etiology of these disorders. Importantly, pinpointing the normal function of disease gene proteins leads to new understanding of the cellular machineries and pathways that are altered in the disease process. One such emerging pathway is membrane trafficking in the endosomal system. This key cellular process controls the localization and levels of a myriad of proteins and is thus critical for normal cell function. In this review we will focus on three neurodegenerative diseases; Parkinson disease, amyotrophic lateral sclerosis, and hereditary spastic paraplegias, for which a large number of newly discovered disease genes encode proteins that function in endosomal membrane trafficking. We will describe how alterations in these proteins affect endosomal function and speculate on the contributions of these disruptions to disease pathophysiology. PMID:26721251

  3. Resveratrol: A Focus on Several Neurodegenerative Diseases

    PubMed Central

    Tellone, Ester; Galtieri, Antonio; Russo, Annamaria; Giardina, Bruno; Ficarra, Silvana

    2015-01-01

    Molecules of the plant world are proving their effectiveness in countering, slowing down, and regressing many diseases. The resveratrol for its intrinsic properties related to its stilbene structure has been proven to be a universal panacea, especially for a wide range of neurodegenerative diseases. This paper evaluates (in vivo and in vitro) the various molecular targets of this peculiar polyphenol and its ability to effectively counter several neurodegenerative disorders such as Parkinson's, Alzheimer's, and Huntington's diseases and amyotrophic lateral sclerosis. What emerges is that, in the deep heterogeneity of the pathologies evaluated, resveratrol through a convergence on the protein targets is able to give therapeutic responses in neuronal cells deeply diversified not only in morphological structure but especially in their function performed in the anatomical district to which they belong. PMID:26180587

  4. Chronic traumatic encephalopathy and other neurodegenerative proteinopathies.

    PubMed

    Tartaglia, Maria Carmela; Hazrati, Lili-Naz; Davis, Karen D; Green, Robin E A; Wennberg, Richard; Mikulis, David; Ezerins, Leo J; Keightley, Michelle; Tator, Charles

    2014-01-01

    "Chronic traumatic encephalopathy" (CTE) is described as a slowly progressive neurodegenerative disease believed to result from multiple concussions. Traditionally, concussions were considered benign events and although most people recover fully, about 10% develop a post-concussive syndrome with persisting neurological, cognitive and neuropsychiatric symptoms. CTE was once thought to be unique to boxers, but it has now been observed in many different athletes having suffered multiple concussions as well as in military personal after repeated blast injuries. Much remains unknown about the development of CTE but its pathological substrate is usually tau, similar to that seen in Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). The aim of this "perspective" is to compare and contrast clinical and pathological CTE with the other neurodegenerative proteinopathies and highlight that there is an urgent need for understanding the relationship between concussion and the development of CTE as it may provide a window into the development of a proteinopathy and thus new avenues for treatment.

  5. Neurodegenerative disorders and nanoformulated drug development

    PubMed Central

    Nowacek, Ari; Kosloski, Lisa M; Gendelman, Howard E

    2009-01-01

    Degenerative and inflammatory diseases of the CNS include, but are not limited to, Alzheimer’s and Parkinson’s disease, amyotrophic lateral sclerosis, stroke, multiple sclerosis and HIV-1-associated neurocognitive disorders. These are common, debilitating and, unfortunately, hold few therapeutic options. In recent years, the application of nanotechnologies as commonly used or developing medicines has served to improve pharmacokinetics and drug delivery specifically to CNS-diseased areas. In addition, nanomedical advances are leading to therapies that target CNS pathobiology and as such, can interrupt disordered protein aggregation, deliver functional neuroprotective proteins and alter the oxidant state of affected neural tissues. This article focuses on the pathobiology of common neurodegenerative disorders with a view towards how nanomedicine may be used to improve the clinical course of neurodegenerative disorders. PMID:19572820

  6. Synthetic prions and other human neurodegenerative proteinopathies.

    PubMed

    Le, Nhat Tran Thanh; Narkiewicz, Joanna; Aulić, Suzana; Salzano, Giulia; Tran, Hoa Thanh; Scaini, Denis; Moda, Fabio; Giachin, Gabriele; Legname, Giuseppe

    2015-09-01

    Transmissible spongiform encephalopathies (TSE) are a heterogeneous group of neurodegenerative disorders. The common feature of these diseases is the pathological conversion of the normal cellular prion protein (PrP(C)) into a β-structure-rich conformer-termed PrP(Sc). The latter can induce a self-perpetuating process leading to amplification and spreading of pathological protein assemblies. Much evidence suggests that PrP(Sc) itself is able to recruit and misfold PrP(C) into the pathological conformation. Recent data have shown that recombinant PrP(C) can be misfolded in vitro and the resulting synthetic conformers are able to induce the conversion of PrP(C) into PrP(Sc)in vivo. In this review we describe the state-of-the-art of the body of literature in this field. In addition, we describe a cell-based assay to test synthetic prions in cells, providing further evidence that synthetic amyloids are able to template conversion of PrP into prion inclusions. Studying prions might help to understand the pathological mechanisms governing other neurodegenerative diseases. Aggregation and deposition of misfolded proteins is a common feature of several neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and other disorders. Although the proteins implicated in each of these diseases differ, they share a common prion mechanism. Recombinant proteins are able to aggregate in vitro into β-rich amyloid fibrils, sharing some features of the aggregates found in the brain. Several studies have reported that intracerebral inoculation of synthetic aggregates lead to unique pathology, which spread progressively to distal brain regions and reduced survival time in animals. Here, we review the prion-like features of different proteins involved in neurodegenerative disorders, such as α-synuclein, superoxide dismutase-1, amyloid-β and tau.

  7. Efficacy of Natural Compounds in Neurodegenerative Disorders.

    PubMed

    Srivastava, Pranay; Yadav, Rajesh Singh

    2016-01-01

    Neurodegenerative disorders represent clusters of serious diseases that results in progressive deterioration of normal structure and physiology of central nervous system. Pathophysiology of Alzheimer's, Parkinson's or other neurodegenerative disorders involves multifaceted permutation of genetic and environmental factors. Combinations of lifestyle modification linked with environmental factor jointly or alone represent the largest share of cases of these disorders. Etiology of such neuronal degeneration involves manifestation of toxic reaction in the form of functional anomalies leading to dysfunction of the ubiquitin-proteasome system, activated inflammatory cascade, compromised neuronal survival pathway, mitochondrial dysfunction and finally neuronal apoptosis/necrosis and cell death. Furthermore, evidences from various studies exhibited role of oxidative stress and compromised anti-oxidant defense system as one of the prime factors associated with activation of various signal transduction pathways that would ultimately lead to the formation of amyloid beta or alpha synuclein in the brain. Keeping in view of complex etiology and pathophysiology along with a miniscule of available treatment options associated with these neurodegenerative disorders, the role of natural agents and herbal extracts as therapeutic alternatives alone or in combination with synthetic drugs could not be ruled out. In the same context the present chapter has been aimed to investigate the role of selected natural plants like Withania somnifera, Bacopa monnieri, Curcuma longa, Centella asiatica, Ocimum sanctum, Nardostachys jatamansi and Emblica officinalis in various neurodegenerative disorders and explore their targets to ameliorate neurotoxicity in various experimental models. The rationale for selection of these plants was based on their strong anti-inflammatory and anti-oxidant potential and large body of evidence that suggest their efficacy in preclinical as well as in clinical studies

  8. Nitric Oxide Homeostasis in Neurodegenerative Diseases.

    PubMed

    Hannibal, Luciana

    2016-01-01

    The role of nitric oxide in the pathogenesis and progression of neurodegenerative illnesses such as Parkinson's and Alzheimer's diseases has become prominent over the years. Increased activity of the enzymes that produce reactive oxygen species, decreased activity of antioxidant enzymes and imbalances in glutathione pools mediate and mark the neurodegenerative process. Much of the oxidative damage of proteins is brought about by the overproduction of nitric oxide by nitric oxide synthases (NOS) and its subsequent reactivity with reactive oxygen species. Proteomic methods have advanced the field tremendously, by facilitating the quantitative assessment of differential expression patterns and oxidative modifications of proteins and alongside, mapping their non-canonical functions. As a signaling molecule involved in multiple biochemical pathways, the level of nitric oxide is subject to tight regulation. All three NOS isoforms display aberrant patterns of expression in Alzheimer's disease, altering intracellular signaling and routing oxidative stress in directions that are uncompounded. This review discusses the prime factors that control nitric oxide biosynthesis, reactivity footprints and ensuing effects in the development of neurodegenerative diseases.

  9. MicroRNAs in neurodegenerative disorders.

    PubMed

    Junn, Eunsung; Mouradian, M Maral

    2010-05-01

    MicroRNAs (miRNAs) are endogenous, small, noncoding RNAs regulating eukaryotic gene expression at the post-transcriptional level. During the last decade, considerable advances have been made in our understanding the biogenesis of miRNAs, the molecular mechanisms by which they regulate gene expression and their functional role in various physiological situations. miRNAs are abundant in the brain where they have crucial roles in development and synaptic plasticity. Accumulating evidence from postmortem brain analyses and animal model studies has begun to suggest that miRNA dysfunction contributes to neurodegenerative disorders. Here, we discuss several examples of investigations demonstrating the role of miRNAs in neurodegenerative disorders. As the expression of disease-causing genes is regulated by certain miRNA(s), changes in these miRNAs could lead to the accumulation of disease-causing proteins, and subsequently to neuronal dysfunction and death. Detailed understanding of these mechanisms can provide potential new therapeutic approaches to slow down or halt the progression of neurodegenerative diseases.

  10. Caloric restriction and the precision-control of autophagy: A strategy for delaying neurodegenerative disease progression.

    PubMed

    Ntsapi, C; Loos, B

    2016-10-01

    Caloric restriction (CR) is known to extend lifespan in most organisms, indicating that nutrient and energy regulatory mechanisms impact aging. The greatest risk factor for neurodegeneration is age; thus, the antiaging effects of CR might attenuate progressive cell death and avert the aggregation of abnormal proteins associated with neurodegenerative diseases. CR is a potent inducer of autophagy, a tightly regulated intracellular process that facilitates recycling of abnormal protein aggregates and damaged organelles into bioenergetic and biosynthetic materials to maintain homeostasis. Thus, dysregulated autophagy can lead to cellular dysfunction, abnormal protein accumulation, proteotoxicity and subsequently the onset of several neurodegenerative diseases. Therefore, the targeted and precision-controlled activation of autophagy represents a promising therapeutic strategy. Non-pharmacological therapeutic interventions that delay aging by modulating specific stages of autophagy might be beneficial against premature aging, neurodegeneration and its associated ailments. However, the dynamic and often compensatory cross-talk that exists between the protein degradation pathways makes clinical translational approaches challenging. Here we review the primary autophagy pathways in the context of age-related neurodegenerative diseases, focusing on compensatory mechanisms and pathway failure. By critically assessing each underlying molecular machinery, we reveal their impact on aging and unmask the role of caloric restriction in changing cellular fate by delayed aging through stimulation of autophagy. This may point towards novel and better targeted interventions that exploit the autophagic machinery in the treatment of neurodegenerative diseases.

  11. Caloric restriction and the precision-control of autophagy: A strategy for delaying neurodegenerative disease progression.

    PubMed

    Ntsapi, C; Loos, B

    2016-10-01

    Caloric restriction (CR) is known to extend lifespan in most organisms, indicating that nutrient and energy regulatory mechanisms impact aging. The greatest risk factor for neurodegeneration is age; thus, the antiaging effects of CR might attenuate progressive cell death and avert the aggregation of abnormal proteins associated with neurodegenerative diseases. CR is a potent inducer of autophagy, a tightly regulated intracellular process that facilitates recycling of abnormal protein aggregates and damaged organelles into bioenergetic and biosynthetic materials to maintain homeostasis. Thus, dysregulated autophagy can lead to cellular dysfunction, abnormal protein accumulation, proteotoxicity and subsequently the onset of several neurodegenerative diseases. Therefore, the targeted and precision-controlled activation of autophagy represents a promising therapeutic strategy. Non-pharmacological therapeutic interventions that delay aging by modulating specific stages of autophagy might be beneficial against premature aging, neurodegeneration and its associated ailments. However, the dynamic and often compensatory cross-talk that exists between the protein degradation pathways makes clinical translational approaches challenging. Here we review the primary autophagy pathways in the context of age-related neurodegenerative diseases, focusing on compensatory mechanisms and pathway failure. By critically assessing each underlying molecular machinery, we reveal their impact on aging and unmask the role of caloric restriction in changing cellular fate by delayed aging through stimulation of autophagy. This may point towards novel and better targeted interventions that exploit the autophagic machinery in the treatment of neurodegenerative diseases. PMID:27473756

  12. Anxiety and Depression during Transition from Hospital to Community in Older Adults: Concepts of a Study to Explain Late Age Onset Depression

    PubMed Central

    Lalor, Aislinn F.; Brown, Ted; Robins, Lauren; Lee, Den-Ching Angel; O’Connor, Daniel; Russell, Grant; Stolwyk, Rene; McDermott, Fiona; Johnson, Christina; Haines, Terry P.

    2015-01-01

    The transition between extended hospitalization and discharge home to community-living contexts for older adults is a critical time period. This transition can have an impact on the health outcomes of older adults such as increasing the risk for health outcomes like falls, functional decline and depression and anxiety. The aim of this work is to identify and understand why older adults experience symptoms of depression and anxiety post-discharge and what factors are associated with this. This is a mixed methods study of adults aged 65 years and over who experienced a period of hospitalization longer than two weeks and return to community-living post-discharge. Participants will complete a questionnaire at baseline and additional monthly follow-up questionnaires for six months. Anxiety and depression and their resulting behaviors are major public health concerns and are significant determinants of health and wellbeing among the ageing population. There is a critical need for research into the impact of an extended period of hospitalization on the health status of older adults post-discharge from hospital. This research will provide evidence that will inform interventions and services provided for older adults after they have been discharged home from hospital care. PMID:27417775

  13. Molecular basis of adult-onset and chronic G sub M2 gangliosidoses in patients of Ashkenazi Jewish origin: Substitution of serine for glycine at position 269 of the. alpha. -subunit of. beta. -hexosaminidase

    SciTech Connect

    Paw, B.H.; Kaback, M.M.; Neufeld, E.F. )

    1989-04-01

    Chronic and adult-onset G{sub M2} gangliosidoses are neurological disorders caused by marked deficiency of the A isoenzyme of {beta}-hexosaminidase; they occur in the Ashkenazi Jewish population, though less frequently than classic (infantile) Tay-Sachs disease. Earlier biosynthetic studies had identified a defective {alpha}-subunit that failed to associate with the {beta}-subunit. The authors have now found a guanosine to adenosine transition at the 3{prime} end of exon 7, which causes substitution of serine for glycine at position 269 of the {alpha}-subunit. An RNase protection assay was used to localize the mutation to a segment of mRNA from fibroblasts of a patient with the adult-onset disorder. That segment of mRNA (after reverse transcription) and a corresponding segment of genomic DNA were amplified by the polymerase chain reaction and sequenced by the dideoxy method. The sequence analysis, together with an assay based on the loss of a ScrFI restriction site, showed that the patient was a compound heterozygote who had inherited the 269 (Gly {yields} Ser) mutation from his father and an allelic null mutation from his mother. The 269 (Gly {yields} Ser) mutation, in compound heterozygosity with a presumed null allele, was also found in fetal fibroblasts with an association-defective phenotype and in cells from five patients with chronic G{sub M2} gangliosidosis.

  14. The effect of age on the onset of pain interference in a general population of older adults: prospective findings from the North Staffordshire Osteoarthritis Project (NorStOP).

    PubMed

    Thomas, Elaine; Mottram, Sara; Peat, George; Wilkie, Ross; Croft, Peter

    2007-05-01

    Pain that interferes with daily life appears to be strongly age-related in cross-sectional studies, although the nature of this relationship over time has not been established. We have investigated the onset and persistence of pain and pain interference over a 3-year period to determine their association with age in older people. A 3-year follow-up postal survey was conducted of adults aged 50 years and over (n=5366) who had previously been recruited as part of the North Staffordshire Osteoarthritis Project. Four thousand two-hundred and thirty-four completed questionnaires were received (adjusted response 84.7%). The occurrence of pain interference at 3 years was 19.7% in persons free of such pain at baseline, higher in females than males (6.0% difference; 95% CI: 2.6%, 9.3%), and showed a clear age-related trend with a more than twofold increase from 50 to 59 years (16.0%) to the 80+ years (35%). Any pain at follow-up was reported by 48% of those pain-free at recruitment, and this figure was similar for males and females, and across 10-year age-groups. Persistence of pain interference (72.1%) at 3 years was high. In adults aged 50 years and over, the onset of pain that interferes with life shows a clear gender difference and a consistent rise with age into the oldest age-group. This was in strong contrast to the onset of pain which showed no gender or age-related trends. The implications for public health, as for the treatment of the individual, are twofold, relating to efforts to prevent disabling pain from occurring and to understand the factors that accelerate the impact which pain has on everyday life when people reach the oldest ages.

  15. Adult Still's disease

    MedlinePlus

    Still's disease - adult; AOSD ... than 1 out of 100,000 people develop adult-onset Still's disease each year. It affects women more often than men. The cause of adult Still's disease is unknown. No risk factors for ...

  16. INTIMATE PARTNER VIOLENCE AND NEW-ONSET DEPRESSION: A LONGITUDINAL STUDY OF WOMEN’S CHILDHOOD AND ADULT HISTORIES OF ABUSE

    PubMed Central

    Ouellet-Morin, Isabelle; Fisher, Helen L.; York-Smith, Marianna; Fincham-Campbell, Stephanie; Moffitt, Terrie E.; Arseneault, Louise

    2015-01-01

    Background Studies indicate that women victims of intimate partner violence are at increased risk for poor mental health. This research disentangled the effect of partner violence on new-onset depression and psychosis spectrum symptoms from effects of child maltreatment and other confounding factors, including substance abuse and antisocial personality. Methods Participants were 1,052 mothers involved in the Environmental Risk (E-Risk) Longitudinal Twin Study, a nationally representative cohort of families followed prospectively. To test the directionality of associations between partner violence and depression, only women without a history of depression at the beginning of the study were considered (n = 978). Partner violence and mental health were assessed during face-to-face interviews with women across three time points. Results Four of 10 women reported being the victim of violence from their partner in a 10-year period. They represent 33% of our cohort and they account for 51% of new-onset depression. These women had a twofold increase in their risk of suffering from new-onset depression once the effect of childhood maltreatment, socioeconomic deprivation, antisocial personality, and young motherhood were controlled. Women who were abused both in childhood and adulthood were four to seven times more likely to suffer from depression than never-abused women. We observed similar associations with psychosis spectrum symptoms. Conclusions Women victims of partner violence account for more than their share of depression. Findings strengthen existing evidence that partner violence independently contributes to women’s poor mental health. Psychological difficulties among a considerable number of women could be reduced by stopping partner violence. PMID:25691224

  17. Thymosin β4 as a restorative/regenerative therapy for neurological injury and neurodegenerative diseases.

    PubMed

    Chopp, Michael; Zhang, Zheng Gang

    2015-01-01

    Thymosin β4 (Tβ4) promotes CNS and peripheral nervous system (PNS) plasticity and neurovascular remodeling leading to neurological recovery in a range of neurological diseases. Treatment of neural injury and neurodegenerative disease 24 h or more post-injury and disease onset with Tβ4 enhances angiogenesis, neurogenesis, neurite and axonal outgrowth, and oligodendrogenesis, and thereby, significantly improves functional and behavioral outcomes. We propose that oligodendrogenesis is a common link by which Tβ4 promotes recovery after neural injury and neurodegenerative disease. The ability to target many diverse restorative processes via multiple molecular pathways that drive oligodendrogenesis and neurovascular remodeling may be mediated by the ability of Tβ4 to alter cellular expression of microRNAs (miRNAs). However, further investigations on the essential role of miRNAs in regulating protein expression and the remarkable exosomal intercellular communication network via exosomes will likely provide insight into mechanisms of action and means to amplify the therapeutic effects of Tβ4.

  18. Estrogen anti-inflammatory activity in brain: a therapeutic opportunity for menopause and neurodegenerative diseases

    PubMed Central

    Vegeto, Elisabetta; Benedusi, Valeria; Maggi, Adriana

    2008-01-01

    Recent studies highlight the prominent role played by estrogens in protecting the central nervous system (CNS) against the noxious consequences of a chronic inflammatory reaction. The neurodegenerative process of several CNS diseases, including Multiple Sclerosis, Alzheimer’s and Parkinson’s Diseases, is associated with the activation of microglia cells, which drive the resident inflammatory response. Chronically stimulated during neurodegeneration, microglia cells are thought to provide detrimental effects on surrounding neurons. The inhibitory activity of estrogens on neuroinflammation and specifically on microglia might thus be considered as a beneficial therapeutic opportunity for delaying the onset or progression of neurodegenerative diseases; in addition, understanding the peculiar activity of this female hormone on inflammatory signalling pathways will possibly lead to the development of selected anti-inflammatory molecules. This review summarises the evidence for the involvement of microglia in neuroinflammation and the anti-inflammatory activity played by estrogens specifically in microglia. PMID:18522863

  19. Neurodegenerative disease high-field imaging

    PubMed Central

    van der Grond, J.; van Buchem, M.A.; van Zijl, P.; Webb, A.G.

    2012-01-01

    High field magnetic resonance imaging is showing potential for imaging of neurodegenerative diseases. 7 T MRI is beginning to be used in a clinical research setting and the theoretical benefits, i.e. higher signal-to-noise, sensitivity to iron, improved MRA and increased spectral resolution in spectroscopy are being confirmed. Despite the limited number of studies to date, initial results in patients with multiple sclerosis, Alzheimer’s disease and Huntington’s disease show promising additional features in contrast that may assist in better diagnosis of these disorders. PMID:22548926

  20. Overcoming obstacles to repurposing for neurodegenerative disease

    PubMed Central

    Shineman, Diana W; Alam, John; Anderson, Margaret; Black, Sandra E; Carman, Aaron J; Cummings, Jeffrey L; Dacks, Penny A; Dudley, Joel T; Frail, Donald E; Green, Allan; Lane, Rachel F; Lappin, Debra; Simuni, Tanya; Stefanacci, Richard G; Sherer, Todd; Fillit, Howard M

    2014-01-01

    Repurposing Food and Drug Administration (FDA)-approved drugs for a new indication may offer an accelerated pathway for new treatments to patients but is also fraught with significant commercial, regulatory, and reimbursement challenges. The Alzheimer’s Drug Discovery Foundation (ADDF) and the Michael J. Fox Foundation for Parkinson’s Research (MJFF) convened an advisory panel in October 2013 to understand stakeholder perspectives related to repurposing FDA-approved drugs for neurodegenerative diseases. Here, we present opportunities on how philanthropy, industry, and government can begin to address these challenges, promote policy changes, and develop targeted funding strategies to accelerate the potential of FDA-approved repurposed drugs. PMID:25356422

  1. Prion-like Mechanisms in Neurodegenerative Diseases

    PubMed Central

    Frost, Bess; Diamond, Marc I.

    2013-01-01

    Many non-infectious neurodegenerative diseases are associated with the accumulation of fibrillar protein. These diseases all exhibit phenotypic diversity and propagation of pathology that is reminiscent of prionopathies. Furthermore, emerging studies of amyloid-β, α–synuclein, and tau proteins suggest that they share key biophysical and biochemical characteristics with prions. Propagation of protein misfolding in these diseases may therefore occur via mechanisms similar to those underlying prion pathogenesis. If verified in vivo, this will suggest new therapeutic strategies to block propagation of protein misfolding throughout the brain. PMID:20029438

  2. [Stem cell therapy for neurodegenerative disorders].

    PubMed

    Meyer, Morten; Jensen, Pia; Rasmussen, Jens Zimmer

    2010-09-20

    Intrastriatal, foetal neural transplants can ameliorate symptoms in patients with Parkinson's and Huntington's disease, although not stop the primary cell-loss. Several issues must, however, be addressed before general or extended clinical use of cell therapy in neurodegenerative diseases can become a reality. Improvements include standardized and safe master cell-lines derived from human embryonic stem cells, induced pluripotent stem cells and neural stem cells. Cells from these sources are expected to become available for cell replacement therapies or therapeutic production of trophic, anti-inflammatory and restorative factors within a few years.

  3. PRENATAL EXPOSURE TO LOW DOSE PFOA INDUCES LOW DEVELOPMENTAL BODY WEIGHT FOLLOWED BY ADULT ONSET OBESITY THAT IS BLUNTED IN OVARIECTOMIZED ANIMALS

    EPA Science Inventory

    The Barker hypothesis, or fetal origins of adult disease, proposes that individuals born to mothers who were pregnant during lean times develop a "thrifty" phenotype with a smaller body size and lowered metabolic rates, leading to a propensity for obesity and development of disor...

  4. Early Diagnosis and Monitoring of Neurodegenerative Langerhans Cell Histiocytosis

    PubMed Central

    Mortilla, Marzia; Savelli, Sara; Grisotto, Laura; Di Giacomo, Gianpiero; Romano, Katiuscia; Fonda, Claudio; Biggeri, Annibale; Guerrini, Renzo; Aricò, Maurizio

    2015-01-01

    Background Neurodegenerative Langerhans Cell Histiocytosis (ND-LCH) is a rare, unpredictable consequence that may devastate the quality of life of patients cured from LCH. We prospectively applied a multidisciplinary diagnostic work-up to early identify and follow-up patients with ND-LCH, with the ultimate goal of better determining the appropriate time for starting therapy. Methods We studied 27 children and young adults with either ND-LCH verified by structural magnetic resonance imaging (MRI) (group 1) or specific risk factors for (diabetes insipidus, craniofacial bone lesions), but no evidence of, neurodegenerative MRI changes (group 2). All patients underwent clinical, neurophysiological and MRI studies. Results Seventeen patients had MRI alterations typical for ND-LCH. Nine showed neurological impairment but only three were symptomatic; 11 had abnormal somatosensory evoked potentials (SEPs), and five had abnormal brainstem auditory evoked potentials (BAEPs). MR spectroscopy (MRS) showed reduced cerebellar NAA/Cr ratio in nine patients. SEPs showed sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for predicting ND-LCH of 70.6% (95%CI, 44.0%-89.7%), 100% (69.2%-100%), 100% (73.5%-100%), and 66.7% (38.4%-88.2%), respectively. Repeated investigations in group 1 revealed increasingly abnormal EP parameters, or neurological examination, or both, in nine of fifteen patients while MRI remained unchanged in all but one patient. Conclusion A targeted MRI study should be performed in all patients with risk factors for ND-LCH for early identification of demyelination. The combined use of SEPs and careful neurological evaluation may represent a valuable, low-cost, well-tolerated and easily available methodology to monitor patients from pre-symptomatic to symptomatic stages. We suggest a multidisciplinary protocol including clinical, MRS, and neurophysiological investigations to identify a population target for future

  5. Lack of miRNA Misregulation at Early Pathological Stages in Drosophila Neurodegenerative Disease Models

    PubMed Central

    Reinhardt, Anita; Feuillette, Sébastien; Cassar, Marlène; Callens, Céline; Thomassin, Hélène; Birman, Serge; Lecourtois, Magalie; Antoniewski, Christophe; Tricoire, Hervé

    2012-01-01

    Late onset neurodegenerative diseases represent a major public health concern as the population in many countries ages. Both frequent diseases such as Alzheimer disease (AD, 14% incidence for 80–84 year-old Europeans) or Parkinson disease (PD, 1.4% prevalence for >55 years old) share, with other low-incidence neurodegenerative pathologies such as spinocerebellar ataxias (SCAs, 0.01% prevalence) and frontotemporal lobar degeneration (FTLD, 0.02% prevalence), a lack of efficient treatment in spite of important research efforts. Besides significant progress, studies with animal models have revealed unexpected complexities in the degenerative process, emphasizing a need to better understand the underlying pathological mechanisms. Recently, microRNAs (miRNAs), a class of small regulatory non-coding RNAs, have been implicated in some neurodegenerative diseases. The current data supporting a role of miRNAs in PD, tauopathies, dominant ataxias, and FTLD will first be discussed to emphasize the different levels of the pathological processes which may be affected by miRNAs. To investigate a potential involvement of miRNA dysregulation in the early stages of these neurodegenerative diseases we have used Drosophila models for seven diseases (PD, 3 FTLD, 3 dominant ataxias) that recapitulate many features of the human diseases. We performed deep sequencing of head small RNAs after 3 days of pathological protein expression in the fly head neurons. We found no evidence for a statistically significant difference in miRNA expression in this early stage of the pathological process. In addition, we could not identify small non-coding CAG repeat RNAs (sCAG) in polyQ disease models. Thus our data suggest that transcriptional deregulation of miRNAs or sCAG is unlikely to play a significant role in the initial stages of neurodegenerative diseases. PMID:23115562

  6. Inflammation in neurodegenerative diseases--an update.

    PubMed

    Amor, Sandra; Peferoen, Laura A N; Vogel, Daphne Y S; Breur, Marjolein; van der Valk, Paul; Baker, David; van Noort, Johannes M

    2014-06-01

    Neurodegeneration, the progressive dysfunction and loss of neurons in the central nervous system (CNS), is the major cause of cognitive and motor dysfunction. While neuronal degeneration is well-known in Alzheimer's and Parkinson's diseases, it is also observed in neurotrophic infections, traumatic brain and spinal cord injury, stroke, neoplastic disorders, prion diseases, multiple sclerosis and amyotrophic lateral sclerosis, as well as neuropsychiatric disorders and genetic disorders. A common link between these diseases is chronic activation of innate immune responses including those mediated by microglia, the resident CNS macrophages. Such activation can trigger neurotoxic pathways leading to progressive degeneration. Yet, microglia are also crucial for controlling inflammatory processes, and repair and regeneration. The adaptive immune response is implicated in neurodegenerative diseases contributing to tissue damage, but also plays important roles in resolving inflammation and mediating neuroprotection and repair. The growing awareness that the immune system is inextricably involved in mediating damage as well as regeneration and repair in neurodegenerative disorders, has prompted novel approaches to modulate the immune system, although it remains whether these approaches can be used in humans. Additional factors in humans include ageing and exposure to environmental factors such as systemic infections that provide additional clues that may be human specific and therefore difficult to translate from animal models. Nevertheless, a better understanding of how immune responses are involved in neuronal damage and regeneration, as reviewed here, will be essential to develop effective therapies to improve quality of life, and mitigate the personal, economic and social impact of these diseases. PMID:24329535

  7. Engineering enhanced protein disaggregases for neurodegenerative disease

    PubMed Central

    Jackrel, Meredith E; Shorter, James

    2015-01-01

    Abstract Protein misfolding and aggregation underpin several fatal neurodegenerative diseases, including Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). There are no treatments that directly antagonize the protein-misfolding events that cause these disorders. Agents that reverse protein misfolding and restore proteins to native form and function could simultaneously eliminate any deleterious loss-of-function or toxic gain-of-function caused by misfolded conformers. Moreover, a disruptive technology of this nature would eliminate self-templating conformers that spread pathology and catalyze formation of toxic, soluble oligomers. Here, we highlight our efforts to engineer Hsp104, a protein disaggregase from yeast, to more effectively disaggregate misfolded proteins connected with PD, ALS, and FTD. Remarkably subtle modifications of Hsp104 primary sequence yielded large gains in protective activity against deleterious α-synuclein, TDP-43, FUS, and TAF15 misfolding. Unusually, in many cases loss of amino acid identity at select positions in Hsp104 rather than specific mutation conferred a robust therapeutic gain-of-function. Nevertheless, the misfolding and toxicity of EWSR1, an RNA-binding protein with a prion-like domain linked to ALS and FTD, could not be buffered by potentiated Hsp104 variants, indicating that further amelioration of disaggregase activity or sharpening of substrate specificity is warranted. We suggest that neuroprotection is achievable for diverse neurodegenerative conditions via surprisingly subtle structural modifications of existing chaperones. PMID:25738979

  8. Biomarker-based dissection of neurodegenerative diseases.

    PubMed

    Olsson, Bob; Zetterberg, Henrik; Hampel, Harald; Blennow, Kaj

    2011-12-01

    The diagnosis of neurodegenerative diseases within neurology and psychiatry are hampered by the difficulty in getting biopsies and thereby validating the diagnosis by pathological findings. Biomarkers for other types of disease have been readily adopted into the clinical practice where for instance troponins are standard tests when myocardial infarction is suspected. However, the use of biomarkers for neurodegeneration has not been fully incorporated into the clinical routine. With the development of cerebrospinal fluid (CSF) biomarkers that reflect pathological events within the central nervous system (CNS), important clinical diagnostic tools are becoming available. This review summarizes the most promising biomarker candidates that may be used to monitor different types of neurodegeneration and protein inclusions, as well as different types of metabolic changes, in living patients in relation to the clinical phenotype and disease progression over time. Our aim is to provide the reader with an updated lexicon on currently available biomarker candidates, how far they have come in development and how well they reflect pathogenic processes in different neurodegenerative diseases. Biomarkers for specific pathogenetic processes would also be valuable tools both to study disease pathogenesis directly in patients and to identify and monitor the effect of novel treatment strategies.

  9. Diffusion-MRI in neurodegenerative disorders.

    PubMed

    Goveas, Joseph; O'Dwyer, Laurence; Mascalchi, Mario; Cosottini, Mirco; Diciotti, Stefano; De Santis, Silvia; Passamonti, Luca; Tessa, Carlo; Toschi, Nicola; Giannelli, Marco

    2015-09-01

    The ability to image the whole brain through ever more subtle and specific methods/contrasts has come to play a key role in understanding the basis of brain abnormalities in several diseases. In magnetic resonance imaging (MRI), "diffusion" (i.e. the random, thermally-induced displacements of water molecules over time) represents an extraordinarily sensitive contrast mechanism, and the exquisite structural detail it affords has proven useful in a vast number of clinical as well as research applications. Since diffusion-MRI is a truly quantitative imaging technique, the indices it provides can serve as potential imaging biomarkers which could allow early detection of pathological alterations as well as tracking and possibly predicting subtle changes in follow-up examinations and clinical trials. Accordingly, diffusion-MRI has proven useful in obtaining information to better understand the microstructural changes and neurophysiological mechanisms underlying various neurodegenerative disorders. In this review article, we summarize and explore the main applications, findings, perspectives as well as challenges and future research of diffusion-MRI in various neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease and degenerative ataxias. PMID:25917917

  10. [The role of thiamine in neurodegenerative diseases].

    PubMed

    Bubko, Irena; Gruber, Beata M; Anuszewska, Elżbieta L

    2015-09-21

    Vitamin B1 (thiamine) plays an important role in metabolism. It is indispensable for normal growth and development of the organism. Thiamine has a favourable impact on a number of systems, including the digestive, cardiovascular and nervous systems. It also stimulates the brain and improves the psycho-emotional state. Hence it is often called the vitamin of "reassurance of the spirit". Thiamine is a water-soluble vitamin. It can be present in the free form as thiamine or as its phosphate esters: mono-, di- or triphosphate. The main source of thiamine as an exogenous vitamin is certain foodstuffs, but trace amounts can be synthesised by microorganisms of the large intestine. The recommended daily intake of thiamine is about 2.0 mg. Since vitamin B1 has no ability to accumulate in the organism, manifestations of its deficiency begin to appear very quickly. The chronic state of thiamine deficiency, to a large extent, because of its function, contributes to the development of neurodegenerative diseases. It was proved that supporting vitamin B1 therapy not only constitutes neuroprotection but can also have a favourable impact on advanced neurodegenerative diseases. This article presents the current state of knowledge as regards the effects of thiamine exerted through this vitamin in a number of diseases such as Parkinson's disease, Alzheimer's disease, Wernicke's encephalopathy or Wernicke-Korsakoff syndrome and Huntington's disease.

  11. Inflammation in neurodegenerative diseases--an update.

    PubMed

    Amor, Sandra; Peferoen, Laura A N; Vogel, Daphne Y S; Breur, Marjolein; van der Valk, Paul; Baker, David; van Noort, Johannes M

    2014-06-01

    Neurodegeneration, the progressive dysfunction and loss of neurons in the central nervous system (CNS), is the major cause of cognitive and motor dysfunction. While neuronal degeneration is well-known in Alzheimer's and Parkinson's diseases, it is also observed in neurotrophic infections, traumatic brain and spinal cord injury, stroke, neoplastic disorders, prion diseases, multiple sclerosis and amyotrophic lateral sclerosis, as well as neuropsychiatric disorders and genetic disorders. A common link between these diseases is chronic activation of innate immune responses including those mediated by microglia, the resident CNS macrophages. Such activation can trigger neurotoxic pathways leading to progressive degeneration. Yet, microglia are also crucial for controlling inflammatory processes, and repair and regeneration. The adaptive immune response is implicated in neurodegenerative diseases contributing to tissue damage, but also plays important roles in resolving inflammation and mediating neuroprotection and repair. The growing awareness that the immune system is inextricably involved in mediating damage as well as regeneration and repair in neurodegenerative disorders, has prompted novel approaches to modulate the immune system, although it remains whether these approaches can be used in humans. Additional factors in humans include ageing and exposure to environmental factors such as systemic infections that provide additional clues that may be human specific and therefore difficult to translate from animal models. Nevertheless, a better understanding of how immune responses are involved in neuronal damage and regeneration, as reviewed here, will be essential to develop effective therapies to improve quality of life, and mitigate the personal, economic and social impact of these diseases.

  12. Chronic traumatic encephalopathy and other neurodegenerative proteinopathies

    PubMed Central

    Tartaglia, Maria Carmela; Hazrati, Lili-Naz; Davis, Karen D.; Green, Robin E. A.; Wennberg, Richard; Mikulis, David; Ezerins, Leo J.; Keightley, Michelle; Tator, Charles

    2014-01-01

    “Chronic traumatic encephalopathy” (CTE) is described as a slowly progressive neurodegenerative disease believed to result from multiple concussions. Traditionally, concussions were considered benign events and although most people recover fully, about 10% develop a post-concussive syndrome with persisting neurological, cognitive and neuropsychiatric symptoms. CTE was once thought to be unique to boxers, but it has now been observed in many different athletes having suffered multiple concussions as well as in military personal after repeated blast injuries. Much remains unknown about the development of CTE but its pathological substrate is usually tau, similar to that seen in Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). The aim of this “perspective” is to compare and contrast clinical and pathological CTE with the other neurodegenerative proteinopathies and highlight that there is an urgent need for understanding the relationship between concussion and the development of CTE as it may provide a window into the development of a proteinopathy and thus new avenues for treatment. PMID:24550810

  13. Polyphenols: Multipotent Therapeutic Agents in Neurodegenerative Diseases

    PubMed Central

    Bhullar, Khushwant S.; Rupasinghe, H. P. Vasantha

    2013-01-01

    Aging leads to numerous transitions in brain physiology including synaptic dysfunction and disturbances in cognition and memory. With a few clinically relevant drugs, a substantial portion of aging population at risk for age-related neurodegenerative disorders require nutritional intervention. Dietary intake of polyphenols is known to attenuate oxidative stress and reduce the risk for related neurodegenerative diseases such as Alzheimer's disease (AD), stroke, multiple sclerosis (MS), Parkinson's disease (PD), and Huntington's disease (HD). Polyphenols exhibit strong potential to address the etiology of neurological disorders as they attenuate their complex physiology by modulating several therapeutic targets at once. Firstly, we review the advances in the therapeutic role of polyphenols in cell and animal models of AD, PD, MS, and HD and activation of drug targets for controlling pathological manifestations. Secondly, we present principle pathways in which polyphenol intake translates into therapeutic outcomes. In particular, signaling pathways like PPAR, Nrf2, STAT, HIF, and MAPK along with modulation of immune response by polyphenols are discussed. Although current polyphenol researches have limited impact on clinical practice, they have strong evidence and testable hypothesis to contribute clinical advances and drug discovery towards age-related neurological disorders. PMID:23840922

  14. HDL and Cognition in Neurodegenerative Disorders

    PubMed Central

    Hottman, David A.; Chernick, Dustin; Cheng, Shaowu; Wang, Zhe; Li, Ling

    2014-01-01

    High-density lipoproteins (HDL) are a heterogeneous group of lipoproteins composed of various lipids and proteins. HDL is formed both in the systemic circulation and in the brain. In addition to being a crucial player in the reverse cholesterol transport pathway, HDL possesses a wide range of other functions including anti-oxidation, anti-inflammation, pro-endothelial function, anti-thrombosis, and modulation of immune function. It has been firmly established that high plasma levels of HDL protect against cardiovascular disease. Accumulating evidence indicates that the beneficial role of HDL extends to many other systems including the central nervous system. Cognition is a complex brain function that includes all aspects of perception, thought, and memory. Cognitive function often declines during aging and this decline manifests as cognitive impairment/dementia in age-related and progressive neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. A growing concern is that no effective therapy is currently available to prevent or treat these devastating diseases. Emerging evidence suggests that HDL may play a pivotal role in preserving cognitive function under normal and pathological conditions. This review attempts to summarize recent genetic, clinical and experimental evidence for the impact of HDL on cognition in aging and in neurodegenerative disorders as well as the potential of HDL-enhancing approaches to improve cognitive function. PMID:25131449

  15. Developing services for the carers of young adults with early-onset psychosis - implementing evidence-based practice on psycho-educational family intervention.

    PubMed

    Sin, J; Moone, N; Newell, J

    2007-05-01

    This paper describes a series of practice and service development initiatives to incorporate the family-inclusive approach into the newly established Early Intervention in Psychosis Service in Berkshire, England. Following a local study on carers' experiences and needs from those who cared for a young adult with a first-episode psychosis (FEP), a series of flexible services for this group of carers has been developed incorporating the much-researched psycho-educational family interventions. The findings of our local phenomenological study on the carers for young adults with FEP clearly specified the unique needs of this group of carers and that well-established approaches in family work and carers support facilities may have to be adapted to meet such needs. This paper reports the service development process through which a series of specially designed carers' services were set up for carers caring for a young adult with FEP. These services were developed to address carers' needs for knowledge, skills and support to cope with their caring roles and situation, from the stressful beginning of a potentially long caring journey. PMID:17430452

  16. Neural stem cells in Parkinson's disease: a role for neurogenesis defects in onset and progression.

    PubMed

    Le Grand, Jaclyn Nicole; Gonzalez-Cano, Laura; Pavlou, Maria Angeliki; Schwamborn, Jens C

    2015-02-01

    Parkinson's disease (PD) is the second most common neurodegenerative disorder, leading to a variety of motor and non-motor symptoms. Interestingly, non-motor symptoms often appear a decade or more before the first signs of motor symptoms. Some of these non-motor symptoms are remarkably similar to those observed in cases of impaired neurogenesis and several PD-related genes have been shown to play a role in embryonic or adult neurogenesis. Indeed, animal models deficient in Nurr1, Pitx3, SNCA and PINK1 display deregulated embryonic neurogenesis and LRRK2 and VPS35 have been implicated in neuronal development-related processes such as Wnt/β-catenin signaling and neurite outgrowth. Moreover, adult neurogenesis is affected in both PD patients and PD animal models and is regulated by dopamine and dopaminergic (DA) receptors, by chronic neuroinflammation, such as that observed in PD, and by differential expression of wild-type or mutant forms of PD-related genes. Indeed, an increasing number of in vivo studies demonstrate a role for SNCA and LRRK2 in adult neurogenesis and in the generation and maintenance of DA neurons. Finally, the roles of PD-related genes, SNCA, LRRK2, VPS35, Parkin, PINK1 and DJ-1 have been studied in NSCs, progenitor cells and induced pluripotent stem cells, demonstrating a role for some of these genes in stem/progenitor cell proliferation and maintenance. Together, these studies strongly suggest a link between deregulated neurogenesis and the onset and progression of PD and present strong evidence that, in addition to a neurodegenerative disorder, PD can also be regarded as a developmental disorder.

  17. An atypical presentation of adult-onset Still’s disease complicated by pulmonary hypertension and macrophage activation syndrome treated with immunosuppression: a case-based review of the literature

    PubMed Central

    Manson, Daniel K.; Horn, Evelyn M.; Haythe, Jennifer

    2016-01-01

    Abstract Pulmonary arterial hypertension (PAH) is a known complication of rheumatologic diseases, but it is only rarely associated with adult-onset Still’s disease (AOSD). We describe the case of a 30-year-old woman who presented in a pulmonary hypertension crisis and was found to have underlying AOSD with PAH and nonspecific interstitial pneumonia (NSIP) with a course complicated by macrophage activation syndrome (MAS). She dramatically improved with steroids, cyclosporine A, and anakinra, with total resolution of the MAS and significant improvement of her pulmonary arterial pressures. While there are only select case reports of AOSD associated with PAH, this is the first reported case of (1) AOSD complicated by both PAH and MAS and (2) AOSD complicated by biopsy-proven NSIP. Clinically, this case highlights the efficacy of immunosuppressive agents in the treatment of PAH and MAS from underlying AOSD and supports their use in this setting. PMID:27162622

  18. Effects of Ashwagandha (roots of Withania somnifera) on neurodegenerative diseases.

    PubMed

    Kuboyama, Tomoharu; Tohda, Chihiro; Komatsu, Katsuko

    2014-01-01

    Neurodegenerative diseases commonly induce irreversible destruction of central nervous system (CNS) neuronal networks, resulting in permanent functional impairments. Effective medications against neurodegenerative diseases are currently lacking. Ashwagandha (roots of Withania somnifera Dunal) is used in traditional Indian medicine (Ayurveda) for general debility, consumption, nervous exhaustion, insomnia, and loss of memory. In this review, we summarize various effects and mechanisms of Ashwagandha extracts and related compounds on in vitro and in vivo models of neurodegenerative diseases such as Alzheimer's disease and spinal cord injury.

  19. Enhancement of social novelty discrimination by positive allosteric modulators at metabotropic glutamate 5 receptors: adolescent administration prevents adult-onset deficits induced by neonatal treatment with phencyclidine.

    PubMed

    Clifton, Nicholas E; Morisot, Nadège; Girardon, Sylvie; Millan, Mark J; Loiseau, Florence

    2013-02-01

    Metabotropic glutamate-5 receptors (mGluR5), which physically and functionally interact with N-methyl-D-Aspartate (NMDA) receptors, likewise control cognitive processes and have been proposed as targets for novel classes of antipsychotic agent. Since social cognition is impaired in schizophrenia and disrupted by NMDA receptor antagonists like dizocilpine, we evaluated its potential modulation by mGluR5. Acute administration (0.63-40 mg/kg) of the mGluR5 positive allosteric modulators (PAMs), 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) and ADX47273, reversed a delay-induced impairment in social novelty discrimination (SND) in adult rats. The action of CDPPB was blocked by the mGluR5 antagonist, 2-methyl-6-(phenylethynyl)-pyridine (2.5-10 mg/kg), and was also expressed upon microinjection into frontal cortex (0.63-10 μg/side), but not striatum. Supporting an interrelationship between mGluR5 and NMDA receptors, enhancement of SND by CDPPB was blocked by dizocilpine (0.08 mg/kg) while, reciprocally, dizocilpine-induced impairment in SND was attenuated by CDPPB (10 mg/kg). The SND deficit elicited by post-natal administration of phencyclidine (10 mg/kg, days 7-11) was reversed by CDPPB or ADX47273 in adults at week 8. This phencyclidine-induced impairment in cognition emerged in adult rats from week 7 on, and chronic, pre-symptomatic treatment of adolescent rats with CDPPB over weeks 5-6 (10 mg/kg per day) prevented the appearance of SND deficits in adults until at least week 13. In conclusion, as evaluated by a SND procedure, mGluR5 PAMs promote social cognition via actions expressed in interaction with NMDA receptors and exerted in frontal cortex. MGluR5 PAMs not only reverse but also (when given during adolescence) prevent the emergence of cognitive impairment associated with a developmental model of schizophrenia.

  20. Characterizing a neurodegenerative syndrome: primary progressive apraxia of speech

    PubMed Central

    Duffy, Joseph R.; Strand, Edythe A.; Machulda, Mary M.; Senjem, Matthew L.; Master, Ankit V.; Lowe, Val J.; Jack, Clifford R.; Whitwell, Jennifer L.

    2012-01-01

    Apraxia of speech is a disorder of speech motor planning and/or programming that is distinguishable from aphasia and dysarthria. It most commonly results from vascular insults but can occur in degenerative diseases where it has typically been subsumed under aphasia, or it occurs in the context of more widespread neurodegeneration. The aim of this study was to determine whether apraxia of speech can present as an isolated sign of neurodegenerative disease. Between July 2010 and July 2011, 37 subjects with a neurodegenerative speech and language disorder were prospectively recruited and underwent detailed speech and language, neurological, neuropsychological and neuroimaging testing. The neuroimaging battery included 3.0 tesla volumetric head magnetic resonance imaging, [18F]-fluorodeoxyglucose and [11C] Pittsburg compound B positron emission tomography scanning. Twelve subjects were identified as having apraxia of speech without any signs of aphasia based on a comprehensive battery of language tests; hence, none met criteria for primary progressive aphasia. These subjects with primary progressive apraxia of speech included eight females and four males, with a mean age of onset of 73 years (range: 49–82). There were no specific additional shared patterns of neurological or neuropsychological impairment in the subjects with primary progressive apraxia of speech, but there was individual variability. Some subjects, for example, had mild features of behavioural change, executive dysfunction, limb apraxia or Parkinsonism. Voxel-based morphometry of grey matter revealed focal atrophy of superior lateral premotor cortex and supplementary motor area. Voxel-based morphometry of white matter showed volume loss in these same regions but with extension of loss involving the inferior premotor cortex and body of the corpus callosum. These same areas of white matter loss were observed with diffusion tensor imaging analysis, which also demonstrated reduced fractional anisotropy

  1. CSF biomarkers in neurodegenerative and vascular dementias.

    PubMed

    Llorens, Franc; Schmitz, Matthias; Ferrer, Isidro; Zerr, Inga

    2016-01-01

    Neurodegenerative diseases with abnormal protein aggregates such as Alzheimer's disease, tauopathies, synucleinopathies, and prionopathies, together with vascular encephalopathies, are cause of cognitive impairment and dementia. Identification of reliable biomarkers in biological fluids, particularly in the cerebrospinal fluid (CSF), is of extreme importance in optimizing the precise early clinical diagnosis of distinct entities and predicting the outcome in particular settings. In addition, the study of CSF biomarkers is useful to identify and monitor the underlying pathological processes developing in the central nervous system of affected individuals. Evidence suggests that levels of key CSF molecules correlate, in some circumstances, with prediction, disease progression, and severity of cognitive decline. Correlation of CSF markers and underlying pathological molecular substrates in brain is an exciting field for further study. However, while some dementias such as Creutzfeldt-Jakob disease have accurate CSF biomarkers, other disease types such as dementia with Lewy bodies, vascular dementia, and frontotemporal dementia lack reliable biomarkers for their specific clinical diagnosis. PMID:27016008

  2. A Potential Alternative against Neurodegenerative Diseases: Phytodrugs

    PubMed Central

    Pérez-Hernández, Jesús; Zaldívar-Machorro, Víctor Javier; Villanueva-Porras, David; Vega-Ávila, Elisa; Chavarría, Anahí

    2016-01-01

    Neurodegenerative diseases (ND) primarily affect the neurons in the human brain secondary to oxidative stress and neuroinflammation. ND are more common and have a disproportionate impact on countries with longer life expectancies and represent the fourth highest source of overall disease burden in the high-income countries. A large majority of the medicinal plant compounds, such as polyphenols, alkaloids, and terpenes, have therapeutic properties. Polyphenols are the most common active compounds in herbs and vegetables consumed by man. The biological bioactivity of polyphenols against neurodegeneration is mainly due to its antioxidant, anti-inflammatory, and antiamyloidogenic effects. Multiple scientific studies support the use of herbal medicine in the treatment of ND; however, relevant aspects are still pending to explore such as metabolic analysis, pharmacokinetics, and brain bioavailability. PMID:26881043

  3. Antisense Gene Silencing: Therapy for Neurodegenerative Disorders?

    PubMed Central

    Nielsen, Troels T.; Nielsen, Jørgen E.

    2013-01-01

    Since the first reports that double-stranded RNAs can efficiently silence gene expression in C. elegans, the technology of RNA interference (RNAi) has been intensively exploited as an experimental tool to study gene function. With the subsequent discovery that RNAi could also be applied to mammalian cells, the technology of RNAi expanded from being a valuable experimental tool to being an applicable method for gene-specific therapeutic regulation, and much effort has been put into further refinement of the technique. This review will focus on how RNAi has developed over the years and how the technique is exploited in a pre-clinical and clinical perspective in relation to neurodegenerative disorders. PMID:24705213

  4. Effects of the hold and relax-agonist contraction technique on recovery from delayed onset muscle soreness after exercise in healthy adults

    PubMed Central

    Cha, Hyun-Gyu; Kim, Myoung-Kwon

    2015-01-01

    [Purpose] This study was conducted to verify the effects of the hold relax-agonist contraction and passive straight leg raising techniques on muscle activity, fatigue, and range of motion of the hip joint after the induction of delayed onset muscle soreness in the hamstring muscle. [Subjects] Sixty subjects were randomly assigned to a hold relax-agonist contraction group and a passive straight leg raising group. [Methods] Subjects in the experimental group underwent hold relax-agonist contraction at the hamstring muscle, while subjects in the control group underwent passive straight leg raising at the hamstring muscle. [Results] Subjects in the hold relax-agonist contraction group showed a significant increase in hamstring muscle activity and hip joint angle and a significant decrease in muscle fatigue. In the passive straight leg raising group, the hip joint angle increased significantly after the intervention. In the hold relax-agonist contraction group, hamstring muscle activity increased significantly and muscle fatigue decreased significantly. [Conclusion] We conclude that the hold relax-agonist contraction technique may be beneficial for improving muscle activation and decreasing muscle fatigue. PMID:26644691

  5. Widespread Lewy body and tau accumulation in childhood and adult onset dystonia-parkinsonism cases with PLA2G6 mutations

    PubMed Central

    Paisán-Ruiz, Coro; Li, Abi; Schneider, Susanne A.; Holton, Janice L.; Johnson, Robert; Kidd, Desmond; Chataway, Jeremy; Bhatia, Kailash P.; Lees, Andrew J.; Hardy, John; Revesz, Tamas; Houlden, Henry

    2012-01-01

    The 2 major types of neurodegeneration with brain iron accumulation (NBIA) are the pantothenate kinase type 2 (PANK2)-associated neurodegeneration (PKAN) and NBIA2 or infantile neuroaxonal dystrophy (INAD) due to mutations in the phospholipase A2, group VI (PLA2G6) gene. We have recently demonstrated clinical heterogeneity in patients with mutations in the PLA2G6 gene by identifying a poorly defined subgroup of patients who present late with dystonia and parkinsonism. We report the clinical and genetic features of 7 cases with PLA2G6 mutations. Brain was available in 5 cases with an age of death ranging from 8 to 36 years and showed widespread alpha-synuclein-positive Lewy pathology, which was particularly severe in the neocortex, indicating that the Lewy pathology spread corresponded to Braak stage 6 and was that of the “diffuse neocortical type”. In 3 cases there was hyperphosphorylated tau accumulation in both cellular processes as threads and neuronal perikarya as pretangles and neurofibrillary tangles. Later onset cases tended to have less tau involvement but still severe alpha-synuclein pathology. The clinical and neuropathological features clearly represent a link between PLA2G6 and parkinsonian disorders. PMID:20619503

  6. How many biomarkers to discriminate neurodegenerative dementia?

    PubMed

    Sancesario, Giulia M; Bernardini, Sergio

    2015-01-01

    A number of cerebrospinal fluid (CSF) biomarkers are currently used for the diagnosis of dementia. Opposite changes in the level of amyloid-β(1-42) versus total tau and phosphorylated-tau181 in the CSF reflect the specific pathology of Alzheimer's disease (AD) in the brain. This panel of biomarkers has proven to be effective to differentiate AD from controls and from the major types of neurodegenerative dementia, and to evaluate the progression from mild cognitive impairment to AD. In the absence of specific biomarkers reflecting the pathologies of the other most common forms of dementia, such as Lewy Body disease, Frontotemporal lobar degeneration, Creutzfeldt-Jakob disease, etc., the evaluation of biomarkers of AD pathology is used, attempting to exclude rather than to confirm AD. Other biomarkers included in the common clinical practice do not clearly relate to the underlying pathology: progranulin (PGRN) is a selective marker of frontotemporal dementia with mutations in the PGRN gene; the 14-3-3 protein is a highly sensitive and specific marker for Creutzfeldt-Jakob disease, but has to be used carefully in differentiating rapid progressive dementia; and α-synuclein is an emerging candidate biomarker of the different forms of synucleinopathy. This review summarizes several biomarkers of neurodegenerative dementia validated based on the neuropathological processes occurring in brain tissue. Notwithstanding the paucity of pathologically validated biomarkers and their high analytical variability, the combinations of these biomarkers may well represent a key and more precise analytical and diagnostic tool in the complex plethora of degenerative dementia. PMID:26292074

  7. Onset Age of Obesity and Variables of Personality and Biography.

    ERIC Educational Resources Information Center

    Steinberg, Carol

    Three hypotheses derived from Hilde Bruch's formulations regarding onset differences among the obese were tested. In Bruch's theory, adult-onset, or reactive, obesity is a result of psychological trauma; the individual uses eating as a defense against anxiety and depression. Child-onset, or developmental, obesity results from a mixture of…

  8. Effects of priming exercise on the speed of adjustment of muscle oxidative metabolism at the onset of moderate-intensity step transitions in older adults.

    PubMed

    De Roia, Gabriela; Pogliaghi, Silvia; Adami, Alessandra; Papadopoulou, Christina; Capelli, Carlo

    2012-05-15

    Aging is associated with a functional decline of the oxidative metabolism due to progressive limitations of both O(2) delivery and utilization. Priming exercise (PE) increases the speed of adjustment of oxidative metabolism during successive moderate-intensity transitions. We tested the hypothesis that such improvement is due to a better matching of O(2) delivery to utilization within the working muscles. In 21 healthy older adults (65.7 ± 5 yr), we measured contemporaneously noninvasive indexes of the overall speed of adjustment of the oxidative metabolism (i.e., pulmonary Vo(2) kinetics), of the bulk O(2) delivery (i.e., cardiac output), and of the rate of muscle deoxygenation (i.e., deoxygenated hemoglobin, HHb) during moderate-intensity step transitions, either with (ModB) or without (ModA) prior PE. The local matching of O(2) delivery to utilization was evaluated by the ΔHHb/ΔVo(2) ratio index. The overall speed of adjustment of the Vo(2) kinetics was significantly increased in ModB compared with ModA (P < 0.05). On the contrary, the kinetics of cardiac output was unaffected by PE. At the muscle level, ModB was associated with a significant reduction of the "overshoot" in the ΔHHb/ΔVo(2) ratio compared with ModA (P < 0.05), suggesting an improved O(2) delivery. Our data are compatible with the hypothesis that, in older adults, PE, prior to moderate-intensity exercise, beneficially affects the speed of adjustment of oxidative metabolism due to an acute improvement of the local matching of O(2) delivery to utilization.

  9. Genistein Improves Neuropathology and Corrects Behaviour in a Mouse Model of Neurodegenerative Metabolic Disease

    PubMed Central

    Langford-Smith, Kia J.; Langford-Smith, Alex; Brown, Jillian R.; Crawford, Brett E.; Vanier, Marie T.; Grynkiewicz, Grzegorz; Wynn, Rob F.; Wraith, J. Ed; Wegrzyn, Grzegorz; Bigger, Brian W.

    2010-01-01

    Background Neurodegenerative metabolic disorders such as mucopolysaccharidosis IIIB (MPSIIIB or Sanfilippo disease) accumulate undegraded substrates in the brain and are often unresponsive to enzyme replacement treatments due to the impermeability of the blood brain barrier to enzyme. MPSIIIB is characterised by behavioural difficulties, cognitive and later motor decline, with death in the second decade of life. Most of these neurodegenerative lysosomal storage diseases lack effective treatments. We recently described significant reductions of accumulated heparan sulphate substrate in liver of a mouse model of MPSIIIB using the tyrosine kinase inhibitor genistein. Methodology/Principal Findings We report here that high doses of genistein aglycone, given continuously over a 9 month period to MPSIIIB mice, significantly reduce lysosomal storage, heparan sulphate substrate and neuroinflammation in the cerebral cortex and hippocampus, resulting in correction of the behavioural defects observed. Improvements in synaptic vesicle protein expression and secondary storage in the cerebral cortex were also observed. Conclusions/Significance Genistein may prove useful as a substrate reduction agent to delay clinical onset of MPSIIIB and, due to its multimodal action, may provide a treatment adjunct for several other neurodegenerative metabolic diseases. PMID:21152017

  10. The role of induced pluripotent stem cells in regenerative medicine: neurodegenerative diseases.

    PubMed

    Peng, Jun; Zeng, Xianmin

    2011-07-28

    Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and Friedreich's ataxia are the most common human neurodegenerative diseases pathologically characterized by a progressive and specific loss of certain neuronal populations. The exact mechanisms of neuronal cell death in these diseases are unclear, although some forms of the diseases are inherited and genes causing these diseases have been identified. Currently there are no effective clinical therapies for many of these diseases. The recently acquired ability to reprogram human adult somatic cells to induced pluripotent stem cells (iPSCs) in culture may provide a powerful tool for in vitro neurodegenerative disease modeling and an unlimited source for cell replacement therapy. In the present review, we summarize recent progress on iPSC generation and differentiation into neuronal cell types and discuss the potential application for in vitro disease mechanism study and in vivo cell replacement therapy.

  11. Natural history of adult-onset Ménétrier's disease: Report of a case with 9-year follow-up

    PubMed Central

    XIONG, LI-SHOU; GONG, YING-YING

    2016-01-01

    Ménétrier's disease (MD) is a rare disease characterized by markedly hypertrophied gastric mucosal folds typically associated with hypoalbuminemia and anemia. However, the natural history of MD in adults remains unclear and is rarely reported in the literature. The current study presents a case of MD with a 9-year follow-up. A 56-year-old man was diagnosed with MD in 2005. The patient was followed up and underwent surveillance endoscopy once or twice each year. In the present case, the anemia and hypoproteinemia were eliminated following red blood cell transfusion and intravenous iron therapies. The symptoms were relieved after 4 years. Treatment with octreotide had little effect on the gastric mucosa, while antimicrobial combination therapy provided no benefit in the present H. pylori-negative case of MD. In addition, despite abnormalities of the gastric mucosa in the patient persisting after 9 years of follow-up with no evidence of malignancy, malignant transformation in MD should not be overlooked, and regular monitoring of the gastric mucosa via endoscopy is necessary. PMID:27284333

  12. HLA-DRB1 and HLA-DQB1 Are Associated with Adult-Onset Immunodeficiency with Acquired Anti-Interferon-Gamma Autoantibodies

    PubMed Central

    Pithukpakorn, Manop; Roothumnong, Ekkapong; Angkasekwinai, Nasikarn; Suktitipat, Bhoom; Assawamakin, Anunchai; Luangwedchakarn, Voravich; Umrod, Pinklow; Thongnoppakhun, Wanna; Foongladda, Suporn; Suputtamongkol, Yupin

    2015-01-01

    Recently a newly identified clinical syndrome of disseminated non-tuberculous mycobacterial diseases (with or without other opportunistic infections in adult patients who were previously healthy, has been recognized in association with an acquired autoantibody to interferon-gamma. This syndrome is emerging as an important cause of morbidity and mortality, especially among people of Asian descent. Trigger for the production of this autoantibody remains unknown, but genetic factors are strongly suspected to be involved. We compared HLA genotyping between 32 patients with this clinical syndrome, and 38 controls. We found that this clinical syndrome was associated with very limited allele polymorphism, with HLA-DRB1 and DQB1 alleles, especially HLA-DRB1*15:01, DRB1*16:02, DQB1*05:01 and DQB1*05:02. Odds ratio of DRB1*15:01, DRB1*16:02, DQB1*05:01 and DQB1*05:02 were 7.03 (95% CI, 2.18–22.69, P<0.0001, 9.06 (95% CI, 2.79–29.46, P<0.0001), 6.68 (95% CI, 2.29–19.52, P = 0.0004), and 6.64 (95% CI, 2.30–19.20, P = 0.0004), respectively. Further investigation is warranted to provide better understanding on pathogenesis of this association. PMID:26011559

  13. Role of Copper and Cholesterol Association in the Neurodegenerative Process

    PubMed Central

    Morel, Gustavo R.; de Alaniz, María J. T.; Castillo, Omar; Marra, Carlos A.

    2013-01-01

    Age is one of the main factors involved in the development of neurological illnesses, in particular, Alzheimer, and it is widely held that the rapid aging of the world population is accompanied by a rise in the prevalence and incidence of Alzheimer disease. However, evidence from recent decades indicates that Cu and Cho overload are emerging causative factors in neurodegeneration, a hypothesis that has been partially investigated in experimental models. The link between these two variables and the onset of Alzheimer disease has opened up interesting new possibilities requiring more in-depth analysis. The aim of the present study was therefore to investigate the effect of the association of Cu + Cho (CuCho) as a possible synergistic factor in the development of an Alzheimer-like pathology in Wistar rats. We measured total- and nonceruloplasmin-bound Cu and Cho (free and sterified) contents in plasma and brain zones (cortex and hippocampus), markers of oxidative stress damage, inflammation, and programmed cell death (caspase-3 and calpain isoforms). The ratio beta-amyloid (1-42)/(1-40) was determined in plasma and brain as neurodegenerative biomarker. An evaluation of visuospatial memory (Barnes maze test) was also performed. The results demonstrate the establishment of a prooxidative and proinflammatory environment after CuCho treatment, hallmarked by increased TBARS, protein carbonyls, and nitrite plus nitrate levels in plasma and brain zones (cortex and hippocampus) with a consequent increase in the activity of calpains and no significant changes in caspase-3. A simultaneous increase in the plasma Aβ1-42/Aβ1-40 ratio was found. Furthermore, a slight but noticeable change in visuospatial memory was observed in rats treated with CuCho. We conclude that our model could reflect an initial stage of neurodegeneration in which Cu and Cho interact with one another to exacerbate neurological damage. PMID:24288650

  14. Human DNA methylomes of neurodegenerative diseases show common epigenomic patterns

    PubMed Central

    Sanchez-Mut, J V; Heyn, H; Vidal, E; Moran, S; Sayols, S; Delgado-Morales, R; Schultz, M D; Ansoleaga, B; Garcia-Esparcia, P; Pons-Espinal, M; de Lagran, M M; Dopazo, J; Rabano, A; Avila, J; Dierssen, M; Lott, I; Ferrer, I; Ecker, J R; Esteller, M

    2016-01-01

    Different neurodegenerative disorders often show similar lesions, such as the presence of amyloid plaques, TAU-neurotangles and synuclein inclusions. The genetically inherited forms are rare, so we wondered whether shared epigenetic aberrations, such as those affecting DNA methylation, might also exist. The studied samples were gray matter samples from the prefrontal cortex of control and neurodegenerative disease-associated cases. We performed the DNA methylation analyses of Alzheimer's disease, dementia with Lewy bodies, Parkinson's disease and Alzheimer-like neurodegenerative profile associated with Down's syndrome samples. The DNA methylation landscapes obtained show that neurodegenerative diseases share similar aberrant CpG methylation shifts targeting a defined gene set. Our findings suggest that neurodegenerative disorders might have similar pathogenetic mechanisms that subsequently evolve into different clinical entities. The identified aberrant DNA methylation changes can be used as biomarkers of the disorders and as potential new targets for the development of new therapies. PMID:26784972

  15. The Role of Oxidative Stress in Neurodegenerative Diseases

    PubMed Central

    Kim, Geon Ha; Kim, Jieun E.; Rhie, Sandy Jeong

    2015-01-01

    Oxidative stress is induced by an imbalanced redox states, involving either excessive generation of reactive oxygen species (ROS) or dysfunction of the antioxidant system. The brain is one of organs especially vulnerable to the effects of ROS because of its high oxygen demand and its abundance of peroxidation-susceptible lipid cells. Previous studies have demonstrated that oxidative stress plays a central role in a common pathophysiology of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Antioxidant therapy has been suggested for the prevention and treatment of neurodegenerative diseases, although the results with regard to their efficacy of treating neurodegenerative disease have been inconsistent. In this review, we will discuss the role of oxidative stress in the pathophysiology of neurodegenerative diseases and in vivo measurement of an index of damage by oxidative stress. Moreover, the present knowledge on antioxidant in the treatment of neurodegenerative diseases and future directions will be outlined. PMID:26713080

  16. The cognitive spectrum in neurodegenerative Langerhans cell histiocytosis.

    PubMed

    Le Guennec, Loïc; Decaix, Caroline; Donadieu, Jean; Santiago-Ribeiro, Maria; Martin-Duverneuil, Nadine; Levy, Richard; Delgadillo, Daniel; Kas, Aurélie; Drier, Aurélie; Magy, Laurent; Bayen, Eleonore; Hoang-Xuan, Khe; Idbaih, Ahmed

    2014-08-01

    Clinical spectrum of cognitive troubles complicating neurodegenerative Langerhans cell histiocytosis (ND-LCH) is poorly known. The aim of this study is to evaluate cognitive functions in ND-LCH. The cognitive functions of a series of eight adult patients (7 males and 1 female; mean age 26 years IQ 25-75; range 20-33) suffering from clinical and/or radiological ND-LCH were evaluated using the following tests: (1) forward/backward digit and spatial span tasks of the WAIS-R scale and the Corsi block task, (2) the French version of the free and cued selective reminding test, (3) verbal fluency tests, (4) the Frontal Assessment Battery (FAB), (5) backward measurement of the verbal and visuospatial memories of the WAIS-R scale, (6) the Rey complex figure test, (7) the trail making tests A and B, (8) digit symbol and symbol search of the WAIS-IV scale, and (9) the Stroop test. Episodic (i.e. autobiographical or personal) memory free recall, categorical verbal fluency, phonological verbal fluency, visuospatial processing skills, attention, speed of processing, and sensitivity to interference were impaired in ND-LCH patients. In contrast, verbal and visuospatial short-term memories (i.e. immediate memories or forward span tasks) were preserved in all patients. Adult ND-LCH patients suffer from a severe but dissociated dysexecutive syndrome, mostly affecting executive strategies and relatively sparing short-term memory. Our study supports the need of assessing executive functions using comprehensive cognitive evaluation in ND-LCH patients for early diagnosis. PMID:24848633

  17. The cognitive spectrum in neurodegenerative Langerhans cell histiocytosis.

    PubMed

    Le Guennec, Loïc; Decaix, Caroline; Donadieu, Jean; Santiago-Ribeiro, Maria; Martin-Duverneuil, Nadine; Levy, Richard; Delgadillo, Daniel; Kas, Aurélie; Drier, Aurélie; Magy, Laurent; Bayen, Eleonore; Hoang-Xuan, Khe; Idbaih, Ahmed

    2014-08-01

    Clinical spectrum of cognitive troubles complicating neurodegenerative Langerhans cell histiocytosis (ND-LCH) is poorly known. The aim of this study is to evaluate cognitive functions in ND-LCH. The cognitive functions of a series of eight adult patients (7 males and 1 female; mean age 26 years IQ 25-75; range 20-33) suffering from clinical and/or radiological ND-LCH were evaluated using the following tests: (1) forward/backward digit and spatial span tasks of the WAIS-R scale and the Corsi block task, (2) the French version of the free and cued selective reminding test, (3) verbal fluency tests, (4) the Frontal Assessment Battery (FAB), (5) backward measurement of the verbal and visuospatial memories of the WAIS-R scale, (6) the Rey complex figure test, (7) the trail making tests A and B, (8) digit symbol and symbol search of the WAIS-IV scale, and (9) the Stroop test. Episodic (i.e. autobiographical or personal) memory free recall, categorical verbal fluency, phonological verbal fluency, visuospatial processing skills, attention, speed of processing, and sensitivity to interference were impaired in ND-LCH patients. In contrast, verbal and visuospatial short-term memories (i.e. immediate memories or forward span tasks) were preserved in all patients. Adult ND-LCH patients suffer from a severe but dissociated dysexecutive syndrome, mostly affecting executive strategies and relatively sparing short-term memory. Our study supports the need of assessing executive functions using comprehensive cognitive evaluation in ND-LCH patients for early diagnosis.

  18. Childhood Onset Schizophrenia: Clinical Features, Course and Outcome

    ERIC Educational Resources Information Center

    Sood, Mamta; Kattimani, Shivanand

    2008-01-01

    Schizophrenia in children is diagnosed by using adult criteria. Based on the age of onset, patients with childhood onset schizophrenia (COS) are subdivided into those with very early onset (before age 12-14 years) and those with early onset (between 14-17 years). The prevalence of COS is reported to be 1 in 10,000 before the age of 12 years;…

  19. Tau Hyperphosphorylation and Oxidative Stress, a Critical Vicious Circle in Neurodegenerative Tauopathies?

    PubMed Central

    Alavi Naini, Seyedeh Maryam; Soussi-Yanicostas, Nadia

    2015-01-01

    Hyperphosphorylation and aggregation of the microtubule-associated protein tau in brain, are pathological hallmarks of a large family of neurodegenerative disorders, named tauopathies, which include Alzheimer's disease. It has been shown that increased phosphorylation of tau destabilizes tau-microtubule interactions, leading to microtubule instability, transport defects along microtubules, and ultimately neuronal death. However, although mutations of the MAPT gene have been detected in familial early-onset tauopathies, causative events in the more frequent sporadic late-onset forms and relationships between tau hyperphosphorylation and neurodegeneration remain largely elusive. Oxidative stress is a further pathological hallmark of tauopathies, but its precise role in the disease process is poorly understood. Another open question is the source of reactive oxygen species, which induce oxidative stress in brain neurons. Mitochondria have been classically viewed as a major source for oxidative stress, but microglial cells were recently identified as reactive oxygen species producers in tauopathies. Here we review the complex relationships between tau pathology and oxidative stress, placing emphasis on (i) tau protein function, (ii) origin and consequences of reactive oxygen species production, and (iii) links between tau phosphorylation and oxidative stress. Further, we go on to discuss the hypothesis that tau hyperphosphorylation and oxidative stress are two key components of a vicious circle, crucial in neurodegenerative tauopathies. PMID:26576216

  20. Cerebral Toxocariasis: Silent Progression to Neurodegenerative Disorders?

    PubMed Central

    Holland, Celia V.; Loxton, Karen; Barghouth, Ursula

    2015-01-01

    SUMMARY Toxocara canis and T. cati are highly prevalent nematode infections of the intestines of dogs and cats. In paratenic hosts, larvae do not mature in the intestine but instead migrate through the somatic tissues and organs of the body. The presence of these migrating larvae can contribute to pathology. Toxocara larvae can invade the brains of humans, and while case descriptions of cerebral toxocariasis are historically rare, improved diagnosis and greater awareness have contributed to increased detection. Despite this, cerebral or neurological toxocariasis (NT) remains a poorly understood phenomenon. Furthermore, our understanding of cognitive deficits due to toxocariasis in human populations remains particularly deficient. Recent data describe an enhanced expression of biomarkers associated with brain injury, such as GFAP, AβPP, transforming growth factor β1 (TGF-β1), NF-L, S100B, tTG, and p-tau, in mice receiving even low doses of Toxocara ova. Finally, this review outlines a hypothesis to explore the relationship between the presence of T. canis larvae in the brain and the progression of Alzheimer's disease (AD) due to enhanced AD-associated neurodegenerative biomarker expression. PMID:26062575

  1. microRNAs and Neurodegenerative Diseases.

    PubMed

    Qiu, Lifeng; Tan, Eng King; Zeng, Li

    2015-01-01

    microRNAs (miRNAs) are small, noncoding RNA molecules that through imperfect base-pairing with complementary sequences of target mRNA molecules, typically cleave target mRNA, causing subsequent degradation or translation inhibition. Although an increasing number of studies have identified misregulated miRNAs in the neurodegenerative diseases (NDDs) Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, which suggests that alterations in the miRNA regulatory pathway could contribute to disease pathogenesis, the molecular mechanisms underlying the pathological implications of misregulated miRNA expression and the regulation of the key genes involved in NDDs remain largely unknown. In this chapter, we provide evidence of the function and regulation of miRNAs and their association with the neurological events in NDDs. This will help improve our understanding of how miRNAs govern the biological functions of key pathogenic genes in these diseases, which potentially regulate several pathways involved in the progression of neurodegeneration. Additionally, given the growing interest in the therapeutic potential of miRNAs, we discuss current clinical challenges to developing miRNA-based therapeutics for NDDs.

  2. Adaptive Immunity in Neurodegenerative and Neuropsychological Disorders.

    PubMed

    Mosley, R Lee

    2015-12-01

    Neurodegenerative and neuropsychological disorders are becoming a greater proportion of the global disease burden; however the pathogenic mechanisms by which these disorders originate and contribute to disease progression are not well-described. Increasing evidence supports neuroinflammation as a common underlying component associated with the neuropathological processes that effect disease progression. This collection of articles explores the role of adaptive immunity in autoimmunity, neurodegeneration, neurotrauma, and psychological disorders. The section emphasizes the interactions of T cells with innate cellular responses within the CNS and the effects on neurological functions. One recurrent theme is that modified and aggregated self-proteins upregulate innate-mediated inflammation and provide a permissive environment for polarization of T cells to proinflammatory effector cells. Moreover, infiltration and reactivation of those T effector cells exacerbate neuroinflammation and oxidative stress to greater neurotoxic levels. Another recurrent theme in these disorders promotes diminished regulatory functions that reduce control over activated T effector cells and microglia, and ultimately augment proinflammatory conditions. Augmentation of regulatory control is discussed as therapeutic strategies to attenuate neuroinflammation, mitigate neurodegeneration or neuronal dysfunction, and lessen disease progression.

  3. History of innate immunity in neurodegenerative disorders.

    PubMed

    McGeer, Patrick L; McGeer, Edith G

    2011-01-01

    The foundations of innate immunity in neurodegenerative disorders were first laid by Del Rio Hortega (1919). He identified and named microglia, recognizing them as cells of mesodermal origin. Van Furth in 1969 elaborated the monocyte phagocytic system with microglia as the brain representatives. Validation of these concepts did not occur until 1987 when HLA-DR was identified on activated microglia in a spectrum of neurological disorders. HLA-DR had already been established as a definitive marker of immunocompetent cells of mesodermal origin. It was soon determined that the observed inflammatory reaction was an innate immune response. A rapid expansion of the field took place as other markers of an innate immune response were found that were made by neurons, astrocytes, oligodendroglia, and endothelial cells. The molecules included complement proteins and their regulators, inflammatory cytokines, chemokines, acute phase reactants, prostaglandins, proteases, protease inhibitors, coagulation factors, fibrinolytic factors, anaphylatoxins, integrins, free radical generators, and other unidentified neurotoxins. The Nimmerjahn movies demonstrated that resting microglia were constantly active, sampling the surround, and responding rapidly to brain damage. Ways of reducing the neurotoxic innate immune response and stimulating a healing response continue to be sought as a means for ameliorating the pathology in a spectrum of chronic degenerative disorders. PMID:22144960

  4. Role of apolipoprotein E in neurodegenerative diseases

    PubMed Central

    Giau, Vo Van; Bagyinszky, Eva; An, Seong Soo A; Kim, Sang Yun

    2015-01-01

    Apolipoprotein E (APOE) is a lipid-transport protein abundantly expressed in most neurons in the central nervous system. APOE-dependent alterations of the endocytic pathway can affect different functions. APOE binds to cell-surface receptors to deliver lipids and to the hydrophobic amyloid-β peptide, regulating amyloid-β aggregations and clearances in the brain. Several APOE isoforms with major structural differences were discovered and shown to influence the brain lipid transport, glucose metabolism, neuronal signaling, neuroinflammation, and mitochondrial function. This review will summarize the updated research progress on APOE functions and its role in Alzheimer’s disease, Parkinson’s disease, cardiovascular diseases, multiple sclerosis, type 2 diabetes mellitus, Type III hyperlipoproteinemia, vascular dementia, and ischemic stroke. Understanding the mutations in APOE, their structural properties, and their isoforms is important to determine its role in various diseases and to advance the development of therapeutic strategies. Targeting APOE may be a potential approach for diagnosis, risk assessment, prevention, and treatment of various neurodegenerative and cardiovascular diseases in humans. PMID:26213471

  5. Biomolecular Modulation of Neurodegenerative Events during Ageing.

    PubMed

    Nebbioso, Marcella; Scarsella, Gianfranco; Librando, Aloisa; Pescosolido, Nicola

    2015-01-01

    The objective is to assess the modulation of retinal and optic nerve degenerative events induced by the combination of α-lipoic acid (ALA) and superoxide dismutase (SOD) in an animal model of ageing. For this study, 24 male Wistar-Harlan strain rats were left to age for up to 24 months. One group of rats was subjected to a diet supplemented with ALA and SOD for 8 weeks, while another group was used as a positive control and not subjected to any dietary treatment. To assess the cytoprotective effects of the antioxidants, a morphological analysis was carried out on sections of retina and optic nerve head, stained with haematoxylin-eosin, followed by an analysis of the modifications to nuclear DNA detected by the TUNEL technique. The lipid peroxidation assay was used to assess the damage induced by oxidative stress at cell membrane level. The molecules involved in apoptosis mediated by oxidative stress, such as caspase-3 and inducible nitric oxide synthase, were also assayed by immunolocalization and western blot. ALA and SOD are able to counteract senile neurodegenerative deterioration to the retina and optic nerve. Indeed, the combination of these antioxidant molecules can reduce oxidative stress levels and thus prevent both nuclear degradation and subsequent cell death.

  6. Structural anatomy of empathy in neurodegenerative disease.

    PubMed

    Rankin, Katherine P; Gorno-Tempini, Maria Luisa; Allison, Stephen C; Stanley, Christine M; Glenn, Shenly; Weiner, Michael W; Miller, Bruce L

    2006-11-01

    Empathy is a complex social behaviour mediated by a network of brain structures. Recently, several functional imaging studies have investigated the neural basis of empathy, but few corroborative human lesion studies exist. Severe empathy loss is a common feature of frontotemporal lobar degeneration (FTLD), and is also seen in other neurodegenerative diseases. In this study, the neuroanatomic basis of empathy was investigated in 123 patients with FTLD, Alzheimer's disease, corticobasal degeneration and progressive supranuclear palsy using the Interpersonal Reactivity Index (IRI). IRI Empathic Concern and Perspective taking scores were correlated with structural MRI brain volume using voxel-based morphometry. Voxels in the right temporal pole, the right fusiform gyrus, the right caudate and right subcallosal gyrus correlated significantly with total empathy score (P < 0.05 after whole-brain correction for multiple comparisons). Empathy score correlated positively with the volume of right temporal structures in semantic dementia, and with subcallosal gyrus volume in frontotemporal dementia. These findings are consistent with previous research suggesting that a primarily right frontotemporal network of brain regions is involved in emotion processing, and highlights the roles of the right temporal pole and inferior frontal/striatal regions in regulating complex social interactions. This is the first large-scale lesion study to investigate the neural basis of empathy using correlational analytic methods. The results suggest that the right anterior temporal and medial frontal regions are essential for real-life empathic behaviour.

  7. Biomolecular Modulation of Neurodegenerative Events during Ageing

    PubMed Central

    Nebbioso, Marcella; Scarsella, Gianfranco; Librando, Aloisa; Pescosolido, Nicola

    2015-01-01

    The objective is to assess the modulation of retinal and optic nerve degenerative events induced by the combination of α-lipoic acid (ALA) and superoxide dismutase (SOD) in an animal model of ageing. For this study, 24 male Wistar-Harlan strain rats were left to age for up to 24 months. One group of rats was subjected to a diet supplemented with ALA and SOD for 8 weeks, while another group was used as a positive control and not subjected to any dietary treatment. To assess the cytoprotective effects of the antioxidants, a morphological analysis was carried out on sections of retina and optic nerve head, stained with haematoxylin-eosin, followed by an analysis of the modifications to nuclear DNA detected by the TUNEL technique. The lipid peroxidation assay was used to assess the damage induced by oxidative stress at cell membrane level. The molecules involved in apoptosis mediated by oxidative stress, such as caspase-3 and inducible nitric oxide synthase, were also assayed by immunolocalization and western blot. ALA and SOD are able to counteract senile neurodegenerative deterioration to the retina and optic nerve. Indeed, the combination of these antioxidant molecules can reduce oxidative stress levels and thus prevent both nuclear degradation and subsequent cell death. PMID:26583065

  8. Apolipoprotein E genotype in diverse neurodegenerative disorders.

    PubMed

    Schneider, J A; Gearing, M; Robbins, R S; de l'Aune, W; Mirra, S S

    1995-07-01

    While the apolipoprotein E (ApoE) epsilon 4 allele is a recognized risk factor for Alzheimer's disease (AD), an association of epsilon 4 with other neurodegenerative diseases (NDs) has not been extensively explored. We examined 51 cases of neuropathologically confirmed ND. After eliminating 18 cases exhibiting pathology sufficient to warrant an additional diagnosis of AD, three disorders characterized by tau-related cytoskeletal pathology, i.e., Pick's disease, corticobasal degeneration, and progressive supra-nuclear palsy, showed increased epsilon 4 frequencies. Since the number of cases within each category was small, these increased epsilon 4 frequencies were not statistically significant. beta-Amyloid (beta A4) immunoreactive diffuse plaques were observed in many of these cases. While we cannot eliminate the possibility that these patients were destined to develop AD, these changes may merely reflect an independent association of epsilon 4 with amyloid deposition. These preliminary data affirm the need for further study of well-characterized cases to explore the relationship of ApoE to cytoskeletal pathology and ND. PMID:7611717

  9. Early-Onset Alzheimer's

    MedlinePlus

    MENU Return to Web version Early-Onset Alzheimer’s What is early-onset Alzheimer’s disease? Early-onset Alzheimer’s disease is when Alzheimer’s affects a person younger than 65 years of age. People ...

  10. Palliative care management of a child with juvenile onset Huntington's disease.

    PubMed

    King, Nicola

    2005-06-01

    This is a case report of the palliative care management of a 13-year-old girl who died of juvenile onset Huntington's disease in a children's hospice in the southeast of England. It outlines her disease progression and describes the care that she received. In particular, the medications and other measures used to control her symptoms during her last 10 days are discussed. The article also explores some of the ethical difficulties of caring for children dying from degenerative disorders. Although juvenile onset Huntington's disease is an extremely rare condition, the issues around terminal care management are very similar to those for any neuro-degenerative disorder, whether in an adult or child. A number of children's hospices have opened in the last 10-15 years in the UK. They accept children with a wide range of life-limiting conditions and have become experts in offering respite care and symptom control to these children and their families. They are chosen increasingly as the place of death for such children.

  11. Fetal programming of the human brain: is there a link with insurgence of neurodegenerative disorders in adulthood?

    PubMed

    Faa, G; Marcialis, M A; Ravarino, A; Piras, M; Pintus, M C; Fanos, V

    2014-01-01

    In recent years, evidence is growing on the role played by gestational factors in shaping brain development and on the influence of intrauterine experiences on later development of neurodegenerative diseases including Parkinson's (PD) and Alzheimer's disease (AD). The nine months of intrauterine development and the first three years of postnatal life are appearing to be extremely critical for making connections among neurons and among neuronal and glial cells that will shape a lifetime of experience. Here, the multiple epigenetic factors acting during gestation - including maternal diet, malnutrition, stress, hypertension, maternal diabetes, fetal hypoxia, prematurity, low birth weight, prenatal infection, intrauterine growth restriction, drugs administered to the mother or to the baby - are reported, and their ability to modulate brain development, resulting in interindividual variability in the total neuronal and glial burden at birth is discussed. Data from recent literature suggest that prevention of neurodegeneration should be identified as the one method to halt the diffusion of neurodegenerative diseases. The "two hits" hypothesis, first introduced for PD and successfully applied to AD and other neurodegenerative human pathologies, should focus our attention on a peculiar period of our life: the intrauterine and perinatal periods. The first hit to our nervous system occurs early in life, determining a PD or AD imprinting to our brain that will condition our resistance or, alternatively, our susceptibility to develop a neurodegenerative disease later in life. In conclusion, how early life events contribute to late-life development of adult neurodegenerative diseases, including PD and AD, is emerging as a new fascinating research focus. This assumption implies that research on prevention of neurodegenerative diseases should center on events taking place early in life, during gestation and in the perinatal periods, thus presenting a new challenge to

  12. Drosophila as a model for human neurodegenerative disease.

    PubMed

    Bilen, Julide; Bonini, Nancy M

    2005-01-01

    Among many achievements in the neurodegeneration field in the past decade, two require special attention due to the huge impact on our understanding of molecular and cellular pathogenesis of human neurodegenerative diseases. First is defining specific mutations in familial neurodegenerative diseases and second is modeling these diseases in easily manipulable model organisms including the fruit fly, nematode, and yeast. The power of these genetic systems has revealed many genetic factors involved in the various pathways affected, as well as provided potential drug targets for therapeutics. This review focuses on fruit fly models of human neurodegenerative diseases, with emphasis on how fly models have provided new insights into various aspects of human diseases.

  13. Molecular imaging of stem cell transplantation for neurodegenerative diseases.

    PubMed

    Wang, Ping; Moore, Anna

    2012-01-01

    Cell replacement therapy with stem cells holds tremendous therapeutic potential for treating neurodegenerative diseases. Over the last decade, molecular imaging techniques have proven to be of great value in tracking transplanted cells and assessing the therapeutic efficacy. This current review summarizes the role and capabilities of different molecular imaging modalities including optical imaging, nuclear imaging and magnetic resonance imaging in the field of stem cell therapy for neurodegenerative disorders. We discuss current challenges and perspectives of these techniques and encompass updated information such as theranostic imaging and optogenetics in stem cell-based treatment of neurodegenerative diseases.

  14. H-ferritin and CD68(+) /H-ferritin(+) monocytes/macrophages are increased in the skin of adult-onset Still's disease patients and correlate with the multi-visceral involvement of the disease.

    PubMed

    Ruscitti, P; Cipriani, P; Ciccia, F; Di Benedetto, P; Liakouli, V; Berardicurti, O; Carubbi, F; Guggino, G; Di Bartolomeo, S; Triolo, G; Giacomelli, R

    2016-10-01

    Adult-onset Still's disease (AOSD) patients may show an evanescent salmon-pink erythema appearing during febrile attacks and reducing without fever. Some patients may experience this eruption for many weeks. During AOSD, exceptionally high serum levels of ferritin may be observed; it is an iron storage protein composed of 24 subunits, heavy (H) subunits and light (L) subunits. The ferritin enriched in L subunits (L-ferritin) and the ferritin enriched in H subunits (H-ferritin) may be observed in different tissues. In this work, we aimed to investigate the skin expression of both H-and L-ferritin and the number of macrophages expressing these molecules from AOSD patients with persistent cutaneous lesions. We observed an increased expression of H-ferritin in the skin, associated with an infiltrate in the biopsies obtained from persistent cutaneous lesions of AOSD patients. Furthermore, a positive correlation between H-ferritin skin levels as well as the number of CD68(+) /H-ferritin(+) cells and the multi-visceral involvement of the disease was observed. Our data showed an increased expression of H-ferritin in the skin of AOSD patients, associated with a strong infiltrate of CD68(+) /H-ferritin(+) cells. Furthermore, a correlation between the levels of H-ferritin as well as of the number of CD68(+) /H-ferritin(+) cells and the multi-visceral involvement of the disease was observed. PMID:27317930

  15. A case of extranodal NK/T-cell lymphoma, nasal type mimicking typical manifestations of adult-onset Still's disease (AOSD) with hemophagocytic syndrome: diagnostic consideration between malignant lymphoma without lymphadenopathy and AOSD.

    PubMed

    Kato, Takashi; Tanabe, Juichi; Kanemoto, Motoko; Kobayashi, Chiharu; Morita, Sho; Karahashi, Taro

    2009-01-01

    A 25-year-old Japanese man was suffering from high fever, sore throat, arthralgia, and macular salmon-pink eruption. The superficial lymph node was not palpable, and computed tomographic scans from the neck to pelvis demonstrated hepatosplenomegaly without apparent lymphadenopathy. Therefore, the possibility of malignant lymphoma was considered to be extremely low. Serology for Epstein Barr virus (EBV) and cytomegalovirus showed a postinfectious state, and blood culture was negative. Serum rheumatoid factor and antinuclear antibody were negative. Leukocytopenia (2.4 x 10(3)/mul) was observed, and thus a diagnosis of adult-onset Still's disease (AOSD) with hemophagocytic syndrome (HPS) was made. Fifty-five milligrams of prednisolone daily improved his symptoms and leukocytopenia promptly, but high fever with severe and progressive thrombocytopenia occurred 12 days later. Bone marrow aspiration revealed the presence of lymphoma cells and hemophagocytosis, and the CD45 gating analysis showed expanding population of CD2(+), CD3(-), and CD56(+) cells. Further, mucosal ulceration in the nasal cavity was detected. Therefore, a diagnosis of extranodal natural killer (NK)/T-cell lymphoma, nasal type, concomitant with HPS was made, and treatment with dexamethasone, etoposide, ifosfamide, carboplatin (DeVIC) regimen ameliorated his symptoms and platelet transfusion dependency. Later, a high titer of serum EBV-DNA was detected, which supported the diagnosis. Diagnosing AOSD, extranodal presentation of malignant lymphoma such as extranodal NK/T-cell lymphoma, nasal type, should be carefully considered. PMID:19609486

  16. Why neurodegenerative diseases are progressive: uncontrolled inflammation drives disease progression

    PubMed Central

    Gao, Hui-Ming; Hong, Jau-Shyong

    2016-01-01

    Neurodegenerative diseases are a group of chronic, progressive disorders characterized by the gradual loss of neurons in discrete areas of the central nervous system (CNS). The mechanism(s) underlying their progressive nature remains unknown but a timely and well-controlled inflammatory reaction is essential for the integrity and proper function of the CNS. Substantial evidence has documented a common inflammatory mechanism in various neurodegenerative diseases. We hypothesize that in the diseased CNS, interactions between damaged neurons and dysregulated, overactivated microglia create a vicious self-propagating cycle causing uncontrolled, prolonged inflammation that drives the chronic progression of neurodegenerative diseases. We further propose that dynamic modulation of this inflammatory reaction by interrupting the vicious cycle might become a disease-modifying therapeutic strategy for neurodegenerative diseases. PMID:18599350

  17. Neuron–astrocyte interactions in neurodegenerative diseases: Role of neuroinflammation

    PubMed Central

    Rama Rao, Kakulavarapu V.; Kielian, Tammy

    2015-01-01

    Selective neuron loss in discrete brain regions is a hallmark of various neurodegenerative disorders, although the mechanisms responsible for this regional vulnerability of neurons remain largely unknown. Earlier studies attributed neuron dysfunction and eventual loss during neurodegenerative diseases as exclusively cell autonomous. Although cell-intrinsic factors are one critical aspect in dictating neuron death, recent evidence also supports the involvement of other central nervous system cell types in propagating non-cell autonomous neuronal injury during neurodegenerative diseases. One such example is astrocytes, which support neuronal and synaptic function, but can also contribute to neuroinflammatory processes through robust chemokine secretion. Indeed, aberrations in astrocyte function have been shown to negatively impact neuronal integrity in several neurological diseases. The present review focuses on neuroinflammatory paradigms influenced by neuron–astrocyte cross-talk in the context of select neurodegenerative diseases. PMID:26543505

  18. A network approach to clinical intervention in neurodegenerative diseases.

    PubMed

    Santiago, Jose A; Potashkin, Judith A

    2014-12-01

    Network biology has become a powerful tool to dissect the molecular mechanisms triggering neurodegeneration. Recent developments in network biology have led to the discovery of disease-causing genes, diagnostic biomarkers, and therapeutic targets for several neurodegenerative diseases including Alzheimer's, Parkinson's, and Huntington's diseases. Network-based approaches have provided the molecular rationale for the relationship among cancer, diabetes, and neurodegenerative diseases, and have uncovered unexpected links between apparently unrelated diseases. Here, we summarize the recent advances in network biology to untangle the molecular underpinnings giving rise to the most prevalent neurodegenerative diseases. We propose that network analysis provides a feasible and practical tool for identifying biologically meaningful biomarkers and potential therapeutic targets for clinical intervention in neurodegenerative diseases. PMID:25455073

  19. Indian Herbs for the Treatment of Neurodegenerative Disease.

    PubMed

    Mannangatti, Padmanabhan; Naidu, Kamalakkannan Narasimha

    2016-01-01

    Ayurveda, an ancient system of medicine that is indigenous to India, is believed to be the world's oldest comprehensive health-care system and is now one of the most recognized and widely practiced disciplines of alternative medicine in the world. Medicinal herbs have been in use for treating diseases since ancient times in India. Ayurvedic therapies with medicinal herbs and herbomineral products generally provide relief without much adverse effects even after prolonged administration. Neurodegenerative disorders are a major cause of mortality and disability, and increasing life spans represent one of the key challenges of medical research. Ayurvedic medicine describes most neurodegenerative diseases and has defined a number of plants with therapeutic benefits for the treatment of neurodegenerative diseases having antioxidant activities. In this chapter, the role of four important Ayurvedic medicinal plants, viz., Withania somnifera (ashwagandha), Bacopa monnieri (brahmi), Centella asiatica (gotu kola), and Mucuna pruriens (velvet bean), on neurodegenerative diseases are discussed. PMID:27651261

  20. Neurodegenerative disease-specific induced pluripotent stem cell research.

    PubMed

    Inoue, Haruhisa

    2010-10-01

    Neurodegenerative disease-specific induced pluripotent stem cell (iPSC) research contributes to the following 3 areas; "Disease modeling", "Disease material" and "Disease therapy". "Disease modeling", by recapitulating the disease phenotype in vitro, will reveal the pathomechanisms. Neurodegenerative disease-specific iPSC-derived non-neuronal cells harboring disease-causative protein(s), which play critical roles in neurodegeneration including motor neuron degeneration in amyotrophic lateral sclerosis, could be "Disease material", the target cell(s) for drug screening. These differentiated cells also could be used for "Disease therapy", an autologous cellular replacement/neuroprotection strategy, for patients with neurodegenerative disease. Further progress in these areas of research can be made for currently incurable neurodegenerative diseases.

  1. Stem cell therapy in neurodegenerative diseases: From principles to practice.

    PubMed

    Sakthiswary, Rajalingham; Raymond, Azman Ali

    2012-08-15

    The lack of curative therapies for neurodegenerative diseases has high economic impact and places huge burden on the society. The contribution of stem cells to cure neurodegenerative diseases has been unraveled and explored extensively over the past few years. Beyond substitution of the lost neurons, stem cells act as immunomodulators and neuroprotectors. A large number of preclinical and a small number of clinical studies have shown beneficial outcomes in this context. In this review, we have summarized the current concepts of stem cell therapy in neurodegenerative diseases and the recent advances in this field, particularly between 2010 and 2012. Further studies should be encouraged to resolve the clinical issues and vague translational findings for maximum optimization of the efficacy of stem cell therapy in neurodegenerative diseases.

  2. The Neurobiological Basis of Adolescent-onset Borderline Personality Disorder

    PubMed Central

    Goodman, Marianne; Mascitelli, Kathryn; Triebwasser, Joseph

    2013-01-01

    Objective: Over the past two decades, neurobiological studies in adult onset borderline personality disorder have made important strides, but inquiry into adolescent-onset BPD is still in its infancy and our understanding of the neurobiology of adolescent BPD remains highly tentative. Methods: This paper highlights recent findings in genetics, neuroendocrinology and neuroimaging for adult and adolescent-onset BPD. Results: Neurobiological studies of adolescent-onset BPD to date have focused mainly on volumetric studies of various brain regions and measurements of HPA axis components, with comparatively few publications on brain functioning. Conclusion: Such information is essential to developing more effective screening, treatment and preventive strategies. PMID:23970910

  3. Reprogramming therapeutics: iPS cell prospects for neurodegenerative disease.

    PubMed

    Abeliovich, Asa; Doege, Claudia A

    2009-02-12

    The recent description of somatic cell reprogramming to an embryonic stem (ES) cell-like phenotype, termed induced pluripotent stem (iPS) cell technology, presents an exciting potential venue toward cell-based therapeutics and disease models for neurodegenerative disorders. Two recent studies (Dimos et al. and Ebert et al.) describe the initial characterization of neurodegenerative disease patient-derived iPS cell cultures as proof of concept for the utility of this technology.

  4. Immunotherapy for neurodegenerative diseases: focus on α-synucleinopathies

    PubMed Central

    Valera, Elvira; Masliah, Eliezer

    2013-01-01

    Immunotherapy is currently being intensively explored as much-needed disease-modifying treatment for neurodegenerative diseases. While Alzheimer’s disease (AD) has been the focus of numerous immunotherapeutic studies, less attention has been paid to Parkinson’s disease (PD) and other neurodegenerative disorders. The reason for this difference is that the amyloid beta (Aβ) protein in AD is a secreted molecule that circulates in blood and is readably recognized by antibodies. In contrast, α-synuclein (α-syn), tau, huntingtin and other proteins involved in neurodegenerative diseases have been considered to be exclusively of intracellular nature. However, the recent discovery that toxic oligomeric versions of α-syn and tau accumulate in the membrane and can be excreted to the extracellular environment has provided a rationale for the development of immunotherapeutic approaches for PD, dementia with Lewy bodies, frontotemporal dementia, and other neurodegenerative disorders characterized by the abnormal accumulation of these proteins. Active immunization, passive immunization, and T cell-mediated cellular immunotherapeutic approaches have been developed targeting Aβ, α-syn and tau. Most advanced studies, including results from phase III clinical trials for passive immunization in AD, have been recently reported. Results suggest that immunotherapy might be a promising therapeutic approach for neurodegenerative diseases that progress with the accumulation and propagation of toxic protein aggregates. In this manuscript we provide an overview on immunotherapeutic advances for neurodegenerative disorders, with special emphasis on α-synucleinopathies. PMID:23384597

  5. Is Modulation of Oxidative Stress an Answer? The State of the Art of Redox Therapeutic Actions in Neurodegenerative Diseases

    PubMed Central

    Chiurchiù, Valerio

    2016-01-01

    The central nervous system is particularly sensitive to oxidative stress due to many reasons, including its high oxygen consumption even under basal conditions, high production of reactive oxygen and nitrogen species from specific neurochemical reactions, and the increased deposition of metal ions in the brain with aging. For this reason, along with inflammation, oxidative stress seems to be one of the main inducers of neurodegeneration, causing excitotoxicity, neuronal loss, and axonal damage, ultimately being now considered a key element in the onset and progression of several neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, and hereditary spastic paraplegia. Thus, the present paper reviews the role of oxidative stress and of its mechanistic insights underlying the pathogenesis of these neurodegenerative diseases, with particular focus on current studies on its modulation as a potential and promising therapeutic strategy. PMID:26881039

  6. Visuospatial memory deficits in adolescent onset schizophrenia.

    PubMed

    Vance, A; Hall, N; Casey, M; Karsz, F; Bellgrove, M A

    2007-07-01

    Visuospatial memory encoding deficits have been reported in adults with schizophrenia, while adolescents with schizophrenia have not been specifically investigated with visuospatial memory encoding and retrieval paradigms. A cross sectional study of delayed matching-to-sample performance in 19 right handed, male, anti-psychotic medication naïve adolescents with undifferentiated schizophrenia and 28 age, gender, IQ and handedness matched healthy participants was completed. The adolescent-onset schizophrenia group demonstrated significant impairment in visuospatial memory, independent of the degree of delay, consistent with an encoding impairment. The impaired encoding phase of visuospatial memory in the adolescent-onset schizophrenia group is consistent with findings in adult onset schizophrenia samples, suggesting a developmental stage-independent deficit.

  7. Young-Onset Parkinson's

    MedlinePlus

    ... idiopathic, or typical, PD. Understanding the roles of environment and genes will ultimately allow us to identify the multiple causes of PD. Is Medication Treatment Different for Young-Onset PD? Medical management of young-onset Parkinson's disease requires an understanding ...

  8. NPC1 is enriched in unexplained early onset ataxia: a targeted high-throughput screening.

    PubMed

    Synofzik, Matthis; Harmuth, Florian; Stampfer, Miriam; Müller Vom Hagen, Jennifer; Schöls, Ludger; Bauer, Peter

    2015-11-01

    Niemann-Pick disease type C (NP-C) is a rare autosomal-recessive neurodegenerative disease featuring pleiotropic neurological, psychiatric and visceral manifestations. Since many of the adult manifestations can be non-specific or missed, NP-C often goes undetected in adult-onset patients. Here we hypothesized that targeted high-throughput sequencing allows identifying NP-C patients among subjects with unexplained early-onset ataxia (EOA) and, moreover, that this population is enriched for NPC1 mutations. From 204 consecutive EOA patients, all 108 subjects with an established diagnosis were removed (including 4 NPC1 patients), yielding a target cohort of 96 subjects with unexplained EOA, but without primary suspicion of NP-C. This cohort was investigated for NPC1/NPC2 mutations using a high-coverage HaloPlex gene panel including 122 ataxia genes. Among 96 samples, we identified 4 known NPC1 mutations, 3 novel NPC1 missense variants of uncertain significance (VUS) and 1 novel NPC2 missense VUS. The total mutant allele frequency (8/192 = 4.17 %) was significantly enriched compared with control population data (1.57 %; p = 0.011). Two NPC1-positive patients were identified (both with non-specific incipient clinical features), giving a NPC1 patient frequency of 2/96 = 2.1 % in unexplained EOA and of 6/204 = 2.9 % in the total EOA series. NPC1 mutations are substantially enriched in unexplained EOA, demonstrating EOA as a risk-group for NP-C disease. Targeted high-throughput sequencing allows to identify also those NP-C patients with non-specific conditions where the diagnosis has initially been missed. This method does not require having considered NP-C during differential diagnosis, but allows identification of NP-C as part of the default analysis.

  9. 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

  10. Alzheimer's disease: An acquired neurodegenerative laminopathy

    PubMed Central

    Frost, Bess

    2016-01-01

    ABSTRACT The nucleus is typically depicted as a sphere encircled by a smooth surface of nuclear envelope. For most cell types, this depiction is accurate. In other cell types and in some pathological conditions, however, the smooth nuclear exterior is interrupted by tubular invaginations of the nuclear envelope, often referred to as a “nucleoplasmic reticulum,” into the deep nuclear interior. We have recently reported a significant expansion of the nucleoplasmic reticulum in postmortem human Alzheimer's disease brain tissue. We found that dysfunction of the nucleoskeleton, a lamin-rich meshwork that coats the inner nuclear membrane and associated invaginations, is causal for Alzheimer's disease-related neurodegeneration in vivo. Additionally, we demonstrated that proper function of the nucleoskeleton is required for survival of adult neurons and maintaining genomic architecture. Here, we elaborate on the significance of these findings in regard to pathological states and physiological aging, and discuss cellular causes and consequences of nuclear envelope invagination. PMID:27167528

  11. Alzheimer's disease: An acquired neurodegenerative laminopathy.

    PubMed

    Frost, Bess

    2016-05-01

    The nucleus is typically depicted as a sphere encircled by a smooth surface of nuclear envelope. For most cell types, this depiction is accurate. In other cell types and in some pathological conditions, however, the smooth nuclear exterior is interrupted by tubular invaginations of the nuclear envelope, often referred to as a "nucleoplasmic reticulum," into the deep nuclear interior. We have recently reported a significant expansion of the nucleoplasmic reticulum in postmortem human Alzheimer's disease brain tissue. We found that dysfunction of the nucleoskeleton, a lamin-rich meshwork that coats the inner nuclear membrane and associated invaginations, is causal for Alzheimer's disease-related neurodegeneration in vivo. Additionally, we demonstrated that proper function of the nucleoskeleton is required for survival of adult neurons and maintaining genomic architecture. Here, we elaborate on the significance of these findings in regard to pathological states and physiological aging, and discuss cellular causes and consequences of nuclear envelope invagination.

  12. Alzheimer's disease: An acquired neurodegenerative laminopathy.

    PubMed

    Frost, Bess

    2016-05-01

    The nucleus is typically depicted as a sphere encircled by a smooth surface of nuclear envelope. For most cell types, this depiction is accurate. In other cell types and in some pathological conditions, however, the smooth nuclear exterior is interrupted by tubular invaginations of the nuclear envelope, often referred to as a "nucleoplasmic reticulum," into the deep nuclear interior. We have recently reported a significant expansion of the nucleoplasmic reticulum in postmortem human Alzheimer's disease brain tissue. We found that dysfunction of the nucleoskeleton, a lamin-rich meshwork that coats the inner nuclear membrane and associated invaginations, is causal for Alzheimer's disease-related neurodegeneration in vivo. Additionally, we demonstrated that proper function of the nucleoskeleton is required for survival of adult neurons and maintaining genomic architecture. Here, we elaborate on the significance of these findings in regard to pathological states and physiological aging, and discuss cellular causes and consequences of nuclear envelope invagination. PMID:27167528

  13. Omega-3 Fatty Acids in Early Prevention of Inflammatory Neurodegenerative Disease: A Focus on Alzheimer's Disease.

    PubMed

    Thomas, J; Thomas, C J; Radcliffe, J; Itsiopoulos, C

    2015-01-01

    Alzheimer's disease (AD) is the leading cause of dementia and the most common neurodegenerative disease in the elderly. Furthermore, AD has provided the most positive indication to support the fact that inflammation contributes to neurodegenerative disease. The exact etiology of AD is unknown, but environmental and genetic factors are thought to contribute, such as advancing age, family history, presence of chronic diseases such as cardiovascular disease (CVD) and diabetes, and poor diet and lifestyle. It is hypothesised that early prevention or management of inflammation could delay the onset or reduce the symptoms of AD. Normal physiological changes to the brain with ageing include depletion of long chain omega-3 fatty acids and brains of AD patients have lower docosahexaenoic acid (DHA) levels. DHA supplementation can reduce markers of inflammation. This review specifically focusses on the evidence in humans from epidemiological, dietary intervention, and supplementation studies, which supports the role of long chain omega-3 fatty acids in the prevention or delay of cognitive decline in AD in its early stages. Longer term trials with long chain omega-3 supplementation in early stage AD are warranted. We also highlight the importance of overall quality and composition of the diet to protect against AD and dementia.

  14. Epidemic Spreading Model to Characterize Misfolded Proteins Propagation in Aging and Associated Neurodegenerative Disorders

    PubMed Central

    Iturria-Medina, Yasser; Sotero, Roberto C.; Toussaint, Paule J.; Evans, Alan C.

    2014-01-01

    Misfolded proteins (MP) are a key component in aging and associated neurodegenerative disorders. For example, misfolded Amyloid-ß (Aß) and tau proteins are two neuropathogenic hallmarks of Alzheimer's disease. Mechanisms underlying intra-brain MP propagation/deposition remain essentially uncharacterized. Here, is introduced an epidemic spreading model (ESM) for MP dynamics that considers propagation-like interactions between MP agents and the brain's clearance response across the structural connectome. The ESM reproduces advanced Aß deposition patterns in the human brain (explaining 46∼56% of the variance in regional Aß loads, in 733 subjects from the ADNI database). Furthermore, this model strongly supports a) the leading role of Aß clearance deficiency and early Aß onset age during Alzheimer's disease progression, b) that effective anatomical distance from Aß outbreak region explains regional Aß arrival time and Aß deposition likelihood, c) the multi-factorial impact of APOE e4 genotype, gender and educational level on lifetime intra-brain Aß propagation, and d) the modulatory impact of Aß propagation history on tau proteins concentrations, supporting the hypothesis of an interrelated pathway between Aß pathophysiology and tauopathy. To our knowledge, the ESM is the first computational model highlighting the direct link between structural brain networks, production/clearance of pathogenic proteins and associated intercellular transfer mechanisms, individual genetic/demographic properties and clinical states in health and disease. In sum, the proposed ESM constitutes a promising framework to clarify intra-brain region to region transference mechanisms associated with aging and neurodegenerative disorders. PMID:25412207

  15. The role of macropinocytosis in the propagation of protein aggregation associated with neurodegenerative diseases.

    PubMed

    Zeineddine, Rafaa; Yerbury, Justin J

    2015-01-01

    With the onset of the rapidly aging population, the impact of age related neurodegenerative diseases is becoming a predominant health and economic concern. Neurodegenerative diseases such as Alzheimer's disease, Creutzfeldt-Jakob disease (CJD), Parkinson's disease, Huntington's disease, frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS) result from the loss of a specific subsets of neurons, which is closely associated with accumulation and deposition of specific protein aggregates. Protein aggregation, or fibril formation, is a well-studied phenomenon that occurs in a nucleation-dependent growth reaction. Recently, there has been a swell of literature implicating protein aggregation and its ability to propagate cell-to-cell in the rapid progression of these diseases. In order for protein aggregation to be kindled in recipient cells it is a requisite that aggregates must be able to be released from one cell and then taken up by others. In this article we will explore the relationship between protein aggregates, their propagation and the role of macropinocytosis in their uptake. We highlight the ability of neurons to undergo stimulated macropinocytosis and identify potential therapeutic targets. PMID:26528186

  16. Epidemic spreading model to characterize misfolded proteins propagation in aging and associated neurodegenerative disorders.

    PubMed

    Iturria-Medina, Yasser; Sotero, Roberto C; Toussaint, Paule J; Evans, Alan C

    2014-11-01

    Misfolded proteins (MP) are a key component in aging and associated neurodegenerative disorders. For example, misfolded Amyloid-ß (Aß) and tau proteins are two neuropathogenic hallmarks of Alzheimer's disease. Mechanisms underlying intra-brain MP propagation/deposition remain essentially uncharacterized. Here, is introduced an epidemic spreading model (ESM) for MP dynamics that considers propagation-like interactions between MP agents and the brain's clearance response across the structural connectome. The ESM reproduces advanced Aß deposition patterns in the human brain (explaining 46∼56% of the variance in regional Aß loads, in 733 subjects from the ADNI database). Furthermore, this model strongly supports a) the leading role of Aß clearance deficiency and early Aß onset age during Alzheimer's disease progression, b) that effective anatomical distance from Aß outbreak region explains regional Aß arrival time and Aß deposition likelihood, c) the multi-factorial impact of APOE e4 genotype, gender and educational level on lifetime intra-brain Aß propagation, and d) the modulatory impact of Aß propagation history on tau proteins concentrations, supporting the hypothesis of an interrelated pathway between Aß pathophysiology and tauopathy. To our knowledge, the ESM is the first computational model highlighting the direct link between structural brain networks, production/clearance of pathogenic proteins and associated intercellular transfer mechanisms, individual genetic/demographic properties and clinical states in health and disease. In sum, the proposed ESM constitutes a promising framework to clarify intra-brain region to region transference mechanisms associated with aging and neurodegenerative disorders.

  17. Omega-3 Fatty Acids in Early Prevention of Inflammatory Neurodegenerative Disease: A Focus on Alzheimer's Disease.

    PubMed

    Thomas, J; Thomas, C J; Radcliffe, J; Itsiopoulos, C

    2015-01-01

    Alzheimer's disease (AD) is the leading cause of dementia and the most common neurodegenerative disease in the elderly. Furthermore, AD has provided the most positive indication to support the fact that inflammation contributes to neurodegenerative disease. The exact etiology of AD is unknown, but environmental and genetic factors are thought to contribute, such as advancing age, family history, presence of chronic diseases such as cardiovascular disease (CVD) and diabetes, and poor diet and lifestyle. It is hypothesised that early prevention or management of inflammation could delay the onset or reduce the symptoms of AD. Normal physiological changes to the brain with ageing include depletion of long chain omega-3 fatty acids and brains of AD patients have lower docosahexaenoic acid (DHA) levels. DHA supplementation can reduce markers of inflammation. This review specifically focusses on the evidence in humans from epidemiological, dietary intervention, and supplementation studies, which supports the role of long chain omega-3 fatty acids in the prevention or delay of cognitive decline in AD in its early stages. Longer term trials with long chain omega-3 supplementation in early stage AD are warranted. We also highlight the importance of overall quality and composition of the diet to protect against AD and dementia. PMID:26301243

  18. Omega-3 Fatty Acids in Early Prevention of Inflammatory Neurodegenerative Disease: A Focus on Alzheimer's Disease

    PubMed Central

    Thomas, J.; Thomas, C. J.; Radcliffe, J.; Itsiopoulos, C.

    2015-01-01

    Alzheimer's disease (AD) is the leading cause of dementia and the most common neurodegenerative disease in the elderly. Furthermore, AD has provided the most positive indication to support the fact that inflammation contributes to neurodegenerative disease. The exact etiology of AD is unknown, but environmental and genetic factors are thought to contribute, such as advancing age, family history, presence of chronic diseases such as cardiovascular disease (CVD) and diabetes, and poor diet and lifestyle. It is hypothesised that early prevention or management of inflammation could delay the onset or reduce the symptoms of AD. Normal physiological changes to the brain with ageing include depletion of long chain omega-3 fatty acids and brains of AD patients have lower docosahexaenoic acid (DHA) levels. DHA supplementation can reduce markers of inflammation. This review specifically focusses on the evidence in humans from epidemiological, dietary intervention, and supplementation studies, which supports the role of long chain omega-3 fatty acids in the prevention or delay of cognitive decline in AD in its early stages. Longer term trials with long chain omega-3 supplementation in early stage AD are warranted. We also highlight the importance of overall quality and composition of the diet to protect against AD and dementia. PMID:26301243

  19. Fermented grape marc (FGM): immunomodulating properties and its potential exploitation in the treatment of neurodegenerative diseases.

    PubMed

    Marzulli, G; Magrone, T; Kawaguchi, K; Kumazawa, Y; Jirillo, E

    2012-01-01

    The onset of neurodegenerative diseases has become more frequent than in the past also in relation to inappropriate dietary habits adopted in the western world. Nutraceuticals are currently investigated in order to prevent or retard the outcome of the so-called diet-related diseases, even including neurodegenerative pathologies. Here, we have in vitro studied the ability of fermented grape marc (FGM) from Negroamaro (N) and Koshu (K) Vitis vinifera to modulate the function of human peripheral blood mononuclear cells (PBMCs). Actually, both FGMs were able to increase the release and the intracellular content of inflammatory and anti-inflammatory cytokines, the induction of FoxP3 (a biomarker of T regulatory cells) and reduce the production of Granzyme B from PBMCs. Since these FGM-induced effects tend to polarize the immune response toward an anti-inflammatory pathway, the potential use of FGMs may represent a valid therapeutic measure to mitigating neuroinflammation in pathologies such as Parkinson disease and Alzheimer disease.

  20. Fluctuations in Protein Aggregation: Design of Preclinical Screening for Early Diagnosis of Neurodegenerative Disease

    NASA Astrophysics Data System (ADS)

    Costantini, Giulio; Budrikis, Zoe; Taloni, Alessandro; Buell, Alexander K.; Zapperi, Stefano; La Porta, Caterina A. M.

    2016-09-01

    Autocatalytic fibril nucleation has recently been proposed to be a determining factor for the spread of neurodegenerative diseases, but the same process could also be exploited to amplify minute quantities of protein aggregates in a diagnostic context. Recent advances in microfluidic technology allow the analysis of protein aggregation in micron-scale samples, potentially enabling such diagnostic approaches, but the theoretical foundations for the analysis and interpretation of such data are, so far, lacking. Here, we study computationally the onset of protein aggregation in small volumes and show that the process is ruled by intrinsic fluctuations whose volume-dependent distribution we also estimate theoretically. Based on these results, we develop a strategy to quantify in silico the statistical errors associated with the detection of aggregate-containing samples. Our work explores a different perspective on the forecasting of protein aggregation in asymptomatic subjects.

  1. Child and Adolescent (Early Onset) Schizophrenia: A Review in Light of DSM-III-R.

    ERIC Educational Resources Information Center

    Werry, John S.

    1992-01-01

    This review of studies of early onset schizophrenia examines the nosological similarity between adult and early onset schizophrenia, differential diagnosis, treatment, and the extent to which children and adolescents diagnosed as having schizophrenia using adult criteria have the characteristic adult correlates. The paper discusses gender…

  2. Association Between Early-Onset Parkinson Disease and 22q11.2 Deletion Syndrome

    PubMed Central

    Butcher, Nancy J.; Kiehl, Tim-Rasmus; Hazrati, Lili-Naz; Chow, Eva W. C.; Rogaeva, Ekaterina; Lang, Anthony E.; Bassett, Anne S.

    2015-01-01

    IMPORTANCE Clinical case reports of parkinsonism co-occurring with hemizygous 22q11.2 deletions and the associated multisystem syndrome, 22q11.2 deletion syndrome (22q11.2DS), suggest that 22q11.2 deletions may lead to increased risk of early-onset Parkinson disease (PD). The frequency of PD and its neuropathological presentation remain unknown in this common genetic condition. OBJECTIVE To evaluate a possible association between 22q11.2 deletions and PD. DESIGN, SETTING, AND PARTICIPANTS An observational study of the occurrence of PD in the world’s largest cohort of well-characterized adults with a molecularly confirmed diagnosis of 22q11.2DS (n = 159 [6 with postmortem tissue]; age range, 18.1–68.6 years) was conducted in Toronto, Ontario, Canada. Rare postmortem brain tissue from individuals with 22q11.2DS and a clinical history of PD was investigated for neurodegenerative changes and compared with that from individuals with no history of a movement disorder. MAIN OUTCOMES AND MEASURES A clinical diagnosis of PD made by a neurologist and neuropathological features of PD. RESULTS Adults with 22q11.2DS had a significantly elevated occurrence of PD compared with standard population estimates (standardized morbidity ratio = 69.7; 95% CI, 19.0–178.5). All cases showed early onset and typical PD symptom pattern, treatment response, and course. All were negative for family history of PD and known pathogenic PD-related mutations. The common use of antipsychotics in patients with 22q11.2DS to manage associated psychiatric symptoms delayed diagnosis of PD by up to 10 years. Postmortem brain tissue revealed classic loss of midbrain dopaminergic neurons in all 3 postmortem 22q11.2DS-PD cases. Typical α-synuclein–positive Lewy bodies were present in the expected distribution in 2 cases but absent in another. CONCLUSIONS AND RELEVANCE These findings suggest that 22q11.2 deletions represent a novel genetic risk factor for early-onset PD with variable neuropathological

  3. Oxidative stress treatment for clinical trials in neurodegenerative diseases.

    PubMed

    Ienco, Elena Caldarazzo; LoGerfo, Annalisa; Carlesi, Cecilia; Orsucci, Daniele; Ricci, Giulia; Mancuso, Michelangelo; Siciliano, Gabriele

    2011-01-01

    Oxidative stress is a metabolic condition arising from imbalance between the production of potentially reactive oxygen species and the scavenging activities. Mitochondria are the main providers but also the main scavengers of cell oxidative stress. The role of mitochondrial dysfunction and oxidative stress in the pathogenesis of neurodegenerative diseases is well documented. Therefore, therapeutic approaches targeting mitochondrial dysfunction and oxidative damage hold great promise in neurodegenerative diseases. Despite this evidence, human experience with antioxidant neuroprotectants has generally been negative with regards to the clinical progress of disease, with unclear results in biochemical assays. Here we review the antioxidant approaches performed so far in neurodegenerative diseases and the future challenges in modern medicine. PMID:21422516

  4. RNA processing-associated molecular mechanisms of neurodegenerative diseases.

    PubMed

    Tang, Anna Y

    2016-08-01

    Dysfunctions of RNA processing and mutations of RNA binding proteins (RBPs) play a fundamental role in the pathogenesis of many neurodegenerative diseases. To elucidate the function of RNA processing and RBPs mutations in neuronal cells and to increase our understanding on the pathogenic mechanisms of neurodegeneration, I have reviewed recent advances on RNA processing-associated molecular mechanisms of neurodegenerative diseases, including RBPs-mediated dysfunction of RNA processing, dysfunctional microRNA (miRNA)-based regulation of gene expression, and oxidative RNA modification. I have focused on neurodegeneration induced by RBPs mutations, by dysfunction of miRNA regulation, and by the oxidized RNAs within neurons, and discuss how these dysfunctions have pathologically contributed to neurodegenerative diseases. The advances overviewed above will be valuable to basic investigation and clinical application of target diagnostic tests and therapies.

  5. Mitochondrial dysfunctions in neurodegenerative diseases: relevance to Alzheimer's disease.

    PubMed

    Hroudová, Jana; Singh, Namrata; Fišar, Zdeněk

    2014-01-01

    Mitochondrial dysfunctions are supposed to be responsible for many neurodegenerative diseases dominating in Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). A growing body of evidence suggests that defects in mitochondrial metabolism and particularly of electron transport chain may play a role in pathogenesis of AD. Structurally and functionally damaged mitochondria do not produce sufficient ATP and are more prominent in producing proapoptotic factors and reactive oxygen species (ROS), and this can be an early stage of several mitochondrial disorders, including neurodegenerative diseases. Mitochondrial dysfunctions may be caused by both mutations in mitochondrial or nuclear DNA that code mitochondrial components and by environmental causes. In the following review, common aspects of mitochondrial impairment concerned about neurodegenerative diseases are summarized including ROS production, impaired mitochondrial dynamics, and apoptosis. Also, damaged function of electron transport chain complexes and interactions between pathological proteins and mitochondria are described for AD particularly and marginally for PD and HD.

  6. Evaluation of Traditional Medicines for Neurodegenerative Diseases Using Drosophila Models

    PubMed Central

    Lee, Soojin; Bang, Se Min; Lee, Joon Woo; Cho, Kyoung Sang

    2014-01-01

    Drosophila is one of the oldest and most powerful genetic models and has led to novel insights into a variety of biological processes. Recently, Drosophila has emerged as a model system to study human diseases, including several important neurodegenerative diseases. Because of the genomic similarity between Drosophila and humans, Drosophila neurodegenerative disease models exhibit a variety of human-disease-like phenotypes, facilitating fast and cost-effective in vivo genetic modifier screening and drug evaluation. Using these models, many disease-associated genetic factors have been identified, leading to the identification of compelling drug candidates. Recently, the safety and efficacy of traditional medicines for human diseases have been evaluated in various animal disease models. Despite the advantages of the Drosophila model, its usage in the evaluation of traditional medicines is only nascent. Here, we introduce the Drosophila model for neurodegenerative diseases and some examples demonstrating the successful application of Drosophila models in the evaluation of traditional medicines. PMID:24790636

  7. Contributions of isolated Pacific populations to understanding neurodegenerative diseases.

    PubMed

    Garruto, Ralph M; Yanagihara, Richard

    2009-01-01

    Isolated human populations have provided a natural experimental laboratory for the ongoing study of human disease. In the mid-20th century a number of high-incidence foci of neurodegenerative diseases were brought to medical attention including kuru, amyotrophic lateral sclerosis, and parkinsonism-dementia. These foci were discovered in Papua New Guinea, West New Guinea, the Kii Peninsula of Japan, and in the Mariana Islands. The study of these diseases in isolated human groups has significantly contributed to our understanding of the cause and mechanisms of pathogenesis of these and related neurodegenerative disorders globally. This paper is dedicated to D. Carleton Gajdusek, a pioneer in the study of neurodegenerative diseases, whose decades of fieldwork and laboratory studies have led to numerous scientific discoveries that have reshaped our thinking and understanding about neurodegeneration.

  8. Biomarker Discovery in Neurodegenerative Diseases: A Proteomic Approach

    PubMed Central

    Shi, Min; Caudle, W. Michael; Zhang, Jing

    2010-01-01

    Biomarkers for neurodegenerative disorders are essential to facilitate disease diagnosis, ideally at early stages, monitor disease progression, and assess response to existing and future treatments. Application of proteomics to the human brain, cerebrospinal fluid and plasma has greatly hastened the unbiased and high-throughput searches for novel biomarkers. There are many steps critical to biomarker discovery, whether for neurodegenerative or other diseases, including sample preparation, protein/peptide separation and identification, as well as independent confirmation and validation. In this review we have summarized current proteomics technologies involved in discovery of biomarkers for neurodegenerative diseases, practical considerations and limitations of several major aspects, as well as the current status of candidate biomarkers revealed by proteomics for Alzheimer and Parkinson diseases. PMID:18938247

  9. Nature, nurture and neurology: gene-environment interactions in neurodegenerative disease. FEBS Anniversary Prize Lecture delivered on 27 June 2004 at the 29th FEBS Congress in Warsaw.

    PubMed

    Spires, Tara L; Hannan, Anthony J

    2005-05-01

    Neurodegenerative disorders, such as Huntington's, Alzheimer's, and Parkinson's diseases, affect millions of people worldwide and currently there are few effective treatments and no cures for these diseases. Transgenic mice expressing human transgenes for huntingtin, amyloid precursor protein, and other genes associated with familial forms of neurodegenerative disease in humans provide remarkable tools for studying neurodegeneration because they mimic many of the pathological and behavioural features of the human conditions. One of the recurring themes revealed by these various transgenic models is that different diseases may share similar molecular and cellular mechanisms of pathogenesis. Cellular mechanisms known to be disrupted at early stages in multiple neurodegenerative disorders include gene expression, protein interactions (manifesting as pathological protein aggregation and disrupted signaling), synaptic function and plasticity. Recent work in mouse models of Huntington's disease has shown that enriching the environment of transgenic animals delays the onset and slows the progression of Huntington's disease-associated motor and cognitive symptoms. Environmental enrichment is known to induce various molecular and cellular changes in specific brain regions of wild-type animals, including altered gene expression profiles, enhanced neurogenesis and synaptic plasticity. The promising effects of environmental stimulation, demonstrated recently in models of neurodegenerative disease, suggest that therapy based on the principles of environmental enrichment might benefit disease sufferers and provide insight into possible mechanisms of neurodegeneration and subsequent identification of novel therapeutic targets. Here, we review the studies of environmental enrichment relevant to some major neurodegenerative diseases and discuss their research and clinical implications.

  10. Nature, nurture and neurology: gene-environment interactions in neurodegenerative disease. FEBS Anniversary Prize Lecture delivered on 27 June 2004 at the 29th FEBS Congress in Warsaw.

    PubMed

    Spires, Tara L; Hannan, Anthony J

    2005-05-01

    Neurodegenerative disorders, such as Huntington's, Alzheimer's, and Parkinson's diseases, affect millions of people worldwide and currently there are few effective treatments and no cures for these diseases. Transgenic mice expressing human transgenes for huntingtin, amyloid precursor protein, and other genes associated with familial forms of neurodegenerative disease in humans provide remarkable tools for studying neurodegeneration because they mimic many of the pathological and behavioural features of the human conditions. One of the recurring themes revealed by these various transgenic models is that different diseases may share similar molecular and cellular mechanisms of pathogenesis. Cellular mechanisms known to be disrupted at early stages in multiple neurodegenerative disorders include gene expression, protein interactions (manifesting as pathological protein aggregation and disrupted signaling), synaptic function and plasticity. Recent work in mouse models of Huntington's disease has shown that enriching the environment of transgenic animals delays the onset and slows the progression of Huntington's disease-associated motor and cognitive symptoms. Environmental enrichment is known to induce various molecular and cellular changes in specific brain regions of wild-type animals, including altered gene expression profiles, enhanced neurogenesis and synaptic plasticity. The promising effects of environmental stimulation, demonstrated recently in models of neurodegenerative disease, suggest that therapy based on the principles of environmental enrichment might benefit disease sufferers and provide insight into possible mechanisms of neurodegeneration and subsequent identification of novel therapeutic targets. Here, we review the studies of environmental enrichment relevant to some major neurodegenerative diseases and discuss their research and clinical implications. PMID:15885086

  11. Circulating miRNAs as biomarkers for neurodegenerative disorders.

    PubMed

    Grasso, Margherita; Piscopo, Paola; Confaloni, Annamaria; Denti, Michela A

    2014-05-23

    Neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD) and frontotemporal dementias (FTD), are considered distinct entities, however, there is increasing evidence of an overlap from the clinical, pathological and genetic points of view. All neurodegenerative diseases are characterized by neuronal loss and death in specific areas of the brain, for example, hippocampus and cortex for AD, midbrain for PD, frontal and temporal lobes for FTD. Loss of neurons is a relatively late event in the progression of neurodegenerative diseases that is typically preceded by other events such as metabolic changes, synaptic dysfunction and loss, neurite retraction, and the appearance of other abnormalities, such as axonal transport defects. The brain's ability to compensate for these dysfunctions occurs over a long period of time and results in late clinical manifestation of symptoms, when successful pharmacological intervention is no longer feasible. Currently, diagnosis of AD, PD and different forms of dementia is based primarily on analysis of the patient's cognitive function. It is therefore important to find non-invasive diagnostic methods useful to detect neurodegenerative diseases during early, preferably asymptomatic stages, when a pharmacological intervention is still possible. Altered expression of microRNAs (miRNAs) in many disease states, including neurodegeneration, and increasing relevance of miRNAs in biofluids in different pathologies has prompted the study of their possible application as neurodegenerative diseases biomarkers in order to identify new therapeutic targets. Here, we review what is known about the role of miRNAs in the pathogenesis of neurodegeneration and the possibilities and challenges of using these small RNA molecules as a signature for neurodegenerative conditions.

  12. Microtubule-Stabilizing Agents as Potential Therapeutics for Neurodegenerative Disease

    PubMed Central

    Brunden, Kurt R.; Trojanowski, John Q.; Smith, Amos B.; Lee, Virginia M.-Y.; Ballatore, Carlo

    2014-01-01

    Microtubules (MTs)1, cytoskeletal elements found in all mammalian cells, play a significant role in cell structure and in cell division. They are especially critical in the proper functioning of post-mitotic central nervous system neurons, where MTs serve as the structures on which key cellular constituents are trafficked in axonal projections. MTs are stabilized in axons by the MT-associated protein tau, and in several neurodegenerative diseases, including Alzheimer’s disease, frontotemporal lobar degeneration, and Parkinson’s disease, tau function appears to be compromised due to the protein dissociating from MTs and depositing into insoluble inclusions referred to as neurofibrillary tangles. This loss of tau function is believed to result in alterations of MT structure and function, resulting in aberrant axonal transport that likely contributes to the neurodegenerative process. There is also evidence of axonal transport deficiencies in other neurodegenerative diseases, including amyotrophic lateral sclerosis and Huntington’s disease, which may result, at least in part, from MT alterations. Accordingly, a possible therapeutic strategy for such neurodegenerative conditions is to treat with MT-stabilizing agents, such as those that have been used in the treatment of cancer. Here, we review evidence of axonal transport and MT deficiencies in a number of neurodegenerative diseases, and summarize the various classes of known MT-stabilizing agents. Finally, we highlight the growing evidence that small molecule MT-stabilizing agents provide benefit in animal models of neurodegenerative disease and discuss the desired features of such molecules for the treatment of these central nervous system disorders. PMID:24433963

  13. Global warming and neurodegenerative disorders: speculations on their linkage.

    PubMed

    Habibi, Laleh; Perry, George; Mahmoudi, Morteza

    2014-01-01

    Climate change is having considerable impact on biological systems. Eras of ice ages and warming shaped the contemporary earth and origin of creatures including humans. Warming forces stress conditions on cells. Therefore, cells evolved elaborate defense mechanisms, such as creation of heat shock proteins, to combat heat stress. Global warming is becoming a crisis and this process would yield an undefined increasing rate of neurodegenerative disorders in future decades. Since heat stress is known to have a degenerative effects on neurons and, conversely, cold conditions have protective effect on these cells, we hypothesize that persistent heat stress forced by global warming might play a crucial role in increasing neurodegenerative disorders.