... Emergency Room? What Happens in the Operating Room? Parkinson's Disease KidsHealth > For Kids > Parkinson's Disease A A ... symptoms of something called Parkinson's disease. What Is Parkinson's Disease? You may have seen the actor Michael ...
Helicobacter pylori (HP) is a common infection of the gastrointestinal system that is usually related to peptic ulcers. However, recent studies have revealed relationships between HP and many other diseases. Although the exact mechanism is unknown, HP can prevent the absorption of certain drugs. A high prevalence of HP has been found in patients with Parkinson's disease, and this bacterium causes motor fluctuations by affecting the absorption of levodopa, which is the main drug used to treat Parkinson's disease. Eradicating HP from patients with Parkinson's disease by applying antibiotic treatment will increase the absorption of levodopa and decrease their motor fluctuations. PMID:26932258
B vitamins may correlate with Parkinson's disease (PD) through regulating homocysteine level. However, there is no comprehensive assessment on the associations between PD and B vitamins. The present study was designed to perform a meta-analytic assessment of the associations between folate, vitamin B6, and vitamin B12 and PD, including the status of B vitamins in PD patients compared with controls, and associations of dietary intakes of B vitamins and risk of PD. A literature search using Medline database obtained 10 eligible studies included in the meta-analyses. Stata 12.0 statistical software was used to perform the meta-analysis. Pooled data revealed that there was no obvious difference in folate level between PD patients and healthy controls, and PD patients had lower level of vitamin B12 than controls. Available data suggested that higher dietary intake of vitamin B6 was associated with a decreased risk of PD (odds ratio (OR) = 0.65, 95% confidence intervals (CI) = (0.30, 1.01)), while no significant association was observed for dietary intake of folate and vitamin B12 and risk of PD. PD patients had lower level of vitamin B12 and similar level of folate compared with controls. Dietary intake of vitamin B6 exhibited preventive effect of developing PD based on the available data. As the number of included studies is limited, more studies are needed to confirm the findings and elucidate the underpinning underlying these associations.
Nyhlén, Jakob; Constantinescu, Radu; Zetterberg, Henrik
This article focuses on biochemical markers that may be used in the diagnostics of Parkinson's disease and associated disorders, and to identify early cases and stratify patients into subgroups. We present an updated account of some currently available candidate fluid biomarkers, and discuss their diagnostic performance and limitations. We also discuss some of the general problems with Parkinson's disease biomarkers and possible ways of moving forward. It may be concluded that a diagnostically useful fluid biomarker for Parkinson's disease is yet to be identified. However, some interesting candidates exist and may prove useful in the future, alone or when analyzed together in patterns.
Nanko, S.; Hattori, M.; Dai, X.Y.
Parkinson`s disease is thought to be caused by a combination of unknown environmental, genetic, and degenerative factors. Evidence from necropsy brain samples and pharmacokinetics suggests involvement of dopamine receptors in the pathogenesis or pathophysiology of Parkinson`s disease. Genetic association studies between Parkinson`s disease and dopamine D2, D3 and D4 receptor gene polymorphisms were conducted. The polymorphism was examined in 71 patients with Parkinson`s disease and 90 controls. There were no significant differences between two groups in allele frequencies at the D2, D3, and D4 dopamine receptor loci. Our findings do not support the hypothesis that susceptibility to Parkinson`s disease is associated with the dopamine receptor polymorphisms examined. 35 refs., 2 tabs.
Suzuki, Keisuke; Miyamoto, Masayuki; Miyamoto, Tomoyuki; Iwanami, Masaoki; Hirata, Koichi
Sleep disturbances are common problems affecting the quality life of Parkinson's disease (PD) patients and are often underestimated. The causes of sleep disturbances are multifactorial and include nocturnal motor disturbances, nocturia, depressive symptoms, and medication use. Comorbidity of PD with sleep apnea syndrome, restless legs syndrome, rapid eye movement sleep behavior disorder, or circadian cycle disruption also results in impaired sleep. In addition, the involvement of serotoninergic, noradrenergic, and cholinergic neurons in the brainstem as a disease-related change contributes to impaired sleep structures. Excessive daytime sleepiness is not only secondary to nocturnal disturbances or dopaminergic medication but may also be due to independent mechanisms related to impairments in ascending arousal system and the orexin system. Notably, several recent lines of evidence suggest a strong link between rapid eye movement sleep behavior disorder and the risk of neurodegenerative diseases such as PD. In the present paper, we review the current literature concerning sleep disorders in PD. PMID:21876839
Mostile, Giovanni; Jankovic, Joseph
Non-motor symptoms are increasingly recognized to adversely impact on the quality of life of patients with in Parkinson's disease (PD), particularly as the disease progresses. Autonomic symptom severity in patients with PD seems to correlate with older age, greater disease severity, psychiatric complications, sleep disorders, and higher doses of dopaminergic medication. The following therapeutic strategies are frequently used in the treatment of PD-related dysautonomia: 1. Orthostatic hypotension: fludrocortisone, midodrine, and droxidopa; 2. Sialorrhea: glycopyrrolate and botulinun toxin injections; 3. Constipation: symbiotic yogurt and bulking agents, macrogol, lubiprostone, mosapride citrate and tegaserod, pyridostigmine bromide, botulinum toxin injections and sacral nerve stimulation; 4. Urinary frequency: oxybutynin, tolterodine, solifenacin, darifenacin, botulinum toxin injections; 5. Erectile dysfunction: sildenafil and other phosphodiesterase type 5 inhibitors. More effective symptomatic and pathogenesis-targeted therapies are needed to ameliorate the non-motor symptoms of PD that usually do not respond well to dopaminergic medications.
Parkinson's disease is a condition that anyone with a modicum of medical knowledge can recognise in the street--as indeed how it was studied by James Parkinson himself. Its three characteristic features are: 1. Increase in the tone of the voluntary muscles (rigidity). 2. Slowness of movement (bradykinesis). 3. Tremor (the characteristic 'pill rolling' movements of the fingers).
Abosch, Aviva; Gupte, Akshay; Eberly, Lynn E.; Tuite, Paul J.; Nance, Martha; Grant, Jon E.
Parkinson's disease (PD) is a degenerative brain disorder accompanied by the loss of dopaminergic neurons and the presence of motor and non-motor symptoms. We performed a cross-sectional, questionnaire-based analysis of impulsive behavior in our PD clinic population to assess prevalence and associated characteristics. We found a higher prevalence of impulsive behavior (29.7%) than previously reported, and found multiple, concurrent impulsive behaviors in 26% of subjects reporting impulsive behavior. Our findings contribute to the growing awareness of impulsive behavior in PD, and support the need for longitudinal studies to assess changes in impulsive behaviors in Parkinson's patients. PMID:21300194
Parkinson's disease (PD) is a type of movement disorder. It happens when nerve cells in the brain don't ... coordination As symptoms get worse, people with the disease may have trouble walking, talking, or doing simple ...
Playfer, J. R.
Parkinson's disease is a common disabling disease of old age. The diagnosis of idiopathic Parkinson's disease is based on clinical signs and has poor sensitivity, with about 25% of patients confidently diagnosed as having the disease actually having other conditions such as multi-system atrophy and other parkinsonism-plus syndromes. Benign essential tremor and arteriosclerotic pseudo-parkinsonism can easily be confused with Parkinson's disease. The cause of Parkinson's disease remains unknown. Speculative research highlights the role of oxidative stress and free radical mediated damage to dopaminergic cells. Parkinson's disease is the one neurodegenerative disorder in which drugs have been demonstrated to be of value. There is now a wide variety of drugs and formulations available, including anticholinergics, amantidine, L-dopa, dopamine agonists including apomorphine, selegiline and soon to be available catechol-O-methyltransferase inhibitors. Disabling side-effects of treatment, fluctuations, dyskinesias and psychiatric problems require strategic use of the drugs available. There is an increasing potential for neurosurgical intervention. PMID:9196696
Kataoka, Hiroshi; Ueno, Satoshi
The antiviral agent amantadine has been used to manage Parkinson's disease or levodopa-induced dyskinesias for nearly 5 decades. Amantadine is often associated with hallucinations as an adverse effect, but a long-term study reported no serious motor complications. We describe an unusual patient who had Parkinson's disease with dropped head syndrome (DHS) caused by amantadine. When the patient, who had DHS while receiving only 2 kinds of antiparkinsonian drugs, was rechallenged with amantadine, DHS developed, accompanied by increased muscle tone in the neck muscles on surface electromyogram. The DHS resolved after the withdrawal of amantadine. Moreover, an intravenous infusion of levodopa did not alter the DHS. These findings collectively suggest that the DHS in our patient was most likely caused directly by amantadine. Our findings suggest that amantadine may carry the risk of augmenting dystonic syndrome in humans.
Kang, Ju-Hee; Mollenhauer, Brit; Coffey, Christopher S; Toledo, Jon B; Weintraub, Daniel; Galasko, Douglas R; Irwin, David J; Van Deerlin, Vivianna; Chen-Plotkin, Alice S; Caspell-Garcia, Chelsea; Waligórska, Teresa; Taylor, Peggy; Shah, Nirali; Pan, Sarah; Zero, Pawel; Frasier, Mark; Marek, Kenneth; Kieburtz, Karl; Jennings, Danna; Tanner, Caroline M; Simuni, Tanya; Singleton, Andrew; Toga, Arthur W; Chowdhury, Sohini; Trojanowski, John Q; Shaw, Leslie M
The development of biomarkers to predict the progression of Parkinson's disease (PD) from its earliest stage through its heterogeneous course is critical for research and therapeutic development. The Parkinson's Progression Markers Initiative (PPMI) study is an ongoing international multicenter, prospective study to validate biomarkers in drug-naïve PD patients and matched healthy controls (HC). We quantified cerebrospinal fluid (CSF) alpha-synuclein (α-syn), amyloid-beta1-42 (Aβ1-42), total tau (t-tau), and tau phosphorylated at Thr181 (p-tau) in 660 PPMI subjects at baseline, and correlated these data with measures of the clinical features of these subjects. We found that CSF α-syn, t-tau and p-tau levels, but not Aβ1-42, were significantly lower in PD compared with HC, while the diagnostic value of the individual CSF biomarkers for PD diagnosis was limited due to large overlap. The level of α-syn, but not other biomarkers, was significantly lower in PD patients with non-tremor-dominant phenotype compared with tremor-dominant phenotype. In addition, in PD patients the lowest Aβ1-42, or highest t-tau/Aβ1-42 and t-tau/α-syn quintile in PD patients were associated with more severe non-motor dysfunction compared with the highest or lowest quintiles, respectively. In a multivariate regression model, lower α-syn was significantly associated with worse cognitive test performance. APOE ε4 genotype was associated with lower levels of Aβ1-42, but neither with PD diagnosis nor cognition. Our data suggest that the measurement of CSF biomarkers in early-stage PD patients may relate to disease heterogeneity seen in PD. Longitudinal observations in PPMI subjects are needed to define their prognostic performance.
... cells make and use a brain chemical called dopamine (say: DOH-puh-meen) to send messages to ... coordinate body movements. When someone has Parkinson's disease, dopamine levels are low. So, the body doesn't ...
Parkinson's disease is associated with an increased risk of falls. The risk is greatest in patients with advanced disease. Because Parkinson's disease usually occurs late in life, the risk factors related to the neurological impairments add to those associated with aging. The incidence of fractures is high in patients with Parkinson's disease, with femoral neck fractures in older women being particularly common. Risk factors for fractures include a low body mass index, limited exposure to sunlight, an inadequate vitamin D intake with low 25-OH vitamin D levels, and bone loss. Several studies found decreased bone mineral density values at the femoral neck and lumbar spine in patients with Parkinson's disease. Although this decrease is ascribable in part to factors unrelated with Parkinson's disease, such as older age and female gender, Parkinson's disease itself also plays a role, most notably in patients with severe neurological impairments (Hoehn and Yahr stages III and IV).
Capriotti, Teri; Terzakis, Kristina
Parkinson disease (PD) is a progressive neurodegenerative disease that affects one million people in the United States. This article reviews the etiology and pathophysiology of PD, risk factors, clinical manifestations, diagnostic criteria, and treatment of this common disease. Implications for home care clinicians are included.
Swan, Matthew; Doan, Nancy; Ortega, Robert A; Barrett, Matthew; Nichols, William; Ozelius, Laurie; Soto-Valencia, Jeannie; Boschung, Sarah; Deik, Andres; Sarva, Harini; Cabassa, Jose; Johannes, Brooke; Raymond, Deborah; Marder, Karen; Giladi, Nir; Miravite, Joan; Severt, William; Sachdev, Rivka; Shanker, Vicki; Bressman, Susan; Saunders-Pullman, Rachel
Mutations in GBA1 are a well-established risk factor for Parkinson disease (PD). GBA-associated PD (GBA-PD) may have a higher burden of nonmotor symptoms than idiopathic PD (IPD). We sought to characterize the relationship between GBA-PD and neuropsychiatric symptoms. Subjects were screened for common GBA1 mutations. GBA-PD (n=31) and non-carrier (IPD; n=55) scores were compared on the Unified Parkinson Disease Rating Scale (UPDRS), Montreal Cognitive Assessment (MoCA), Beck Depression Inventory (BDI), and the State-Trait Anxiety Index (STAI). In univariate comparisons, GBA-PD had a greater prevalence of depression (33.3%) versus IPD (13.2%) (p<0.05). In regression models controlling for age, sex, disease duration, motor disability, and MoCA score, GBA-PD had an increased odds of depression (OR 3.66, 95% CI 1.13-11.8) (p=0.03). Post-hoc analysis stratified by sex showed that, among men, GBA-PD had a higher burden of trait anxiety and depression than IPD; this finding was sustained in multivariate models. Among women, GBA-PD did not confer greater psychiatric morbidity than IPD. These results suggest that GBA1 mutations confer greater risk of neuropsychiatric morbidity in PD, and that sex may affect this association.
Wolters, E C; Calne, D B
In Parkinson's disease there is degeneration of neurons in the substantia nigra, with consequent depletion of the neurotransmitter dopamine. The triad of tremor, rigidity and bradykinesia is the clinical hallmark. Drugs currently used for palliative therapy fall into three categories: anticholinergic agents, dopamine precursors (levodopa combined with extracerebral decarboxylase inhibitors) and artificial dopamine agonists. It has been argued, on theoretical grounds, that some drugs slow the progress of Parkinson's disease, although no firm evidence has supported this. Treatment must be individualized, and more than one type of drug can be given concurrently after a careful build-up in dosage. We review the adverse effects of various drugs and consider new developments such as slow-release preparations, selective D-1 and D-2 agonists and transplants of dopaminergic cells into the brain. The treatment of Parkinson's disease can be demanding, rewarding and sometimes frustrating, but it remains a most challenging exercise in pharmacotherapy. Images Fig. 1 Fig. 2 Fig. 3 PMID:2563667
Siddique, M M; Tan, E K
Parkinson's disease (PD), a common neurodegenerative disease, is characterized by the progressive loss of dopamine neurons and the accumulation of Lewy bodies and neurites. The exact role of genetic and environmental factors in the pathogenesis of PD has frequently been debated. The association of MPTP (methyl-4-phenyl-1, 2, 3, 6- tetrahydropyridine) and toxins (such as rotenone) with parkinsonism highlights the potential etiologic role of environmental toxins in disease causation. The recent discoveries of monogenic (such as α-synuclein, Parkin, UCHL1, PINK1, DJ-1, LRRK2) forms of PD have provided considerable insights into its pathophysiology. Parkin, an ubiquitin protein ligase assists in the degradation of toxic substrates via the ubiquitin proteasome system. It can also mediate a nondegradative form of ubiquitination. PINK1 and LRRK2 are possibly involved in the phosphorylation of substrates important for various cellular functions. Some toxins could interact with α-synuclein, an endogenous protein that is implicated in pathology of PD. Increasing in vitro and in vivo studies suggest that deficits in mitochondrial function, oxidative and nitrosative stress, the accumulation of aberrant or misfolded proteins, and ubiquitin-proteasome system dysfunction underpin the pathogenesis of sporadic and familial forms of PD. Elucidation of the functions of the proteins encoded by the diseasecausing genes will provide an opportunity for identification of specific pathways that could be targeted in neurotherapeutics.
Latourelle, Jeanne C; Pankratz, Nathan; Dumitriu, Alexandra; Wilk, Jemma B; Goldwurm, Stefano; Pezzoli, Gianni; Mariani, Claudio B; DeStefano, Anita L; Halter, Cheryl; Gusella, James F; Nichols, William C; Myers, Richard H; Foroud, Tatiana
Background Age at onset in Parkinson disease (PD) is a highly heritable quantitative trait for which a significant genetic influence is supported by multiple segregation analyses. Because genes associated with onset age may represent invaluable therapeutic targets to delay the disease, we sought to identify such genetic modifiers using a genomewide association study in familial PD. There have been previous genomewide association studies (GWAS) to identify genes influencing PD susceptibility, but this is the first to identify genes contributing to the variation in onset age. Methods Initial analyses were performed using genotypes generated with the Illumina HumanCNV370Duo array in a sample of 857 unrelated, familial PD cases. Subsequently, a meta-analysis of imputed SNPs was performed combining the familial PD data with that from a previous GWAS of 440 idiopathic PD cases. The SNPs from the meta-analysis with the lowest p-values and consistency in the direction of effect for onset age were then genotyped in a replication sample of 747 idiopathic PD cases from the Parkinson Institute Biobank of Milan, Italy. Results Meta-analysis across the three studies detected consistent association (p < 1 × 10-5) with five SNPs, none of which reached genomewide significance. On chromosome 11, the SNP with the lowest p-value (rs10767971; p = 5.4 × 10-7) lies between the genes QSER1 and PRRG4. Near the PARK3 linkage region on chromosome 2p13, association was observed with a SNP (rs7577851; p = 8.7 × 10-6) which lies in an intron of the AAK1 gene. This gene is closely related to GAK, identified as a possible PD susceptibility gene in the GWAS of the familial PD cases. Conclusion Taken together, these results suggest an influence of genes involved in endocytosis and lysosomal sorting in PD pathogenesis. PMID:19772629
Fasano, Alfonso; Ginevrino, Monia; Petrucci, Simona; Ricciardi, Lucia; Bove, Francesco; Criscuolo, Chiara; Moccia, Marcello; De Rosa, Anna; Sorbera, Chiara; Bentivoglio, Anna Rita; Barone, Paolo; De Michele, Giuseppe; Pellecchia, Maria Teresa; Valente, Enza Maria
Objective: The aim of this multicenter, case-control study was to investigate the prevalence and severity of impulsive-compulsive behaviors (ICBs) in a cohort of patients with parkin-associated Parkinson disease (PD) compared to a group of patients without the mutation. Methods: We compared 22 patients with biallelic parkin mutations (parkin-PD) and 26 patients negative for parkin, PINK1, DJ-1, and GBA mutations (PD-NM), matched for age at onset, disease duration, levodopa, and dopamine agonist equivalent daily dose. A semistructured interview was used to diagnose each of the following ICBs: compulsive sexual behavior, compulsive buying, binge eating, punding, hobbyism, and compulsive medication use. The Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease–Rating Scale (QUIP-RS) was adopted to rate ICB severity. Results: Frequency of patients with at least one ICB was comparable between parkin-PD and PD-NM. Nevertheless, when analyzing the distribution of specific ICBs, a higher frequency of compulsive shopping, binge eating, and punding/hobbyism was found in the parkin-PD group. Compared to PD-NM, parkin-PD patients with ICB had younger onset age and higher frequency of smokers; in 5 patients, ICB had predated PD onset. Total and partial (compulsive buying, compulsive sexual behavior, binge eating, hobbyism/punding) QUIP-RS scores were higher in patients with parkin-PD compared to patients with PD-NM. Logistic regression analysis showed that the presence of parkin mutations was associated with smoking status and higher QUIP-RS total score. Conclusions: Our data expand the parkin-associated phenotypic spectrum demonstrating higher frequency and severity of specific ICBs, and suggesting an association between the parkin genotype, smoking status, and ICB severity. PMID:27590295
Barkhuizen, Melinda; Anderson, David G; Grobler, Anne F
GBA mutations are to date the most common genetic risk factor for Parkinson's disease. The GBA gene encodes the lysomal hydrolase glucocerebrosidase. Whilst bi-allelic GBA mutations cause Gaucher disease, both mono- and bi-allelic mutations confer risk for Parkinson's disease. Clinically, Parkinson's disease patients with GBA mutations resemble idiopathic Parkinson's disease patients. However, these patients have a modest reduction in age-of-onset of disease and a greater incidence of cognitive decline. In some cases, GBA mutations are also responsible for familial Parkinson's disease. The accumulation of α-synuclein into Lewy bodies is the central neuropathological hallmark of Parkinson's disease. Pathologic GBA mutations reduce enzymatic function. A reduction in glucocerebrosidase function increases α-synuclein levels and propagation, which in turn inhibits glucocerebrosidase in a feed-forward cascade. This cascade is central to the neuropathology of GBA-associated Parkinson's disease. The lysosomal integral membrane protein type-2 is necessary for normal glucocerebrosidase function. Glucocerebrosidase dysfunction also increases in the accumulation of β-amyloid and amyloid-precursor protein, oxidative stress, neuronal susceptibility to metal ions, microglial and immune activation. These factors contribute to neuronal death. The Mendelian Parkinson's disease genes, Parkin and ATP13A2, intersect with glucocerebrosidase. These factors sketch a complex circuit of GBA-associated neuropathology. To clinically interfere with this circuit, central glucocerebrosidase function must be improved. Strategies based on reducing breakdown of mutant glucocerebrosidase and increasing the fraction that reaches the lysosome has shown promise. Breakdown can be reduced by interfering with the ability of heat-shock proteins to recognize mutant glucocerebrosidase. This underlies the therapeutic efficacy of certain pharmacological chaperones and histone deacetylase inhibitors. These
Vilariño-Güell, Carles; Ross, Owen A; Wider, Christian; Jasinska-Myga, Barbara; Cobb, Stephanie A; Soto-Ortolaza, Alexandra I; Kachergus, Jennifer M; Keeling, Brett H; Dachsel, Justus C; Melrose, Heather L; Behrouz, Bahareh; Wszolek, Zbigniew K; Uitti, Ryan J; Aasly, Jan O; Rajput, Alex; Farrer, Matthew J
Recently, a variant in LINGO1 (rs9652490) was found to associate with increased risk of essential tremor. We set out to replicate this association in an independent case-control series of essential tremor from North America. In addition, given the clinical and pathological overlap between essential tremor and Parkinson disease, we also evaluate the effect of LINGO1 rs9652490 in two case-control series of Parkinson disease. Our study demonstrates a significant association between LINGO1 rs9652490 and essential tremor (P = 0.014) and Parkinson disease (P = 0.0003), thus providing the first evidence of a genetic link between both diseases.
Liu, Feng-Cheng; Huang, Wen-Yen; Lin, Te-Yu; Shen, Chih-Hao; Chou, Yu-Ching; Lin, Cheng-Li; Lin, Kuen-Tze; Kao, Chia-Hung
The effects of the inflammatory mediators involved in systemic lupus erythematous (SLE) on subsequent Parkinson disease have been reported, but no relevant studies have focused on the association between the 2 diseases. This nationwide population-based study evaluated the risk of Parkinson disease in patients with SLE.We identified 12,817 patients in the Taiwan National Health Insurance database diagnosed with SLE between 2000 and 2010 and compared the incidence rate of Parkinson disease among these patients with that among 51,268 randomly selected age and sex-matched non-SLE patients. A Cox multivariable proportional-hazards model was used to evaluate the risk factors of Parkinson disease in the SLE cohort.We observed an inverse association between a diagnosis of SLE and the risk of subsequent Parkinson disease, with the crude hazard ratio (HR) being 0.60 (95% confidence interval 0.45-0.79) and adjusted HR being 0.68 (95% confidence interval 0.51-0.90). The cumulative incidence of Parkinson disease was 0.83% lower in the SLE cohort than in the non-SLE cohort. The adjusted HR of Parkinson disease decreased as the follow-up duration increased and was decreased among older lupus patients with comorbidity.We determined that patients with SLE had a decreased risk of subsequent Parkinson disease. Further research is required to elucidate the underlying mechanism.
Chen, Meng-Hsiang; Lu, Cheng-Hsien; Chen, Pei-Chin; Tsai, Nai-Wen; Huang, Chih-Cheng; Chen, Hsiu-Ling; Yang, I-Hsiao; Yu, Chiun-Chieh; Lin, Wei-Che
Abstract Patients with Parkinson disease (PD) have impaired autonomic function and altered brain structure. This study aimed to evaluate the relationship of gray matter volume (GMV) determined by voxel-based morphometry (VBM) to autonomic impairment in patients with PD. Whole-brain VBM analysis was performed on 3-dimensional T1-weighted images in 23 patients with PD and 15 sex- and age-matched healthy volunteers. The relationship of cardiovascular autonomic function (determined by survey) to baroreflex sensitivity (BRS) (determined from changes in heart rate and blood pressure during the early phase II of the Valsalva maneuver) was tested using least-squares regression analysis. The differences in GMV, autonomic parameters, and clinical data were correlated after adjusting for age and sex. Compared with controls, patients with PD had low BRS, suggesting worse cardiovascular autonomic function, and smaller GMV in several brain locations, including the right amygdala, left hippocampal formation, bilateral insular cortex, bilateral caudate nucleus, bilateral cerebellum, right fusiform, and left middle frontal gyri. The decreased GMVs of the selected brain regions were also associated with increased presence of epithelial progenitor cells (EPCs) in the circulation. In patients with PD, decrease in cardiovascular autonomic function and increase in circulating EPC level are associated with smaller GMV in several areas of the brain. Because of its possible role in the modulation of the circulatory EPC pool and baroreflex control, the left hippocampal formation may be a bio-target for disease-modifying therapy and treatment monitoring in PD. PMID:26986144
Drey, Michael; Hasmann, Sandra E.; Krenovsky, Jan-Peter; Hobert, Markus A.; Straub, Stefanie; Elshehabi, Morad; von Thaler, Anna-Katharina; Fallgatter, Andreas J.; Eschweiler, Gerhard W.; Suenkel, Ulrike; Berg, Daniela; Maetzler, Walter
Introduction: Sarcopenia and Parkinson's disease (PD) are both common age-related syndromes, and there is preliminary evidence that the probability of the co-occurrence of these syndromes within one individual is higher than expected. However, it is unclear to date whether one of the syndromes induces the other, or whether there may be common underlying causes. This pilot study thus aimed at investigating the association of the features of increased risk for PD with early stage sarcopenia (ESS). Method: Two hundred and fifty-five community-dwelling individuals were recruited from the Tübinger evaluation of Risk factors for Early detection of NeuroDegeneration (TREND) study. The following features that are associated with an increased risk for future PD were evaluated: the motor part of the Unified PD Rating Scale (UPDRS-III), hyperechogenicity of the substantia nigra, prevalence of lifetime depression, hyposmia, REM sleep behavior disorder and the recently introduced probability score for prodromal PD. Sarcopenia was defined according to the European Working Group on Sarcopenia in Older People, which was adapted to this cohort of healthy adults. Multiple linear regression analysis was used to identify associations of PD-related features with ESS. Results: The UPDRS-III score was significantly associated with ESS. The result remained significant after the adjustment for age, gender and physical activity. No association was found between the other PD-related features and ESS. Conclusion: The significant association of the UPDRS-III score with ESS in this cohort might indicate a common and early pathway in both diseases and supports the existence of an “extended neurodegenerative overlap syndrome.” Moreover, the potential of EES to serve as a prodromal marker of PD should be evaluated in future studies. PMID:28326036
James, Katherine A; Hall, Deborah A
It is unclear whether exposure to environmentally relevant levels of pesticides in groundwater is associated with an increased risk of Parkinson disease (PD). The purpose of this study was to examine the relationship between PD and pesticide levels in groundwater. This cross-sectional study included 332 971 Medicare beneficiaries, including 4207 prevalent cases of PD from the 2007 Colorado Medicare Beneficiary Database. Residential pesticide levels were estimated from a spatial model based on 286 well water samples with atrazine, simazine, alachlor, and metolachlor measurements. A logistic regression model with known PD risk factors was used to assess the association between residential groundwater pesticide levels and prevalent PD. We found that for every 1.0 µg/L of pesticide in groundwater, the risk of PD increases by 3% (odds ratio = 1.03; 95% confidence interval: 1.02-1.04) while adjusting for age, race/ethnicity, and gender suggesting that higher age-standardized PD prevalence ratios are associated with increasing levels of pesticides in groundwater.
Rodríguez-Violante, Mayela; González-Latapi, Paulina; Cervantes-Arriaga, Amin; Martínez-Ramírez, Daniel; Velázquez-Osuna, Salvador; Camacho-Ordoñez, Azyadeh
Apathy is one of the most common behavioral disturbances in Parkinson's disease (PD) with a reported prevalence of 17-51 %. Apathy has been associated with depression, cognitive deficits, and poor quality of life. The objective of this study was to determine the prevalence of apathy in Mexican subjects with PD and its correlation with clinical and demographic characteristics. A cross-sectional, descriptive, and analytic study was carried out. Consecutive subjects with PD attending the National Institute of Neurology and Neurosurgery in Mexico City were included. Demographic and other relevant clinical data were collected. The Apathy Scale was applied to all subjects. A cut-off score of ≥ 14 was used. A total of 241 non-demented patients (52.7 % male) were included. Apathy was found in 43 % of subjects. Lower body mass index, older age of PD onset, cognitive decline and disease severity were all related to apathy. The use of dopamine agonists or rasagiline was more common in patients with low apathy scores. Our results show that the prevalence of apathy in Mexican subjects with PD is similar to other reports.
Sterling, Nicholas W; Du, Guangwei; Lewis, Mechelle M; Swavely, Steven; Kong, Lan; Styner, Martin; Huang, Xuemei
Cortical atrophy has been documented in both Parkinson's disease (PD) and healthy aging, but its relationship to changes in subcortical white matter is unknown. This was investigated by obtaining T1- and diffusion-weighted images from 76 PD and 70 controls at baseline and 18 and 36 months, from which cortical volumes and underlying subcortical white matter axial diffusivity (AD), radial diffusivity (RD), and fractional anisotropy (FA) were determined. Twelve of 69 cortical subregions had significant group differences, and for these, underlying subcortical white matter was explored. At baseline, higher cortical volumes were significantly correlated with lower underlying subcortical white matter AD, RD, and higher FA (ps ≤ 0.017) in PD. Longitudinally, higher rates of cortical atrophy in PD were associated with increased rates of change in AD RD, and FA values (ps ≤ 0.0013) in 2 subregions explored. The significant gray-white matter associations were not found in controls. Thus, unlike healthy aging, cortical atrophy and subcortical white matter changes may not be independent events in PD.
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Zokaei, Nahid; McNeill, Alisdair; Proukakis, Christos; Beavan, Michelle; Jarman, Paul; Korlipara, Prasad; Hughes, Derralynn; Mehta, Atul; Hu, Michele T M; Schapira, Anthony H V; Husain, Masud
Individuals with mutation in the lysosomal enzyme glucocerebrosidase (GBA) gene are at significantly high risk of developing Parkinson's disease with cognitive deficit. We examined whether visual short-term memory impairments, long associated with patients with Parkinson's disease, are also present in GBA-positive individuals-both with and without Parkinson's disease. Precision of visual working memory was measured using a serial order task in which participants observed four bars, each of a different colour and orientation, presented sequentially at screen centre. Afterwards, they were asked to adjust a coloured probe bar's orientation to match the orientation of the bar of the same colour in the sequence. An additional attentional 'filtering' condition tested patients' ability to selectively encode one of the four bars while ignoring the others. A sensorimotor task using the same stimuli controlled for perceptual and motor factors. There was a significant deficit in memory precision in GBA-positive individuals-with or without Parkinson's disease-as well as GBA-negative patients with Parkinson's disease, compared to healthy controls. Worst recall was observed in GBA-positive cases with Parkinson's disease. Although all groups were impaired in visual short-term memory, there was a double dissociation between sources of error associated with GBA mutation and Parkinson's disease. The deficit observed in GBA-positive individuals, regardless of whether they had Parkinson's disease, was explained by a systematic increase in interference from features of other items in memory: misbinding errors. In contrast, impairments in patients with Parkinson's disease, regardless of GBA status, was explained by increased random responses. Individuals who were GBA-positive and also had Parkinson's disease suffered from both types of error, demonstrating the worst performance. These findings provide evidence for dissociable signature deficits within the domain of visual short
Tkaczynska, Zuzanna; Pilotto, Andrea; Becker, Sara; Gräber-Sultan, Susanne; Berg, Daniela; Liepelt-Scarfone, Inga
Urinary dysfunction (UD) is a common non-motor feature of Parkinson's disease (PD), and might be secondary to neurodegeneration involving cortical and subcortical brain areas. The possible link between UD and cognitive deficits has never been examined in frontal cortex impairment, and is still not completely understood in PD. In the present study, 94 PD patients underwent a comprehensive motor, cognitive and non-motor assessment. It was shown that 55.3% of patients reported UD, of which 17% needed specific urological treatment. Patients who reported UD performed worse on global cognition (PANDA, p = .05), visuo-constructive functions (CERAD/praxis, p = .03; and Figure Test, p = .03), and instrumental activities of daily living functions (IADL, p = .03), than patients without UD. The group with UD medication performed worse on global cognition (PANDA, p = .02) and visuo-constructive functions (CERAD/praxis, p = .05; CERAD/praxis recall, p = .05) than the UD group without medication, independent of anticholinergic treatment effect. Our findings suggest an association between cognitive impairment and UD in PD independent from symptomatic treatment.
... results in reduction of a critical neurotransmitter called dopamine, a chemical responsible for transmitting messages to parts ... that coordinate muscle movement. Parkinson's patients have less dopamine. Studies have shown that the symptoms of Parkinson's ...
Sherif, Eskender; Valko, Philipp O; Overeem, Sebastiaan; Baumann, Christian R
Sleep benefit in Parkinson's disease is characterized by restoration of mobility upon awakening from sleep and prior to drug intake. With this study, we aimed at assessing clinical and nocturnal sleep correlates of this phenomenon. We recorded motor and non-motor symptoms in 131 Parkinson patients with and without sleep benefit, as assessed by questionnaires. Polysomnography recordings were performed in 60 of these patients. Thirty-nine Parkinson patients (30%) reported sleep benefit. Motor symptoms, measures of sleepiness, fatigue, depression, anxiety, sleep-wake disorders, and dopaminergic treatment were not associated with sleep benefit, and most polysomnography measures were similar between both groups. However, Parkinson patients with sleep benefit had shorter total sleep times and longer sleep latencies at nocturnal polysomnography. The link between the occurrence of sleep benefit and shorter nocturnal sleep in Parkinson's disease remains unclear.
Azmin, Shahrul; Khairul Anuar, Abdul Manaf; Nafisah, Wan Yahya; Tan, Hui Jan; Raymond, Azman Ali; Hanita, Othman; Shah, Shamsul Azhar; Norlinah, Mohamed Ibrahim
Introduction. Restless legs syndrome has been shown to negatively impact the quality of life of patients. Studies have shown an association between restless legs syndrome and Parkinson's disease. We attempted to investigate the prevalence of restless legs syndrome in Parkinson's disease patients and to identify associated risk factors. Method. This was a cross-sectional study among patients with idiopathic Parkinson's disease. Exclusion criterion was a Mini Mental State Examination score of less than 21/30. The International Restless Legs Syndrome Study Group criterion was used to identify patients with restless legs syndrome. Results. A total of 113 patients were recruited. The prevalence rate of restless legs syndrome in our cohort was 9.7% and was significantly associated with a younger onset of Parkinson's disease (P = 0.023), male gender (P = 0.045), higher Mini Mental State Examination score (P = 0.004), and less advanced Hoehn & Yahr stage (P = 0.014). Conclusion. The prevalence rate of restless legs syndrome in our Parkinson's disease population is in keeping with other studies published worldwide. The significance of the association between a younger onset of Parkinson's disease and restless legs syndrome needs to be further investigated.
The characteristic oily skin in individuals with parkinsonism has long been observed by clinicians. The oiliness seems to be associated with periods when the disease is most active. This seborrhea has been observed particularly in post-encephalitic parkinsonism, as well as in idiopathic paralysis agitans. It also occurs in phenothiazine-induced parkinsonism.
Rodríguez-Blázquez, Carmen; Forjaz, Maria João; Lizán, Luis; Paz, Silvia; Martínez-Martín, Pablo
Parkinson's disease (PD) is a progressive, neurodegenerative disorder whose symptoms and manifestations greatly deteriorate the health, functional status and quality of life of patients, has severe consequences on their families and caregivers and supposes a challenge for the healthcare system and society. The aim of this paper is to comprehensively and descriptively review studies on the economic impact of the disease and interventions, analyzing major contributing factors to direct and indirect costs in PD. Cost-of-illness studies have shown that costs of PD are high, mainly due to drug, hospitalization and productivity loss, and tend to increase as the disease progresses. Studies on PD treatment have suggested that therapies for advanced PD (levodopa/carbidopa intestinal gel and apomorphine) and surgical procedures are cost-effective and cost saving, despite their high expenditures; however, further research such as on the economic impact of non-motor manifestations or on the cost-effectiveness of non-medical interventions is still needed.
Your doctor has told you that you have Parkinson disease . This disease affects the brain and leads ... have you take different medicines to treat your Parkinson disease and many of the problems that may ...
Benninger, David H
In advanced Parkinson's disease (PD), the emergence of symptoms refractory to conventional therapy poses therapeutic challenges. The success of deep brain stimulation (DBS) and advances in the understanding of the pathophysiology of PD have raised interest in noninvasive brain stimulation as an alternative therapeutic tool. The rationale for its use draws from the concept that reversing abnormalities in brain activity and physiology thought to cause the clinical deficits may restore normal functioning. Currently the best evidence in support of this concept comes from DBS, which improves motor deficits, and modulates brain activity and motor cortex physiology, although whether a causal interaction exists remains largely undetermined. Most trials of noninvasive brain stimulation in PD have applied repetitive transcranial magnetic stimulation (rTMS), targeting the motor cortex. Current studies suggest a possible therapeutic potential for rTMS and transcranial direct current stimulation (tDCS), but clinical effects so far have been small and negligible with regard to functional independence and quality of life. Approaches to potentiate the efficacy of rTMS include increasing stimulation intensity and novel stimulation parameters that derive their rationale from studies on brain physiology. These novel parameters are intended to simulate normal firing patterns or to act on the hypothesized role of oscillatory activity in the motor cortex and basal ganglia with regard to motor control and its contribution to the pathogenesis of motor disorders. Noninvasive brain stimulation studies will enhance our understanding of PD pathophysiology and might provide further evidence for potential therapeutic applications.
Hoshiyama, M; Kaneoke, Y; Koike, Y; Takahashi, A; Watanabe, S
We compared the degrees of impairment between intended voluntary movement and its simultaneous automatic associated movement in Parkinson's disease (PD). We studied wrist dorsiflexion as a movement associated with grip in 20 patients with PD and in 20 normal controls. The patients showed a significantly smaller dorsiflexion as compared with the controls. The decrease in associated movement was related to the severity of clinical stage of the disease, while gripping was performed well in each stage. The temporal relationship between grip and associated movement was the same for both groups of subjects. The patients showed no disturbance of amplitude or velocity for a single motor act of wrist dorsiflexion. Persons with PD have a greater reduction of automatic associated movement than intended voluntary movement. This may be one of the bases of clinical symptoms of PD patients in early stages of the disease.
Locascio, Joseph J; Eberly, Shirley; Liao, Zhixiang; Liu, Ganqiang; Hoesing, Ashley N; Duong, Karen; Trisini-Lipsanopoulos, Ana; Dhima, Kaltra; Hung, Albert Y; Flaherty, Alice W; Schwarzschild, Michael A; Hayes, Michael T; Wills, Anne-Marie; Shivraj Sohur, U; Mejia, Nicte I; Selkoe, Dennis J; Oakes, David; Shoulson, Ira; Dong, Xianjun; Marek, Ken; Zheng, Bin; Ivinson, Adrian; Hyman, Bradley T; Growdon, John H; Sudarsky, Lewis R; Schlossmacher, Michael G; Ravina, Bernard; Scherzer, Clemens R
There are no cures for neurodegenerative diseases and this is partially due to the difficulty of monitoring pathogenic molecules in patients during life. The Parkinson's disease gene α-synuclein (SNCA) is selectively expressed in blood cells and neurons. Here we show that SNCA transcripts in circulating blood cells are paradoxically reduced in early stage, untreated and dopamine transporter neuroimaging-supported Parkinson's disease in three independent regional, national, and international populations representing 500 cases and 363 controls and on three analogue and digital platforms with P < 0.0001 in meta-analysis. Individuals with SNCA transcripts in the lowest quartile of counts had an odds ratio for Parkinson's disease of 2.45 compared to individuals in the highest quartile. Disease-relevant transcript isoforms were low even near disease onset. Importantly, low SNCA transcript abundance predicted cognitive decline in patients with Parkinson's disease during up to 5 years of longitudinal follow-up. This study reveals a consistent association of reduced SNCA transcripts in accessible peripheral blood and early-stage Parkinson's disease in 863 participants and suggests a clinical role as potential predictor of cognitive decline. Moreover, the three independent biobank cohorts provide a generally useful platform for rapidly validating any biological marker of this common disease.
Resources - Parkinson disease ... The following organizations are good resources for information on Parkinson disease : The Michael J. Fox Foundation -- www.michaeljfox.org National Institute of Neurological Disorders and Stroke -- www. ...
Klopstock, Thomas; Elstner, Matthias; Lücking, Christoph B; Müller-Myhsok, Bertram; Gasser, Thomas; Botz, Evelyn; Lichtner, Peter; Hörtnagel, Konstanze
Pantothenate kinase-associated neurodegeneration (PKAN) may serve as a model for Parkinson disease (PD) since many PKAN patients suffer from parkinsonism and both conditions lead to iron accumulation in the basal ganglia. We screened the gene coding for pantothenate kinase 2 (PANK2) for sequence variants in PD. We found no mutations in 67 PD patients with affected sibs or early-onset disease. Moreover, PANK2 polymorphisms were not associated with late-onset idiopathic PD in 339 patients. We conclude that PANK2 variants exert, if any, only a very small effect in the genetic risk of PD.
Chae, Younbyoung; Lee, Hyejung; Kim, Hackjin; Kim, Chang-Hwan; Chang, Dae-Il; Kim, Kyung-Mi; Park, Hi-Joon
Acupuncture, a common treatment modality within complementary and alternative medicine, has been widely used for Parkinson's disease (PD). Using functional magnetic resonance imaging (fMRI), we explored the neural mechanisms underlying the effect of specific and genuine acupuncture treatment on the motor function in patients with PD. Three fMRI scans were performed in random order in a block design, one for verum acupuncture (VA) treatment, another one for a covert placebo (CP), and the third one for an overt placebo (OP) at the motor function implicated acupoint GB34 on the left foot of 10 patients with PD. We calculated the contrast that subtracts the blood-oxygen-level dependent (BOLD) response for the acupuncture effect (VA vs. CP) and the placebo effect (CP vs. OP). We found a significant improvement in the motor function of the affected hand after acupuncture treatment. The putamen and the primary motor cortex were activated when patients with PD received the acupuncture treatment (VA vs. CP) and these activations correlated with individual enhanced motor function. Expectation towards acupuncture modality (CP vs. OP) elicited activation over the anterior cingulate gyrus, the superior frontal gyrus, and the superior temporal gyrus. These findings suggest that acupuncture treatment might facilitate improvement in the motor functioning of patients with PD via the basal ganglia-thalamocortical circuit.
Koshimori, Yuko; Segura, Barbara; Christopher, Leigh; Lobaugh, Nancy; Duff-Canning, Sarah; Mizrahi, Romina; Hamani, Clement; Lang, Anthony E; Aminian, Kelly; Houle, Sylvain; Strafella, Antonio P
The current study investigates both gray and white matter changes in non-demented Parkinson's disease (PD) patients with varying degrees of mild cognitive deficits and elucidates the relationships between the structural changes and clinical sequelae of PD. Twenty-six PD patients and 15 healthy controls (HCs) were enrolled in the study. Participants underwent T1-weighted and diffusion tensor imaging (DTI) scans. Their cognition was assessed using a neuropsychological battery. Compared with HCs, PD patients showed significant cortical thinning in sensorimotor (left pre- and postcentral gyri) and cognitive (left dorsolateral superior frontal gyrus [DLSFG]) regions. The DLSFG cortical thinning correlated with executive and global cognitive impairment in PD patients. PD patients showed white matter abnormalities as well, primarily in bilateral frontal and temporal regions, which also correlated with executive and global cognitive impairment. These results seem to suggest that both gray and white matter changes in the frontal regions may constitute an early pathological substrate of cognitive impairment of PD providing a sensitive biomarker for brain changes in PD.
Young Blood, Marcelo Rezende; Munhoz, Renato Puppi
Neuropsychiatric symptoms and pain are among the most common nonmotor symptoms of Parkinson's disease (PD). The correlation between pain and PD has been recognized since its classic descriptions. Pain occurs in about 60% of PD patients, two to three times more frequent in this population than in age matched healthy individuals. It is an early and potentially disabling symptom that can precede motor symptoms by several years. The lower back and lower extremities are the most commonly affected areas. The most used classification for pain in PD defines musculoskeletal, dystonic, central, or neuropathic/radicular forms. Its different clinical characteristics, variable relationship with motor symptoms, and inconsistent response to dopaminergic drugs suggest that the mechanism underlying pain in PD is complex and multifaceted, involving the peripheral nervous system, generation and amplification of pain by motor symptoms, and neurodegeneration of areas related to pain modulation. Although pain in DP is common and a significant source of disability, its clinical characteristics, pathophysiology, classification, and management remain to be defined. PMID:27800210
Gazewood, John D; Richards, D Roxanne; Clebak, Karl
Parkinson disease is a progressive neurologic disorder afflicting approximately 1 percent of Americans older than 60 years. The cardinal features of Parkinson disease are bradykinesia, rigidity, tremor, and postural instability. There are a number of neurologic conditions that mimic the disease, making it difficult to diagnose in its early stages. Physicians who rarely diagnose Parkinson disease should refer patients suspected of having it to physicians with more experience in making the diagnosis, and should periodically reevaluate the accuracy of the diagnosis. Treatment is effective in reducing motor impairment and disability, and should be started when a patient begins to experience functional impairment. The combination of carbidopa and levodopa is the most effective treatment, but dopamine agonists and monoamine oxidase-B inhibitors are also effective, and are less likely to cause dyskinesias. For patients taking carbidopa/levodopa who have motor complications, adjunctive therapy with a dopamine agonist, a monoamine oxidase-B inhibitor, or a catechol O-methyltransferase inhibitor will improve motor symptoms and functional status, but with an increase in dyskinesias. Deep brain stimulation is effective in patients who have poorly controlled symptoms despite optimal medical therapy. Occupational, physical, and speech therapy improve patient function. Fatigue, sleep disturbances, dementia, and depression are common in patients with Parkinson disease. Although these conditions are associated with significantly lower quality of life, they may improve with treatment.
Chen, Yang; Lü, Ying-Hui; Li, Zhao-Fa
Vectors used to carry foreign genes play an important role in gene therapy, among which, the adeno-associated virus (AAV) has many advantages, such as nonpathogenicity, low immunogenicity, stable and long-term expression and multiple-tissue-type infection, etc. These advantages have made AAV one of the most potential vectors in gene therapy, and widely used in many clinical researches, for example, Parkinson's disease. This paper introduces the biological characteristics of AAV and the latest research progress of AAV carrying neurotrophic factor, dopamine synthesis related enzymes and glutamic acid decarboxylase gene in the gene therapy of Parkinson's disease.
Sherer, Todd B
Biomarkers for detecting the early stages of Parkinson's disease (PD) could accelerate development of new treatments. Such biomarkers could be used to identify individuals at risk for developing PD, to improve early diagnosis, to track disease progression with precision, and to test the efficacy of new treatments. Although some progress has been made, there are many challenges associated with developing biomarkers for detecting PD in its earliest stages.
Ma, Joan K.-Y.; Whitehill, Tara L.; So, Susanne Y.-S.
Purpose: Speech produced by individuals with hypokinetic dysarthria associated with Parkinson's disease (PD) is characterized by a number of features including impaired speech prosody. The purpose of this study was to investigate intonation contrasts produced by this group of speakers. Method: Speech materials with a question-statement contrast…
Niccolini, Flavia; Foltynie, Thomas; Reis Marques, Tiago; Muhlert, Nils; Tziortzi, Andri C; Searle, Graham E; Natesan, Sridhar; Kapur, Shitij; Rabiner, Eugenii A; Gunn, Roger N; Piccini, Paola; Politis, Marios
pallidal loss of PDE10A expression, which is associated with Parkinson's duration and severity of motor symptoms and complications. PDE10A is an enzyme that could be targeted with novel pharmacotherapy, and this may help improve dopaminergic signalling and striatal output, and therefore alleviate symptoms and complications of Parkinson's disease.
Bohnen, Nicolaas I; Gedela, Satyanarayana; Herath, Priyantha; Constantine, Gregory M; Moore, Robert Y
Olfactory dysfunction is common in patients with Parkinson disease (PD) and has been attributed to early pathological deposition of Lewy bodies and Lewy neurites in primary olfactory centers. However, olfactory deficits do not always worsen over time despite progression of disease raising the possibility of additional pathobiological mechanisms contributing to olfactory functions in PD, such as changes in olfactory neurotransmitter functions. Neurotransmitter changes, such as altered dopaminergic status, may also better explain the selective nature of odor identification deficits in PD. Proper odor identification depends on higher order structures, such as the hippocampus, for olfactory cognitive or memory processing. Using the University of Pennsylvania Smell Identification Test (UPSIT), we previously identified three odors (banana, licorice, dill pickle, labeled as UPSIT-3) that PD subjects most frequently failed to recognize compared to age- and gender-matched controls. We also identified six odors that were equally successfully identified by controls and PD subjects (NPD-Olf6). A ratio of UPSIT-3 divided by NPD-Olf6 scores provides another descriptor of selective hyposmia in PD ("olfactory ratio"). In this study we investigated the pathophysiology of hyposmia in PD using dopamine transporter (DAT) PET. Twenty-nine PD patients (Hoehn and Yahr stages I-III; 7f/22m; age 60.2+/-10.8) underwent olfactory testing using the UPSIT and [(11)C]beta-CFT DAT PET. DAT binding potentials (BP) were assessed in the hippocampus, amygdala, ventral and dorsal striatum. We found that correlation coefficients between total UPSIT scores and regional brain DAT BP were highest for the hippocampus (Rs=0.54, P=0.002) and lower for the amygdala (Rs=0.44, P=0.02), ventral (Rs=0.48, P=0.008) and dorsal striatum (Rs=0.39, P=0.03). Correlations were most significant for the selective hyposmia measures and hippocampal DAT: UPSIT-3 (Rs=0.65, P=0.0001) and the olfactory ratio (Rs=0.74, P<0
Lu, Bingwei; Gehrke, Stephan; Wu, Zhihao
Neurodegenerative diseases such as Parkinson׳s disease are progressive disorders of the nervous system that affect the function and maintenance of specific neuronal populations. While most disease cases are sporadic with no known cause, a small percentage of disease cases are caused by inherited genetic mutations. The identification of genes associated with the familial forms of the diseases and subsequent studies of proteins encoded by the disease genes in cellular or animal models have offered much-needed insights into the molecular and cellular mechanisms underlying disease pathogenesis. Recent studies of the familial Parkinson׳s disease genes have emphasized the importance of RNA metabolism, particularly mRNA translation, in the disease process. It is anticipated that continued studies on the role of RNA metabolism in Parkinson׳s disease will offer unifying mechanisms for understanding the cause of neuronal dysfunction and degeneration and facilitate the development of novel and rational strategies for treating this debilitating disease.
Granado, Noelia; Ares-Santos, Sara; Moratalla, Rosario
Parkinson's disease (PD) is a neurodegenerative disorder predominantly affecting the elderly. The aetiology of the disease is not known, but age and environmental factors play an important role. Although more than a dozen gene mutations associated with familial forms of Parkinson's disease have been described, fewer than 10% of all cases can be explained by genetic abnormalities. The molecular basis of Parkinson's disease is the loss of dopamine in the basal ganglia (caudate/putamen) due to the degeneration of dopaminergic neurons in the substantia nigra, which leads to the motor impairment characteristic of the disease. Methamphetamine is the second most widely used illicit drug in the world. In rodents, methamphetamine exposure damages dopaminergic neurons in the substantia nigra, resulting in a significant loss of dopamine in the striatum. Biochemical and neuroimaging studies in human methamphetamine users have shown decreased levels of dopamine and dopamine transporter as well as prominent microglial activation in the striatum and other areas of the brain, changes similar to those observed in PD patients. Consistent with these similarities, recent epidemiological studies have shown that methamphetamine users are almost twice as likely as non-users to develop PD, despite the fact that methamphetamine abuse and PD have distinct symptomatic profiles. PMID:23476887
Nieuwhof, Freek; Bloem, Bastiaan R; Reelick, Miriam F; Aarts, Esther; Maidan, Inbal; Mirelman, Anat; Hausdorff, Jeffrey M; Toni, Ivan; Helmich, Rick C
Impaired dual tasking, namely the inability to concurrently perform a cognitive and a motor task (e.g. 'stops walking while talking'), is a largely unexplained and frequent symptom of Parkinson's disease. Here we consider two circuit-level accounts of how striatal dopamine depletion might lead to impaired dual tasking in patients with Parkinson's disease. First, the loss of segregation between striatal territories induced by dopamine depletion may lead to dysfunctional overlaps between the motor and cognitive processes usually implemented in parallel cortico-striatal circuits. Second, the known dorso-posterior to ventro-anterior gradient of dopamine depletion in patients with Parkinson's disease may cause a funnelling of motor and cognitive processes into the relatively spared ventro-anterior putamen, causing a neural bottleneck. Using functional magnetic resonance imaging, we measured brain activity in 19 patients with Parkinson's disease and 26 control subjects during performance of a motor task (auditory-cued ankle movements), a cognitive task (implementing a switch-stay rule), and both tasks simultaneously (dual task). The distribution of task-related activity respected the known segregation between motor and cognitive territories of the putamen in both groups, with motor-related responses in the dorso-posterior putamen and task switch-related responses in the ventro-anterior putamen. During dual task performance, patients made more motor and cognitive errors than control subjects. They recruited a striatal territory (ventro-posterior putamen) not engaged during either the cognitive or the motor task, nor used by controls. Relatively higher ventro-posterior putamen activity in controls was associated with worse dual task performance. These observations suggest that dual task impairments in Parkinson's disease are related to reduced spatial focusing of striatal activity. This pattern of striatal activity may be explained by a loss of functional segregation
Pal, Amit; Kumar, Ashok; Prasad, Rajendra
Neurodegenerative diseases, Alzheimer's disease (AD) and Parkinson's disease (PD), constitute a major worldwide health problem. Several hypothesis have been put forth to elucidate the basis of onset and pathogenesis of AD and PD; however, till date, none of these seems to clearly elucidate the complex pathoetiology of these disorders. Notably, copper dyshomeostasis has been shown to underlie the pathophysiology of several neurodegenerative diseases including AD and PD. Numerous studies have concluded beyond doubt that imbalance in copper homeostatic mechanisms in conjunction with aging causes an acceleration in the copper toxicity elicited oxidative stress, which is detrimental to the central nervous system. Amyloid precursor protein and α-synuclein protein involved in AD and PD are copper binding proteins, respectively. In this review, we have discussed the possible association of copper metabolism proteins with AD and PD along with briefly outlining the expanding proportion of "copper interactome" in human biology. Using network biology, we found that copper metabolism proteins, superoxide dismutase 1 and ceruloplasmin may represent direct and indirect link with AD and PD, respectively.
McKenzie, Jordan Alexander; Spielman, Lindsay J; Pointer, Caitlin B; Lowry, Jessica R; Bajwa, Ekta; Lee, Carolyn W; Klegeris, Andis
Alzheimer's disease (AD) and Parkinson's disease (PD) are among the most common causes of dementia, which increasingly contribute to morbidity and mortality worldwide. A common hallmark in the pathogenesis of these two diseases is neuroinflammation, which is initially triggered by the presence of pathological structures associated with these disorders. Chronic neuroinflammation is sustained by persistent and aberrant microglial activation in the brain, which results in damage and death of neighboring cells, including neurons and glial cells. Two types of risk factors contribute to the development of AD and PD: non-modifiable risk factors and modifiable risk factors. Non-modifiable risk factors include genetic susceptibility that increases an individual's risk of developing the disease, whereas modifiable risk factors include a wide variety of health- and lifestyle-related factors that may be altered by changing individual behaviors. Exposure to environmental toxins could be viewed as a partially modifiable risk factor. This review focuses on four modifiable risk factors including physical inactivity, vascular disease-related conditions, obesity and type two diabetes mellitus, all of which have been identified as risk factors for the development of AD and PD. We highlight that control of the modifiable risk factors is a valid approach for managing the increased incidence of AD and PD. We describe neuroinflammatory mechanisms, which are common to AD and PD, that may link both these neurodegenerative diseases with the four common modifiable risk factors. Understanding these mechanisms could help identify novel therapeutic targets for combating these neurodegenerative diseases.
Vanhauwaert, Roeland; Verstreken, Patrik
Parkinson's disease is an incurable neurodegenerative disease. Most cases of the disease are of sporadic origin, but about 10% of the cases are familial. The genes thus far identified in Parkinson's disease are well conserved. Drosophila is ideally suited to study the molecular neuronal cell biology of these genes and the pathogenic mutations in Parkinson's disease. Flies reproduce quickly, and their elaborate genetic tools in combination with their small size allow researchers to analyze identified cells and neurons in large numbers of animals. Furthermore, fruit flies recapitulate many of the cellular and molecular defects also seen in patients, and these defects often result in clear locomotor and behavioral phenotypes, facilitating genetic modifier screens. Hence, Drosophila has played a prominent role in Parkinson's disease research and has provided invaluable insight into the molecular mechanisms of this disease.
Ventre-Dominey, Jocelyne; Mollion, Hélène; Thobois, Stephane; Broussolle, Emmanuel
Evidence has been provided in Parkinson's disease patients of cognitive impairments including visual memory and learning which can be partially compensated by dopamine medication or subthalamic nucleus stimulation. The effects of these two therapies can differ according to the learning processes involving the dorsal vs ventral part of the striatum. Here we aimed to investigate and compare the outcomes of dopamine vs stimulation treatment in Parkinson patient's ability to acquire and maintain over successive days their performance in visual working memory. Parkinson patients performed conditional associative learning embedded in visual (spatial and non spatial) working memory tasks over two consecutive days either ON or OFF dopaminergic drugs or STN stimulation depending on the group of patients studied. While Parkinson patients were more accurate and faster in memory tasks ON vs OFF stimulation independent of the day of testing, performance in medicated patients differed depending on the medication status during the initial task acquisition. Patients who learnt the task ON medication the first day were able to maintain or even improve their memory performance both OFF and ON medication on the second day after consolidation. These effects were observed only in patients with dopamine replacement with or without motor fluctuations. This enhancement in memory performance after having learnt under dopamine medication and not under STN stimulation was mostly significant in visuo-spatial working memory tasks suggesting that dopamine replacement in the depleted dorsal striatum is essential for retention and consolidation of learnt skill.
Multidisciplinary working and co-ordination between different parts of the care pathway are key to improving services for Parkinson's disease patients. Benefits of this approach include care continuity and increased sharing of skills between professionals. Specialist Parkinson's nurses form a key part of the multidisciplinary workforce, and have formed peer networks to keep up to date on best practice.
... The NINDS also collaborates with the Michael J. Fox Foundation for Parkinson's Research (MJFF) on BioFIND , a ... an Art / Symptoms of Parkinson's Disease / Michael J. Fox: Spurring Research on Parkinson's / Diagnosis and Treatment / Research ...
Amano, Shinichi; Roemmich, Ryan T; Skinner, Jared W; Hass, Chris J
Parkinson disease is a progressive neurodegenerative disorder characterized by a variety of motor and nonmotor features. This article reviews the problems of postural instability and gait disturbance in persons with Parkinson disease through the discussion of (1) the neuropathology of parkinsonian motor deficits, (2) behavioral manifestations of gait and postural abnormalities observed in persons with Parkinson disease, and (3) pharmacologic, surgical, and physical therapy-based interventions to combat postural instability and gait disturbance. This article advances the treatment of postural instability and gait disturbance by condensing up-to-date knowledge and making it available to clinicians and rehabilitation professionals.
Zhang, Ping; Liu, Ling; Huang, Jinsha; Shao, Liang; Wang, Hongcai; Xiong, Nian; Wang, Tao
Previous studies have indicated that non-SMC condensin I complex, subunit D2 (NCAPD2), an important protein in chromosome condensation, gene polymorphisms are associated with Alzheimer's disease. But no study has shown the relationship between NCAPD2 polymorphisms and Parkinson's disease. Here, we conducted a case-control study to investigate the relationship between NCAPD2 polymorphisms and the risk of Parkinson's disease in a Han Chinese population. Two single nuclear polymorphisms (SNPs) of NCAPD2 (rs7311174 and rs2072374) showed significant p values (p = 0.046 and p = 0.043, respectively) in 265 patients and 267 controls. Further analysis showed an effect of age and gender on the relationship between the two SNPs and the risk for Parkinson's disease. The A allele of rs7311174 and the T allele of rs2072374 were protective in the male patients (p = 0.016 and p = 0.019, respectively). The frequencies of the T allele of rs7311174 and the C allele of rs2072374 were significantly associated with late-onset Parkinson's disease (p = 0.048 and p = 0.044, respectively). This research demonstrates a positive relationship between the NCAPD2 gene and the risk for Parkinson's disease in a Han Chinese population and provides a potential genetic marker for sporadic Parkinson's disease.
... our 24/7 Helpline at 800.272.3900. Michael J. Fox Foundation for Parkinson's Research website offers ... as a Therapeutic Target in Alzheimer's Disease 2007 Michael Vitek Novel Therapeutic Reduces Abeta Deposition and Alzheimer's ...
Verma, Akhilesh Kumar; Keshari, Anand Kumar; Raj, Janak; Kumari, Renu; Kumar, Tarun; Sharma, Vivek; Singh, Tej Bali; Srivastava, Shalabh; Srivastava, Ragini
Micronutrients and trace elements have been identified to play an important role in the development of Parkinson's disease (PD). In our previous study, we observed that prolidase activity is associated with oxidative stress and progression of PD. In present study, we aimed to study the association of prolidase-associated trace elements, such as Co, Mn, Ni, and Zn in the plasma of patients with PD by inductively coupled plasma spectrometry. Plasma levels of Co, Mn, and Ni were significantly increased, whereas plasma levels of Zn was significantly decreased (all P < 0.05) in the patients with PD than healthy controls. Plasma prolidase activity was not correlated to its associated trace elements in PD. A positive, linear, and significant correlation was observed between age and Co, and Mn, and Ni while negative and non-significant between age and status of Zn in the patients. Co, Mn, and Ni were continually elevated with increase in age as well as duration of disease in the patients with PD, whereas status of Zn was continually decreased. Thus, the study concluded that trace elements Co, Ni, and Mn status were increased and Zn status was decreased in the plasma of patients with PD. It is also concluded that elevated Co, Mn, and Ni has been associated with progression of Parkinson's disease.
Vetrano, Davide L; Pisciotta, Maria S; Lo Monaco, Maria R; Onder, Graziano; Laudisio, Alice; Brandi, Vincenzo; La Carpia, Domenico; Guglielmo, Mauro; Nacchia, Antonio; Fusco, Domenico; Ricciardi, Diego; Bentivoglio, Anna R; Bernabei, Roberto; Zuccalà, Giuseppe
To assess whether among patients with Parkinson's disease (PD) depression, a common non-motor symptom associated with reduced survival, is associated with cardiovascular dysautonomia. We enrolled 125 subjects with PD consecutively admitted to a geriatric day hospital. All participants underwent comprehensive evaluation, fasting blood sampling, and 24-h ambulatory blood pressure monitoring. The percent reduction in nocturnal blood pressure (dipping) was calculated. Depressive symptoms were assessed through the 15-item Geriatric Depression Scale (GDS); a score ≥5 identified moderate to severe symptoms. Among participants (mean age 72.7 ± 7.8 years, 32 % women) 61 subjects (49 %) presented with a GDS score ≥ 5. When compared with other participants, subjects with a GDS score ≥ 5 had reduced adjusted levels of percent systolic (-2.6 ± 2.7 vs. 4.7 ± 2.5; p = 0.003), diastolic (0.6 ± 2.8 vs. 7.4 ± 2.6; p = 0.007), and mean blood pressure dipping (-0.7 ± 2.6 vs. 6.8 ± 2.5; p = 0.002). In separate logistic regression models, depressive symptoms were associated with reduced systolic (OR 0.94; 95 % CI 0.89; 0.98), diastolic (OR 0.94; 95 % CI 0.90; 0.99), and mean blood pressure dipping (OR 0.93; 95 % CI 0.89; 0.98), after adjusting for potential confounders. Depressive symptoms are prevalent, and independently associated with cardiovascular dysautonomia among patients with Parkinson's disease. This might explain the remarkable incidence of sudden death, as well as the association of depressive symptoms with reduced survival reported in these patients. The finding of depressive symptoms in subjects with Parkinson's disease should therefore prompt assessment of cardiovascular autonomic function.
Grace, Janet; Amick, Melissa M; D'Abreu, Anelyssa; Festa, Elena K; Heindel, William C; Ott, Brian R
Neuropsychological and motor deficits in Parkinson's disease that may contribute to driving impairment were examined in a cohort study comparing patients with Parkinson's disease (PD) to patients with Alzheimer's disease (AD) and to healthy elderly controls. Nondemented individuals with Parkinson's disease [Hoehn & Yahr (H&Y) stage I-III], patients with Alzheimer's disease [Clinical Demetia Rating scale (CDR) range 0-1], and elderly controls, who were actively driving, completed a neuropsychological battery and a standardized road test administered by a professional driving instructor. On-road driving ability was rated on number of driving errors and a global rating of safe, marginal, or unsafe. Overall, Alzheimer's patients were more impaired drivers than Parkinson's patients. Parkinson's patients distinguished themselves from other drivers by a head-turning deficiency. Drivers with neuropsychological impairment were more likely to be unsafe drivers in both disease groups compared to controls. Compared to controls, unsafe drivers with Alzheimer's disease were impaired across all neuropsychological measures except finger tapping. Driving performance in Parkinson's patients was related to disease severity (H&Y), neuropsychological measures [Rey Osterreith Complex Figure (ROCF), Trails B, Hopkins Verbal List Learning Test (HVLT)-delay], and specific motor symptoms (axial rigidity, postural instability), but not to the Unified Parkinson Disease Rating Scale (UPDRS) motor score. Multifactorial measures (ROCF, Trails B) were useful in distinguishing safe from unsafe drivers in both patient groups.
Alcock, Lisa; Galna, Brook; Lord, Sue; Rochester, Lynn
Tripping is a common cause of falls in older adults and people with Parkinson׳s disease (PD). Foot clearance during gait may be impaired when distracted by a dual task and thus inform trip risk. This study aimed to evaluate whether foot clearance is impaired in PD and is adversely affected by a dual task. 81 older adults and 76 PD walked at a comfortable pace for two minutes under single and dual task conditions (digit recall). Temporal spatial gait was measured using an instrumented walkway. Heel and toe trajectories were obtained bilaterally using 3-dimensional motion capture. Foot clearance was reduced in PD (p<.001) and under dual task (p<.027). The take-off (toe) gradient was reduced under dual task irrespective of group and the landing (heel) gradient was reduced in PD irrespective of task (p<.001). An increased proportion of unimodal toe distributions were observed for PD, particularly under dual task. Group differences were retained when controlling for step length (landing gradient and peak toe clearance in late swing) and gait velocity (landing gradient). Distinct differences in foot clearance were observed even in the early clinical stages of PD. Dual tasking may increase trip risk due to insufficient toe clearance (early swing) for both older adults and PD. Inadequate heel clearance (late swing) may increase falls risk in PD. Clearance deficits in PD are partially related to a reduced gait velocity and step length which may be targeted in tailored therapies. Further work is necessary to understand the mechanisms underlying this pathology-associated deficit.
Ylikoski, Ari; Martikainen, Kirsti; Sieminski, Mariusz; Partinen, Markku
There is a broad spectrum of sleep disturbances observed in Parkinson's disease (PD). The prevalence of symptoms of insomnia and chronic inability to sleep and their association with other sleep disorders were studied. Altogether 1447 randomly selected Parkinson patients, aged 43-89 years, participated in a questionnaire study. A structured questionnaire with 207 items was based on the Basic Nordic Sleep questionnaire. Questions on demographics, PD, REM Sleep Behavior Disorder, and other issues were included. The response rate was 59 % (N = 854), and of these 81 % returned fully answered questionnaire (N = 689). Prevalence of chronic inability to sleep was 36.9 % (95 % CI 33.3-40.5). Difficulty of initiating sleep was 18.0 % (95 % CI 15.1-20.9), disrupted sleep 81.54 % (78.5-84.4), awakenings during night 31.3 % (27.8-34.8), early morning awakenings 40.4 % (36.8-44.1) and non-restorative sleep 38.5 % (34.8-42.1). In the logistic regression models, poor quality of life and restless legs syndrome correlated significantly with chronic insomnia disorder. Disrupted sleep and early morning awakenings were the most common insomnia symptoms. PD patients do not seem to have difficulties in sleep initiation. Insomnia symptoms including disruptive sleep and non-restorative sleep are common in patients with Parkinson's disease. Inability to sleep is more common as comorbidity than a single sleep problem.
Chung, Seockhoon; Bohnen, Nicolaas I.; Albin, Roger L.; Frey, Kirk A.; Müller, Martijn L. T. M.; Chervin, Ronald D.
Study Objectives: Insomnia and daytime sleepiness are common complaints in Parkinson disease (PD), but the main causes remain unclear. We examined the potential impact of both motor and non-motor symptoms of PD on sleep problems. Methods: Patients with PD (n = 128) were assessed using the Insomnia Severity Index, Epworth Sleepiness Scale, Unified Parkinson Disease Rating Scale, Beck Depression Inventory, Fatigue Severity Scale, Survey of Autonomic Symptoms, and the 39-item Parkinson Disease Questionnaire. A subset of subjects (n = 38, 30%) also completed nocturnal polysomnography and a multiple sleep latency test (MSLT). Results: Multivariate stepwise logistic regression models revealed that subjective insomnia was independently associated with depressed mood (odds ratio [OR] = 1.79; 95% confidence interval (CI) [1.01-3.19]), autonomic symptoms (1.77 [1.08-2.90]), fatigue (1.19 [1.02-1.38]), and age (0.61 [0.39-0.96]). Subjective daytime sleepiness was associated with dosage of dopaminergic medication (1.74 [1.08-2.80]) and fatigue (1.14 [1.02-1.28]). On polysomnography, longer sleep latency correlated with autonomic symptoms (rho = 0.40, p = 0.01) and part I (non-motor symptoms) of the Unified PD Rating Scale (rho = 0.38, p = 0.02). Decreased sleep efficiency correlated with autonomic symptoms (rho = -0.42, p < 0.0001). However, no significant difference emerged on polysomnography and MSLTs between patients with or without insomnia or daytime sleepiness. Higher rates of apneic events did predict shorter sleep latencies on the MSLTs. Conclusions: Non-motor symptoms appear to be associated with subjective insomnia, whereas fatigue and dopaminergic medication are associated with subjective daytime sleepiness. Objective sleep laboratory data provided little insight into complaints of insomnia and sleepiness, though obstructive sleep apnea predicted worsened sleepiness when measured objectively. Citation: Chung S; Bohnen NI; Albin RL; Frey KA; Müller MLTM; Chervin RD
Jankovic, Joseph; Stacy, Mark
Parkinson's disease is a neurodegenerative disorder that affects approximately 1% of people over the age of 60 years. Levodopa is standard, and often initial, therapy for patients with this condition; however, with continued treatment and as the disease progresses, up to 80% of patients experience 'wearing-off' symptoms, dyskinesias and other motor complications. These levodopa-associated problems may become disabling and profoundly affect quality of life. Medications commonly used to manage these symptoms include monoamine oxidase type B (MAO-B) inhibitors, catechol-O-methyltransferase (COMT) inhibitors, the NMDA receptor antagonist amantadine and dopamine receptor agonists. Agents that block MAO-B, such as rasagiline and selegiline, are used as both initial and adjunctive therapy in patients with Parkinson's disease. These medications increase concentrations of dopamine in the brain by blocking its reuptake from the synaptic cleft, a mechanism that can slow motor decline, increase 'on' time and improve symptoms of Parkinson's disease. Adverse events with these agents can include confusion, hallucination and orthostatic hypotension. MAO-B inhibition may elicit drug-drug interactions if administered with TCAs, SSRIs or SNRIs. Conventional oral selegiline is associated with potentially harmful plasma concentrations of three major amphetamine metabolites, although metabolite concentrations are significantly lower with a new orally disintegrating tablet (ODT) selegiline formulation. Selegiline ODT is also absorbed more efficiently and shows less pharmacokinetic variability than conventional oral selegiline.COMT mediates peripheral catabolism of levodopa. Therefore, agents that block COMT, such as tolcapone and entacapone, increase the elimination half-life of levodopa. Given adjunctively with levodopa, COMT inhibitors can decrease 'off' time and increase 'on' time, as well as lower the daily levodopa dose. Although more potent than entacapone, tolcapone requires
Mok, Kin Y; Sheerin, Una; Simón-Sánchez, Javier; Salaka, Afnan; Chester, Lucy; Escott-Price, Valentina; Mantripragada, Kiran; Doherty, Karen M; Noyce, Alastair J; Mencacci, Niccolo E; Lubbe, Steven J; Williams-Gray, Caroline H; Barker, Roger A; van Dijk, Karin D; Berendse, Henk W; Heutink, Peter; Corvol, Jean-Christophe; Cormier, Florence; Lesage, Suzanne; Brice, Alexis; Brockmann, Kathrin; Schulte, Claudia; Gasser, Thomas; Foltynie, Thomas; Limousin, Patricia; Morrison, Karen E; Clarke, Carl E; Sawcer, Stephen; Warner, Tom T; Lees, Andrew J; Morris, Huw R; Nalls, Mike A; Singleton, Andrew B; Hardy, John; Abramov, Andrey Y; Plagnol, Vincent; Williams, Nigel M; Wood, Nicholas W
Summary Background Parkinson's disease has been reported in a small number of patients with chromosome 22q11.2 deletion syndrome. In this study, we screened a series of large, independent Parkinson's disease case-control studies for deletions at 22q11.2. Methods We used data on deletions spanning the 22q11.2 locus from four independent case-control Parkinson's disease studies (UK Wellcome Trust Case Control Consortium 2, Dutch Parkinson's Disease Genetics Consortium, US National Institute on Aging, and International Parkinson's Disease Genomics Consortium studies), which were independent of the original reports of chromosome 22q11.2 deletion syndrome. We did case-control association analysis to compare the proportion of 22q11.2 deletions found, using the Fisher's exact test for the independent case-control studies and the Mantel-Haenszel test for the meta-analyses. We retrieved clinical details of patients with Parkinson's disease who had 22q11.2 deletions from the medical records of these patients. Findings We included array-based copy number variation data from 9387 patients with Parkinson's disease and 13 863 controls. Eight patients with Parkinson's disease and none of the controls had 22q11.2 deletions (p=0·00082). In the 8451 patients for whom age at onset data were available, deletions at 22q11.2 were associated with Parkinson's disease age at onset (Mann-Whitney U test p=0·001). Age at onset of Parkinson's disease was lower in patients carrying a 22q11.2 deletion (median 37 years, 95% CI 32·0–55·5; mean 42·1 years [SD 11·9]) than in those who did not carry a deletion (median 61 years, 95% CI 60·5–61·0; mean 60·3 years [SD 12·8]). A 22q11.2 deletion was present in more patients with early-onset (p<0·0001) and late-onset Parkinson's disease (p=0·016) than in controls, and in more patients with early-onset than late-onset Parkinson's disease (p=0·005). Interpretation Clinicians should be alert to the possibility of 22q11.2 deletions in
Rodríguez-Arribas, M; Yakhine-Diop, S M S; Pedro, J M Bravo-San; Gómez-Suaga, P; Gómez-Sánchez, R; Martínez-Chacón, G; Fuentes, J M; González-Polo, R A; Niso-Santano, M
Mitochondria-associated membranes (MAMs) are structures that regulate physiological functions between endoplasmic reticulum (ER) and mitochondria in order to maintain calcium signaling and mitochondrial biogenesis. Several proteins located in MAMs, including those encoded by PARK genes and some of neurodegeneration-related proteins (huntingtin, presenilin, etc.), ensure this regulation. In this regard, MAM alteration is associated with neurodegenerative diseases such as Parkinson's (PD), Alzheimer's (AD), and Huntington's diseases (HD) and contributes to the appearance of the pathogenesis features, i.e., autophagy dysregulation, mitochondrial dysfunction, oxidative stress, and lately, neuronal death. Moreover,, ER stress and/or damaged mitochondria can be the cause of these disruptions. Therefore, ER-mitochondria contact structure and function are crucial to multiple cellular processes. This review is focused on the molecular interaction between ER and mitochondria indispensable to MAM formation and on MAM alteration-induced etiology of neurodegenerative diseases.
Parkinson Disease 6, Early-Onset; Parkinson Disease (Autosomal Recessive, Early Onset) 7, Human; Parkinson Disease Autosomal Recessive, Early Onset; Parkinson Disease, Autosomal Recessive Early-Onset, Digenic, Pink1/Dj1
Invernizzi, Marco; Carda, Stefano; Viscontini, Giovanni Sguazzini; Cisari, Carlo
Patients affected by Parkinson's disease are at a high risk for fractures, mainly of the hip. These fractures are caused by falls due to postural imbalance, neurological impairment and reduced bone mass. The purpose of this study was (1) to investigate the correlations and the pathophysiological mechanisms underlying bone loss in Parkinson's disease and appraise bone loss or fracture risk reduction interventions; (2) to develop a research agenda that informs the design and development of risk reduction strategies. Osteoporosis and osteopenia are very common findings in patients with Parkinson's disease, affecting up to 91% of women and 61% of men. Reduced bone mass in Parkinsonian patients seems to be caused mainly by reduced mobility through a mechanism similar to that observed in other neurological diseases. Endocrine (such as vitamin D deficiency), nutritional and iatrogenic factors also play an important role in bone mass depletion. Female gender, disease duration and severity (Hoehn and Yahr stages III and IV), old age and low body mass index are related to more severe osteoporosis. Vitamin D supplementation and bisphosphonates seem to be effective in reducing the risk of nonvertebral fractures in patients affected by Parkinson's disease. Prevention and evaluation of osteoporosis through bone mass density assessment should be considered in all patients with Parkinson's disease.
De Pablo-Fernández, Eduardo; Breen, David P; Bouloux, Pierre M; Barker, Roger A; Foltynie, Thomas; Warner, Thomas T
Neuroendocrine abnormalities are common in Parkinson's disease (PD) and include disruption of melatonin secretion, disturbances of glucose, insulin resistance and bone metabolism, and body weight changes. They have been associated with multiple non-motor symptoms in PD and have important clinical consequences, including therapeutics. Some of the underlying mechanisms have been implicated in the pathogenesis of PD and represent promising targets for the development of disease biomarkers and neuroprotective therapies. In this systems-based review, we describe clinically relevant neuroendocrine abnormalities in Parkinson's disease to highlight their role in overall phenotype. We discuss pathophysiological mechanisms, clinical implications, and pharmacological and non-pharmacological interventions based on the current evidence. We also review recent advances in the field, focusing on the potential targets for development of neuroprotective drugs in Parkinson's disease and suggest future areas for research.
Son, Andre Y; Biagioni, Milton C; Kaminski, Dorian; Gurevich, Alec; Stone, Britt; Di Rocco, Alessandro
Epilepsy is an uncommon comorbidity of Parkinson's disease (PD) and has been considered not directly associated with PD. We present five patients (3 men and 2 women; ages 49-85) who had concomitant PD and cryptogenic epilepsy. Although rare, epilepsy can coexist with PD and their coexistence may influence the progression of PD. While this may be a chance association, an evolving understanding of the neurophysiological basis of either disease may suggest a mechanistic association.
Kaminski, Dorian; Gurevich, Alec; Stone, Britt; Di Rocco, Alessandro
Epilepsy is an uncommon comorbidity of Parkinson's disease (PD) and has been considered not directly associated with PD. We present five patients (3 men and 2 women; ages 49–85) who had concomitant PD and cryptogenic epilepsy. Although rare, epilepsy can coexist with PD and their coexistence may influence the progression of PD. While this may be a chance association, an evolving understanding of the neurophysiological basis of either disease may suggest a mechanistic association. PMID:27688919
In the majority of cases, mitochondrial disorders are multisystem conditions that most frequently affect the skeletal muscle, followed by the central nervous system. One of the clinical manifestations of central nervous system involvement is Parkinson's syndrome (PS). Evidence for an association of mitochondrial defects with PS comes from mitochondrial disorder patients who have developed Parkinson's syndrome and from Parkinson's syndrome patients who have developed a mitochondrial disorder. In addition, there are a number of patients with Parkinson's syndrome or Parkinson's disease (PD) who later develop subclinical immunohistological or biochemical indications of mitochondrial defects or accumulates mitochondrial DNA mutations within various cerebral regions. There are also Parkinson's syndrome patients who present with elevated cerebrospinal-fluid lactate by magnetic resonance spectroscopy. Furthermore, it has been shown that mutations in genes causing PD, such as PINK1, parkin, DJ1, alpha-synuclein, and LRRK2, also cause mitochondrial dysfunction, which is one of the reasons why they are called mitochondrial nigropathies. Parkinson's syndrome in patients with a mitochondrial disorder may also result from oxidative stress or exogenous toxins. Treatment of mitochondrial Parkinson's syndrome is not at variance with the treatment of Parkinson's syndrome due to other causes, but because of the multisystem nature of mitochondrial disorders, mitochondrial Parkinson's syndrome requires additional therapeutic support.
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Friedman, J. H.
Psychotic symptoms are common in drug treated patients with Parkinson's disease (PD). Visual hallucinations occur in about 30% and delusions, typically paranoid in nature, occur in about 5%. These problems, particularly the delusions, cause great distress for patient and caregivers, and are among the most important precipitants for nursing home placement. Psychotic symptoms carry a poor prognosis. They often herald dementia, and are associated with increased mortality. These symptoms often abate with medication reductions, but this may not be tolerated due to worsened motor function. Only clozapine has level A evidence to support its use in PD patients with psychosis (PDP), whether demented or not. While quetiapine has been recommended by the American Academy of Neurology for “consideration,” double blind placebo controlled trials have demonstrated safety but not efficacy. Other antipsychotic drugs have been reported to worsen motor function and data on the effectiveness of cholinesterase inhibitors is limited. PDP remains a serious problem with limited treatment options. PMID:23242358
Fitzmaurice, Arthur G.; Rhodes, Shannon L.; Cockburn, Myles; Ritz, Beate
Objective: The objective of this study was to determine whether environmental and genetic alterations of neuronal aldehyde dehydrogenase (ALDH) enzymes were associated with increased Parkinson disease (PD) risk in an epidemiologic study. Methods: A novel ex vivo assay was developed to identify pesticides that can inhibit neuronal ALDH activity. These were investigated for PD associations in a population-based case-control study, the Parkinson's Environment & Genes (PEG) Study. Common variants in the mitochondrial ALDH2 gene were genotyped to assess effect measure modification (statistical interaction) of the pesticide effects by genetic variation. Results: All of the metal-coordinating dithiocarbamates tested (e.g., maneb, ziram), 2 imidazoles (benomyl, triflumizole), 2 dicarboxymides (captan, folpet), and 1 organochlorine (dieldrin) inhibited ALDH activity, potentially via metabolic byproducts (e.g., carbon disulfide, thiophosgene). Fifteen screened pesticides did not inhibit ALDH. Exposures to ALDH-inhibiting pesticides were associated with 2- to 6-fold increases in PD risk; genetic variation in ALDH2 exacerbated PD risk in subjects exposed to ALDH-inhibiting pesticides. Conclusion: ALDH inhibition appears to be an important mechanism through which environmental toxicants contribute to PD pathogenesis, especially in genetically vulnerable individuals, suggesting several potential interventions to reduce PD occurrence or slow or reverse its progression. PMID:24491970
Santiago, Jose A; Potashkin, Judith A
Early diagnosis of Parkinson's disease (PD) continues to be a major challenge in the field. The lack of a robust biomarker to detect early stage PD patients has considerably slowed the progress toward the development of potential therapeutic agents. We have previously evaluated several RNA biomarkers in whole blood from participants enrolled in two independent clinical studies. In these studies, PD patients were medicated, thus, expression of these biomarkers in de novo patients remains unknown. To this end, we tested ten RNA biomarkers in blood samples from 99 untreated PD patients and 101 HC nested in the cross-sectional Parkinson's Progression Markers Initiative by quantitative real-time PCR. One biomarker out of ten, COPZ1 trended toward significance (nominal p = 0.009) when adjusting for age, sex, and educational level. Further, COPZ1, EFTUD2 and PTBP1 mRNAs correlated with clinical features in PD patients including the Hoehn and Yahr scale, Movement Disorder Society revision of Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and Montreal Cognitive Assessment (MoCA) score. Levels of EFTUD2 and PTBP1 were significantly higher in cognitively normal PD patients (PD-CN) compared to cognitively impaired PD patients (PD-MCI). Interestingly, blood glucose levels were significantly higher in PD and PD-MCI patients (≥ 100 mg/dL, pre-diabetes) compared to HC. Collectively, we report the association of three RNA biomarkers, COPZ1, EFTUD2 and PTBP1 with clinical features including cognitive decline in early drug-naïve PD patients. Further, our results show that drug-naïve PD and PD-MCI patients have glucose levels characteristic of pre-diabetes patients, suggesting that impaired glucose metabolism is an early event in PD. Evaluation of these potential biomarkers in a larger longitudinal study is warranted.
DeStefano, Anita L.; Latourelle, Jeanne; Lew, Mark F.; Suchowersky, Oksana; Klein, Christine; Golbe, Lawrence I.; Mark, Margery H.; Growdon, John H.; Wooten, G. Fredrick; Watts, Ray; Guttman, Mark; Racette, Brad A.; Perlmutter, Joel S.; Marlor, Lynn; Shill, Holly A.; Singer, Carlos; Goldwurm, Stefano; Pezzoli, Gianni; Saint-Hilaire, Marie H.; Hendricks, Audrey E.; Gower, Adam; Williamson, Sally; Nagle, Michael W.; Wilk, Jemma B.; Massood, Tiffany; Huskey, Karen W.; Baker, Kenneth B.; Itin, Ilia; Litvan, Irene; Nicholson, Garth; Corbett, Alastair; Nance, Martha; Drasby, Edward; Isaacson, Stuart; Burn, David J.; Chinnery, Patrick F.; Pramstaller, Peter P.; Al-hinti, Jomana; Moller, Anette T.; Ostergaard, Karen; Sherman, Scott J.; Roxburgh, Richard; Snow, Barry; Slevin, John T.; Cambi, Franca; Gusella, James F.; Myers, Richard H.
Genetic variants in embryonic lethal, abnormal vision, Drosophila-like 4 (ELAVL4) have been reported to be associated with onset age of Parkinson disease (PD) or risk for PD affection in Caucasian populations. In the current study we genotyped three single nucleotide polymorphisms in ELAVL4 in a Caucasian study sample consisting of 712 PD patients and 312 unrelated controls from the GenePD study. The minor allele of rs967582 was associated with increased risk of PD (odds ratio = 1.46, nominal P value = 0.011) in the GenePD population. The minor allele of rs967582 was also the risk allele for PD affection or earlier onset age in the previously studied populations. This replication of association with rs967582 in a third cohort further implicates ELAVL4 as a PD susceptibility gene. PMID:18587682
Tan, Eng-King; Foo, Jia-Nee; Tan, Louis; Au, Wing-Lok; Prakash, Kumar M; Ng, Ebonne; Ikram, M Kamran; Wong, Tien-Yin; Liu, Jian-Jun; Zhao, Yi
Essential tremor (ET) is characterized by postural and action tremor.(1-3) A genome-wide association study (GWAS) identified a LINGO1 gene variant to be associated with ET.(4) Subsequent GWAS further identified an intronic variant (rs3794087) of the main glial glutamate transporter (SLC1A2) gene to be associated with ET with an odds ratio (OR) of approximately 1.4.(5) We conducted a case-control study to examine the SLC1A2 gene variant in an Asian cohort of ET. In addition, we also investigated the variant in patients with Parkinson disease (PD) because the GWAS LINGO1 variant has been implicated in both ET and PD and etiologic links between the conditions have been suggested.(6.)
Kim, Ji Hyun; Hwang, Jinah; Shim, Eugene; Chung, Eun-Jung; Jang, Sung Hee
BACKGROUND/OBJECTIVES A pivotal role of oxidative stress has been emphasized in the pathogenesis as well as in the disease progression of Parkinson's disease (PD). We aimed at investigating serum levels of antioxidant vitamins and elucidating whether they could be associated with the pathogenesis and progression of PD. MATERIALS/METHODS Serum levels of retinol, α- and γ-tocopherols, α- and β-carotenes, lutein, lycopene, zeaxanthin and β-cryptoxanthin were measured and compared between 104 patients with idiopathic PD and 52 healthy controls matched for age and gender. In order to examine the relationship between antioxidant vitamins and the disease progression, multiple group comparisons were performed among the early PD (Hoehn and Yahr stage I and II, N = 47), advanced PD (stage III and IV, N = 57) and control groups. Separate correlation analyses were performed between the measured antioxidant vitamins and clinical variables, such as Hoehn and Yahr stage and Unified Parkinson's Disease Rating Scale (UPDRS) motor score. RESULTS Compared to controls, PD patients had lower levels of α- and β-carotenes and lycopene. α-carotene, β-carotene and lycopene levels were significantly reduced in advanced PD patients relative to early PD patients and were negatively correlated with Hoehn and Yahr stage and UPDRS motor score in PD patients. No significant differences were found in serum levels of retinol, α- and γ-tocopherols, and other carotenoids between PD patients and controls. No significant correlations were found between these vitamin levels and clinical variables in PD patients. CONCLUSIONS We found that serum levels of some carotenoids, α-carotene, β-carotene and lycopene, were lower in PD patients, and that these carotenoids inversely correlated with clinical variables representing disease progression. Our findings suggest that decreases in serum α-carotene, β-carotene and lycopene may be associated with the pathogenesis as well as progression of PD
Růžička, Filip; Jech, Robert; Nováková, Lucie; Urgošík, Dušan; Vymazal, Josef; Růžička, Evžen
The aim of our study was to assess changes in body-weight in relation to active electrode contact position in the subthalamic nucleus. Regular body weight measurements were done in 20 patients with advanced Parkinson's disease within a period of 18 months after implantation. T1-weighted (1.5T) magnetic resonance images were used to determine electrode position in the subthalamic nucleus and the Unified Parkinson's disease rating scale (UPDRS-III) was used for motor assessment. The distance of the contacts from the wall of the third ventricle in the mediolateral direction inversely correlated with weight gain (r = -0.55, p<0.01) and with neurostimulation-related motor condition expressed as the contralateral hemi-body UPDRS-III (r = -0.42, p<0.01). Patients with at least one contact within 9.3 mm of the wall experienced significantly greater weight gain (9.4 ± (SD)4.4 kg, N = 11) than those with both contacts located laterally (3.9 ± 2.7 kg, N = 9) (p<0.001). The position of the active contact is critical not only for motor outcome but is also associated with weight gain, suggesting a regional effect of subthalamic stimulation on adjacent structures involved in the central regulation of energy balance, food intake or reward.
Fenu, Sandro; Wardas, Jadwiga; Morelli, Micaela
Over the last decade, evidence has emerged linking disorders in the impulsive-compulsive spectrum in Parkinson's disease to dopamine receptor agonist treatment. These disorders include hypersexuality, gambling and, to a minor extent, compulsive shopping and eating, as well as dopamine dysregulation syndrome, characterized by an addictive pattern toward dopamine replacement therapy and stereotyped behaviors, such as punding. These syndromes, which have only recently been recognized and are still underdiagnosed, have deleterious social consequences that warrant interventions at the clinical level and promotion of research at the preclinical level. In this review, we first provide a summary of features of Parkinson's disease and current pharmacological therapies associated with the development of dopamine dysregulation syndrome and impulsive-compulsive disorders. We also examine the dopamine receptors and brain areas important in reward and compulsive behaviors. We then critically examine the neuroadaptations in dopaminergic circuitries and the literature concerning gambling, hypersexuality, and other addictive behaviors in parkinsonian patients. Finally, we focus on suggestions pointing to a role for dopamine D(3) receptors and sensitization phenomena as the main factors which may be the origin of these disorders.
Zhu, Dan; Liu, Gui-you; Lv, Zheng; Wen, Shi-rong; Bi, Sheng; Wang, Wei-zhi
Early studies had suggested that vitamin D intake was inversely associated with neurodegenerative diseases, such as Alzheimer's disease and multiple sclerosis. However, the associations of vitamin D intake and outdoor activities with Parkinson's disease (PD) are still unclear, so this study is to evaluate these relationships from a case-control study in elderly Chinese. The study population involved 209 cases with new onsets of PD and 210 controls without neurodegenerative diseases. The data on dietary vitamin D and outdoor activities were collected using a food-frequency questionnaire and self-report questionnaire. Multivariable logistic regressions were used to examine the associations between dietary outdoor activities, vitamin D intake and PD. Adjustment was made for sex, age, smoking, alcohol use, education, and body mass index (BMI). Adjusted odds ratios (ORs) for PD in quartiles for outdoor physical activity were 1 (reference), 0.739 (0.413, 1.321), 0.501 (0.282, 0.891), and 0.437 (0.241, 0.795), respectively (P=0.002 for trend). Adjusted ORs for PD in quartiles for total vitamin D intake were 1 (reference), 0.647 (0.357, 1.170), 0.571 (0.318, 1.022), and 0.538 (0.301, 0.960), respectively (P=0.011 for trend). Our study suggested that outdoor activity and total vitamin D intake were inversely associated with PD, and outdoor activity seems to be more significantly associated with decreased risk for PD.
Lange, Johannes; Lunde, Kristin Aaser; Sletten, Camilla; Møller, Simon Geir; Tysnes, Ole-Bjørn; Alves, Guido; Larsen, Jan Petter; Maple-Grødem, Jodi
Background. Parkinson's disease (PD) and Alzheimer's disease (AD) share pathological features, including amyloid-beta pathology. Amyloid-beta peptide is generated by sequential proteolysis of amyloid precursor protein (APP), and genetic variations in the processing pathway genes have been found to increase the risk of AD; however, the contribution in PD is unknown. Methods. The aim of this study was to investigate whether candidate polymorphisms in five genes (ADAM10, BACE1, BACE2, PSEN2, and CLU) involved in the APP processing pathway affect PD risk in a population-based cohort of patients with incident PD and control subjects from the Norwegian ParkWest study. Results. We found an association of rs638405 in BACE1 with increased risk of PD, thus providing a novel link, at the genetic level, between amyloid-beta pathology and PD.
Lange, Johannes; Lunde, Kristin Aaser; Sletten, Camilla; Møller, Simon Geir; Tysnes, Ole-Bjørn; Alves, Guido; Larsen, Jan Petter; Maple-Grødem, Jodi
Background. Parkinson's disease (PD) and Alzheimer's disease (AD) share pathological features, including amyloid-beta pathology. Amyloid-beta peptide is generated by sequential proteolysis of amyloid precursor protein (APP), and genetic variations in the processing pathway genes have been found to increase the risk of AD; however, the contribution in PD is unknown. Methods. The aim of this study was to investigate whether candidate polymorphisms in five genes (ADAM10, BACE1, BACE2, PSEN2, and CLU) involved in the APP processing pathway affect PD risk in a population-based cohort of patients with incident PD and control subjects from the Norwegian ParkWest study. Results. We found an association of rs638405 in BACE1 with increased risk of PD, thus providing a novel link, at the genetic level, between amyloid-beta pathology and PD. PMID:26788404
De Virgilio, Armando; Greco, Antonio; Fabbrini, Giovanni; Inghilleri, Maurizio; Rizzo, Maria Ida; Gallo, Andrea; Conte, Michela; Rosato, Chiara; Ciniglio Appiani, Mario; de Vincentiis, Marco
Parkinson's disease is a neurodegenerative disease that causes the death of dopaminergic neurons in the substantia nigra. The resulting dopamine deficiency in the basal ganglia leads to a movement disorder that is characterized by classical parkinsonian motor symptoms. Parkinson's disease is recognized as the most common neurodegenerative disorder after Alzheimer's disease. PD ethiopathogenesis remains to be elucidated and has been connected to genetic, environmental and immunologic conditions. The past decade has provided evidence for a significant role of the immune system in PD pathogenesis, either through inflammation or an autoimmune response. Several autoantibodies directed at antigens associated with PD pathogenesis have been identified in PD patients. This immune activation may be the cause of, rather than a response to, the observed neuronal loss. Parkinsonian motor symptoms include bradykinesia, muscular rigidity and resting tremor. The non-motor features include olfactory dysfunction, cognitive impairment, psychiatric symptoms and autonomic dysfunction. Microscopically, the specific degeneration of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies, which are brain deposits containing a substantial amount of α-synuclein, have been recognized. The progression of Parkinson's disease is characterized by a worsening of motor features; however, as the disease progresses, there is an emergence of complications related to long-term symptomatic treatment. The available therapies for Parkinson's disease only treat the symptoms of the disease. A major goal of Parkinson's disease research is the development of disease-modifying drugs that slow or stop the neurodegenerative process. Drugs that enhance the intracerebral dopamine concentrations or stimulate dopamine receptors remain the mainstay treatment for motor symptoms. Immunomodulatory therapeutic strategies aiming to attenuate PD neurodegeneration have become an attractive option and
Ma, Ling-Yan; Chan, Piu; Gu, Zhu-Qin; Li, Fang-Fei; Feng, Tao
The clinical heterogeneity of Parkinson's disease (PD) reveals the presence of several PD subtypes. The objectives of this study were to identify PD subtypes using cluster analysis (CA) and to determine the association between the subtypes and the polymorphisms in LRRK2 (G2385R and R1628P) and GBA (L444P) genes. A k-means CA of demographics, disease progression, motor and non-motor symptoms was performed from 1,510 Chinese PD patients from the Chinese National Consortium on Neurodegenerative Diseases. Pearson correlation analysis was performed to eliminate uninformative characteristics. Blood samples from 852 patients were obtained for genetic analysis of LRRK2 and GBA. Genotypic associations between various subtypes and genetic variants were examined using chi-square test. We identified four different subtypes: subtype 1 was non-tremor dominant (NTD, n=469; 31.1%); subtype 2 had a rapid disease progression with late onset (RDP-LO, n=67; 4.4%); subtype 3 had benign pure motor characteristics (BPM, n=778; 51.5%) without non-motor disturbances; and subtype 4 was tremor dominant with slow disease progression (TD-SP, n=196; 13.0%). Subtypes 1, 2, and 4 had similar mean age of onset. No associations were identified between polymorphisms in LRRK2 (R1628P) and GBA (L444P) genes and the four subtypes (P>0.05).
Weintraub, Daniel; Sohr, Mandy; Potenza, Marc N; Siderowf, Andrew D; Stacy, Mark; Voon, Valerie; Whetteckey, Jacqueline; Wunderlich, Glen R; Lang, Anthony E
A recent controlled clinical trial suggested a role for amantadine as a treatment for pathological gambling in patients with Parkinson disease (PD). Analyzing data from a large cross-sectional study of impulse control disorders (ICDs) in PD, amantadine use (n = 728), vs no amantadine use (n = 2,357), was positively associated with a diagnosis of any ICD (17.6% vs 12.4%, p < 0.001) and compulsive gambling specifically (7.4% vs 4.2%, p < 0.001). This amantadine association remained after controlling for covariates of amantadine use, including both dopamine agonist use and levodopa dosage. Further research, including larger clinical trials, is needed to assess the role of amantadine in the development and treatment of ICDs in PD.
Coune, Philippe G; Schneider, Bernard L; Aebischer, Patrick
With the recent development of effective gene delivery systems, gene therapy for the central nervous system is finding novel applications. Here, we review existing viral vectors and discuss gene therapy strategies that have been proposed for Parkinson's disease. To date, most of the clinical trials were based on viral vectors to deliver therapeutic transgenes to neurons within the basal ganglia. Initial trials used genes to relieve the major motor symptoms caused by nigrostriatal degeneration. Although these new genetic approaches still need to prove more effective than existing symptomatic treatments, there is a need for disease-modifying strategies. The investigation of the genetic factors implicated in Parkinson's disease is providing precious insights in disease pathology that, combined with innovative gene delivery systems, will hopefully offer novel opportunities for gene therapy interventions to slow down, or even halt disease progression.
Strecker, Karl; Schwarz, Johannes
Parkinson's disease (PD) is the second most common neurodegenerative disease. The prevalence is increasing with age and averages approximately 0.3% in the entire population. The clinical picture is dominated by the cardinal motor symptoms such as tremor at rest, bradykinesia, muscular rigidity, stooped posture and postural instability. Psychiatric comorbidity is common, comprising dementia, depression, anxiety and psychosis. Although many drugs have been developed and introduced into the market to provide symptomatic treatment, there is still no cure for PD and not even solid evidence for disease-modifying strategies. In addition, motor complications in advanced stages of the disease, side effects of the dopaminergic therapy, and non-motor symptoms remain huge challenges during long-term therapy. Thus, new therapeutic agents are desperately needed. Here, we describe current therapies and possible future developments that we hope will contribute to sustaining quality of life in patients suffering from Parkinson's disease for many years.
Tian, You-yong; Tang, Cui-Ju; Wang, Jia-ning; Feng, Yuan; Chen, Xiao-wu; Wang, Lan; Qiao, Xian; Sun, Sheng-gang
Vascular endothelial growth factor (VEGF) is a specific angiogenic peptide, which has been identified to play a critical role in neurodegeneration, and has beneficial effects on neurons. In this study, we investigated whether neurodegeneration in a rat model of Parkinson disease could be prevented by VEGF gene transfer mediated by adeno-associated virus (AAV) vectors. Our results demonstrated that a single injection of a VEGF-expressing AAV vector into striatum improved the rotational behavior of rat Parkinson disease models, and promoted the survival of dopaminergic neurons and fibers. Meanwhile, AAV-VEGF injection significantly increased the reactive astrocytes and the levels of glial cell line-derived neurotrophic factor in striatum, but did not induce extra angiogenesis and remarkable disorder of blood-brain barrier. We thus conclude that intrastriatal delivery of VEGF gene mediated by AAV has favorable effects on the dopaminergic neurons in a rat Parkinson disease model.
Ciaramella, Antonio; Salani, Francesca; Bizzoni, Federica; Pontieri, Francesco E; Stefani, Alessandro; Pierantozzi, Mariangela; Assogna, Francesca; Caltagirone, Carlo; Spalletta, Gianfranco; Bossù, Paola
The role of inflammation in Parkinson's Disease (PD) is well appreciated, but its underlying mechanisms are still unclear. Our objective was to determine whether dendritic cells (DC), a unique type of migratory immune cells that regulate immunological response and inflammation have an impact on PD. In a case-control study including 80 PD patients and 80 age- and gender-matched healthy control subjects, the two main blood subsets of plasmacytoid and myeloid DC were defined by flow cytometry analysis. Clinical evaluation of subjects consisting of cognition and depression assessment was performed using the Mini Mental State Examination and the Beck Depression Inventory. The severity of motor symptoms was measured using the Unified Parkinson's Disease Rating Scale-Part III. Comparison between patient and control DC measures and their relationships with clinical assessments were evaluated.The following main results were obtained: 1) the level of circulating DC (mainly the myeloid subset) was significantly reduced in PD patients in comparison with healthy controls; 2) after controlling for depressive and cognitive characteristics, the frequency of myeloid DC was confirmed as one of the independent determinants of PD; 3) the number of both myeloid and plasmacytoid DC was negatively associated with motor symptom severity. Overall, the decline of blood DC, perhaps due to the recruitment of immune cells to the site of disease-specific lesions, can be considered a clue of the immune alteration that characterizes PD, suggesting innovative exploitations of DC monitoring as a clinically significant tool for PD treatment. Indeed, this study suggests that reduced peripheral blood DC are a pathologically-relevant factor of PD and also displays the urgency to better understand DC role in PD for unraveling the immune system contribution to disease progression and thus favoring the development of innovative therapies ideally based on immunomodulation.
Camicioli, Richard M; Bouchard, Thomas P; Somerville, Martin J
Levodopa (L-dopa) treatment of Parkinson's disease (PD) is associated with elevated homocysteine (Hcy). To examine the relationship between Hcy, methylenetetrahydrofolate reductase polymorphisms (MTHFR: 677C/T; 1298A/C), and B-vitamins in older PD patients and whether Hcy or MTHFR polymorphisms were associated with clinical measures. MTHFR polymorphisms, B-vitamin intake, and blood concentrations of Hcy, vitamin B12 and folate, and creatinine were determined and compared between groups (PD and controls). The relationship of Hcy to clinical measures was examined in PD. Among 51 patients [30M/21F, mean age (SD): 71.5 (4.7)] and 50 controls [29M/21F, 71.5 (4.8)], Hcy was higher in PD [13.6 (3.8); controls: 10.5 (2.5), P < 0.0005]. Hcy was associated with B-vitamin intake [F = 21.7, P < 0.0005], folate level (R = 0.31, P = 0.035), and the interaction of intake with MTHFR 677T (F = 5.2, P = 0.007), but not MTHFR 1298C genotype. Hcy did not correlate with global measures of cognition, mood, or parkinsonism in PD or with dyskinesias, fluctuations, or freezing. Higher vitamin B12 levels were associated with lower dyskinesia risk. Hcy was influenced by PD, MTHFR 677 genotype, and vitamin use, but not by the MTHFR 1298 genotype. There was no clear association with motor or cognitive measures, but dyskinesias were less likely with higher B12.
Martin, Eden R.; Scott, William K.; Nance, Martha A.; Watts, Ray L.; Hubble, Jean P.; Koller, William C.; Lyons, Kelly; Pahwa, Rajesh; Stern, Matthew B.; Colcher, Amy; Hiner, Bradley C.; Jankovic, Joseph; Ondo, William G.; Allen, Fred H.; Goetz, Christopher G.; Small, Gary W.; Masterman, Donna; Mastaglia, Frank; Laing, Nigel G.; Stajich, Jeffrey M.; Ribble, Robert C.; Booze, Michael W.; Rogala, Allison; Hauser, Michael A.; Zhang, Fengyu; Gibson, Rachel A.; Middleton, Lefkos T.; Roses, Allen D.; Haines, Jonathan L.; Scott, Burton L.; Pericak-Vance, Margaret A.; Vance, Jeffery M.
Context The human tau gene, which promotes assembly of neuronal microtubules, has been associated with several rare neurologic diseases that clinically include parkinsonian features. We recently observed linkage in idiopathic Parkinson disease (PD) to a region on chromosome 17q21 that contains the tau gene. These factors make tau a good candidate for investigation as a susceptibility gene for idiopathic PD, the most common form of the disease. Objective To investigate whether the tau gene is involved in idiopathic PD. Design, Setting, and Participants Among a sample of 1056 individuals from 235 families selected from 13 clinical centers in the United States and Australia and from a family ascertainment core center, we tested 5 single-nucleotide polymorphisms (SNPs) within the tau gene for association with PD, using family-based tests of association. Both affected (n = 426) and unaffected (n = 579) family members were included; 51 individuals had unclear PD status. Analyses were conducted to test individual SNPs and SNP haplotypes within the tau gene. Main Outcome Measure Family-based tests of association, calculated using asymptotic distributions. Results Analysis of association between the SNPs and PD yielded significant evidence of association for 3 of the 5 SNPs tested: SNP 3, P = .03; SNP 9i, P = .04; and SNP 11, P = .04. The 2 other SNPs did not show evidence of significant association (SNP 9ii, P = .11, and SNP 9iii, P = .87). Strong evidence of association was found with haplotype analysis, with a positive association with one haplotype (P = .009) and a negative association with another haplotype (P = .007). Substantial linkage disequilibrium (P<.001) was detected between 4 of the 5 SNPs (SNPs 3,9i, 9ii, and 11). Conclusions This integrated approach of genetic linkage and positional association analyses implicates tau as a susceptibility gene for idiopathic PD. PMID:11710889
Tjaden, Kris; Wilding, Greg
The primary purpose of this study was to investigate how speakers with Parkinson's disease (PD) and Multiple Sclerosis (MS) accomplish voluntary reductions in speech rate. A group of talkers with no history of neurological disease was included for comparison. This study was motivated by the idea that knowledge of how speakers with dysarthria…
Turner, Alexander P; Lones, Michael A; Trefzer, Martin A; Smith, Stephen L; Jamieson, Stuart; Alty, Jane E; Cosgrove, Jeremy; Tyrrell, Andy M
Levodopa is a drug that is commonly used to treat movement disorders associated with Parkinson's disease. Its dosage requires careful monitoring, since the required amount changes over time, and excess dosage can lead to muscle spasms known as levodopa-induced dyskinesia. In this work, we investigate the potential for using epiNet, a novel artificial gene regulatory network, as a classifier for monitoring accelerometry time series data collected from patients undergoing levodopa therapy. We also consider how dynamical analysis of epiNet classifiers and their transitions between different states can highlight clinically useful information which is not available through more conventional data mining techniques. The results show that epiNet is capable of discriminating between different movement patterns which are indicative of either insufficient or excessive levodopa.
Bronnick, K; Ehrt, U; Emre, M; De Deyn, P P; Wesnes, K; Tekin, S; Aarsland, D
Objective To investigate the effects of attentional deficits on activities of daily living (ADL) in patients with dementia associated with Parkinson's disease (PDD). Method 461 patients were assessed neuropsychologically. Factor analyses were used to differentiate attention from other cognitive functions and to differentiate different aspects of ADL functions. The effects of the attentional measure on ADL were examined using sequential multiple regression, controlling for age, sex, education, severity of motor symptoms and other cognitive functions. Results Three cognitive factors were identified, with one factor emerging as a measure of vigilance and focused attention. This factor predicted different aspects of ADL status even after controlling for motor functions and other cognitive factors. The attention factor was the single strongest cognitive predictor of ADL status, matching the strength of the effects of motor functions on ADL status. Conclusion Impaired attention is an important determinant of ADL functions in patients with PDD. PMID:16801351
Grossi, Dario; Santangelo, Gabriella; Barbarulo, Anna Maria; Vitale, Carmine; Castaldo, Giovanna; Proto, Maria Grazia; Siano, Pietro; Barone, Paolo; Trojano, Luigi
Apathy is defined as a lack of motivation and has been reported to be common in Alzheimer's disease (AD) and Parkinson's disease (PD). To explore the neuropsychological correlates of apathy in patients with PD related dementia (PDD) and AD and to identify the specific cognitive profile of apathy in the two forms of neurodegenerative disease, 61 non-depressed patients (29 PDD and 32 AD) were selected. Out of these, 29 patients (47.5%) were detected as apathetic (14 PDD-A+ and 15 AD-A+), and 32 patients as non-apathetic (15 PDD-A- and 17 AD-A-). All patients underwent cognitive tasks tapping memory, visuospatial and executive functions, behavioral rating scales and Clinical Judgment for Apathy Syndrome (CJ-AS), an inventory developed to measure severity of apathy. The four subgroups differed significantly on memory and frontal tasks. The PDD-A+ performed significantly worse than PDD-A- on frontal tasks. The AD-A+ had poorer performance than AD-A- on frontal tasks. Last, PDD-A+ achieved significantly higher scores than AD-A+ on memory tasks. The four groups differed significantly on CJ-AS and behavioral rating scales.The results showed that apathetic patients with both forms of dementia showed a common neuropsychological and behavioral picture, characterized by defects on frontal tasks, thus strongly supporting the existence of an 'apathetic syndrome', characterized by specific cognitive and psychological symptoms.
Lulla, Aaron; Barnhill, Lisa; Bitan, Gal; Ivanova, Magdalena I.; Nguyen, Binh; O’Donnell, Kelley; Stahl, Mark C.; Yamashiro, Chase; Klärner, Frank-Gerrit; Schrader, Thomas; Sagasti, Alvaro; Bronstein, Jeff M.
Background: Exposure to the commonly used dithiocarbamate (DTC) pesticides is associated with an increased risk of developing Parkinson disease (PD), although the mechanisms by which they exert their toxicity are not completely understood. Objective: We studied the mechanisms of ziram’s (a DTC fungicide) neurotoxicity in vivo. Methods: Zebrafish (ZF) embryos were utilized to determine ziram’s effects on behavior, neuronal toxicity, and the role of synuclein in its toxicity. Results: Nanomolar-range concentrations of ziram caused selective loss of dopaminergic (DA) neurons and impaired swimming behavior. Because ziram increases α-synuclein (α-syn) concentrations in rat primary neuronal cultures, we investigated the effect of ziram on ZF γ-synuclein 1 (γ1). ZF express 3 synuclein isoforms, and ZF γ1 appears to be the closest functional homologue to α-syn. We found that recombinant ZF γ1 formed fibrils in vitro, and overexpression of ZF γ1 in ZF embryos led to the formation of neuronal aggregates and neurotoxicity in a manner similar to that of α-syn. Importantly, knockdown of ZF γ1 with morpholinos and disruption of oligomers with the molecular tweezer CLR01 prevented ziram’s DA toxicity. Conclusions: These data show that ziram is selectively toxic to DA neurons in vivo, and this toxicity is synuclein-dependent. These findings have important implications for understanding the mechanisms by which pesticides may cause PD. Citation: Lulla A, Barnhill L, Bitan G, Ivanova MI, Nguyen B, O’Donnell K, Stahl MC, Yamashiro C, Klärner FG, Schrader T, Sagasti A, Bronstein JM. 2016. Neurotoxicity of the Parkinson disease-associated pesticide ziram is synuclein-dependent in zebrafish embryos. Environ Health Perspect 124:1766–1775; http://dx.doi.org/10.1289/EHP141 PMID:27301718
Winder-Rhodes, Sophie E; Hampshire, Adam; Rowe, James B; Peelle, Jonathan E; Robbins, Trevor W; Owen, Adrian M; Barker, Roger A
Genetic variation is associated with differences in the function of the brain as well as its susceptibility to disease. The common H1 haplotypic variant of the microtubule-associated protein tau gene (MAPT) has been related to an increased risk for Parkinson's disease (PD). Furthermore, among PD patients, H1 homozygotes have an accelerated progression to dementia. We investigated the neurocognitive correlates of MAPT haplotypes using functional magnetic resonance imaging. Thirty-seven nondemented patients with PD (19 H1/H1, 18 H2 carriers) and 40 age-matched controls (21 H1/H1, 19 H2 carriers) were scanned during performance of a picture memory encoding task. Behaviorally, H1 homozygosity was associated with impaired picture recognition memory in PD patients and control subjects. These impairments in the H1 homozygotes were accompanied by an altered blood-oxygen level-dependent response in the medial temporal lobe during successful memory encoding. Additional age-related differences in blood-oxygen level-dependent response were observed in the medial temporal lobes of H1 homozygotes with PD. These results suggest that common variation in MAPT is not only associated with the dementia of PD but also differences in the neural circuitry underlying aspects of cognition in normal aging.
Loriaut, Philippe; Rozenberg, Sylvie; Boyer, Patrick; Dallaudière, Benjamin; Khiami, Frederic; Sariali, Elhadi; Pascal-Moussellard, Hugues
Charcot spine is rare condition whose association with Parkinson's disease (PD) has not been reported yet. The authors reported the cases of two patients with PD who developed Charcot spine. Both patients presented with a history of back pain and bilateral radicular leg pain. They had complete clinical and radiological assessment. Lumbar spine was involved in both patients. Clinical features and response to treatment were described. In the first case, circumferential fusion and stabilization were performed on the dislocated vertebral levels. A solid and stable fusion of the spine was obtained with satisfactory clinical outcome. Surgical treatment has been recommended to the other patient. In both cases, no other neurological etiology was found to account for Charcot spine. In conclusion, Charcot spine is associated with several neurological affections but has not previously been reported in association with Parkinson's disease. PMID:25165591
Bereznai, Benjamin; Molnar, Mária Judit
In the past years, six monogenic forms of Parkinson disease have clearly been associated with this movement disorder. The most frequent forms are LRRK2- and Parkin-associated Parkinson disease. Currently, a genetic diagnosis does not change the therapy, the genes involved in genetic Parkinson disease help to understand the underlying pathophysiologic mechanisms of Parkinson disease. Beside the overview of the molecular-genetic basis, we give a review about genetic testing, pharmacological and other multidisciplinary treatment options.
Aminoff, M J
Pharmacotherapy with levodopa for Parkinson's disease provides symptomatic benefit, but fluctuations in (or loss of) response may eventually occur. Dopamine agonists are also helpful and, when taken with low doses of levodopa, often provide sustained benefit with fewer side effects; novel agonists and new methods for their administration are therefore under study. Other therapeutic strategies are being explored, including the use of type B monoamine oxidase inhibitors to reduce the metabolic breakdown of dopamine, catechol-O-methyltransferase inhibitors to retard the breakdown of levodopa, norepinephrine precursors to compensate for deficiency of this neurotransmitter, glutamate antagonists to counteract the effects of the subthalamic nucleus, and various neurotrophic factors to influence dopaminergic nigrostriatal cells. Surgical procedures involving pallidotomy are sometimes helpful. Those involving cerebral transplantation of adrenal medullary or fetal mesencephalic tissue have yielded mixed results; benefits may relate to the presence of growth factors in the transplanted tissue. The transplantation of genetically engineered cell lines will probably become the optimal transplantation procedure. The cause of Parkinson's disease may relate to oxidant stress and the generation of free radicals. It is not clear whether treatment with selegiline hydrochloride (a type B monoamine oxidase inhibitor) delays the progression of Parkinson's disease, because the drug also exerts a mild symptomatic effect. Daily treatment with vitamin E (a scavenger of free radicals) does not influence disease progression, perhaps because of limited penetration into the brain. Images PMID:7975571
Gatto, Emilia Mabel; Melcon, Carlos; Parisi, Virginia L; Bartoloni, Leonardo; Gonzalez, Claudio D
Yerba mate tea is a very common beverage in some countries of South America. We conducted a case-control study on an individual basis using hospital records to investigate the association between Parkinson's disease (PD) and yerba mate intake. A case was defined as an age of ≥ 40 years with ≥ 1 year of PD. Each case was individually matched by two controls. Exposure was measured by yerba mate consumption, coffee, tea, and alcohol intake and smoking status. The sample consisted of 223 PD patients (mean age 68 years and mean disease duration 7.3 years) and 406 controls. There was an inverse association between yerba mate "bombilla" consumption and PD (OR 0.64, 95% CI: 0.54-0.76, p=0.00001). A multivariate analysis with a logistic regression adjusted by sex, alcohol intake and smoking provided the following results: yerba mate (OR 0.63, 95% CI: 0.53-0.76), tea (OR 0.60, 95% CI: 0.42-0.86), coffee (OR 0.51, 95% CI: 0.35-0.73). We found an inverse association between yerba mate consumption and PD. These results led us to hypothesize that yerba mate may have a potential protective role in the development of PD.
Sagna, Atami; Gallo, Joseph J; Pontone, Gregory M
Depression and anxiety disorders have a substantial impact on the quality of life, the functioning and mortality of older adults with Parkinson's disease (PD). The purpose of this systematic review was to examine the factors associated with the prevalence of depression and anxiety disorders among individuals with PD aged 60 years and older. Following a literature search in PubMed, PsycINFO, CINAHL, and EMBASE, 5 articles met the inclusion criteria (adults aged 60 years and older, individuals with PD, and with depression and anxiety disorders, and English-language peer reviewed articles) and were included in this review. These studies were conducted in the U.S (n = 3), in Italy (n = 1) and the U.K (n = 1). Findings indicated that autonomic symptoms, motor fluctuations, severity and frequency of symptoms, staging of the disease, and PD onset and duration were associated with the prevalence of depression and anxiety disorders among older adults suffering from PD. Despite the limited number of studies included in the review, depression and anxiety disorders are often unrecognized and untreated and the comorbidity greatly exacerbates PD symptoms. The identification of factors associated with the development of depression and anxiety disorders could help in designing preventive interventions that would decrease the risk and burden of depression and anxiety disorders among older adults with PD.
Connolly, John G; Bykov, Katsiaryna; Gagne, Joshua J
Thiazolidinediones, a class of medications indicated for the treatment of type 2 diabetes mellitus, reduce inflammation and have been shown to provide a therapeutic benefit in animal models of Parkinson disease. We examined the association between treatment with thiazolidinediones and the onset of Parkinson disease in older individuals. We performed a cohort study of 29,397 Medicare patients enrolled in state pharmaceutical benefits programs who initiated treatment with thiazolidinediones or sulfonylureas during the years 1997 through 2005 and had no prior diagnosis of Parkinson disease. New users of thiazolidinediones were propensity score matched to new users of sulfonylureas and followed to determine whether they were diagnosed with Parkinson disease. We used Cox proportional hazards models to compare time to diagnosis of Parkinson disease in the propensity score-matched populations. To assess the association with duration of use, we performed several analyses that required longer continuous use of medications. In the primary analysis, thiazolidinedione users had a hazard ratio for a diagnosis of Parkinson disease of 1.09 (95% confidence interval: 0.71, 1.66) when compared with sulfonylurea users. Increasing the duration-of-use requirements to 10 months did not substantially change the association; the hazard ratios ranged from 1.00 (95% confidence interval: 0.49, 2.05) to 1.17 (95% confidence interval: 0.60, 2.25). Thiazolidinedione use was not associated with a longer time to diagnosis of Parkinson disease than was sulfonylurea use, regardless of duration of exposure.
Caviness, John N; Adler, Charles H; Sabbagh, Marwan N; Connor, Donald J; Hernandez, Jose L; Lagerlund, Terrence D
Coherence is the degree of time-locked correlation between two signals as a function of frequency. The purpose of this study was to test the following hypotheses: (1) corticomuscular coherence is abnormally increased in those Parkinson's disease (PD) patients with small amplitude cortical myoclonus, and (2) corticomuscular coherence peaks around the time of the myoclonus electromyographic (EMG) discharge. We studied Parkinson's disease patients with and without myoclonus and controls. The data were digitally collected and processed off-line with EMG rectification, creation of 511-msec epochs, Fast-Fourier transform, and coherence analysis. In the 12 to 30 Hz frequency band, but not at 30 to 60 Hz or above, coherence peaks were observed in the PD subjects with myoclonus that were significantly greater than in the control subjects (P < 0.001) and in PD subjects without myoclonus (P < 0.001). The abnormal coherence values are evidence for abnormal rhythmic activity in cortical motor areas in those Parkinson's disease patients with myoclonus. In combination with previous findings on back-averaging, our results show that this myoclonus occurs when neuronal populations are driven to an extreme amount of synchronous activity with higher corticomuscular coherence values. These results have mechanistic implications for cortical dysfunction in Parkinson's disease and for cortical myoclonus in general.
Vanbellingen, T.; Kersten, B.; Bellion, M.; Temperli, P.; Baronti, F.; Muri, R.; Bohlhalter, S.
A controversial concept suggests that impaired finger dexterity in Parkinson's disease may be related to limb kinetic apraxia that is not explained by elemental motor deficits such as bradykinesia. To explore the nature of dexterous difficulties, the aim of the present study was to assess the relationship of finger dexterity with ideomotor praxis…
Diederich, Nico J; Fénelon, Gilles; Stebbins, Glenn; Goetz, Christopher G
Patients with Parkinson disease (PD) can experience hallucinations (spontaneous aberrant perceptions) and illusions (misinterpretations of real perceptual stimuli). Of such phenomena, visual hallucinations (VHs) and illusions are the most frequently encountered, although auditory, olfactory and tactile hallucinations can also occur. In cross-sectional studies, VHs occur in approximately one-third of patients, but up to three-quarters of patients might develop VHs during a 20-year period. Hallucinations can have substantial psychosocial effects and, historically, were the main reason for placing patients in nursing homes. Concomitant or overlapping mechanisms are probably active during VHs, and these include the following: central dopaminergic overactivity and an imbalance with cholinergic neurotransmission; dysfunction of the visual pathways, including specific PD-associated retinopathy and functional alterations of the extrastriate visual pathways; alterations of brainstem sleep-wake and dream regulation; and impaired attentional focus. Possible treatments include patient-initiated coping strategies, a reduction of antiparkinson medications, atypical neuroleptics and, potentially, cholinesterase inhibitors. Evidence-based studies, however, only support the use of one atypical neuroleptic, clozapine, and only in patients without dementia. Better phenomenological discrimination, combined with neuroimaging tools, should refine therapeutic options and improve prognosis. The aim of this Review is to present epidemiological, phenomenological, pathophysiological and therapeutic aspects of hallucinations in PD.
Calne, Donald B; Mizuno, Yoshikuni
Over the last century three central points have become the orthodox dogma accepted and taught by those who study Parkinson's Disease. These are: Parkinson's Disease is one disease. Lewy bodies in the substantia nigra are an acceptable hallmark of Parkinson's Disease. Lewy bodies are responsible for the death of nigral neurons in Parkinson's Disease. Each of these tenets now present difficulties, and we are beginning to enter an era in which we must look critically at the current evidence to decide whether each dictum can be sustained.
Suttrup, Inga; Warnecke, Tobias
More than 80 % of patients with Parkinson's disease (PD) develop dysphagia during the course of their disease. Swallowing impairment reduces quality of life, complicates medication intake and leads to malnutrition and aspiration pneumonia, which is a major cause of death in PD. Although the underlying pathophysiology is poorly understood, it has been shown that dopaminergic and non-dopaminergic mechanisms are involved in the development of dysphagia in PD. Clinical assessment of dysphagia in PD patients is challenging and often delivers unreliable results. A modified water test assessing maximum swallowing volume is recommended to uncover oropharyngeal dysphagia in PD. PD-specific questionnaires may also be useful to identify patients at risk for swallowing impairment. Fiberoptic endoscopic evaluation of swallowing and videofluoroscopic swallowing study are both considered to be the gold standard for evaluation of PD-related dysphagia. In addition, high-resolution manometry may be a helpful tool. These instrumental methods allow a reliable detection of aspiration events. Furthermore, typical patterns of impairment during the oral, pharyngeal and/or esophageal swallowing phase of PD patients can be identified. Therapy of dysphagia in PD consists of pharmacological interventions and swallowing treatment by speech and language therapists (SLTs). Fluctuating dysphagia with deterioration during the off-state should be treated by optimizing dopaminergic medication. The methods used during swallowing treatment by SLTs shall be selected according to the individual dysphagia pattern of each PD patient. A promising novel method is an intensive training of expiratory muscle strength. Deep brain stimulation does not seem to have a clinical relevant effect on swallowing function in PD. The goal of this review is giving an overview on current stages of epidemiology, pathophysiology, diagnosis, and treatment of PD-associated dysphagia, which might be helpful for neurologists
Huang, Xuemei; Chen, Honglei; Miller, William C; Mailman, Richard B; Woodard, Jennifer L; Chen, Peter C; Xiang, Dong; Murrow, Richard W; Wang, Yi-Zhe; Poole, Charles
The apolipoprotein E (APOE) epsilon2 allele has been associated with both Parkinson's disease (PD) and lower low-density lipoprotein cholesterol (LDL-C). We tested the hypothesis that lower LDL-C may be associated with PD. This case-control study used fasting lipid profiles obtained from 124 PD cases and 112 controls. The PD cases were recruited from consecutive cases presenting at our tertiary Movement Disorder Clinic, and the controls were recruited from the spouse populations of the same clinic. Multivariate odds ratios (ORs) and 95% confidence intervals (CIs) were calculated from unconditional logistic regressions, adjusting for age, gender, smoking status, and use of cholesterol-lowering agents. Lower LDL-C concentrations were associated with a higher occurrence of PD. Compared with participants with the highest LDL-C (> or =138 mg/dL), the OR was 2.2 (95% CI = 0.9-5.1) for participants with LDL-C of 115 to 137, 3.5 (95% CI = 1.6-8.1) for LDL-C of 93 to 114, and 2.6 (95% CI = 1.1-5.9) for LDL-C of < or = 92. Interestingly, use of either cholesterol-lowering drugs, or statins alone, was related to lower PD occurrence. Thus, our data provide preliminary evidence that low LDL-C may be associated with higher occurrence of PD, and/or that statin use may lower PD occurrence, either of which finding warrants further investigation.
Furlong, Melissa; Tanner, Caroline M; Goldman, Samuel M; Bhudhikanok, Grace S; Blair, Aaron; Chade, Anabel; Comyns, Kathleen; Hoppin, Jane A; Kasten, Meike; Korell, Monica; Langston, J William; Marras, Connie; Meng, Cheryl; Richards, Marie; Ross, G Webster; Umbach, David M; Sandler, Dale P; Kamel, Freya
Pesticides have been associated with Parkinson's disease (PD), and protective gloves and workplace hygiene can reduce pesticide exposure. We assessed whether use of gloves and workplace hygiene modified associations between pesticides and PD. The Farming and Movement Evaluation (FAME) study is a nested case-control study within the Agricultural Health Study. Use of protective gloves, other PPE, and hygiene practices were determined by questionnaire (69 cases and 237 controls were included). We considered interactions of gloves and hygiene with ever-use of pesticides for all pesticides with ≥5 exposed and unexposed cases and controls in each glove-use stratum (paraquat, permethrin, rotenone, and trifluralin). 61% of respondents consistently used protective gloves and 87% consistently used ≥2 hygiene practices. Protective glove use modified the associations of paraquat and permethrin with PD: neither pesticide was associated with PD among protective glove users, while both pesticides were associated with PD among non-users (paraquat OR 3.9 [95% CI 1.3, 11.7], interaction p=0.15; permethrin OR 4.3 [95% CI 1.2, 15.6] interaction p=0.05). Rotenone was associated with PD regardless of glove use. Trifluralin was associated with PD among participants who used <2 hygiene practices (OR 5.5 [95% CI 1.1, 27.1]) but was not associated with PD among participants who used 2 or more practices (interaction p=0.02). Although sample size was limited in the FAME study, protective glove use and hygiene practices appeared to be important modifiers of the association between pesticides and PD and may reduce risk of PD associated with certain pesticides.
Lee, Jae Jung; Oh, Jungsu S; Ham, Jee H; Lee, Dong H; Lee, Injoo; Sohn, Young H; Kim, Jae S; Lee, Phil Hyu
Several antecedent studies had reported close relationship between low body weight and Parkinson's disease (PD). However, there have been few investigations about the role of body weight to nigrostriatal dopaminergic neurodegeneration. This study enrolled 398 de novo patients with PD whom underwent [18F] N-(3-Fluoropropyl)-2β-carbon ethoxy-3β-(4-iodophenyl) nortropane positron emission tomography scan and body mass index (BMI) measurement. The relationships between BMI and dopamine transporter (DAT) activity were analyzed using linear regression analysis. A multivariate analysis adjusted for age, gender, disease duration, smoking status, coffee and tea consumption, and residence area revealed that BMI remained independently and significantly associated with DAT activity in all striatal subregions. Moreover, multiple logistic regression analyses showed that BMI was a significant predictor for the lowest quartile of DAT activity in the anterior putamen, ventral striatum, caudate nucleus, and total striatum. The present findings suggest that a low BMI might be closely associated with low density of nigrostriatal dopaminergic neurons in PD, which could support the evidence for the role of low body weight to PD-related pathologies.
Nombela, Cristina; Vuono, Romina; Jones, P. Simon; Fisher, Kate; Burn, David J.; Brooks, David J.; Reddy, Akhilesh B.; Rowe, James B.; Barker, Roger A.
ABSTRACT Background Recent studies have suggested that melatonin—a hormone produced by the pineal gland under circadian control—contributes to PD‐related sleep dysfunction. We hypothesized that degenerative changes to the neural structures controlling pineal function (especially the suprachiasmatic nuclei of the anterior hypothalamus) may be responsible for reduced melatonin output in these patients. We compared hypothalamic volumes in PD patients with matched controls and determined whether volume loss correlated with reduced melatonin output in the PD group. Methods A total of 12 PD patients and 12 matched controls underwent magnetic resonance imaging to determine hypothalamic volume. In addition, PD patients underwent 24‐hour blood sampling in a controlled environment to determine serum melatonin concentrations using enzyme‐linked immunosorbent assays. Results PD patients had significantly reduced hypothalamic gray matter volume when compared with matched controls. Melatonin levels were significantly associated with hypothalamic gray matter volume and disease severity in PD patients. Conclusion Melatonin levels are associated with hypothalamic gray matter volume loss and disease severity in PD patients. This provides anatomical and physiological support for an intrinsic sleep and circadian phenotype in PD. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society PMID:26971528
Wu, Yubin; Zhang, Yingying; Han, Xun; Li, Xiaoyuan; Xue, Li; Xie, Anmu
Recent evidence indicates that vascular endothelial growth factor (VEGF) is capable of protecting dopaminergic (DA) neurons. Parkinson's disease (PD) is a progressive neurodegenerative disease caused by the degeneration of nigrostriatal dopaminergic neurons. To evaluate the role of VEGF single nucleotide polymorphisms (SNPs) and haplotypes in PD, we performed a case-control study including 400 PD patients and 400 healthy-matched controls. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis and DNA sequencing were used to detect the rs699947, rs2010963 and rs3025039 polymorphisms of the VEGF gene in cases and controls. Our study revealed that T allelic frequency of rs3025039 polymorphism was significantly higher in PD subjects (OR 1.497, 95 % CI 1.099-2.040, P = 0.013) than that in controls. Significant association for rs3025039 could be found in additive model (TT vs. CT vs. CC: OR 1.489, 95 % CI 1.018-2.177, P = 0.040) and dominant model (TT + CT vs. CC: OR 1.538, 95 % CI 1.068-2.216, P = 0.021). Subgroup analyses performed by gender suggested that this association could be found in male, but not in female. Moreover, it also demonstrated a significant association in the subgroup of late-onset PD (LOPD). However, for rs699947 and rs2010963 polymorphisms, genotype or allele frequencies did not differ between groups. No significant association could be found between rs699947 and rs2010963 polymorphism and PD risk. None of the observed haplotypes showed significant association with PD. Therefore, these results suggested that the VEGF gene might be associated with risk of developing sporadic PD in Han Chinese and the rs3025039 polymorphism may be a risk factor for sporadic PD.
Wissemann, William T.; Hill-Burns, Erin M.; Zabetian, Cyrus P.; Factor, Stewart A.; Patsopoulos, Nikolaos; Hoglund, Bryan; Holcomb, Cherie; Donahue, Ryan J.; Thomson, Glenys; Erlich, Henry; Payami, Haydeh
Historically, association of disease with the major histocompatibility complex (HLA) genes has been tested with HLA alleles that encode antigen-binding affinity. The association with Parkinson disease (PD), however, was discovered with noncoding SNPs in a genome-wide association study (GWAS). We show here that several HLA-region SNPs that have since been associated with PD form two blocks tagged by rs3129882 (p = 9 × 10−11) and by rs9268515 and/or rs2395163 (p = 3 × 10−11). We investigated whether these SNP-associations were driven by HLA-alleles at adjacent loci. We imputed class I and class II HLA-alleles for 2000 PD cases and 1986 controls from the NeuroGenetics Research Consortium GWAS and sequenced a subset of 194 cases and 204 controls. We were therefore able to assess accuracy of two imputation algorithms against next-generation-sequencing while taking advantage of the larger imputed data sets for disease study. Additionally, we imputed HLA alleles for 843 cases and 856 controls from another GWAS for replication. PD risk was positively associated with the B∗07:02_C∗07:02_DRB5∗01_DRB1∗15:01_DQA1∗01:02_DQB1∗06:02 haplotype and negatively associated with the C∗03:04, DRB1∗04:04 and DQA1∗03:01 alleles. The risk haplotype and DQA1∗03:01 lost significance when conditioned on the SNPs, but C∗03:04 (OR = 0.72, p = 8 × 10−6) and DRB1∗04:04 (OR = 0.65, p = 4 × 10−5) remained significant. Similarly, rs3129882 and the closely linked rs9268515 and rs2395163 remained significant irrespective of HLA alleles. rs3129882 and rs2395163 are expression quantitative trait loci (eQTLs) for HLA-DR and HLA-DQ (9 × 10−5 ≥ PeQTL ≥ 2 × 10−79), suggesting that HLA gene expression might influence PD. Our data suggest that PD is associated with both structural and regulatory elements in HLA. Furthermore, our study demonstrates that noncoding SNPs in the HLA region can be associated with disease irrespective of HLA alleles, and that
Berry, C; La Vecchia, C; Nicotera, P
As evidence emerges that complex gene alterations are involved in the onset of Parkinson's disease (PD), the role of environmental chemicals in the pathogenesis of this disease becomes intensely debated. Although it is undisputed that acute exposure to certain chemicals such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is sufficient to cause human parkinsonism, the evidence that the risk for PD increases because of environmental exposure is generally weaker. Several studies have suggested that pesticide exposure and life in rural areas are significant risks factors for PD. Among other pesticides, paraquat (PQ) has been linked to PD by epidemiological studies and experimental work in rodents, in which it causes lesions in the substantia nigra, pars compacta. However, the evidence that human exposure to the chemical results in an increased risk for PD is rather limited and based on insufficient epidemiological data. This review critically analyses the evidence that implicates PQ in parkinsonism and discusses the limitations of chemical modelling of PD.
Cooper, Scott E.; McIntyre, Cameron C.; Fernandez, Hubert H.; Vitek, Jerrold L.
Background Deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves symptoms of Parkinson disease (PD), including bradykinesia. When stimulation ceases abruptly, bradykinesia returns gradually. The duration of the gradual, slow washout varies across patients, and although the origin of this variability is unclear, it is hypothesized to be related to 1 or more clinical characteristics of patients. Objective To determine if a correlation exists between clinical characteristics of patients with Parkinson disease (age, age at disease onset, disease severity, disease duration, medication dose, or time since surgery) and the washout rate for bradykinesia when STN DBS is discontinued. Design Serial quantitative assessments of bradykinesia were performed during a defined period following cessation of STN DBS. Setting Academic research. Patients Twenty-four patients with Parkinson disease who underwent STN DBS were enrolled in the study. Patients were assessed while off medication (medication had been discontinued 10½ to 16½ hours before testing), and stimulator settings were unchanged for a mean (median) of 20 (14) months. Main Outcome Measures We measured bradykinesia in the dominant hand by assessing finger tapping (item 23 on the Unified Parkinson Disease Rating Scale), which was quantified using an angular velocity transducer strapped on the index finger. Finger tapping was assessed every 2 minutes for 20 seconds at a time. This was performed during a 20-minute period with DBS on (baseline period), during a 50-minute period following discontinuation of STN DBS for the dominant hand, and again during a 20-minute period after turning on the device. Results When STN DBS was turned off, an initial fast but partial loss of benefit was observed, which was followed by a further slow washout of the residual therapeutic effect. The half-life of the slow washout phase varied significantly across patients, and this variation was strongly related to disease
Nisticò, R; Pirritano, D; Salsone, M; Novellino, F; Del Giudice, F; Morelli, M; Trotta, M; Bilotti, G; Condino, F; Cherubini, A; Valentino, P; Quattrone, A
Rest tremor associated with essential tremor (ET) is a condition that poses challenges in diagnosing Parkinson's disease (PD). We investigated tremor parameters in PD and ET patients with rest tremor. Fifteen patients with PD and 15 patients with ET underwent electrophysiological examination to evaluate characteristics of muscle bursting in rest postures. Rest tremor amplitude of PD patients was significantly higher than that of patients with ET (p = 0.002), whereas burst duration and frequency were significantly higher in ET than in PD group (p = 0.002, p < 0.001, respectively). Patients with PD, however, showed some overlap of these electrophysiological values with values from patients with ET. By contrast, rest tremor pattern showed no overlap between the two diseases, because all patients with ET presented a synchronous pattern whereas PD patients had an alternating pattern (p < 0.001), a finding that differentiated the patients on an individual basis. The electromyographic pattern of rest tremor may help to differentiate PD from ET.
Miura, Kayoko; Matsui, Mie; Takashima, Shutaro; Tanaka, Kortaro
Background/Aims Little is known about the relationship between cognitive functions and higher-level functional capacity (e.g. intellectual activity, social role, and social participation) in Parkinson's disease (PD). The purpose of this study was to clarify neuropsychological characteristics and their association with higher-level functional capacity in PD patients. Methods Participants were 31 PD patients and 23 demographically matched healthy controls. Neuropsychological tests were conducted. One year later, a questionnaire survey evaluated higher-level functional capacity in daily living. Results The PD group scored significantly lower than the control group in all cognitive domains, particularly executive function and processing. Executive function, processing speed, language, and memory were significantly correlated with higher-level functional capacity in PD patients. Stepwise regression showed that only executive function (Trail Making Test-B), together with disease severity (HY stage), predicted the higher-level functional capacity. Conclusion Our findings provide evidence of a relationship between executive function and higher-level functional capacity in patients with PD. PMID:26273243
West, Andrew B.; Moore, Darren J.; Biskup, Saskia; Bugayenko, Artem; Smith, Wanli W.; Ross, Christopher A.; Dawson, Valina L.; Dawson, Ted M.
Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) cause late-onset Parkinson's disease (PD) with a clinical appearance indistinguishable from idiopathic PD. Initial studies suggest that LRRK2 mutations are the most common yet identified determinant of PD susceptibility, transmitted in an autosomal-dominant mode of inheritance. Herein, we characterize the LRRK2 gene and transcript in human brain and subclone the predominant ORF. Exogenously expressed LRRK2 protein migrates at ≈280 kDa and is present largely in the cytoplasm but also associates with the mitochondrial outer membrane. Familial-linked mutations G2019S or R1441C do not have an obvious effect on protein steady-state levels, turnover, or localization. However, in vitro kinase assays using full-length recombinant LRRK2 reveal an increase in activity caused by familial-linked mutations in both autophosphorylation and the phosphorylation of a generic substrate. These results suggest a gain-of-function mechanism for LRRK2-linked disease with a central role for kinase activity in the development of PD. PMID:16269541
Qiu, Chengxuan; Hu, Gang; Kivipelto, Miia; Laatikainen, Tiina; Antikainen, Riitta; Fratiglioni, Laura; Jousilahti, Pekka; Tuomilehto, Jaakko
Cardiovascular risk factors, such as diabetes mellitus and central obesity, have been associated with Parkinson disease (PD), but data on blood pressure and PD are lacking. We sought to examine the association of blood pressure and hypertension with the risk of PD among men and women. This study consisted of 7 surveys (1972-2002) on representative samples of the general population in Finland (National FINRISK Study). A total number of 59 540 participants (age 25 to 74 years; 51.8% women) who were free of PD and stroke at baseline were prospectively followed until December 31, 2006, to identify incident PD cases using the National Social Insurance Register database. Cox proportional hazards models were constructed to estimate the hazard ratio of PD associated with blood pressure. During a mean follow-up period of 18.8 years (SD: 10.2 years), 423 men and 371 women were ascertained to have developed PD. In women, compared with normotensive subjects (<130/80 mm Hg), the multivariable-adjusted hazard ratios of PD associated with high-normal blood pressure (130 to 139/80 to 89 mm Hg) and hypertension (≥140/90 mm Hg or use of antihypertensive agents) were 1.63 (95% CI: 1.07 to 2.47) and 1.62 (95% CI: 1.09 to 2.42). There was no significant association between blood pressure and PD risk in men. The multivariable-adjusted hazard ratios of PD associated with use of antihypertensive agents were 1.08 (95% CI: 0.79 to 1.48) in men and 1.03 (95% CI: 0.76 to 1.38) in women. This study suggests that, in women, above-optimal blood pressure, including high-normal blood pressure and hypertension, is associated with an increased risk of PD. Optimal control of blood pressure in women may reduce the incidence of PD.
Pankratz, Nathan; Wilk, Jemma B; Latourelle, Jeanne C; DeStefano, Anita L; Halter, Cheryl; Pugh, Elizabeth W; Doheny, Kimberly F; Gusella, James F; Nichols, William C; Foroud, Tatiana; Myers, Richard H
Five genes have been identified that contribute to Mendelian forms of Parkinson disease (PD); however, mutations have been found in fewer than 5% of patients, suggesting that additional genes contribute to disease risk. Unlike previous studies that focused primarily on sporadic PD, we have performed the first genomewide association study (GWAS) in familial PD. Genotyping was performed with the Illumina HumanCNV370Duo array in 857 familial PD cases and 867 controls. A logistic model was employed to test for association under additive and recessive modes of inheritance after adjusting for gender and age. No result met genomewide significance based on a conservative Bonferroni correction. The strongest association result was with SNPs in the GAK/DGKQ region on chromosome 4 (additive model: p = 3.4 x 10(-6); OR = 1.69). Consistent evidence of association was also observed to the chromosomal regions containing SNCA (additive model: p = 5.5 x 10(-5); OR = 1.35) and MAPT (recessive model: p = 2.0 x 10(-5); OR = 0.56). Both of these genes have been implicated previously in PD susceptibility; however, neither was identified in previous GWAS studies of PD. Meta-analysis was performed using data from a previous case-control GWAS, and yielded improved p values for several regions, including GAK/DGKQ (additive model: p = 2.5 x 10(-7)) and the MAPT region (recessive model: p = 9.8 x 10(-6); additive model: p = 4.8 x 10(-5)). These data suggest the identification of new susceptibility alleles for PD in the GAK/DGKQ region, and also provide further support for the role of SNCA and MAPT in PD susceptibility.
Pankratz, Nathan; Wilk, Jemma B.; Latourelle, Jeanne C.; DeStefano, Anita L.; Halter, Cheryl; Pugh, Elizabeth W.; Doheny, Kimberly F.; Gusella, James F.; Nichols, William C.
Five genes have been identified that contribute to Mendelian forms of Parkinson disease (PD); however, mutations have been found in fewer than 5% of patients, suggesting that additional genes contribute to disease risk. Unlike previous studies that focused primarily on sporadic PD, we have performed the first genomewide association study (GWAS) in familial PD. Genotyping was performed with the Illumina HumanCNV370Duo array in 857 familial PD cases and 867 controls. A logistic model was employed to test for association under additive and recessive modes of inheritance after adjusting for gender and age. No result met genomewide significance based on a conservative Bonferroni correction. The strongest association result was with SNPs in the GAK/DGKQ region on chromosome 4 (additive model: p = 3.4 × 10−6; OR = 1.69). Consistent evidence of association was also observed to the chromosomal regions containing SNCA (additive model: p = 5.5 × 10−5; OR = 1.35) and MAPT (recessive model: p = 2.0 × 10−5; OR = 0.56). Both of these genes have been implicated previously in PD susceptibility; however, neither was identified in previous GWAS studies of PD. Meta-analysis was performed using data from a previous case–control GWAS, and yielded improved p values for several regions, including GAK/DGKQ (additive model: p = 2.5 × 10−7) and the MAPT region (recessive model: p = 9.8 × 10−6; additive model: p = 4.8 × 10−5). These data suggest the identification of new susceptibility alleles for PD in the GAK/DGKQ region, and also provide further support for the role of SNCA and MAPT in PD susceptibility. PMID:18985386
Leibson, Cynthia L; Long, Kirsten Hall; Maraganore, Demetrius M; Bower, James H; Ransom, Jeanine E; O'Brien, Peter C; Rocca, Walter A
The objective was to provide population-based estimates of incremental medical costs associated with Parkinson's disease (PD) from onset forward. All Olmsted County, Minnesota, residents with confirmed PD onset from 1987 through 1995 (n = 92) and one age- and sex-matched non-PD referent subject per case were identified with retrospective record review and followed in provider-linked billing data for direct medical costs (excluding outpatient pharmaceutical costs) from 1 year before index (i.e., year of symptom onset) through 10 years after index. Costs for each referent subject were subtracted from those for his/her matched case. Tests for statistical significance used Wilcoxon signed ranks. Preindex costs were similar [median difference in annual costs (MD) = -3 dollars; P = 0.59]. One year post index, PD subjects exhibited borderline significantly higher costs compared to referent subjects (MD = 581 dollars; P = 0.052); the difference diminished over 5 years (MD = 118 dollars; P = 0.82). By 5 to 10 years, however, PD subjects exhibited significantly higher costs (MD = 1,146 dollars; P = 0.01). Over the full 10 years, excess costs were concentrated among PD subjects without rest tremor (MD = 2,261 dollars, P < 0.01, for those without tremor and -229 dollars, P = 0.99, for those with tremor). These population-based estimates of PD-associated direct medical costs from onset forward can uniquely inform policy decisions and cost-effectiveness research.
Feng, Yinling; Wang, Xuefeng
In order to investigate commonly disturbed genes and pathways in various brain regions of patients with Parkinson's disease (PD), microarray datasets from previous studies were collected and systematically analyzed. Different normalization methods were applied to microarray datasets from different platforms. A strategy combining gene co-expression networks and clinical information was adopted, using weighted gene co-expression network analysis (WGCNA) to screen for commonly disturbed genes in different brain regions of patients with PD. Functional enrichment analysis of commonly disturbed genes was performed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID). Co-pathway relationships were identified with Pearson's correlation coefficient tests and a hypergeometric distribution-based test. Common genes in pathway pairs were selected out and regarded as risk genes. A total of 17 microarray datasets from 7 platforms were retained for further analysis. Five gene coexpression modules were identified, containing 9,745, 736, 233, 101 and 93 genes, respectively. One module was significantly correlated with PD samples and thus the 736 genes it contained were considered to be candidate PD-associated genes. Functional enrichment analysis demonstrated that these genes were implicated in oxidative phosphorylation and PD. A total of 44 pathway pairs and 52 risk genes were revealed, and a risk gene pathway relationship network was constructed. Eight modules were identified and were revealed to be associated with PD, cancers and metabolism. A number of disturbed pathways and risk genes were unveiled in PD, and these findings may help advance understanding of PD pathogenesis. PMID:28098893
Wang, Wenzhang; Wang, Xinglong; Fujioka, Hisashi; Hoppel, Charles; Whone, Alan L; Caldwell, Maeve A; Cullen, Peter J; Liu, Jun; Zhu, Xiongwei
Mitochondrial dysfunction represents a critical step during the pathogenesis of Parkinson's disease (PD), and increasing evidence suggests abnormal mitochondrial dynamics and quality control as important underlying mechanisms. The VPS35 gene, which encodes a key component of the membrane protein-recycling retromer complex, is the third autosomal-dominant gene associated with PD. However, how VPS35 mutations lead to neurodegeneration remains unclear. Here we demonstrate that PD-associated VPS35 mutations caused mitochondrial fragmentation and cell death in cultured neurons in vitro, in mouse substantia nigra neurons in vivo and in human fibroblasts from an individual with PD who has the VPS35(D620N) mutation. VPS35-induced mitochondrial deficits and neuronal dysfunction could be prevented by inhibition of mitochondrial fission. VPS35 mutants showed increased interaction with dynamin-like protein (DLP) 1, which enhanced turnover of the mitochondrial DLP1 complexes via the mitochondria-derived vesicle-dependent trafficking of the complexes to lysosomes for degradation. Notably, oxidative stress increased the VPS35-DLP1 interaction, which we also found to be increased in the brains of sporadic PD cases. These results revealed a novel cellular mechanism for the involvement of VPS35 in mitochondrial fission, dysregulation of which is probably involved in the pathogenesis of familial, and possibly sporadic, PD.
Foo, Jia Nee; Tan, Louis C; Irwan, Ishak D; Au, Wing-Lok; Low, Hui Qi; Prakash, Kumar-M; Ahmad-Annuar, Azlina; Bei, Jinxin; Chan, Anne Yy; Chen, Chiung Mei; Chen, Yi-Chun; Chung, Sun Ju; Deng, Hao; Lim, Shen-Yang; Mok, Vincent; Pang, Hao; Pei, Zhong; Peng, Rong; Shang, Hui-Fang; Song, Kyuyoung; Tan, Ai Huey; Wu, Yih-Ru; Aung, Tin; Cheng, Ching-Yu; Chew, Fook Tim; Chew, Soo-Hong; Chong, Siow-Ann; Ebstein, Richard P; Lee, Jimmy; Saw, Seang-Mei; Seow, Adeline; Subramaniam, Mythily; Tai, E-Shyong; Vithana, Eranga N; Wong, Tien-Yin; Heng, Khai Koon; Meah, Wee-Yang; Khor, Chiea Chuen; Liu, Hong; Zhang, Furen; Liu, Jianjun; Tan, Eng-King
Genome-wide association studies (GWAS) on Parkinson's disease (PD) have mostly been done in Europeans and Japanese. No study has been done in Han Chinese, which make up nearly a fifth of the world population. We conducted the first Han Chinese GWAS analysing a total of 22,729 subjects (5,125 PD cases and 17,604 controls) from Singapore, Hong Kong, Malaysia, Korea, mainland China and Taiwan. We performed imputation, merging and logistic regression analyses of 2,402,394 SNPs passing quality control filters in 779 PD cases, 13,227 controls, adjusted for the first three principal components. 90 SNPs with association P < 10-4 were validated in 9 additional sample collections and the results were combined using fixed-effects inverse-variance meta-analysis. We observed strong associations reaching genome-wide significance at SNCA, LRRK2 and MCCC1, confirming their important roles in both European and Asian PD. We also identified significant (P < 0.05) associations at 5 loci (DLG2, SIPA1L2, STK39, VPS13C and RIT2), and observed the same direction of associations at 9 other loci including BST1 and PARK16. Allelic heterogeneity was observed at LRRK2 while European risk SNPs at 6 other loci including MAPT and GBA-SYT11 were non-polymorphic or very rare in our cohort. Overall, we replicate associations at SNCA, LRRK2, MCCC1 and 14 other European PD loci but did not identify Asian-specific loci with large effects (OR > 1.45) on PD risk. Our results also demonstrate some differences in the genetic contribution to PD between Europeans and Asians. Further pan-ethnic meta-analysis with European GWAS cohorts may unravel new PD loci.
Kadastik-Eerme, Liis; Muldmaa, Mari; Lilles, Stella; Rosenthal, Marika; Taba, Nele; Taba, Pille
Introduction. The purpose of this study was to demonstrate the frequency and severity of nonmotor symptoms and their correlations with a wide range of demographic and clinical factors in a large cohort of patients with Parkinson's disease (PD). Methods. 268 PD patients were assessed using the validated Movement Disorders Society's Unified Parkinson's Disease Rating Scale (MDS-UPDRS), the Beck Depression Inventory (BDI), Parkinson's Disease Questionnaire (PDQ-39), the Hoehn and Yahr scale (HY), the Schwab and England Activities of Daily Living (SE-ADL) Scale, and the Minimental State Examination (MMSE). Results. Nonmotor symptoms had a strong positive relationship with depression and lower quality of life. Also, age, duration and severity of PD, cognitive impairment, daily dose, and duration of levodopa treatment correlated with the burden of nonmotor symptoms. Patients with postural instability and gait disorder (PIGD) dominance or with the presence of motor complications had higher MDS-UPDRS Part I scores expressing the load of nonmotor features, compared to participants with other disease subtypes or without motor complications. Conclusions. Though the severity of individual nonmotor symptoms was generally rated by PD patients as “mild” or less, we found a significant cumulative effect of nonmotor symptoms on patients' mood, daily activities, and quality of life. PMID:27195172
Kadastik-Eerme, Liis; Muldmaa, Mari; Lilles, Stella; Rosenthal, Marika; Taba, Nele; Taba, Pille
Introduction. The purpose of this study was to demonstrate the frequency and severity of nonmotor symptoms and their correlations with a wide range of demographic and clinical factors in a large cohort of patients with Parkinson's disease (PD). Methods. 268 PD patients were assessed using the validated Movement Disorders Society's Unified Parkinson's Disease Rating Scale (MDS-UPDRS), the Beck Depression Inventory (BDI), Parkinson's Disease Questionnaire (PDQ-39), the Hoehn and Yahr scale (HY), the Schwab and England Activities of Daily Living (SE-ADL) Scale, and the Minimental State Examination (MMSE). Results. Nonmotor symptoms had a strong positive relationship with depression and lower quality of life. Also, age, duration and severity of PD, cognitive impairment, daily dose, and duration of levodopa treatment correlated with the burden of nonmotor symptoms. Patients with postural instability and gait disorder (PIGD) dominance or with the presence of motor complications had higher MDS-UPDRS Part I scores expressing the load of nonmotor features, compared to participants with other disease subtypes or without motor complications. Conclusions. Though the severity of individual nonmotor symptoms was generally rated by PD patients as "mild" or less, we found a significant cumulative effect of nonmotor symptoms on patients' mood, daily activities, and quality of life.
Pascual, J; Misiego, M
The neurochemistry of Parkinson's disease and other degenerative parkinsonisms is reviewed, emphasizing the changes described in the dopaminergic system. Presynaptic dopaminergic markers are reduced over the striatum in all these degenerative parkinsonisms, dopamine receptor changes being more heterogeneous. While in Parkinson's disease D1 and D2 receptors remain preserved as compared to controls, in progressive supranuclear palsy there is a loss of nigral D1 receptors and of striatal D2 receptors. This finding has also been described in striatonigral degeneration. There are no clear data about the status of D3, D4 and D5 dopamine receptors in these conditions. The alterations in other neurotransmission systems, cholinegic, adrenergic, serotoninergic and peptidergic are, in general, less dramatic, although they have not been studied in detail. To conclude, further studies are necessary in these field, in these moment, however, the preservation of striatal D2 dopamine receptors is the neurochemical finding with the best correlation with the response to levodopa or other dopaminergic agonists.
Crispo, James A. G.; Willis, Allison W.; Thibault, Dylan P.; Fortin, Yannick; Hays, Harlen D.; McNair, Douglas S.; Bjerre, Lise M.; Kohen, Dafna E.; Perez-Lloret, Santiago; Mattison, Donald R.; Krewski, Daniel
Background Elderly adults should avoid medications with anticholinergic effects since they may increase the risk of adverse events, including falls, delirium, and cognitive impairment. However, data on anticholinergic burden are limited in subpopulations, such as individuals with Parkinson disease (PD). The objective of this study was to determine whether anticholinergic burden was associated with adverse outcomes in a PD inpatient population. Methods Using the Cerner Health Facts® database, we retrospectively examined anticholinergic medication use, diagnoses, and hospital revisits within a cohort of 16,302 PD inpatients admitted to a Cerner hospital between 2000 and 2011. Anticholinergic burden was computed using the Anticholinergic Risk Scale (ARS). Primary outcomes were associations between ARS score and diagnosis of fracture and delirium. Secondary outcomes included associations between ARS score and 30-day hospital revisits. Results Many individuals (57.8%) were prescribed non-PD medications with moderate to very strong anticholinergic potential. Individuals with the greatest ARS score (≥4) were more likely to be diagnosed with fractures (adjusted odds ratio (AOR): 1.56, 95% CI: 1.29–1.88) and delirium (AOR: 1.61, 95% CI: 1.08–2.40) relative to those with no anticholinergic burden. Similarly, inpatients with the greatest ARS score were more likely to visit the emergency department (adjusted hazard ratio (AHR): 1.32, 95% CI: 1.10–1.58) and be readmitted (AHR: 1.16, 95% CI: 1.01–1.33) within 30-days of discharge. Conclusions We found a positive association between increased anticholinergic burden and adverse outcomes among individuals with PD. Additional pharmacovigilance studies are needed to better understand risks associated with anticholinergic medication use in PD. PMID:26939130
Misra, Stuti L; Kersten, Hannah M; Roxburgh, Richard H; Danesh-Meyer, Helen V; McGhee, Charles N J
Ocular surface changes and blink abnormalities are well-established in Parkinson's disease. Blink rate may be influenced by corneal sub-basal nerve density, however, this relationship has not yet been investigated in Parkinson's disease. This case-control study examined the ocular surface in patients with moderately severe Parkinson's disease, including confocal microscopy of the cornea. Fifteen patients with moderately severe Parkinson's disease (modified Hoehn and Yahr grade 3 or 4) and fifteen control participants were recruited. Ophthalmic assessment included slit-lamp examination, blink rate assessment, central corneal aesthesiometry and in vivo corneal confocal microscopy. The effect of disease laterality was also investigated. Of the 15 patients with Parkinson's disease, ten were male and the mean age was 65.5±8.6years. The corneal sub-basal nerve plexus density was markedly reduced in patients with Parkinson's disease (7.56±2.4mm/mm(2)) compared with controls (15.91±2.6mm/mm(2)) (p<0.0001). Corneal sensitivity did not differ significantly between the patients with Parkinson's disease (0.79±1.2mBAR) and the control group (0.26±0.35mBAR), p=0.12. Sub-basal nerve density was not significantly different between the eye ipsilateral to the side of the body with most-severe motor symptoms, and the contralateral eye. There was a significant positive correlation between ACE-R scores and sub-basal corneal nerve density (R(2)=0.66, p=0.02). This is the first study to report a significant reduction in corneal sub-basal nerve density in Parkinson's disease and demonstrate an association with cognitive dysfunction. These results provide further evidence to support the involvement of the peripheral nervous system in Parkinson's disease, previously thought to be a central nervous system disorder.
Möller, Jens Carsten; Menig, Alexandra; Oechsner, Matthias
Parkinson's disease (PD) is a chronic neurodegenerative disease which is characterized by the cardinal symptoms akinesia, rigidity, rest tremor and postural instability. Besides PD features also a wide range of non-motor symptoms. Physical activity is recommended for all stages of PD and may hypothetically even have a positive influence on the course of the disease. Rehabilitative treatments become increasingly important in the advanced stage of the disease and include mainly physiotherapy, occupational therapy and speech therapy. Neurorehabilitation is arguably most important for the treatment of axial symptoms such as freezing, hypophonia, dysphagia, postural instability and postural disturbances that respond poorly to drug therapy. This article provides an overview of current developments in the field of neurorehabilitation in PD.
González, Hugo; Contreras, Francisco; Pacheco, Rodrigo
Neuroinflammation constitutes a fundamental process involved in the physiopathology of Parkinson's disease (PD). Microglial cells play a central role in the outcome of neuroinflammation and consequent neurodegeneration of dopaminergic neurons in the substantia nigra. Current evidence indicates that CD4+ T-cells infiltrate the central nervous system (CNS) in PD, where they play a critical role determining the functional phenotype of microglia, thus regulating the progression of the neurodegenerative process. Here, we first analysed the pathogenic role of inflammatory phenotypes and the beneficial role of anti-inflammatory phenotypes of encephalitogenic CD4+ T-cells involved in the physiopathology of PD. Next, we discussed how alterations of neurotransmitter levels observed in the basal ganglia throughout the time course of PD progression could be strongly affecting the behaviour of encephalitogenic CD4+ T-cells and thereby the outcome of the neuroinflammatory process and the consequent neurodegeneration of dopaminergic neurons. Afterward, we integrated the evidence indicating the involvement of an antigen-specific immune response mediated by T-cells and B-cells against CNS-derived self-constituents in PD. Consistent with the involvement of a relevant autoimmune component in PD, we also reviewed the polymorphisms of both, class I and class II major histocompatibility complexes, associated to the risk of PD. Overall, this study gives an overview of how an autoimmune component involved in PD plays a fundamental role in the progression of the neurodegenerative process.
Deng, Xiao; Xiao, Bin; Li, Hui-Hua; Lo, Yew-Long; Chew, Lai-Mun; Prakash, Kumar M; Tan, Eng-King
The pathophysiology of the postural instability gait difficulty (PIGD) subtype of Parkinson's disease (PD) is unclear. Information on the spectrum of non-motor symptoms (NMS) in PIGD phenotype is limited. Our objective is to compare the spectrum of NMS in PIGD subtype compared to non-PIGD subgroup in PD patients and to determine predictive factors that are associated with PIGD phenotype. A total of 432 PD patients comprising 158 PIGD and 274 non-PIGD patients were recruited. NMS burden (frequency and severity) was assessed using non-motor symptom scale (NMSS). In the univariable analysis, NMSS total score (P = 0.0132), NMSS domain 3 (mood/apathy) score (P = 0.0108), NMSS domain 5 (attention/memory) score (P = 0.0048) and NMSS domain 8 (sexual function) score (P = 0.0052) were significantly higher in the PIGD group than in the non-PIGD group. Using multivariable logistic regression, UPDRS tremor score, UPDRS PIGD score, H&Y staging score and NMSS domain 8 (sexual function) score were found to be significantly different in the PIGD group compared to the non-PIGD group. We disclosed for the first time that PIGD patients demonstrated a greater overall NMS burden and sexual dysfunction and was an independent predictor of PIGD phenotype. Early intervention of sexual dysfunction symptoms in PIGD patients may improve their clinical management.
Ma, Huizi; Chen, Huimin; Fang, Jinping; Gao, Liyan; Ma, Lingyan; Wu, Tao; Hou, Yanan; Zhang, Jiarong; Feng, Tao
Cerebello-thalamo-cortical circuit has been indicated important for tremor in Parkinson's disease (PD), but the role of dentate nucleus (DN) in parkinsonian tremor remains unclear. To investigate whether DN plays a role in PD tremor, we recruited 50 PD and 29 age-matched health controls (HC). The patients were divided into tremor-dominant (TD) and non-tremor-dominant (NTD) groups. We collected resting-state fMRIs data for each subject. The bilateral DN was then chosen as the region of interest to examine PD tremor-related network changes, as well as its correlation with tremor severity. Voxel-wise functional connectivity analysis revealed that the bilateral DN had higher connectivity with the bilateral cerebellar anterior lobe, and had lower connectivity with the bilateral prefrontal cortex in TD compared to the HC and NTD groups. Functional connectivity of the bilateral DN with the bilateral cerebellar posterior lobe was also higher in TD than NTD group. Functional connectivity between the bilateral DN and the bilateral cerebellar posterior lobe showed positive correlation with tremor severity, while that between the bilateral DN and the bilateral prefrontal cortex displayed negative correlation. Our study demonstrates higher dentato-cerebellar connectivity and lower dentato-prefrontal connectivity in TD patients, which might be involved in the pathogenesis of PD tremor. And we conclude that DN might be associated with the pathogenesis of PD tremor.
Bouchard, Thomas P; Malykhin, Nikolai; Martin, W R Wayne; Hanstock, Christopher C; Emery, Derek J; Fisher, Nancy J; Camicioli, Richard M
The hippocampus (HC) and amygdala (AG) decrease in volume with age and in Parkinson's disease (PD) with (PDD) and without dementia. We compared 44 PD to 44 age, sex and education-matched subjects without PD (non-PD) and 13 PDD subjects. T1-weighted MR images were used to manually segment the head, body and tail of the HC and the AG. HC volumes, corrected to intracranial volume, were smaller in PDD than non-PD (p=0.04), reflected predominantly by head atrophy. Right AG volumes were smaller in PD compared to non-PD (p=0.03). HC volumes in older (>70), but not younger, non-demented PD differed from non-PD (HC, p=0.02; head, p=0.03). Age correlated negatively with overall HC (r=-0.43, p=0.004) and head (r=-0.48, p=0.001) in PD, but not in non-PD. In PD, left HC head volumes correlated with recall, but not recognition scores on the CVLT-II (r=0.35, p=0.02) and BVMT-R (r=0.35, p=0.02); AG volumes correlated with CVLT-II recall (r=0.35, p=0.02). No correlations were found in non-PD (p>0.4). In conclusion, functionally meaningful age-associated hippocampal and amygdala atrophy occurs in PD.
Koerts, Janneke; van Beilen, Marije; Leenders, Klaus L; Brouwer, Wiebo H; Tucha, Lara; Tucha, Oliver
Impairments in executive functions are frequently reported in Parkinson's disease (PD). However, little is known about patients' experience regarding these impairments. This knowledge is crucial because if patients do not experience their cognitive impairments they do not report them to their attending neurologist. Consequently, patients might not get appropriate treatment. This study investigated if patients with a mild to moderate PD experience impairments in executive functions in daily life and whether these correspond with impairments as measured in neuropsychological assessments. Forty-three PD patients and 25 healthy participants were included. Groups did not differ in age, sex and education. All participants and their closest relatives completed a standardized questionnaire measuring executive functions in daily life. Furthermore, all participants were assessed with a test battery measuring executive functions. PD patients reported significantly more problems with executive functions in daily life than healthy participants. Furthermore, co-morbid depression had a negative impact on the number of problems with executive functions in daily life as reported by PD patients. The experienced daily life problems in executive functions were not associated with the patients' performance on objective cognitive measures. In conclusion, PD patients were aware of problems with executive functions in daily life and reported considerably more problems than healthy controls. These problems were however not reflected by neuropsychological tests and may indicate a lack of ecological validity of neuropsychological assessment.
Kaiserova, Michaela; Prikrylova Vranova, Hana; Galuszka, Jan; Stejskal, David; Mensikova, Katerina; Zapletalova, Jana; Mares, Jan; Kanovsky, Petr
An association between the CSF chromogranin A (CgA) and orthostatic blood pressure changes was investigated in 20 patients in the early stage of Parkinson disease (PD). There was a positive correlation between the CSF CgA and diastolic blood pressure change, when CSF CgA levels were lower in patients with orthostatic hypotension (OH). Decreased CSF CgA may be useful in predicting OH in the early stage of PD.
Picillo, Marina; Santangelo, Gabriella; Moccia, Marcello; Erro, Roberto; Amboni, Marianna; Prestipino, Elio; Longo, Katia; Vitale, Carmine; Spina, Emanuele; Orefice, Giuseppe; Barone, Paolo; Pellecchia, Maria Teresa
Both low serum uric acid (UA) levels and apathy are considered biomarkers of cognitive decline and dementia in Parkinson's disease (PD). There is an urgent need to combine different biomarkers to predict disease course in PD. Data on the relationship between serum UA levels and apathy in PD are lacking. The aim of this study is to evaluate the relationship between serum UA levels and pure apathy in early, drug-naïve PD patients. Forty-nine early, drug-naïve PD patients were enrolled and stratified into two groups using the median serum UA levels at diagnosis (Group 1 serum UA ≤ 4.8 mg/dl; Group 2 serum UA > 4.8 mg/dl). The cohort was followed for the first 2 years of disease. Apathy was evaluated with the Apathy Evaluation Scale (AES). Patients with lower serum UA levels presented significant higher AES score compared to patients with higher serum UA levels. Regression analysis showed that baseline serum UA levels were significant determinants of AES scores at both baseline and 2-year follow up, irrespective of gender, age, attention/executive functions and dopamine replacement therapy when applicable. This is the first study showing a link between serum UA levels and apathy in non-demented, non-depressed, early, drug-naïve PD, being lower serum UA levels associated with greater apathy. Further follow up of our patients and replication of this observation in independent cohorts are needed to establish if this combination of biomarkers may help in characterizing a subgroup of PD patients at diagnosis.
Guo, Xiaoyan; Song, Wei; Chen, Ke; Chen, XuePing; Zheng, Zhenzhen; Cao, Bei; Huang, Rui; Zhao, Bi; Wu, Ying; Shang, Hui-Fang
The associations between neuropsychiatric symptoms and cognition, frontal lobe function and frontal behavioral changes in the Chinese idiopathic Parkinson's disease (PD) population are largely unknown. This study included 348 idiopathic PD patients from southwest China. Neuropsychiatric symptoms were investigated using the Neuropsychiatric Inventory Questionnaire (NPI), and cognition was assessed using Addenbrooke's Cognitive Examination-Revised (ACE-R). The Frontal Assessment Battery (FAB) was used to evaluate frontal function and the Frontal Behavior Inventory (FBI) was used to assess frontal behavioral changes. The mean (± standard deviation) age of the PD patients was 60.24 ± 12.07 years, and the mean disease duration was 3.88 ± 3.34 years. The mean NPI score was 3.49 ± 4.00. The mean score of ACE-R was 76.82 ± 16.73. The mean score of FAB was 15.27 ± 2.90, and the mean score of FBI was 3.18 ± 5.17. Weak negative correlations between the NPI and ACE-R scores as well as FAB score were found in the total sample, the male patient subgroup, the early onset PD subgroup and the late onset PD subgroup. Strong positive correlations were found between the NPI and FBI scores in the total sample (r=0.661, p<0.001), the male patient subgroup (r=0.789, p<0.001) and the late onset PD subgroup (r=0.749, p<0.001). Moderate positive correlations were found between the NPI and FBI scores in the female patient subgroup (r=0.536, p<0.001) and the early onset PD subgroup (r=0.462, p<0.001). Neuropsychiatric symptoms were closely associated with frontal behavioral changes but were not closely related with worse cognition and frontal lobe function in the Chinese idiopathic PD population.
Stocchi, Fabrizio; Marconi, Stefano
Parkinson disease is a progressive movement disorder caused by loss of dopaminergic neurons in the substantia nigra. Of unknown etiology, Parkinson disease is characterized by 4 cardinal symptoms: tremor at rest, bradykinesia, postural instability, and rigidity. The current criterion-standard drug used in the management of parkinsonian symptoms is levodopa (l-dopa). However, long-term l-dopa therapy is associated with the development of motor complications; approximately 50% to 80% of patients will develop motor complications within 5 to 10 years of l-dopa treatment initiation. Motor complications can be divided into motor fluctuations, caused largely through pulsatile dopamine stimulation and low l-dopa concentrations, and dyskinesia, associated more often with peak l-dopa concentrations. Ultimately, the main goal was to provide steady l-dopa concentrations, without peaks and troughs. Empirical investigations using parenteral infusions of l-dopa and highly soluble l-dopa prodrugs have shown that there is benefit in ameliorating the peaks and troughs associated with traditional oral l-dopa formulations. Recently, the development of highly soluble oral l-dopa prodrugs has facilitated rapid, regular, and reliable l-dopa availability. This review evaluates some of the pharmacologic strategies in the management of motor complications in Parkinson disease and therapy optimization, with a focus on the use of CHF 1512 (Sirio), a combination of melevodopa (l-dopa methylester, a highly soluble prodrug of l-dopa) plus carbidopa in an effervescent tablet formulation.
Morgan, John C; Mehta, Shyamal H; Sethi, Kapil D
Biomarkers are objectively measured characteristics that are indicators of normal biological processes, pathogenic processes, or responses to therapeutic interventions. To date, clinical assessment remains the gold standard in the diagnosis of Parkinson's disease (PD) and clinical rating scales are well established as the gold standard for tracking progression of PD. Researchers have identified numerous potential biomarkers that may aid in the differential diagnosis of PD and/or tracking disease progression. Clinical, genetic, blood and cerebrospinal fluid (proteomics, transcriptomics, metabolomics), and neuroimaging biomarkers may provide useful tools in the diagnosis of PD and in measuring disease progression and response to therapies. Some potential biomarkers are inexpensive and do not require much technical expertise, whereas others are expensive or require specialized equipment and technical skills. Many potential biomarkers in PD show great promise; however, they need to be assessed for their sensitivity and specificity over time in large and varied samples of patients with and without PD.
There are a number of tremors that may affect patients with Parkinson's disease, but the classic is tremor-at-rest. The tremor is also seen during postural action after a short pause, and is often called re-emergent tremor although it appears that the physiology is the same. As a manifestation of Parkinson's disease, it is separate from bradykinesia and rigidity as the magnitude of tremor is not related to dopamine deficiency nor does it respond readily to dopamine treatment. Cellular activity in the different basal ganglia nuclei can be coherent with tremor, but cellular activity in the VIM nucleus of the thalamus, a cerebellar relay nucleus, is more coherent than cellular activity in basal ganglia. It is also notable that different body parts may have similar tremor frequencies, but are generally not exactly the same and are not phase locked. This suggests that each body part has a separate tremor generator. The ability to stay separate may be due to the somatotopic segregation of basal ganglia loops. Analysis of cellular behavior in the thalamus shows that the thalamus is not the generator of tremor. New data suggest that the basal ganglia trigger a cerebellar circuit to produce the tremor.
Haaxma, Charlotte A; Borm, George F; van der Linden, Dimitri; Kappelle, Arnoud C; Bloem, Bastiaan R
Parkinson's disease (PD) is preceded by a premotor phase of unknown duration. Dopaminergic degeneration during this phase may lead to subtle cognitive and behavioural changes, such as decreased novelty seeking. Consequently, premotor subjects might be most comfortable in jobs that do not require optimal dopamine levels, leading to an overrepresentation in structured and predictable occupations, or an underrepresentation in artistic occupations. In a case-control study, 750 men with PD (onset ≥40 years) and 1300 healthy men completed a validated questionnaire about their lifetime occupational status. Occupations were classified using the RIASEC model. Odds ratios (ORs) were calculated for the conventional and artistic categories, both for the most recent occupation before symptom onset, and for the very first occupation. Because farming has been associated with a PD risk, ORs were calculated separately for farming. A reduced risk of PD was found for men with an artistic occupation late in life (OR 0.14, 95% CI 0.04-0.53), while an artistic first occupation did not prevent PD (OR 0.72, CI 0.32-1.59). Conventional occupations showed no increased risk (recent: OR 1.07, CI 0.70-1.64; first: OR 1.14, CI 0.77-1.71). In support of previous reports, farming was associated with an increased risk of PD (recent: OR 2.6, CI 1.4-4.6; first: OR 2.7, CI 1.6-4.5). PD patients were older than controls, but various statistical corrections for age all lead to similar results. Artistic occupations late in life are associated with a reduced risk of subsequent PD, perhaps because this reflects a better preserved dopaminergic state. No initial occupation predicted PD, suggesting that the premotor phase starts later in life.
Yu, Ri-li; Guo, Ji-feng; Wang, Ya-qin; Liu, Zhen-hua; Sun, Zhan-fang; Su, Li; Zhang, Yuan; Yan, Xin-xiang; Tang, Bei-sha
A recent meta-analysis of datasets from five of the published Parkinson's disease (PD) genome-wide association studies implicated the single nucleotide polymorphism (SNP) rs12817488 in coiled-coil domain containing 62 (CCDC62)/huntingtin interacting protein 1 related (HIP1R) as a risk factor for PD. We conducted a case-control study to evaluate the possible association between rs12817488 and PD in Chinese people. All patients (515 PD patients and 518 age and sex-matched controls) were successfully genotyped using polymerase chain reaction restriction fragment length polymorphism analysis. We observed that the rs12817488 polymorphism is associated with PD (p=0.003) and that the genotype and allele frequencies showed a difference between late-onset PD patients and male controls (p=0.025 and p=0.007, respectively). However, there was no difference in the early-onset PD patients and controls. We found a difference in the genotype and allele frequencies between the male PD patients and the male controls (p=0.034 and p=0.017, respectively). However, there was no difference in females. Patients with the A allele were susceptible to PD in both dominant (GA+AA versus GG; odds ratio [OR] 1.365, 95% confidence interval [CI] 1.041-1.788) and recessive (AA versus GG+GA; OR 1.606, 95% CI 1.194-2.158) models. Therefore, our findings support the conclusion that the rs12817488 in CCDC62/HIP1R polymorphism may increase the risk of PD in the Chinese Han population.
Lee, Kyung Duck; Koo, Jung Hoi; Song, Sun Hong; Jo, Kwang Deog; Lee, Moon Kyu; Jang, Wooyoung
Dysphagia is an important issue in the prognosis of Parkinson's disease (PD). Although several studies have reported that oropharyngeal dysphagia may be associated with cognitive dysfunction, the exact relationship between cortical function and swallowing function in PD patients is unclear. Therefore, we investigated the association between an electrophysiological marker of central cholinergic function, which reflected cognitive function, and swallowing function, as measured by videofluoroscopic studies (VFSS). We enrolled 29 early PD patients. Using the Swallowing Disturbance Questionnaire (SDQ), we divided the enrolled patients into two groups: PD with dysphagia and PD without dysphagia. The videofluoroscopic dysphagia scale (VDS) was applied to explore the nature of the dysphagia. To assess central cholinergic dysfunction, short latency afferent inhibition (SAI) was evaluated. We analyzed the relationship between central cholinergic dysfunction and oropharyngeal dysphagia and investigated the characteristics of the dysphagia. The SAI values were significantly different between the two groups. The comparison of each VFSS component between the PD with dysphagia group and the PD without dysphagia group showed statistical significance for most of the oral phase components and for a single pharyngeal phase component. The total score on the VDS was higher in the PD with dysphagia group than in the PD without dysphagia group. The Mini-Mental State Examination and SAI values showed significant correlations with the total score of the oral phase components. According to binary logistic regression analysis, SAI value independently contributed to the presence of dysphagia in PD patients. Our findings suggest that cholinergic dysfunction is associated with dysphagia in early PD and that an abnormal SAI value is a good biomarker for predicting the risk of dysphagia in PD patients.
Raskin, Sergey; Durst, Rimona
Parkinson disease (PD) is a chronic progressive degenerative disorder that affects over 6 million people worldwide. It is manifested by motor and psychiatric signs. The latter inflicts up to 88% of PD patients. With the prolongation of life expectancy, it is presumed that the prevalence of PD will further rise, together with comorbid depression. As a result, the need for an adequate therapeutic answer for compounded PD with depression is called for urgently. Several theories try to explain the trigger of depression in PD patients by impaired activity in dopamine, norepinephrine and serotonin systems. Various treatment to combat depressive symptoms in PD patients were proposed and are in use, with ambiguous results and disturbing side effects. These anti-depressive modalities include SSRI's, SNRI, TCA, NRI and ECT. Dopamine agonists showed some anti-depressant activity in several studies in depressive PD, but may cause side effects such as dizziness, somnolence, confusion and even hallucinations. The role of dopamine agonists in the treatment of depression is still being explored because of no sufficient number of controlled studies in this area. Our hypothesis is to suggest NDRI - Bupropion - as the first line of treatment in PD patients with depression, in PD induced depression and/or in depression triggered by one of the treatments given for PD. Dual norepinephrine and dopamine reuptake inhibition is associated with unique clinical profile that compounds together anti-depressant efficacy without serotonin associated side effects such as weight gain, sedation, sexual dysfunction. Bupropion, as mainly dopaminergic and noradrenergic anti-depressant can alleviate therapeutically depressive symptoms associated with PD. Clinical controlled studies on Bupropion use in PD depressed patients are required to support this hypothesis.
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Nalls, Mike A; Saad, Mohamad; Noyce, Alastair J; Keller, Margaux F; Schrag, Anette; Bestwick, Jonathan P; Traynor, Bryan J; Gibbs, J Raphael; Hernandez, Dena G; Cookson, Mark R; Morris, Huw R; Williams, Nigel; Gasser, Thomas; Heutink, Peter; Wood, Nick; Hardy, John; Martinez, Maria; Singleton, Andrew B
Parkinson's disease (PD) has a number of known genetic risk factors. Clinical and epidemiological studies have suggested the existence of intermediate factors that may be associated with additional risk of PD. We construct genetic risk profiles for additional epidemiological and clinical factors using known genome-wide association studies (GWAS) loci related to these specific phenotypes to estimate genetic comorbidity in a systematic review. We identify genetic risk profiles based on GWAS variants associated with schizophrenia and Crohn's disease as significantly associated with risk of PD. Conditional analyses adjusting for SNPs near loci associated with PD and schizophrenia or PD and Crohn's disease suggest that spatially overlapping loci associated with schizophrenia and PD account for most of the shared comorbidity, while variation outside of known proximal loci shared by PD and Crohn's disease accounts for their shared genetic comorbidity. We examine brain methylation and expression signatures proximal to schizophrenia and Crohn's disease loci to infer functional changes in the brain associated with the variants contributing to genetic comorbidity. We compare our results with a systematic review of epidemiological literature, while the findings are dissimilar to a degree; marginal genetic associations corroborate the directionality of associations across genetic and epidemiological data. We show a strong genetically defined level of comorbidity between PD and Crohn's disease as well as between PD and schizophrenia, with likely functional consequences of associated variants occurring in brain.
Nalls, Mike A.; Saad, Mohamad; Noyce, Alastair J.; Keller, Margaux F.; Schrag, Anette; Bestwick, Jonathan P.; Traynor, Bryan J.; Gibbs, J. Raphael; Hernandez, Dena G.; Cookson, Mark R.; Morris, Huw R.; Williams, Nigel; Gasser, Thomas; Heutink, Peter; Wood, Nick; Hardy, John; Martinez, Maria; Singleton, Andrew B.
Parkinson's disease (PD) has a number of known genetic risk factors. Clinical and epidemiological studies have suggested the existence of intermediate factors that may be associated with additional risk of PD. We construct genetic risk profiles for additional epidemiological and clinical factors using known genome-wide association studies (GWAS) loci related to these specific phenotypes to estimate genetic comorbidity in a systematic review. We identify genetic risk profiles based on GWAS variants associated with schizophrenia and Crohn's disease as significantly associated with risk of PD. Conditional analyses adjusting for SNPs near loci associated with PD and schizophrenia or PD and Crohn's disease suggest that spatially overlapping loci associated with schizophrenia and PD account for most of the shared comorbidity, while variation outside of known proximal loci shared by PD and Crohn's disease accounts for their shared genetic comorbidity. We examine brain methylation and expression signatures proximal to schizophrenia and Crohn's disease loci to infer functional changes in the brain associated with the variants contributing to genetic comorbidity. We compare our results with a systematic review of epidemiological literature, while the findings are dissimilar to a degree; marginal genetic associations corroborate the directionality of associations across genetic and epidemiological data. We show a strong genetically defined level of comorbidity between PD and Crohn's disease as well as between PD and schizophrenia, with likely functional consequences of associated variants occurring in brain. PMID:24057672
Bohnen, Nicolaas I.; Kotagal, Vikas; Müller, Martijn L.T.M; Koeppe, Robert A; Scott, Peter J.H.; Albin, Roger L.; Frey, Kirk A; Petrou, Myria
Background There is increasing interest in interactions between metabolic syndromes and neurodegeneration. Diabetes mellitus (DM) contributes to cognitive impairment in the elderly but its effect in Parkinson disease (PD) is not well studied. Objective To investigate effects of comorbid DM on cognition in PD independent from PD-specific primary neurodegenerations. Methods Cross-sectional study. Patients with PD (n=148; age 65.6±7.4 years, Hoehn and Yahr stage 2.4±0.6, with (n=15) and without (n=133) comorbid type II DM, underwent [11C]methyl-4-piperidinyl propionate (PMP) acetylcholinesterase (AChE) PET imaging to assess cortical cholinergic denervation, [11C]dihydrotetrabenazine (DTBZ) PET imaging to assess nigrostriatal denervation, and neuropsychological assessments. A global cognitive Z-score was calculated based on normative data. Analysis of covariance was performed to determine cognitive differences between subjects with and without DM while controlling for nigrostriatal denervation, cortical cholinergic denervation, levodopa equivalent dose and education covariates. Results There were no significant differences in age, gender, Hoehn and Yahr stage or duration of disease between diabetic and non-diabetic PD subjects. There was a non-significant trend toward lower years of education in the diabetic PD subjects compared with non-diabetic PD subjects. PD diabetics had significantly lower mean (±SD) global cognitive Z-scores (−0.98±1.01) compared to the non-diabetics (−0.36±0.91; F=7.78, P=0.006) when controlling for covariate effects of education, striatal dopaminergic denervation, and cortical cholinergic denervation (total model F=8.39, P<0.0001). Conclusion Diabetes mellitus is independently associated with more severe cognitive impairment in PD likely through mechanisms other than diseasespecific neurodegenerations. PMID:25454317
Wang, Liyong; Evatt, Marian L; Maldonado, Lizmarie G; Perry, William R; Ritchie, James C; Beecham, Gary W; Martin, Eden R; Haines, Jonathan L; Pericak-Vance, Margaret A; Vance, Jeffery M; Scott, William K
An inverse association between Parkinson disease (PD) and total vitamin D levels has been reported, but whether vitamin D from different sources, that is, 25(OH)D2 (from diet and supplements) and 25(OH)D3 (mainly from sunlight exposure), all contribute to the association is unknown. Plasma total 25(OH)D, 25(OH)D2, and 25(OH)D3 levels were measured by liquid chromatography-tandem mass spectrometry in PD patients (n = 478) and controls (n = 431). Total 25(OH)D was categorized by clinical insufficiency or deficiency; 25(OH)D2 and 25(OH)D3 were analyzed in quartiles. Vitamin D deficiency (total 25[OH]D < 20 ng/mL) and vitamin D insufficiency (total 25[OH]D < 30 ng/mL) are associated with PD risk (odds ratio [OR] = 2.6 [deficiency] and 2.1 [insufficiency]; P < 0.0001), adjusting for age, sex, and sampling season. Both 25(OH)D2 and 25(OH)D3 levels are inversely associated with PD (P(trend) < 0.0001). The association between 25(OH)D2 and PD risk is largely confined to individuals with low 25(OH)D3 levels (P(trend) = 0.0008 and 0.12 in individuals with 25[OH]D3 < 20 ng/mL and 25[OH]D3 ≥ 20 ng/mL, respectively). Our data confirm the association between vitamin D deficiency and PD, and for the first time demonstrate an inverse association of 25(OH)D2 with PD. Given that 25(OH)D2 concentration is independent of sunlight exposure, this new finding suggests that the inverse association between vitamin D levels and PD is not simply attributable to lack of sunlight exposure in PD patients with impaired mobility. The current study, however, cannot exclude the possibility that gastrointestinal dysfunction, a non-motor PD symptom, contributes to the lower vitamin D2 levels in PD patients.
Friedman, Joseph H
Most of the neurobehavioral aspects of Parkinson's disease have been well established and studied, but many are not well known, and hardly studied. This article focuses on several behavioral abnormalities that are common, and frequently cause difficulty for the patient and family due to lack of recognition as part of the disease. While it is well known that L-Dopa dyskinesias are frequently not recognized or under appreciated by patients, a similar lack of recognition may affect the patient's own speech volume, where their center of gravity is located, whether they are tilted to one side, and their under-recognition of others' emotional displays. In addition, PD patients are often misperceived by others incorrect impression of their emotional and cognitive state based purely on facial expression. These changes and others are briefly reviewed.
Csoti, Ilona; Jost, Wolfgang H; Reichmann, Heinz
General medical problems and complications have a major impact on the quality of life in all stages of Parkinson's disease. To introduce an effective treatment, a comprehensive analysis of the various clinical symptoms must be undertaken. One must distinguish between (1) diseases which arise independently of Parkinson's disease, and (2) diseases which are a direct or indirect consequence of Parkinson's disease. Medical comorbidity may induce additional limitations to physical strength and coping strategies, and may thus restrict the efficacy of the physical therapy which is essential for treating hypokinetic-rigid symptoms. In selecting the appropriate medication for the treatment of any additional medical symptoms, which may arise, its limitations, contraindications and interactions with dopaminergic substances have to be taken into consideration. General medical symptoms and organ manifestations may also arise as a direct consequence of the autonomic dysfunction associated with Parkinson's disease. As the disease progresses, additional non-parkinsonian symptoms can be of concern. Furthermore, the side effects of Parkinson medications may necessitate the involvement of other medical specialists. In this review, we will discuss the various general medical aspects of Parkinson's disease.
Carriere, Nicolas; Besson, Pierre; Dujardin, Kathy; Duhamel, Alain; Defebvre, Luc; Delmaire, Christine; Devos, David
Apathy is characterized by lack of interest, loss of initiative, and flattening of affect. It is a frequent, very disabling nonmotor complication of Parkinson's disease (PD). The condition may notably occur when dopaminergic medications are tapered after the initiation of subthalamic stimulation and thus can be referred to as "dopaminergic apathy." Even in the absence of tapering, some patients may develop a form of apathy as PD progresses. This form is often related to cognitive decline and does not respond to dopaminergic medications (dopa-resistant apathy). We aimed at determining whether dopa-resistant apathy in PD is related to striatofrontal morphological changes. We compared the shape of the striatum (using spherical harmonic parameterization and sampling in a three-dimensional point distribution model [SPHARM-PDM]), cortical thickness, and fractional anisotropy (using tract-based spatial statistics) in 10 consecutive patients with dopamine-refractory apathy, 10 matched nonapathetic PD patients and 10 healthy controls. Apathy in PD was associated with atrophy of the left nucleus accumbens. The SPHARM-PDM analysis highlighted (1) a positive correlation between the severity of apathy and atrophy of the left nucleus accumbens, (2) greater atrophy of the dorsolateral head of the left caudate in apathetic patients than in nonapathetic patients, and (3) greater atrophy in the bilateral nucleus accumbens in apathetic patients than in controls. There were no significant intergroup differences in cortical thickness or fractional anisotropy. Dopa-resistant apathy in PD was associated with atrophy of the left nucleus accumbens and the dorsolateral head of the left caudate.
Aarts, Esther; Helmich, Rick C; Janssen, Marcel J R; Oyen, Wim J G; Bloem, Bastiaan R; Cools, Roshan
Dopamine has been implicated in reward-related impulsivity, but the exact relationship between dopamine, reward and impulsivity in humans remains unknown. We address this question in Parkinson's disease (PD), which is characterized by severe dopamine depletion. PD is associated primarily with motor and cognitive inflexibility, but can also be accompanied by reward-related impulsivity. This paradoxical symptom of PD has often been attributed to dopaminergic overstimulation by antiparkinson medication, which is necessary to relieve the motor and cognitive inflexibility. However, factors other than medication may also contribute to aberrant impact of reward. Here we assess whether cognitive inflexibility and aberrant reward impact in PD are two sides of the same coin, namely dopamine cell loss. To measure dopamine cell loss, we employed (123)I-FP-CIT Single Photon Emission Computed Tomography (SPECT) in 32 PD patients (10 never-medicated patients and 22 patients after withdrawal of all medication for >12h) and related the values to behavior on a rewarded task-switching paradigm. Dopamine cell loss was associated not only with cognitive inflexibility (under low reward), but also with aberrant impact of reward. These effects could not be attributed to medication use. Relative to controls (n=26), aberrant reward processing in PD was particularly expressed as reduced capacity to maintain (i.e., repeat) the current task-set under high reward. Our findings demonstrate that factors intrinsically related to PD may underlie the paradoxical symptoms of inflexibility and reward-related impulsivity in PD. The present results concur with observations that low baseline dopamine states predispose to drug and other addictions.
Han, Xun; Xue, Li; Li, Yongsheng; Chen, Biao; Xie, Anmu
Vitamin D plays an important role in neurodegenerative disorders as a crucial neuro-immunomodulator, and accumulating data have provided evidence for that vitamin D receptor (VDR) gene is a candidate gene for susceptibility to Parkinson's disease (PD). In this study, we performed a case-control study to demonstrate whether the risk for the development of onset of sporadic PD might be influenced by VDR gene polymorphisms in a Chinese cohort. Two hundred and sixty PD patients and 282 matched-healthy controls were genotyped for two representative single nucleotide polymorphisms (SNPs) in VDR gene (FokI C/T and BsmI G/A) by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) analysis in. Results from our study revealed that FokI C allele carriers were likely to associate with an increased risk of PD (P=0.004) as well as early-onset PD (EOPD) (P=0.010). Moreover, the frequency of FokI C allele was significantly increased in PD group and late-onset PD (LOPD) group relative to the control groups respectively (P=0.023 and P=0.033, respectively). For BsmI polymorphisms, no significant difference in genotype or allele distribution was found between PD patients and the controls, as well as gender- and age-related differences between PD patients and the controls subgroup. This study demonstrated a possible association between the VDR FokI T/C polymorphism and PD, indicating that VDR polymorphisms may well change genetic susceptibility to sporadic PD in a Han Chinese population.
Bertrand, Josie-Anne; McIntosh, Anthony R; Postuma, Ronald B; Kovacevic, Natasha; Latreille, Véronique; Panisset, Michel; Chouinard, Sylvain; Gagnon, Jean-François
Dementia affects a high proportion of Parkinson's disease (PD) patients and poses a burden on caregivers and healthcare services. Electroencephalography (EEG) is a common nonevasive and nonexpensive technique that can easily be used in clinical settings to identify brain functional abnormalities. Only few studies had identified EEG abnormalities that can predict PD patients at higher risk for dementia. Brain connectivity EEG measures, such as multiscale entropy (MSE) and phase-locking value (PLV) analyses, may be more informative and sensitive to brain alterations leading to dementia than previously used methods. This study followed 62 dementia-free PD patients for a mean of 3.4 years to identify cerebral alterations that are associated with dementia. Baseline resting state EEG of patients who developed dementia (N = 18) was compared to those of patients who remained dementia-free (N = 44) and of 37 healthy subjects. MSE and PLV analyses were performed. Partial least squares statistical analysis revealed group differences associated with the development of dementia. Patients who developed dementia showed higher signal complexity and lower PLVs in low frequencies (mainly in delta frequency) than patients who remained dementia-free and controls. Conversely, both patient groups showed lower signal variability and higher PLVs in high frequencies (mainly in gamma frequency) compared to controls, with the strongest effect in patients who developed dementia. These findings suggest that specific disruptions of brain communication can be measured before PD patients develop dementia, providing a new potential marker to identify patients at highest risk of developing dementia and who are the best candidates for neuroprotective trials.
Parkinson's disease (PD) is a progressive neurodegenerative disease primarily characterized by the hallmarks of motor symptoms, such as tremor, bradykinesia, rigidity, and postural instability. However, through clinical investigations in patients and experimental findings in animal models of Parkinson's disease for years, it is now well recognized that Parkinson's disease is more than just a motor-deficit disorder. The majority of Parkinson's disease patients suffer from nonmotor disabilities, for instance, cognitive impairment, autonomic dysfunction, sensory dysfunction, and sleep disorder. So far, anti-PD prescriptions and surgical treatments have been mainly focusing on motor dysfunctions, leaving cognitive impairment a marginal clinical field. Within the nonmotor symptoms, cognitive impairment is one of the most common and significant aspects of Parkinson's disease, and cognitive deficits such as dysexecutive syndrome and visuospatial disturbances could seriously affect the quality of life, reduce life expectancy, prolong the duration of hospitalization, and therefore increase burdens of caregiver and medical costs. In this review, we have done a retrospective study of the recent related researches on epidemiology, clinical manifestation and diagnosis, genetics, and potential treatment of cognitive deficits in Parkinson's disease, aiming to provide a summary of cognitive impairment in Parkinson's disease and make it easy for clinicians to tackle this challenging issue in their future practice. PMID:28058128
Yang, Yang; Tang, Bei-Sha; Guo, Ji-Feng
Parkinson's disease (PD) is a progressive neurodegenerative disease primarily characterized by the hallmarks of motor symptoms, such as tremor, bradykinesia, rigidity, and postural instability. However, through clinical investigations in patients and experimental findings in animal models of Parkinson's disease for years, it is now well recognized that Parkinson's disease is more than just a motor-deficit disorder. The majority of Parkinson's disease patients suffer from nonmotor disabilities, for instance, cognitive impairment, autonomic dysfunction, sensory dysfunction, and sleep disorder. So far, anti-PD prescriptions and surgical treatments have been mainly focusing on motor dysfunctions, leaving cognitive impairment a marginal clinical field. Within the nonmotor symptoms, cognitive impairment is one of the most common and significant aspects of Parkinson's disease, and cognitive deficits such as dysexecutive syndrome and visuospatial disturbances could seriously affect the quality of life, reduce life expectancy, prolong the duration of hospitalization, and therefore increase burdens of caregiver and medical costs. In this review, we have done a retrospective study of the recent related researches on epidemiology, clinical manifestation and diagnosis, genetics, and potential treatment of cognitive deficits in Parkinson's disease, aiming to provide a summary of cognitive impairment in Parkinson's disease and make it easy for clinicians to tackle this challenging issue in their future practice.
Gao, Xiang; Chen, Honglei; Schwarzschild, Michael A; Glasser, Dale B; Logroscino, Giancarlo; Rimm, Eric B; Ascherio, Alberto
Erectile dysfunction is common among individuals with Parkinson's disease, but it is unknown whether it precedes the onset of the classic features of Parkinson's disease. To address this question, the authors examined whether erectile dysfunction was associated with Parkinson's disease risk in the Health Professionals Follow-up Study. Analyses included 32,616 men free of Parkinson's disease at baseline in 1986 who in 2000 completed a retrospective questionnaire with questions on erectile dysfunction in different time periods. Relative risks were computed using Cox proportional hazards models adjusting for age, smoking, caffeine intake, history of diabetes, and other covariates. Among men who reported their erectile function before 1986, 200 were diagnosed with Parkinson's disease during 1986-2002. Men with erectile dysfunction before 1986 were 3.8 times more likely to develop Parkinson's disease during the follow-up than were those with very good erectile function (relative risk = 3.8, 95% confidence interval: 2.4, 6.0; p < 0.0001). Multivariate-adjusted relative risks of Parkinson's disease were 2.7, 3.7, and 4.0 (95% confidence interval: 1.4, 11.1; p = 0.008) for participants with first onset of erectile dysfunction (before 1986) at 60 or more, 50-59, and less than 50 years of age, respectively, relative to those without erectile dysfunction. In conclusion, in this retrospective analysis in a large cohort of men, the authors observed that erectile dysfunction was associated with a higher risk of developing Parkinson's disease.
van der Holst, Helena M.; van Uden, Inge W.M.; Tuladhar, Anil M.; de Laat, Karlijn F.; van Norden, Anouk G.W.; Norris, David G.; van Dijk, Ewoud J.; Esselink, Rianne A.J.; Platel, Bram
Objective: To investigate the relation between baseline cerebral small vessel disease (SVD) and the risk of incident parkinsonism using different MRI and diffusion tensor imaging (DTI) measures. Methods: In the Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Cohort (RUN DMC) study, a prospective cohort study, 503 elderly participants with SVD and without parkinsonism were included in 2006. During follow-up (2011–2012), parkinsonism was diagnosed according to UK Brain Bank criteria. Cox regression analysis was used to investigate the association between baseline imaging measures and incident all-cause parkinsonism and vascular parkinsonism (VP). Tract-based spatial statistics analysis was used to identify differences in baseline DTI measures of white matter (WM) tracts between participants with VP and without parkinsonism. Results: Follow-up was available from 501 participants (mean age 65.6 years; mean follow-up duration 5.2 years). Parkinsonism developed in 20 participants; 15 were diagnosed with VP. The 5-year risk of (any) parkinsonism was increased for those with a high white matter hyperintensity (WMH) volume (hazard ratio [HR] 1.8 per SD increase, 95% confidence interval [CI] 1.3–2.4) and a high number of lacunes (HR 1.4 per number increase, 95% CI 1.1–1.8) at baseline. For VP, this risk was also increased by the presence of microbleeds (HR 5.7, 95% CI 1.9–16.8) and a low gray matter volume (HR 0.4 per SD increase, 95% CI 0.2–0.8). Lower fractional anisotropy values in bifrontal WM tracts involved in movement control were observed in participants with VP compared to participants without parkinsonism. Conclusions: SVD at baseline, especially a high WMH volume and a high number of lacunes, is associated with incident parkinsonism. Our findings favor a role of SVD in the etiology of parkinsonism. PMID:26446068
Rieu, I; Boirie, Y; Morio, B; Derost, P; Ulla, M; Marques, A; Debilly, B; Bannier, S; Durif, F
Parkinson's disease is a neurodegenerative disorder clinically characterized by motor impairments (tremor, bradykinesia, rigidity and postural instability) associated or not with non-motor complications (cognitive disorders, dysautonomia). Most of patients loose weight during evolution of their disease. Dysregulations of hypothalamus, which is considered as the regulatory center of satiety and energy metabolism, could play a major role in this phenomenon. Deep brain stimulation of the subthalamic nucleus (NST) is an effective method to treat patients with advanced Parkinson's disease providing marked improvement of motor impairments. This chirurgical procedure also induces a rapid and strong body weight gain and sometimes obesity. This post-operative weight gain, which exceeds largely weight lost recorded in non-operated patient, could be responsible of metabolic disorders (such as diabetes) and cardiovascular diseases. This review describes body weight variations generated by Parkinson' disease and deep brain stimulation of the NST, and focuses on metabolic disorders capable to explain them. Finally, this review emphasizes on the importance of an adequate nutritional follow up care for parkinsonian patient.
Aarts, Esther; Nusselein, Abraham A M; Smittenaar, Peter; Helmich, Rick C; Bloem, Bastiaan R; Cools, Roshan
Dopaminergic medication in Parkinson's disease has been proposed to improve cognitive processing by modulating the severely depleted dorsal striatum, while impairing reward processing by modulating the relatively intact ventral striatum. However, there is no direct (neural) evidence for this hypothesis. Here we fill this gap by scanning Parkinson's disease patients (n=15) ON and relatively OFF their dopaminergic medication using functional magnetic resonance imaging. During scanning, patients performed a task that enabled the simultaneous measurement of task-switching and reward-related processing. Brain-behavior correlations revealed that medication-related increases (ON-OFF) in switch-related BOLD signal (switch-repeat) in the dorsomedial striatum were associated, on an individual basis, with improvements in task-switching (i.e. a decreased switch cost). Conversely, medication-related increases (ON-OFF) in reward-related BOLD signal (high-low) in the ventromedial striatum were associated, on an individual basis, with impairments in performance in anticipation of reward (i.e. an increased reward cost). Linear regression analyses demonstrated that the positive relationship between medication-related changes in BOLD and the reward cost was unique to the ventromedial striatum, whereas the negative relationship between medication-related changes in BOLD and the switch cost was not unique to the dorsomedial striatum. These findings extend the dopamine overdose hypothesis, according to which dopamine-induced changes in dorsal and ventral striatal processing lead to cognitive improvement and impairment respectively.
Falkenburger, Björn H; Saridaki, Theodora; Dinter, Elisabeth
Developing new therapeutic strategies for Parkinson's disease requires cellular models. Current models reproduce the two most salient changes found in the brains of patients with Parkinson's disease: The degeneration of dopaminergic neurons and the existence of protein aggregates consisting mainly of α-synuclein. Cultured cells offer many advantages over studying Parkinson's disease directly in patients or in animal models. At the same time, the choice of a specific cellular model entails the requirement to focus on one aspect of the disease while ignoring others. This article is intended for researchers planning to use cellular models for their studies. It describes for commonly used cell types the aspects of Parkinson's disease they model along with technical advantages and disadvantages. It might also be helpful for researchers from other fields consulting literature on cellular models of Parkinson's disease. Important models for the study of dopaminergic neuron degeneration include Lund human mesencephalic cells and primary neurons, and a case is made for the use of non-dopaminergic cells to model pathogenesis of non-motor symptoms of Parkinson's disease. With regard to α-synuclein aggregates, this article describes strategies to induce and measure aggregates with a focus on fluorescent techniques. Cellular models reproduce the two most salient changes of Parkinson's disease, the degeneration of dopaminergic neurons and the existence of α-synuclein aggregates. This article is intended for researchers planning to use cellular models for their studies. It describes for commonly used cell types and treatments the aspects of Parkinson's disease they model along with technical advantages and disadvantages. Furthermore, this article describes strategies to induce and measure aggregates with a focus on fluorescent techniques. This article is part of a special issue on Parkinson disease.
Ricciardi, Lucia; De Nigris, Francesca; Specchia, Alessandro; Fasano, Alfonso
Homotaurine is a natural compound of red algae, which has been demonstrated to have a neuroprotective effect and has been evaluated as a possible therapeutic agent for Alzheimer's disease. This was a single blind, randomized, controlled study to evaluate the safety and efficacy of homotaurine in patients with Parkinson's disease (PD) and cognitive impairment. Patients were evaluated at baseline and 6 months later. Assessments included, the evaluation of: motor and non-motor conditions and complications (Unified Parkinson's Disease Rating Scale, UPDRS); disability and quality of life; depression; excessive daytime sleepiness and fatigue. An extensive neuropsychological tests battery was administered evaluating specific cognitive domains: memory, phonemic verbal fluency, executive functions and selective visual attention. After baseline testing, patients were allocated to one of the two groups: (A) treatment group: patients treated with homotaurine 100 mg; (B) control group: patients not treated with homotaurine. Forty-seven patients were evaluated at baseline, 24 (51 %) completed the study (PD-homotaurine: n = 11; 44 % and PD-controls: n = 13; 59 %); discontinuation rate was similar across subjects (p = 1.0). Intention to treat analyses to evaluate homotaurine safety showed mild side effects (gastrointestinal upsetting) in 3 patients. Per protocol analyses of homotaurine efficacy showed no difference between groups. Within group analyses showed that PD-homotaurine patients had better score at UPDRS-I at the end of the study compared to baseline (p = 0.017) and at Epworth Sleepiness Scale (p = 0.01). No other differences were found. No significant difference arose for the PD-ctrl group. Homotaurine is a safe drug. Our data suggest a beneficial effect of homotaurine on excessive sleepiness. Future studies are encouraged to confirm this promising role of homotaurine in promoting the sleep/awake cycle in patients with PD.
Delaville, Claire; Deurwaerdère, Philippe De; Benazzouz, Abdelhamid
Parkinson's disease (PD) is characterized by the degeneration of dopamine (DA) neurons in the substantia nigra pars compacta, and motor symptoms including bradykinesia, rigidity, and tremor at rest. These symptoms are exhibited when striatal dopamine concentration has decreased by around 70%. In addition to motor deficits, PD is also characterized by the non-motor symptoms. However, depletion of DA alone in animal models has failed to simultaneously elicit both the motor and non-motor deficits of PD, possibly because the disease is a multi-system disorder that features a profound loss in other neurotransmitter systems. There is growing evidence that additional loss of noradrenaline (NA) neurons of the locus coeruleus, the principal source of NA in the brain, could be involved in the clinical expression of motor as well as in non-motor deficits. In the present review, we analyze the latest evidence for the implication of NA in the pathophysiology of PD obtained from animal models of parkinsonism and from parkinsonian patients. Recent studies have shown that NA depletion alone, or combined with DA depletion, results in motor as well as in non-motor dysfunctions. In addition, by using selective agonists and antagonists of noradrenaline alpha receptors we, and others, have shown that α2 receptors are implicated in the control of motor activity and that α2 receptor antagonists can improve PD motor symptoms as well as l-Dopa-induced dyskinesia. In this review we argue that the loss of NA neurons in PD has an impact on all PD symptoms and that the addition of NAergic agents to dopaminergic medication could be beneficial in the treatment of the disease. PMID:21647359
Mo, Ming-Shu; Huang, Wei; Sun, Cong-Cong; Zhang, Li-Min; Cen, Luan; Xiao, You-Sheng; Li, Guo-Fei; Yang, Xin-Ling; Qu, Shao-Gang; Xu, Ping-Yi
Background: Proteasome subunits (PSMB) and transporter associated with antigen processing (TAP) loci are located in the human leukocyte antigen (HLA) Class II region play important roles in immune response and protein degradation in neurodegenerative diseases. This study aimed to explore the association between single nucleotide polymorphisms (SNPs) of PSMB and TAP and Parkinson's disease (PD). Methods: A case–control study was conducted by genotyping SNPs in PSMB8, PSMB9, TAP1, and TAP2 genes in the Chinese population. Subjects included 542 sporadic patients with PD and 674 healthy controls. Nine identified SNPs in PSMB8, PSMB9, TAP1, and TAP2 were genotyped through SNaPshot testing. Results: The stratified analysis of rs17587 was specially performed on gender. Data revealed that female patients carry a higher frequency of rs17587-G/G versus (A/A + G/A) compared with controls. But there was no significant difference with respect to the genotypic frequencies of the SNPs in PSMB8, TAP1, and TAP2 loci in PD patients. Conclusion: Chinese females carrying the rs17587-G/G genotype in PSMB9 may increase a higher risk for PD, but no linkage was found between other SNPs in HLA Class II region and PD. PMID:27098790
Magnard, R; Vachez, Y; Carcenac, C; Krack, P; David, O; Savasta, M; Boulet, S; Carnicella, S
In addition to classical motor symptoms, Parkinson's disease (PD) patients display incapacitating neuropsychiatric manifestations, such as apathy, anhedonia, depression and anxiety. These hitherto generally neglected non-motor symptoms, have gained increasing interest in medical and scientific communities over the last decade because of the extent of their negative impact on PD patients' quality of life. Although recent clinical and functional imaging studies have provided useful information, the pathophysiology of apathy and associated affective impairments remains elusive. Our aim in this review is to summarize and discuss recent advances in the development of rodent models of PD-related neuropsychiatric symptoms using neurotoxin lesion-based approaches. The data collected suggest that bilateral and partial lesions of the nigrostriatal system aimed at inducing reliable neuropsychiatric-like deficits while avoiding severe motor impairments that may interfere with behavioral evaluation, is a more selective and efficient strategy than medial forebrain bundle lesions. Moreover, of all the different classes of pharmacological agents, D2/D3 receptor agonists such as pramipexole appear to be the most efficient treatment for the wide range of behavioral deficits induced by dopaminergic lesions. Lesion-based rodent models, therefore, appear to be relevant tools for studying the pathophysiology of the non-motor symptoms of PD. Data accumulated so far confirm the causative role of dopaminergic depletion, especially in the nigrostriatal system, in the development of behavioral impairments related to apathy, depression and anxiety. They also put forward D2/D3 receptors as potential targets for the treatment of such neuropsychiatric symptoms in PD. PMID:26954980
Uncini, Antonino; Eleopra, Roberto; Onofrj, Marco
Patients with Parkinson's disease (PD) treated with oral levodopa have a higher prevalence of chronic, prevalently sensory, usually mild axonal polyneuropathy (PNP). Several studies showed a positive association among PNP, cumulative levodopa dosage, low serum B12 and high-homocysteine and methylmalonic acid level. Anecdotal severe acute or subacute PNPs thought to be Guillain-Barré syndrome have been reported in patients receiving continuous intraduodenal infusion of levodopa/carbidopa intestinal gel (LCIG). We report an additional acute case and by a systematic literature search we also reviewed the clinical and laboratory features of 13 other acute and 21 subacute PNP cases occurring during LCIG treatment. In series with at least nine patients, the mean frequency of acute and subacute PNP is 13.6% and the mortality rate at 6 months in acute cases is 14%. The great majority of PNP cases displayed axonal sensory-motor and reduced vitamin B12 levels, and alterations of metabolites of 1-carbon pathway were found in most patients. We discuss the possible role of high-levodopa dosage, vitamin B12, B6 and folate deficiency and accumulation of homocysteine and methylmalonic acid in the pathogenesis to conclude that there is enough, although circumstantial, evidence that alterations of 1-carbon pathway are implicated also in acute and subacute PNP during LCIG usage. There is no solid proof for a dysimmune pathogenesis and in our opinion acute, subacute and chronic PNP, either after oral levodopa or LCIG, represent a continuum. Finally, we propose recommendations for prevention and management of PNP occurring during LCIG treatment.
Among the 41 soil elements analyzed from 4856 sites across the contiguous 48 states, average Parkinson's disease (PD) mortality rates between 1999 and 2014 have the most significant positive correlation with the average soil strontium (Sr) concentrations (correlation r = 0.47, significance level p = 0.00), and average PD mortality rates have the most significant inverse correlation with the average soil selenium (Se) concentrations (r = -0.44, p = 0.00). Multivariate regression models indicate that soil Sr and Se concentrations can explain 35.4% of spatial disparities of the state average PD mortality rates between 1999 and 2014 (R (2) = 0.354). When the five outlier states were removed from the model, concentrations of soil Sr and Se can explain 62.4% (R (2) = 0.624) of the spatial disparities of PD mortality rates of the 43 remaining states. The results also indicate that high soil magnesium (Mg) concentrations suppressed the growth rate of the PD mortality rates between 1999 and 2014 in the 48 states (r = -0.42, p = 0.000). While both Se and Sr have been reported to affect the nervous system, this study is the first study that reported the statistically significant association between the PD mortality rates and soil concentrations of Se, Sr, and Mg in the 48 states. Given that soil elemental concentration in a region is broad indicator of the trace element intake from food, water, and air by people, implications of the results are that high soil Se and Mg concentrations helped reduce the PD mortality rates and benefited the PD patients in the 48 states.
Bovolenta, Tânia M.; de Azevedo Silva, Sônia Maria Cesar; Arb Saba, Roberta; Ferraz, Henrique Ballalai
Parkinson's disease (PD) is the second most prevalent neurodegenerative disease worldwide, affecting more than four million people. Typically, it affects individuals above 45, when they are still productive, compromising both aging and quality of life. Therefore, the cost of the disease must be identified, so that the use of resources can be rational and efficient. Additionally, in Brazil, there is a lack of research on the costs of neurodegenerative diseases, such as PD, a gap addressed in this study. This systematic review critically addresses the various methodologies used in original research around the world in the last decade on the subject, showing that costs are hardly comparable. Nonetheless, the economic and social impacts are implicit, and important information for public health agents is provided. PMID:28357150
Varçin, Mustafa; Bentea, Eduard; Michotte, Yvette; Sarre, Sophie
There is extensive evidence in Parkinson's disease of a link between oxidative stress and some of the monogenically inherited Parkinson's disease-associated genes. This paper focuses on the importance of this link and potential impact on neuronal function. Basic mechanisms of oxidative stress, the cellular antioxidant machinery, and the main sources of cellular oxidative stress are reviewed. Moreover, attention is given to the complex interaction between oxidative stress and other prominent pathogenic pathways in Parkinson's disease, such as mitochondrial dysfunction and neuroinflammation. Furthermore, an overview of the existing genetic mouse models of Parkinson's disease is given and the evidence of oxidative stress in these models highlighted. Taken into consideration the importance of ageing and environmental factors as a risk for developing Parkinson's disease, gene-environment interactions in genetically engineered mouse models of Parkinson's disease are also discussed, highlighting the role of oxidative damage in the interplay between genetic makeup, environmental stress, and ageing in Parkinson's disease. PMID:22829959
Poletti, Michele; Logi, Chiara; Lucetti, Claudio; Del Dotto, Paolo; Baldacci, Filippo; Vergallo, Andrea; Ulivi, Martina; Del Sarto, Simone; Rossi, Giuseppe; Ceravolo, Roberto; Bonuccelli, Ubaldo
The current study aimed at establishing the prevalence of impulse control disorders (ICDs) in patients with Parkinson disease (PD) and their association with demographic, drug-related, and disease-related characteristics. We performed a single-center cross-sectional study of 805 PD patients. Impulse control disorders were investigated with the Questionnaire for Impulsive Compulsive Disorders in Parkinson's Disease; also comorbid neuropsychiatric complications (dementia, delusions, visual hallucinations) were investigated with clinical interviews and ad hoc instruments (Parkinson Psychosis Questionnaire and Neuropsychiatry Inventory). Impulse control disorders were identified in 65 patients (prevalence, 8.1%), with pathological gambling and hypersexuality the most frequent. Impulse control disorders were present in 57 of 593 cognitively preserved patients (prevalence, 9.6%) and in 8 of 212 demented patients (prevalence, 3.8%). Impulse control disorders were significantly associated with dopamine agonists (odds ratio [OR], 5.50; 95% confidence interval [CI], 2.60-12.46; P < 0.0001) and levodopa (OR, 2.43; 95% CI, 1.06-6.35; P = 0.034). Impulse control disorders frequency was similar for pramipexole and ropinirole (16.6% vs 12.5%; OR, 1.45; 95% CI, 0.79-2.74; P = 0.227). Additional variables associated with ICDs were male sex and younger age. These findings suggested that dopaminergic treatments in PD are associated with increased odds of having an ICD, but also other demographic and clinical variables are associated with ICDs, suggesting the multifactorial nature of the ICD phenomenon in PD.
This article reports on a meta-analysis of 13 studies of the effects of Argentine tango (AT) as a music-based movement therapy for people with Parkinson's disease (PD). Nine studies involved randomised controlled trials.
Evarts, E V; Teräväinen, H; Calne, D B
Both reaction time and movement time tend to be prolonged in Parkinson's disease, but they are often impaired independently of each other. Prolongation of RT is relatively slight, while MT undergoes more substantial and consistent disturbance. Choice RT and kinaesthetic RT do not have any advantage over simple visual RT as measurements of neurological deficit in parkinsonism, since they are all impaired to the same extent. MT is more useful than RT as an objective indicator of therapeutic efficacy, but further studies of RT (with tests requiring programming of displacement, velocity, and accuracy) may provide insights into the nature of the central motor disorder in Parkinson's disease.
The clinical use of biotherapies in Parkinson disease already has 30 years' history. The transplantation of dopamine fetal cells in the striatum of advanced patients has proved to be relevant in some patients but randomized efficacy trials in the US have provided disappointing results. However, cell therapies might come back on stage with the use of stem cells in the future. Gene therapy is a more recent strategy relying on viral vectors able to transduce genes coding either for the enzymes that can increase neurotransmitters production or genes for trophic factors. Several approaches have been developed in PD and have been experimented in patients. Although, some of the studies have evidenced insufficient clinical benefit, other programs, such as those using dopamine replacement techniques are promising. We find fresh hope in this field that might be the future of PD treatment. It remains however that advanced PD might not be the ideal condition to properly benefit from biotherapies and there is a need of studies at earlier stages of the disease, a time where major change in the disease course might be expected.
Earhart, Gammon M; Falvo, Michael J
Parkinson disease (PD) is a progressive, neurodegenerative movement disorder. PD was originally attributed to neuronal loss within the substantia nigra pars compacta, and a concomitant loss of dopamine. PD is now thought to be a multisystem disorder that involves not only the dopaminergic system, but other neurotransmitter systems whose role may become more prominent as the disease progresses (189). PD is characterized by four cardinal symptoms, resting tremor, rigidity, bradykinesia, and postural instability, all of which are motor. However, PD also may include any combination of a myriad of nonmotor symptoms (195). Both motor and nonmotor symptoms may impact the ability of those with PD to participate in exercise and/or impact the effects of that exercise on those with PD. This article provides a comprehensive overview of PD, its symptoms and progression, and current treatments for PD. Among these treatments, exercise is currently at the forefront. People with PD retain the ability to participate in many forms of exercise and generally respond to exercise interventions similarly to age-matched subjects without PD. As such, exercise is currently an area receiving substantial research attention as investigators seek interventions that may modify the progression of the disease, perhaps through neuroprotective mechanisms.
Amboni, M; Stocchi, F; Abbruzzese, G; Morgante, L; Onofrj, M; Ruggieri, S; Tinazzi, M; Zappia, M; Attar, M; Colombo, D; Simoni, L; Ori, A; Barone, P; Antonini, A
Freezing of Gait (FOG) is a common and disabling symptom in patients with Parkinson disease (PD). The relationship between FOG and dopaminergic medication is complex. The aim of the present study was to estimate the prevalence of self-reported FOG, its associated clinical features, and its relationship with wearing-off in a wide PD population. This is an observational multicenter study of 634 consecutive non-demented PD patients. Patients were identified either as freezers or non-freezers based on item-3 of the Freezing of Gait-Questionnaire. FOG was then classified as on, off and onoff freezing based on its relationship with wearing-off. Patients were assessed with Unified Parkinson's Disease Rating Scale, Hoehn and Yahr scale, 8-item Parkinson's disease Questionnaire, Mini-Mental State Examination. Data from 593 patients were analyzed, 325 (54.3%) were freezers of whom 200 (61.6%) experienced FOG only during off state (off-freezers), 6 (1.8%) only during on state and 119 (36.6%) either in on and off states or independently of dopaminergic response-related symptoms (onoff-freezers). Overall, freezers vs non-freezers had longer disease duration, more advanced disease and greater disability. Moreover, freezers more frequently reported wearing-off and experienced worse quality of life. Onoff-freezers vs off-freezers were older, more severely disabled, less likely to experience wearing-off, treated with lower levodopa equivalent daily dose and with poorer cognitive performance. Self-reported FOG is mainly recognizable in advanced PD and is associated with more disability and worse quality of life. Onoff-FOG may represent the result of under-treatment or rather interpretable as a distinct clinical entity.
Ferrari, Carina C; Tarelli, Rodolfo
Peripheral inflammation triggers exacerbation in the central brain's ongoing damage in several neurodegenerative diseases. Systemic inflammatory stimulus induce a general response known as sickness behaviour, indicating that a peripheral stimulus can induce the synthesis of cytokines in the brain. In Parkinson's disease (PD), inflammation was mainly associated with microglia activation that can underlie the neurodegeneration of neurons in the substantia nigra (SN). Peripheral inflammation can transform the "primed" microglia into an "active" state, which can trigger stronger responses dealing with neurodegenerative processes. Numerous evidences show that systemic inflammatory processes exacerbate ongoing neurodegeneration in PD patient and animal models. Anti-inflammatory treatment in PD patients exerts a neuroprotective effect. In the present paper, we analyse the effect of peripheral infections in the etiology and progression in PD patients and animal models, suggesting that these peripheral immune challenges can exacerbate the symptoms in the disease.
Ferrari, Carina C.; Tarelli, Rodolfo
Peripheral inflammation triggers exacerbation in the central brain's ongoing damage in several neurodegenerative diseases. Systemic inflammatory stimulus induce a general response known as sickness behaviour, indicating that a peripheral stimulus can induce the synthesis of cytokines in the brain. In Parkinson's disease (PD), inflammation was mainly associated with microglia activation that can underlie the neurodegeneration of neurons in the substantia nigra (SN). Peripheral inflammation can transform the “primed” microglia into an “active” state, which can trigger stronger responses dealing with neurodegenerative processes. Numerous evidences show that systemic inflammatory processes exacerbate ongoing neurodegeneration in PD patient and animal models. Anti-inflammatory treatment in PD patients exerts a neuroprotective effect. In the present paper, we analyse the effect of peripheral infections in the etiology and progression in PD patients and animal models, suggesting that these peripheral immune challenges can exacerbate the symptoms in the disease. PMID:21403862
Henderson, J M; Yiannikas, C; Morris, J G; Einstein, R; Jackson, D; Byth, K
Previous studies have reported the resting tremor (RT) of Parkinson's disease to occur at frequencies between 3-7 Hz and to be characterised by an alternating pattern of electromyographic (EMG) bursting activity between opposing muscles. A postural tremor (PT), of higher frequency (> 6 Hz) and with a synchronous pattern of EMG activity, has also been previously described in Parkinson's disease. We investigated the electrophysiological and pharmacological properties of both the RT and PT of 11 patients with Parkinson's disease and 10 patients with essential tremor in a double-blind, placebo-controlled study of L-Dopa/benserazide and propranolol. Tremor amplitude and frequency were assessed via bidirectional accelerometry, and the pattern of activation of the antagonist muscles of the forearm was determined with use of surface EMG. In the Parkinson's disease group studied, the frequency, EMG pattern of bursts, and response to L-Dopa were similar for the two tremors (median improvement of RT by 70% and PT by 61%). Despite some overlap between the Parkinson's disease and essential tremor groups in the electrophysiology of the tremor, there was no such dramatic pharmacological response in the latter group. These results suggest that the RT and PT of Parkinson's disease share a common pathophysiology and are distinct from essential tremor.
Do, Chuong B.; Tung, Joyce Y.; Dorfman, Elizabeth; Kiefer, Amy K.; Drabant, Emily M.; Francke, Uta; Mountain, Joanna L.; Goldman, Samuel M.; Tanner, Caroline M.; Langston, J. William; Wojcicki, Anne; Eriksson, Nicholas
Although the causes of Parkinson's disease (PD) are thought to be primarily environmental, recent studies suggest that a number of genes influence susceptibility. Using targeted case recruitment and online survey instruments, we conducted the largest case-control genome-wide association study (GWAS) of PD based on a single collection of individuals to date (3,426 cases and 29,624 controls). We discovered two novel, genome-wide significant associations with PD–rs6812193 near SCARB2 (, ) and rs11868035 near SREBF1/RAI1 (, )—both replicated in an independent cohort. We also replicated 20 previously discovered genetic associations (including LRRK2, GBA, SNCA, MAPT, GAK, and the HLA region), providing support for our novel study design. Relying on a recently proposed method based on genome-wide sharing estimates between distantly related individuals, we estimated the heritability of PD to be at least 0.27. Finally, using sparse regression techniques, we constructed predictive models that account for 6%–7% of the total variance in liability and that suggest the presence of true associations just beyond genome-wide significance, as confirmed through both internal and external cross-validation. These results indicate a substantial, but by no means total, contribution of genetics underlying susceptibility to both early-onset and late-onset PD, suggesting that, despite the novel associations discovered here and elsewhere, the majority of the genetic component for Parkinson's disease remains to be discovered. PMID:21738487
Wersinger, Christophe; Sidhu, Anita
Numerous recent findings indicate the possible involvement of an immune mechanism in the pathogenesis of neurodegeneration. The immune reaction could either act as a primary event, generating changes leading to cell death, or could be a secondary response to neuronal injury. In various neurodegenerative disorders such as Alzheimer's, Huntington's or Pick's disease, Down's syndrome, multiple sclerosis and the AIDS-dementia complex, the inflammatory pathomechanism is strongly supported by experimental and clinical studies. Such inflammatory mechanisms have also been postulated in Parkinson's disease (PD). This review summarizes some generalities about inflammation and immune reactions in the context of the brain, and provides clinical, epidemiological and experimental data showing that inflammation and immunity, or even auto-immunity, could be implicated in PD, either in its initial step or in its progression. Different experimental models useful for studying the role(s) of inflammation and (auto)immunity in the neurodegenerative process of the dopaminergic neurons in PD are examined. The major similarities and differences between PD and other neurodegenerative disorders are discussed.
Montes, Sergio; Rivera-Mancia, Susana; Diaz-Ruiz, Araceli; Tristan-Lopez, Luis; Rios, Camilo
Copper is a transition metal that has been linked to pathological and beneficial effects in neurodegenerative diseases. In Parkinson's disease, free copper is related to increased oxidative stress, alpha-synuclein oligomerization, and Lewy body formation. Decreased copper along with increased iron has been found in substantia nigra and caudate nucleus of Parkinson's disease patients. Copper influences iron content in the brain through ferroxidase ceruloplasmin activity; therefore decreased protein-bound copper in brain may enhance iron accumulation and the associated oxidative stress. The function of other copper-binding proteins such as Cu/Zn-SOD and metallothioneins is also beneficial to prevent neurodegeneration. Copper may regulate neurotransmission since it is released after neuronal stimulus and the metal is able to modulate the function of NMDA and GABA A receptors. Some of the proteins involved in copper transport are the transporters CTR1, ATP7A, and ATP7B and the chaperone ATOX1. There is limited information about the role of those biomolecules in the pathophysiology of Parkinson's disease; for instance, it is known that CTR1 is decreased in substantia nigra pars compacta in Parkinson's disease and that a mutation in ATP7B could be associated with Parkinson's disease. Regarding copper-related therapies, copper supplementation can represent a plausible alternative, while copper chelation may even aggravate the pathology.
Rivera-Mancia, Susana; Diaz-Ruiz, Araceli; Tristan-Lopez, Luis; Rios, Camilo
Copper is a transition metal that has been linked to pathological and beneficial effects in neurodegenerative diseases. In Parkinson's disease, free copper is related to increased oxidative stress, alpha-synuclein oligomerization, and Lewy body formation. Decreased copper along with increased iron has been found in substantia nigra and caudate nucleus of Parkinson's disease patients. Copper influences iron content in the brain through ferroxidase ceruloplasmin activity; therefore decreased protein-bound copper in brain may enhance iron accumulation and the associated oxidative stress. The function of other copper-binding proteins such as Cu/Zn-SOD and metallothioneins is also beneficial to prevent neurodegeneration. Copper may regulate neurotransmission since it is released after neuronal stimulus and the metal is able to modulate the function of NMDA and GABA A receptors. Some of the proteins involved in copper transport are the transporters CTR1, ATP7A, and ATP7B and the chaperone ATOX1. There is limited information about the role of those biomolecules in the pathophysiology of Parkinson's disease; for instance, it is known that CTR1 is decreased in substantia nigra pars compacta in Parkinson's disease and that a mutation in ATP7B could be associated with Parkinson's disease. Regarding copper-related therapies, copper supplementation can represent a plausible alternative, while copper chelation may even aggravate the pathology. PMID:24672633
Goetz, Christopher G; Leurgans, Sue; Raman, Rema
The Unified Parkinson's Disease Rating Scale (UPDRS) is primarily composed of an investigator-derived objective rating of motor function and a patient-derived assessment of activities of daily living (ADL). Using a stringent definition of placebo effect, we examined the frequency, temporal development, and stability of improvements during placebo treatment over 6 months in a large placebo-controlled trial of deprenyl and tocopherol in early Parkinson's disease (DATATOP). One hundred ninety-nine subjects received placebo treatment in the randomized, multicenter, placebo-controlled DATATOP study. We compared the baseline UPDRS motor section scores with follow-up scores at 4, 13, and 26 weeks. Placebo-associated improvement was defined as an improvement over baseline score in motor UPDRS of at least 50% or a change in at least two motor items at any one visit by two or more points. Seventeen percent of the 185 subjects who qualified for analysis met the placebo response criteria. The group prevalence of response was steady (7% to 10%) at any one visit without a marked predominance of an early study effect. Older subjects with more motor impairment at baseline were most likely to show a placebo-associated improvement. ADL scores were low throughout the study, and ADL improvements did not identify the subjects with objectively defined placebo-associated improvement. Prominent improvements in investigator-derived objective measures of Parkinson's disease motor impairment occur during clinical trials, including one that was not aimed at showing improved short-term efficacy. Although the notion of placebo effect often implies patient-based perceptions, we found subjective changes to be infrequent in placebo-treated patients, suggesting that either: (1) the placebo effect was rater-driven; (2) the ADL questionnaire is insensitive to transient but objectively demonstrable motor changes; or (3) that the objective changes, albeit major, are within the realm of natural
Liu, Guiyou; Bao, Xinjie; Jiang, Yongshuai; Liao, Mingzhi; Jiang, Qinghua; Feng, Rennan; Zhang, Liangcai; Ma, Guoda; Chen, Zugen; Wang, Guangyu; Wang, Renzhi; Zhao, Bin; Li, Keshen
Alzheimer's disease (AD) and Parkinson's disease (PD) are the first and second most common neurodegenerative diseases in the elderly. Shared clinical and pathological features have been reported. Recent large-scale genome-wide association studies (GWAS) have been conducted and reported a number of AD and PD variants. Until now, the underlying genetic mechanisms for all these newly identified PD variants as well as the association between AD and PD are still unclear exactly. We think that PD variants may contribute to AD and PD by influence on brain gene expression. Here, we conducted a systems analysis using (1) AD and PD variants (P < 5.00E-08) identified by the published GWAS; (2) four brain expression GWAS datasets using expression quantitative trait loci from the cerebellum and temporal cortex; (3) large-scale AD GWAS from the Alzheimer Disease Genetics Consortium (ADGC); (4) a protein-protein interaction network. Our results indicated that PD variants around the 17q21 were associated with gene expression and suggestive AD risk. We also identified significant interaction among AD and PD susceptibility genes. We believe that our findings may explain the underlying genetic mechanisms for newly identified PD variants in PD and AD, as well as the association between AD and PD, which may be very useful for future genetic studies for both diseases.
Goetz, Christopher G; Laska, Eugene; Hicking, Christine; Damier, Philippe; Müller, Thomas; Nutt, John; Warren Olanow, C; Rascol, Olivier; Russ, Hermann
Clinical features that are prognostic indicators of placebo response among dyskinetic Parkinson's disease patients were determined. Placebo-associated improvements occur in Parkinsonism, but responses in dyskinesia have not been studied. Placebo data from two multicenter studies with identical design comparing sarizotan to placebo for treating dyskinesia were accessed. Sarizotan (2 mg/day) failed to improve dyskinesia compared with placebo, but both treatments improved dyskinesia compared with baseline. Stepwise regression identified baseline characteristics that influenced dyskinesia response to placebo, and these factors were entered into a logistic regression model to quantify their influence on placebo-related dyskinesia improvements and worsening. Because placebo-associated improvements in Parkinsonism have been attributed to heightened dopaminergic activity, we also examined the association between changes in Parkinsonism and dyskinesia. Four hundred eighty-four subjects received placebo treatment; 178 met criteria for placebo-associated dyskinesia improvement and 37 for dyskinesia worsening. Older age, lower baseline Parkinsonism score, and lower total daily levodopa doses were associated with placebo-associated improvement, whereas lower baseline dyskinesia score was associated with placebo-associated worsening. Placebo-associated dyskinesia changes were not correlated with Parkinsonism changes, and all effects in the sarizotan group were statistically explained by the placebo-effect regression model. Dyskinesias are affected by placebo treatment. The absence of correlation between placebo-induced changes in dyskinesia and Parkinsonism argues against a dopaminergic activation mechanism to explain placebo-associated improvements in dyskinesia. The magnitude and variance of placebo-related changes and the factors that influence them can be helpful in the design of future clinical trials of antidyskinetic agents.
Watt, F.; Lee, T.; Thong, P. S. P.; Tang, S. M.
Rats have been subjected to unilateral lesioning with the selective neurotoxin 6-OHDA in order to induce Parkinsonism. Analysis using the NUS Nuclear Microscope facility have shown that iron levels are raised by an average of 26% in the lesioned subtantia nigra region of the brain compared with the non-lesioned side. In addition the background tissue level of iron is also elevated by 31% in the lesioned side, indicating that there is a general increase in iron levels as a result of the lesioning. This result is consistent with the other observations that other diseases of the brain are frequently associated with altered iron levels (eg. progressive nuclear palsy, multiple system atrophy, Alzheimers disease, multiple sclerosis).
Jiang, Si-Ming; Yuan, Yong-Sheng; Tong, Qing; Zhang, Li; Xu, Qin-Rong; Ding, Jian; Zhang, Ke-Zhong
Anxiety disorders in patients with Parkinson's disease (PD) are often missed due to an overlap with other non-motor symptoms. The relationships between anxiety and other non-motor symptoms in PD still remain unclear. We used the Hamilton anxiety rating scale and the Non-motor Symptoms Questionnaire to measure anxiety and the complex range of non-motor symptoms in 99 PD patients. The relationships between anxiety and other PD-related non-motor symptoms were examined through regression analyses. 25 % of PD patients were diagnosed with clinically relevant anxiety. Non-motor symptoms were more prominent in patients with anxiety. Depression, urinary disorders, and sleep disruption were the factors most likely to influence anxiety in PD. Our findings have revealed a strong interplay between anxiety and other non-motor symptoms of PD and have highlighted the need for a holistic approach towards the clinical treatment of this disabling condition.
Kataoka, Hiroshi; Ueno, Satoshi
Auditory musical hallucinations (AMHs) are rare complex auditory hallucinations in Parkinson's disease (PD) that have been limited previously. The characteristics of AMHs in PD remain uncertain. We describe a 72-year-old woman with PD who presented with AMHs. The AMHs occurred after immediate-release pramipexole was switched to extended-release pramipexole. The AMHs were a quiet piano or often songs on a loud radio or background music over other sounds. The music was unpleasant, but not objectionable, threatening, or ego-syntonic, and it did not interrupt her daily activities. AMHs in PD were non-threatening, and dopaminergic treatment may predispose patients to AMHs or be a unique possible cause of AMHs. The hallucinations can occur after immediate-release pramipexole was switched to extended-release pramipexole.
Kataoka, Hiroshi; Ueno, Satoshi
Abstract Auditory musical hallucinations (AMHs) are rare complex auditory hallucinations in Parkinson's disease (PD) that have been limited previously. The characteristics of AMHs in PD remain uncertain. We describe a 72-year-old woman with PD who presented with AMHs. The AMHs occurred after immediate-release pramipexole was switched to extended-release pramipexole. The AMHs were a quiet piano or often songs on a loud radio or background music over other sounds. The music was unpleasant, but not objectionable, threatening, or ego-syntonic, and it did not interrupt her daily activities. AMHs in PD were non-threatening, and dopaminergic treatment may predispose patients to AMHs or be a unique possible cause of AMHs. The hallucinations can occur after immediate-release pramipexole was switched to extended-release pramipexole. PMID:25501095
Abe, Nobuhito; Mori, Etsuro
Parkinson disease is a progressive neurodegenerative disorder resulting in motor symptoms and cognitive deficits. Neuropsychological studies have suggested that patients with Parkinson disease exhibit a broad range of cognitive deficits even in the early stages of the disease. In this review, we discuss the neuropsychological evidence for cognitive impairment in patients with Parkinson disease, outlining the different domains of cognitive disturbance. First, we review previous findings on executive dysfunction, which is associated with a disruption in frontostriatal circuitry mainly driven by dopaminergic dysmodulation. Executive dysfunction is the core symptom in the cognitive deficits in Parkinson disease. Second, we focus on impairment in different domains of memory function, such as short-term and long-term memory. Third, we discuss the pattern of cognitive deficits in visuospatial ability, ranging from basic perceptual processes to rather complex motor skills. Next, we summarize the profile of cognitive deficits in language, although previous findings are mixed and hence this topic is relatively controversial. Finally, we introduce several recent findings on social cognitive deficits, which is a new area of research that has emerged in the past decade. We also discuss the possible neural mechanisms underlying each domain of cognitive deficits in patients with Parkinson disease.
Nalls, Mike A; Pankratz, Nathan; Lill, Christina M; Do, Chuong B; Hernandez, Dena G; Saad, Mohamad; DeStefano, Anita L; Kara, Eleanna; Bras, Jose; Sharma, Manu; Schulte, Claudia; Keller, Margaux F; Arepalli, Sampath; Letson, Christopher; Edsall, Connor; Stefansson, Hreinn; Liu, Xinmin; Pliner, Hannah; Lee, Joseph H; Cheng, Rong; Ikram, M Arfan; Ioannidis, John P A; Hadjigeorgiou, Georgios M; Bis, Joshua C; Martinez, Maria; Perlmutter, Joel S; Goate, Alison; Marder, Karen; Fiske, Brian; Sutherland, Margaret; Xiromerisiou, Georgia; Myers, Richard H; Clark, Lorraine N; Stefansson, Kari; Hardy, John A; Heutink, Peter; Chen, Honglei; Wood, Nicholas W; Houlden, Henry; Payami, Haydeh; Brice, Alexis; Scott, William K; Gasser, Thomas; Bertram, Lars; Eriksson, Nicholas; Foroud, Tatiana; Singleton, Andrew B
We conducted a meta-analysis of Parkinson's disease genome-wide association studies using a common set of 7,893,274 variants across 13,708 cases and 95,282 controls. Twenty-six loci were identified as having genome-wide significant association; these and 6 additional previously reported loci were then tested in an independent set of 5,353 cases and 5,551 controls. Of the 32 tested SNPs, 24 replicated, including 6 newly identified loci. Conditional analyses within loci showed that four loci, including GBA, GAK-DGKQ, SNCA and the HLA region, contain a secondary independent risk variant. In total, we identified and replicated 28 independent risk variants for Parkinson's disease across 24 loci. Although the effect of each individual locus was small, risk profile analysis showed substantial cumulative risk in a comparison of the highest and lowest quintiles of genetic risk (odds ratio (OR) = 3.31, 95% confidence interval (CI) = 2.55-4.30; P = 2 × 10(-16)). We also show six risk loci associated with proximal gene expression or DNA methylation.
Hawkes, C H; Shephard, B C; Daniel, S E
OBJECTIVE: To evaluate olfactory function in Parkinson's disease. METHODS: A standardised odour identification test was used, together with an evoked potential assessment with hydrogen sulphide. In addition, histological analysis was performed on the olfactory bulbs of cadavers who died from Parkinson's disease. RESULTS: Over 70% of patients studied (71 of 96) were outside the 95% limit of normal on the identification test in an age matched sample and there was an unusual pattern of selective loss to certain odours, not hitherto described. The evoked potentials were significantly delayed but of comparable amplitude to a control matched population. Of the 73 patients studied only 37 had a technically satisfactory record containing a clear response to both gases and of these, 12 were delayed. For H2S there was more delay on stimulating the right nostril than the left. Some patients with normal smell identification test scores had delayed evoked potentials. In the pathological examination of olfactory bulbs from eight brains, changes characteristic of Parkinson's disease (Lewy bodies) were seen in every olfactory bulb, particularly in the anterior olfactory nucleus, and were sufficiently distinct to allow a presumptive diagnosis of Parkinson's disease. CONCLUSIONS: Olfactory damage in Parkinson's disease is consistent and severe and may provide an important clue to the aetiology of the disease. Images PMID:9153598
Romero-Ramos, Marina; von Euler Chelpin, Marianne; Sanchez-Guajardo, Vanesa
Parkinson disease is the second most common neurodegenerative disease in the world, but there is currently no available cure for it. Current treatments only alleviate some of the symptoms for a few years, but they become ineffective in the long run and do not stop the disease. Therefore it is of outmost importance to develop therapeutic strategies that can prevent, stop, or cure Parkinson disease. A very promising target for these therapies is the peripheral immune system due to its probable involvement in the disease and its potential as a tool to modulate neuroinflammation. But for such strategies to be successful, we need to understand the particular state of the peripheral immune system during Parkinson disease in order to avoid its weaknesses. In this review we examine the available data regarding how dopamine regulates the peripheral immune system and how this regulation is affected in Parkinson disease; the specific cytokine profiles observed during disease progression and the alterations documented to date in patients’ peripheral blood mononuclear cells. We also review the different strategies used in Parkinson disease animal models to modulate the adaptive immune response to salvage dopaminergic neurons from cell death. After analyzing the evidence, we hypothesize the need to prime the immune system to restore natural tolerance against α-synuclein in Parkinson disease, including at the same time B and T cells, so that T cells can reprogram microglia activation to a beneficial pattern and B cell/IgG can help neurons cope with the pathological forms of α-synuclein. PMID:24670306
de Araujo, Narahyana Bom; Barca, Maria Lage; Engedal, Knut; Coutinho, Evandro Silva Freire; Deslandes, Andrea Camaz; Laks, Jerson
OBJECTIVE: To compare verbal fluency among Alzheimer's disease, Parkinson's disease, and major depression and to assess the sociodemographic and clinical factors associated with the disease severity. METHODS: Patients from an outpatient university center with a clinical diagnosis of Alzheimer's disease, Parkinson's disease or major depression were studied. Severity was staged using the Hoehn & Yahr scale, the Hamilton Depression scale and the Clinical Dementia Rating for Parkinson's disease, major depression, and Alzheimer's disease, respectively. All subjects were tested with the Mini-Mental State Examination, the digit span test, and the verbal fluency test (animals). We fit four types of regression models for the count variable: Poisson model, negative binomial model, zero-inflated Poisson model, and zero-inflated negative binomial model. RESULTS: The mean digit span and verbal fluency scores were lower in patients with Alzheimer's disease (n = 34) than in patients with major depression (n = 52) or Parkinson's disease (n = 17) (p<0.001). The average number of words listed was much lower for Alzheimer's disease patients (7.2 words) compared to the patients presenting with major depression (14.6 words) or Parkinson's disease (15.7 words) (KW test = 32.4; p<0.01). Major depression and Parkinson's disease groups listed 44% (ROM = 1.44) and 48% (ROM = 1.48) more words, respectively, compared to those patients with Alzheimer's disease; these results were independent of age, education, disease severity and attention. Independently of diagnosis, age, and education, severe disease showed a 26% (ROM = 0.74) reduction in the number of words listed when compared to mild cases. CONCLUSIONS: Verbal fluency provides a better characterization of Alzheimer's disease, major depression, and Parkinson's disease, even at later stages. PMID:21655757
Chaudhuri, K; Pal, S; DiMarco, A; Whately-Smith, C; Bridgman, K; Mathew, R; Pezzela, F; Forbes, A; Hogl, B; Trenkwalder, C
Background: No formal instruments are available for quantifying sleep problems in Parkinson's disease. Objective: To develop a new sleep scale to quantify the various aspects of nocturnal sleep problems in Parkinson's disease, which may occur in up to 96% of affected individuals. Methods: Employing a multidisciplinary team approach, a visual analogue scale was devised addressing 15 commonly reported symptoms associated with sleep disturbance in Parkinson's disease—the Parkinson's disease sleep scale (PDSS). In all, 143 patients with Parkinson's disease completed the PDSS, covering the entire spectrum of disease from newly diagnosed to advanced stage. As controls, 137 age healthy matched subjects also completed the scale. Test–retest reliability was assessed in a subgroup of subjects. The Epworth sleepiness scale was also satisfactorily completed by 103 of the patients with Parkinson's disease. Results: PDSS scores in the Parkinson group were significantly different from the healthy controls. Patients with advanced Parkinson's disease had impaired scores compared with early/moderate disease. Individual items of the scale showed good discriminatory power between Parkinson's disease and healthy controls. Relevant items of the PDSS correlated with excessive daytime sleepiness. The scale showed robust test–retest reliability. Conclusions: This appears to be the first description of a simple bedside screening instrument for evaluation of sleep disturbances in Parkinson's disease. A combination of subitems may help identify specific aspects of sleep disturbance, which in turn may help target treatment. PMID:12438461
Tell-Marti, Gemma; Puig-Butille, Joan Anton; Potrony, Miriam; Badenas, Celia; Milà, Montserrat; Malvehy, Josep; Martí, María José; Ezquerra, Mario; Fernández-Santiago, Rubén; Puig, Susana
Epidemiological studies have reported the co-occurrence of Parkinson disease (PD) and melanoma. Common genetic variants in the MC1R (melanocortin 1 receptor) gene, which determines skin and hair color, are associated with melanoma. Here we investigated whether genetic variants in MC1R modulate the risk of PD by sequencing the entire gene in 870 PD patients and 736 controls ascertained from Spain. We found that the MC1R variant p.R160W (rs1805008) is marginally associated with PD (odds ratio = 2.10, gender- and age-adjusted p = 0.009, Bonferroni-corrected p = 0.063). Our results suggest that MC1R genetic variants modulate the risk of PD disease in the Spanish population.
Ziegler, David A; Ashourian, Paymon; Wonderlick, Julien S; Sarokhan, Alison K; Prelec, Drazen; Scherzer, Clemens R; Corkin, Suzanne
Parkinson disease (PD) is an age-related degenerative disease of the brain, characterized by motor, cognitive, and psychiatric symptoms. Neurologists and neuroscientists now understand that several symptoms of the disease, including hallucinations and impulse control behaviors, stem from the dopaminergic medications used to control the motor aspects of PD. Converging evidence from animals and humans suggests that individual differences in the genes that affect the dopamine system influence the response of PD patients to dopaminergic medication. In this study, we tested the hypothesis that patients taking dopamine replacement therapy who carry candidate alleles that increase dopamine signaling, exhibit greater amounts of motor impulsivity. We examined the relation between inhibitory ability (measured by the Stop Signal Task) and polymorphisms of COMT Val158Met and DRD2 C957T in patients with idiopathic PD. On the Stop Signal Task, carriers of COMT Val/Met and Met/Met genotypes were more impulsive than Val/Val carriers, but we did not find a link between DRD2 polymorphisms and inhibitory ability. These results support the hypothesis that the Met allele of COMT confers an increased risk for behavioral impulsivity in PD patients, whereas DRD2 polymorphisms appear to be less important in determining whether PD patients exhibit a dopamine overdose in the form of motor impulsivity.
Malochet-Guinamand, Sandrine; Durif, Franck; Thomas, Thierry
Parkinson's disease is the most common neurodegenerative disease after Alzheimer's disease. On the long term, it may be complicated by various musculoskeletal problems, such as osteoporotic fractures, that have significant socioeconomic consequences. Indeed, patients suffering from Parkinson's disease have a higher fracture risk, particularly hip fracture risk, than other subjects of the same age because of both a higher risk of falls and lower bone mineral density. Bone loss in Parkinson's disease may be associated with the severity and duration of the disease. We review here the different suspected mechanisms of accelerated bone loss in Parkinson's disease, amongst which weight loss and reduced mobility appear to play key roles. Antiparkinsonian drugs, particularly levodopa, may also be associated with decreased bone mineral density as a result of hyperhomocysteinaemia. We discuss the role of other nutritional deficiencies, such as vitamin B12, folate or vitamin K. In conclusion, it seems necessary to screen for and treat osteoporosis in this at-risk population, while actions to prevent falls are still disappointing. A better understanding of the factors explaining bone loss in this population would help implementing preventive actions.
Ben-Shlomo, Y; Sieradzan, K
Since the introduction of levodopa therapy for idiopathic Parkinson's disease over 20 years ago, there has been an awakening of research interest in this chronic neuro-degenerative disorder. This paper describes current understanding of the role of genetic and environmental factors in the aetiology of idiopathic Parkinson's disease and problems associated with both diagnosis and management. It briefly outlines both pharmacological and non-pharmacological options for treatment. Despite an increasing armoury of available treatments, the optimum management for this condition remains controversial. PMID:7619574
... news/fullstory_163751.html Could Parkinson's Disease Raise Stroke Risk? Or is the link the other way ... link between Parkinson's disease and the risk for stroke. However, the study can't prove that one ...
Diaz, Alexandre Paim; Freitas, Fernando Cini; de Oliveira Thais, Maria Emília; da Silva Areas, Fernando Zanela; Schwarzbold, Marcelo Liborio; Debona, Rodrigo; Nunes, Jean Costa; Guarnieri, Ricardo; Martinez-Ramirez, Daniel; Prediger, Rui Daniel; Wagle Shukla, Aparna; Linhares, Marcelo Neves; Walz, Roger
Deep brain stimulation (DBS) benefits Parkinson's disease (PD) patient's quality of life specially in domains as mobility, activities of daily living (ADL) and bodily discomfort (BD), but little is known about the variables associated with these HRQOL domains in patients presenting for DBS. The objective is to evaluate variables associated with of HRQOL in a Brazilian sample of PD patients presenting for DBS treatment, specifically in the domains related with motor symptoms. In a cross-sectional study of 59 PD patients evaluated at outpatient Unit for Movement Disorders, multiple linear regression analysis was performed to identify independent variables associated with mobility, ADL and BD domains of the 39-item Parkinson's disease questionnaire (PDQ-39). UPDRS III "on" scores, duration of the disease, age, presence of comorbidities and anxiety and depressive symptoms quantified by hospital anxiety and depression scale (HADS), were the independent variables. In our results, HADS scores were independently associated to mobility domain: β coefficient 1.36 (95 % CI 0.55-2.15) and BD domain: β coefficient 1.57 (95 % CI 0.67-2.48). UPDRS III "on" scores were independently associated to mobility domain: 0.42 (95 % CI 0.03-0.81). The model of each multiple linear regression analysis explains 25 % of the mobility domain variability (p < 0.01) and 24 % of the BD domain variability (p < 0.01). Psychiatric symptoms were at least as relevant to quality of life as motor symptoms in PD patients presenting for DBS treatment. The effect of treating these psychiatric symptoms on patients' HRQOL deserves further investigation.
Fiske, J; Hyland, K
Parkinson's disease is a relatively common, progressive, neurological disorder. Its key features of resting tremor, bradykinesia, akinesia, restricted mobility and postural instability militate against independence for daily living, mobility, good nutrition and oral health. The successful management of the disease requires a multi-disciplinary approach in which the dietician, speech therapist, nurse and dental staff are pivotal members of the care team.
Bento, Carla F; Ashkenazi, Avraham; Jimenez-Sanchez, Maria; Rubinsztein, David C
Forms of Parkinson's disease (PD) are associated with lysosomal and autophagic dysfunction. ATP13A2, which is mutated in some types of early-onset Parkinsonism, has been suggested as a regulator of the autophagy-lysosome pathway. However, little is known about the ATP13A2 effectors and how they regulate this pathway. Here we show that ATP13A2 depletion negatively regulates another PD-associated gene (SYT11) at both transcriptional and post-translational levels. Decreased SYT11 transcription is controlled by a mechanism dependent on MYCBP2-induced ubiquitination of TSC2, which leads to mTORC1 activation and decreased TFEB-mediated transcription of SYT11, while increased protein turnover is regulated by SYT11 ubiquitination and degradation. Both mechanisms account for a decrease in the levels of SYT11, which, in turn, induces lysosomal dysfunction and impaired degradation of autophagosomes. Thus, we propose that ATP13A2 and SYT11 form a new functional network in the regulation of the autophagy-lysosome pathway, which is likely to contribute to forms of PD-associated neurodegeneration.
Bento, Carla F.; Ashkenazi, Avraham; Jimenez-Sanchez, Maria; Rubinsztein, David C.
Forms of Parkinson's disease (PD) are associated with lysosomal and autophagic dysfunction. ATP13A2, which is mutated in some types of early-onset Parkinsonism, has been suggested as a regulator of the autophagy–lysosome pathway. However, little is known about the ATP13A2 effectors and how they regulate this pathway. Here we show that ATP13A2 depletion negatively regulates another PD-associated gene (SYT11) at both transcriptional and post-translational levels. Decreased SYT11 transcription is controlled by a mechanism dependent on MYCBP2-induced ubiquitination of TSC2, which leads to mTORC1 activation and decreased TFEB-mediated transcription of SYT11, while increased protein turnover is regulated by SYT11 ubiquitination and degradation. Both mechanisms account for a decrease in the levels of SYT11, which, in turn, induces lysosomal dysfunction and impaired degradation of autophagosomes. Thus, we propose that ATP13A2 and SYT11 form a new functional network in the regulation of the autophagy–lysosome pathway, which is likely to contribute to forms of PD-associated neurodegeneration. PMID:27278822
Pastor, P; Tolosa, E
Cabergoline (1-[(6-allelylergolin-8 beta-yl)carbonyl]-1-[3-(dimethylamino)propyl]-3-ethyl-urea) is a new agonist of the D2 dopaminergic receptors used in the treatment of Parkinson's disease. Cabergoline is characterized by unique pharmacologic properties, such as its long plasma half-life (about 68 hours), which allows for once a day administration. Cabergoline is well tolerated, as has been shown in several clinical trials. Based on the information available, we suggest that cabergoline produces an improvement in the symptoms of Parkinson's disease similar to those produced by other dopaminergic agonists. Cabergoline monotherapy, when used in previously untreated patients, is an appropriate option for the symptomatic treatment of Parkinson's disease. Cabergoline improves motor symptoms, delays the presentation of levodopa-induced motor complications, and diminishes the amount of levodopa required for the control of the symptoms. We suggest that cabergoline is an adequate adjuvant treatment for Parkinson' disease. There is improvement in motor symptoms (without substantially increased dyskinesias), reduced severity and duration of the wearing-off period, and diminished need for levodopa. Cabergoline can also be useful in the treatment of sleep disturbances associated with advanced Parkinson's disease such as nocturnal akinesia and dystonia. However, additional studies on cabergoline's effects in nocturnal disturbances associated with Parkinson's disease are still required. Cabergoline is a well tolerated drug. Its side effects are seen mainly in the digestive and nervous system (central and peripheral). The efficacy of cabergoline in comparison to other dopaminergic agonists should be tested in future clinical studies.
Palacios, Natalia; Gao, Xiang; McCullough, Marjorie L; Jacobs, Eric J; Patel, Alpa V; Mayo, Tinisha; Schwarzschild, Michael A; Ascherio, Alberto
The aim of this work was to investigate whether obesity and diabetes are related to risk of Parkinson's disease. We prospectively followed 147,096 participants in the Cancer Prevention Study II Nutrition Cohort from 1992 to 2005. Participants provided information on anthropometric variables and medical history at baseline and on waist circumference in 1997. Incident cases of Parkinson's disease (n = 656) were confirmed by treating neurologists and medical record review. Relative risks were estimated using proportional hazards models, adjusting for age, gender, smoking, and other risk factors. Neither body mass index nor waist circumference significantly predicted Parkinson's disease risk. Relative risk comparing individuals with a baseline body mass index of ≥ 30 to those with a body mass index <23 was 1.00 (95% confidence interval: 0.75, 1.34; P trend: 0.79), and that comparing individuals with a waist circumference in the top category (≥ 40.3 inches in men and ≥ 35 inches in women) to those in the bottom category (<34.5 inches in men and <28 inches in women) was 1.35 (95% confidence interval: 0.95, 1.93; P trend: 0.08). History of diabetes was not significantly associated with Parkinson's disease risk (combined relative risks = 0.88; 95% confidence interval: 0.62, 1.25; P heterogeneity = 0.96). In addition, neither body mass index at age 18 nor changes in weight between age 18 and baseline were significantly associated with Parkinson's disease risk. The results did not differ significantly by gender. Our results do not provide evidence for a relationship between body mass index, weight change, waist circumference, or baseline diabetes and risk of Parkinson's disease.
Kim, Hee-Jung; Kim, Hyun Jung; Jeong, Jae-Eun; Baek, Jeong Yeob; Jeong, Jaeho; Kim, Sun; Kim, Young-Mee; Kim, Youhwa; Nam, Jin Han; Huh, Sue Hee; Seo, Jawon; Jin, Byung Kwan; Lee, Kong-Joo
Ubiquitin C-terminal hydrolase-L1 (UCH-L1) has been proposed as one of the Parkinson's disease (PD) related genes, but the possible molecular connection between UCH-L1 and PD is not well understood. In this study, we discovered an N-terminal 11 amino acid truncated variant UCH-L1 that we called NT-UCH-L1, in mouse brain tissue as well as in NCI-H157 lung cancer and SH-SY5Y neuroblastoma cell lines. In vivo experiments and hydrogen-deuterium exchange (HDX) with tandem mass spectrometry (MS) studies showed that NT-UCH-L1 is readily aggregated and degraded, and has more flexible structure than UCH-L1. Post-translational modifications including monoubiquitination and disulfide crosslinking regulate the stability and cellular localization of NT-UCH-L1, as confirmed by mutational and proteomic studies. Stable expression of NT-UCH-L1 decreases cellular ROS levels and protects cells from H2O2, rotenone and CCCP-induced cell death. NT-UCH-L1-expressing transgenic mice are less susceptible to degeneration of nigrostriatal dopaminergic neurons seen in the MPTP mouse model of PD, in comparison to control animals. These results suggest that NT-UCH-L1 may have the potential to prevent neural damage in diseases like PD. PMID:24959670
Guidi, Marco; Paciaroni, Lucia; Paolini, Susy; Scarpino, Osvaldo; Burn, David J
The temporal and the prefrontal cortices have different roles in semantic information processing: the temporal lobe is where knowledge is stored (Graham and Hodges, 1997), whereas the prefrontal cortex is more specifically involved in executive aspects of semantic processing. Relatively little is known about the semantic profiles of mild cognitive impairment (MCI) in Alzheimer's disease (AD) and Parkinson's disease (PD). This observational study investigated naming and semantic questionnaire performances in three groups of subjects: 10 patients with the amnestic-type MCI prodrome of AD (aMCI), 10 patients with early-stage executive-type MCI in PD (MCI-PD), and 10 normal subjects. The MCI-PD subjects demonstrated inferior performances on a semantic questionnaire, whereas the aMCI group displayed modest difficulties in a naming task. These differences may be explained by topographical differences in pathological involvement. Since the frontal areas are more functionally impaired in PD, we hypothesize that the semantic deficit may be a consequence of a deficiency in control of semantic processing. On the other hand, the semantic deficit in aMCI may be related to a lexical-semantic storage dysfunction resulting from pathological involvement of the temporal lobe.
Nagashayana, N; Sankarankutty, P; Nampoothiri, M R; Mohan, P K; Mohanakumar, K P
Ayurveda, the Indian system of traditional medicine, uses a concoction of several spices, herbs and minerals for the treatment of diseases. In a clinical prospective study we have evaluated the efficacy of Ayurveda treatment (a concoction in cow's milk of powdered Mucuna pruriens and Hyoscyamus reticulatus seeds and Withania somnifera and Sida cordifolia roots) in 18 clinically diagnosed (with a mean Hoen and Yahr value of 2.22) parkinsonian patients. As per Ayurveda principles, 13 patients underwent both cleansing (for 28 days) and palliative therapy (56 days), 5 patients underwent palliative therapy alone (84 days). Only the former group showed significant improvement in activities of daily living (ADL) and on motor examination as per UPDRS rating. Symptomatically, they exhibited better response in tremor, bradykinesia, stiffness and cramps as compared to the latter group. Excessive salivation worsened in both the groups. Analyses of powdered samples in milk, as administered in patients, revealed about 200 mg of L-DOPA per dose. The study establishes the necessity of cleansing therapy in Ayurveda medication prior to palliative therapy. It also reveals contribution of L-DOPA in the recovery as observed in Parkinson' disease following Ayurveda medication.
Khoo, Tien K; Burn, David J
Parkinson's disease is the second most common neurodegenerative disorder, after Alzheimer's disease. It predominantly affects the elderly. Age is the most clearly established risk factor and there is a male:female ratio of 1.5:1. Current incidence in the general population is 8.4-19 per 100,000 population per year with an approximate prevalence of 120 per 100,000 population. NICE recommends that patients with suspected Parkinson's disease should be referred untreated to a specialist with expertise in parkinsonian disorders. The diagnosis is primarily clinical. Parkinson's disease should be suspected in all patients presenting with bradykinesia (which is essential for the diagnosis of any form of parkinsonism, including Parkinson's disease), muscular rigidity, resting tremor (4-6 Hz) and postural instability not caused by a primary visual, vestibular, cerebellar, or proprioceptive dysfunction. At present, there are no specific biochemical, imaging or genetic tests to assist in the diagnosis of Parkinson's disease. Structural brain imaging (MRI or CT) has no role in the diagnosis of Parkinson's disease but may be useful to exclude cerebrovascular disease, hydrocephalus and Wilson's disease in selected cases. Parkinson's disease is a condition that results in both motor and non-motor symptoms. Morbidity associated with non-motor symptoms in Parkinson's disease is becoming increasingly recognised and some non-motor symptoms such as hyposmia, apathy, depression and REM sleep behaviour disorder may precede the onset of motor symptoms.
Koseki, Yuji; Kinjo, Tomohiro; Kuroki, Masato; Aoki, Shunsuke
Ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) is a neuron-specific deubiquitinating enzyme. Single amino acid changes (S18Y and I93M) within UCH-L1 are associated with decreased and increased risk of Parkinson's disease (PD), respectively. However, the molecular mechanism of pathogenesis in UCH-L1-associated PD remains to be elucidated. In this study, we performed molecular dynamics simulations of UCH-L1 variants. The simulation results show that I93M UCH-L1 is less stable than S18Y UCH-L1. In particular, the H7 and H8 α-helices in I93M UCH-L1 are partially denatured. Information regarding the aberrant UCH-L1 structures provides new insight into UCH-L1-associated PD.
Partial Contents: Description of Parkinson’s Disease as a Clinical Syndrome. Physiology and Pathophysiology of Parkinson’s Disease . PET Studies on...the Function of Dopamine in Health and Parkinson’s Disease . Midbrain Dopaminergic Neurons: Determination of Their Developmental Fate by Transcription...Developmental Programmed Cell Death in Dopamine Neurons The Cast of Molecular Characters Parkinson’s Disease : Felons,Conspirators, and Suspects. Oxidative
Although the basic underlying mechanisms of Parkinson’s disease remain unknown, considerable efforts have centered on developing effective strategies...dopamine in the nigrostriatal system have the potential for overcoming the lack of dopamine neuronal function in Parkinson’s disease patients. Results...application of neuregulins to the treatment of neurotoxin-induced neurodegenerative disorders such as Parkinson’s disease .
Smeyne, Michelle; Smeyne, Richard Jay
It has been established that oxidative stress, defined as the condition in which the sum of free radicals in a cell exceeds the antioxidant capacity of the cell, contributes to the pathogenesis of Parkinson disease. Glutathione is a ubiquitous thiol tripeptide that acts alone or in concert with enzymes within cells to reduce superoxide radicals, hydroxyl radicals, and peroxynitrites. In this review, we examine the synthesis, metabolism, and functional interactions of glutathione and discuss how these relate to the protection of dopaminergic neurons from oxidative damage and its therapeutic potential in Parkinson disease.
Prakash, Kumar M; Tan, Eng-King
Parkinson's disease (PD) is the most common neurodegenerative movement disorder, affecting over 6 million people worldwide. It is anticipated that the number of affected individuals may increase significantly in the most populous nations by 2030. During the past 20 years, much progress has been made in identifying and assessing various potential clinical, biochemical, imaging and genetic biomarkers for PD. Despite the wealth of information, development of a validated biomarker for PD is still ongoing. It is hoped that reliable and well-validated biomarkers will provide critical clues to assist in the diagnosis and management of Parkinson's disease patients in the near future.
Falquetto, Barbara; Tuppy, Marina; Potje, Simone R; Moreira, Thiago S; Antoniali, Cristina; Takakura, Ana C
Patients with Parkinson's disease (PD) exhibit both motor and non-motor symptoms. Among the non-motor symptoms, cardiovascular autonomic dysfunction is frequently observed. Here, we evaluated baroreflex function, vascular reactivity and neuroanatomical changes in brainstem regions involved in the neural control of circulation in the 6-hydroxydopamine (6-OHDA) model of PD. Male Wistar rats received a bilateral injection of 6-OHDA or vehicle into the striatum. After 61days, baroreflex function and vascular reactivity were assessed. The 6-OHDA and vehicle groups showed similar increases in mean arterial pressure (MAP) in response to phenylephrine (PE). However, the bradycardia observed in the vehicle group was blunted in the 6-OHDA-treated rats. Injection of sodium nitroprusside (SNP) decreased hypotension, tachycardia and vascular relaxation in 6-OHDA-treated rats. Bilateral intrastriatal 6-OHDA led to massive degeneration of tyrosine hydroxylase (TH)-immunoreactive neurons in the substantia nigra and to reductions in the numbers of A1/C1 and A5 catecholaminergic neurons while sparing A2 neurons within the nucleus of the solitary tract (NTS). 6-OHDA-treated rats also showed decreases in Phox2b-expressing neurons in the NTS and in choline acetyltransferase (ChAT) immunoreactivity in the nucleus ambiguus. Altogether, our data suggest that this model of PD includes neuroanatomical and functional changes that lead to cardiovascular impairment.
Summary Impulse control disorders (ICD) (most commonly pathologic gambling, hypersexuality, and uncontrollable spending) and compulsive behaviors can be triggered by dopaminergic therapies in Parkinson disease (PD). ICD are especially prevalent in patients receiving a dopamine agonist as part of their treatment regimen for PD, and have also been reported when dopamine agonists are used for other indications (e.g., restless legs syndrome). Although these iatrogenic disorders are common, affecting 1 in 7 patients with PD on dopamine agonists, they often elude detection by the treating physician. ICD lead to serious consequences, causing significant financial loss and psychosocial morbidity for many patients and families. ICD can appear at any time during treatment with dopamine agonists, sometimes within the first few months, but most often after years of treatment, particularly when patients receive dopamine agonists and levodopa together. In most cases ICD resolve if the dopamine agonist is withdrawn, and PD motor symptoms are managed with levodopa monotherapy. Familiarity with the clinical aspects, risk factors, pathophysiology, and management of ICD is essential for physicians using dopaminergic therapies to treat PD and other disorders. PMID:23634371
Meray, Robin K; Lansbury, Peter T
Deubiquitinating enzymes (DUBs) are negative regulators of protein ubiquitination and play an important role in ubiquitin-dependent processes. Recent studies have found that diverse cellular mechanisms are employed to control the activity of DUBs. Ubiquitin C-terminal hydrolase-L1 (UCH-L1) is a highly expressed neuronal DUB linked to Parkinson disease; however, little is known about its specific functions or modes of regulation. Here, we demonstrate that UCH-L1 is post-translationally modified by monoubiquitin in cells, at lysine residues near the active site. This modification restricts enzyme activity by preventing binding to ubiquitinated targets, and permanent monoubiquitination, as mimicked by a ubiquitin-UCH-L1 fusion, inhibits UCH-L1 in its capacity to increase free ubiquitin levels in cells. Interestingly, UCH-L1 catalyzes its own deubiquitination in an intramolecular manner, thereby regulating the lifetime of this modification. Our results illustrate monoubiquitination as a reversible regulatory mechanism for DUB activity involving auto-deubiquitination.
of Parkinson’s Disease and the MPTP model of Parkinsonism. In the past year, we have developed a novel column switching assay for measurement of...oxidative damage to DNA in human body fluids. We have applied to this plasma samples of Parkinson’s Disease patients. We have also developed a novel...methodology. We have found a relatively high mutation rate and control samples and intend to apply this to Parkinson’s Disease . We have continued our
Nakamura, Ken; Nemani, Venu M.; Azarbal, Farnaz; Skibinski, Gaia; Levy, Jon M.; Egami, Kiyoshi; Munishkina, Larissa; Zhang, Jue; Gardner, Brooke; Wakabayashi, Junko; Sesaki, Hiromi; Cheng, Yifan; Finkbeiner, Steven; Nussbaum, Robert L.; Masliah, Eliezer; Edwards, Robert H.
The protein α-synuclein has a central role in Parkinson disease, but the mechanism by which it contributes to neural degeneration remains unknown. We now show that the expression of α-synuclein in mammalian cells, including neurons in vitro and in vivo, causes the fragmentation of mitochondria. The effect is specific for synuclein, with more fragmentation by α- than β- or γ-isoforms, and it is not accompanied by changes in the morphology of other organelles or in mitochondrial membrane potential. However, mitochondrial fragmentation is eventually followed by a decline in respiration and neuronal death. The fragmentation does not require the mitochondrial fission protein Drp1 and involves a direct interaction of synuclein with mitochondrial membranes. In vitro, synuclein fragments artificial membranes containing the mitochondrial lipid cardiolipin, and this effect is specific for the small oligomeric forms of synuclein. α-Synuclein thus exerts a primary and direct effect on the morphology of an organelle long implicated in the pathogenesis of Parkinson disease. PMID:21489994
About one third of patients with Parkinson's disease (PD) experience hallucinations, mostly of a complex visual type, less often auditory or tactile. Minor hallucinatory phenomena, including sense of presence, passage hallucinations and visual illusions are frequent. Hallucinations primarily occur in a context of clear sensorium in patients with longstanding PD. They are more frequent in the evening or during the night. Insight in the hallucinatory nature of the phenomenon may be retained, partial, fluctuating, or abolished. An altered insight is common when cognitive impairment is present, and may be associated with delusions and (or) delusional misidentifications. Pharmacological factors such as dopaminergic treatment clearly trigger or increase the occurence of hallucinations in PD. However, in the recent years, emphasis has been made on disease-related factors including cognitive impairment, diurnal somnolence, visual disorders (either contrast and color discrimination impairment due to PD, or coincident ocular disorders), long duration of PD, late onset, severe axial impairment and autonomic dysfunction. The pathophysiology of hallucinations of PD is poorly understood but is likely to be multifactorial. The first steps of the treatment consist in giving information and reassurance to the patient and his/her caregiver, re-evaluating the antiparkinsonian treatment and associated medications, and evaluating the patient for mood disorder, visual impairment, and cognitive impairment. Cholinesterase inhibitors, when prescribed for associated cognitive impairment, may be beneficial on hallucinations. In the more severe forms, clozapine has been proved to be safe and effective.
Samaranch, Lluis; Lorenzo-Betancor, Oswaldo; Arbelo, Jose M.; Ferrer, Isidre; Lorenzo, Elena; Irigoyen, Jaione; Pastor, Maria A.; Marrero, Carmen; Isla, Concepcion; Herrera-Henriquez, Joanna; Pastor, Pau
Phosphatase and tensin homolog-induced putative kinase 1 gene mutations have been associated with autosomal recessive early-onset Parkinson's disease. To date, no neuropathological reports have been published from patients with Parkinson's disease with both phosphatase and tensin homolog-induced putative kinase 1 gene copies mutated. We analysed…
Henchcliffe, Claire; Severt, W Lawrence
Parkinson's disease (PD) is an age-related, progressive, multisystem neurodegenerative disorder resulting in significant morbidity and mortality, as well as a growing social and financial burden in an aging population. The hallmark of PD is loss of dopaminergic neurons of the substantia nigra pars compacta, leading to bradykinesia, rigidity and tremor. Current pharmacological treatment is therefore centred upon dopamine replacement to alleviate symptoms. However, two major problems complicate this approach: (i) motor symptoms continue to progress, requiring increasing doses of medication, which result in both short-term adverse effects and intermediate- to long-term motor complications; (ii) dopamine replacement does little to treat non-dopaminergic motor and non-motor symptoms, which are an important source of morbidity, including dementia, sleep disturbances, depression, orthostatic hypotension, and postural instability leading to falls. It is critical, therefore, to develop a broader and more fundamental therapeutic approach to PD, and major research efforts have focused upon developing neuroprotective interventions. Despite many encouraging preclinical data suggesting the possibility of addressing the underlying pathophysiology by slowing cell loss, efforts to translate this into the clinical realm have largely proved disappointing in the past. Barriers to finding neuroprotective or disease-modifying drugs in PD include a lack of validated biomarkers of progression, which hampers clinical trial design and interpretation; difficulties separating symptomatic and neuroprotective effects of candidate neuroprotective therapies; and possibly fundamental flaws in some of the basic preclinical models and testing. However, three recent clinical trials have used a novel delayed-start design in an attempt to overcome some of these roadblocks. While not examining markers of cell loss and function, which would determine neuroprotective effects, this trial design
Pienaar, Ilse S.; Elson, Joanna L.; Racca, Claudia; Nelson, Glyn; Turnbull, Douglass M.; Morris, Christopher M.
Cholinergic neuronal loss in the pedunculopontine nucleus (PPN) associates with abnormal functions, including certain motor and nonmotor symptoms. This realization has led to low-frequency stimulation of the PPN for treating patients with Parkinson disease (PD) who are refractory to other treatment modalities. However, the molecular mechanisms underlying PPN neuronal loss and the therapeutic substrate for the clinical benefits following PPN stimulation remain poorly characterized, hampering progress toward designing more efficient therapies aimed at restoring the PPN's normal functions during progressive parkinsonism. Here, we investigated postmortem pathological changes in the PPN of PD cases. Our study detected a loss of neurons producing gamma-aminobutyric acid (GABA) as their output and glycinergic neurons, along with the pronounced loss of cholinergic neurons. These losses were accompanied by altered somatic cell size that affected the remaining neurons of all neuronal subtypes studied here. Because studies showed that mitochondrial dysfunction exists in sporadic PD and in PD animal models, we investigated whether altered mitochondrial composition exists in the PPN. A significant up-regulation of several mitochondrial proteins was seen in GABAergic and glycinergic neurons; however, cholinergic neurons indicated down-regulation of the same proteins. Our findings suggest an imbalance in the activity of key neuronal subgroups of the PPN in PD, potentially because of abnormal inhibitory activity and altered cholinergic outflow. PMID:24099985
Nikam, Shashikant; Nikam, Padmaja; Ahaley, S K; Sontakke, Ajit V
Oxidative stress contributes to the cascade, leading to dopamine cell degeneration in Parkinson's disease. However, oxidative stress is intimately linked to other components of the degenerative process, such as mitochondrial dysfunction, excitotoxicity, nitric oxide toxicity and inflammation. It is therefore difficult to determine whether oxidative stress leads to or is a consequence of, these events. Oxidative stress was assessed by estimating lipid peroxidation product in the form of thiobarbituric acid reactive substances, nitric oxide in the form of nitrite & nitrate. Enzymatic antioxidants in the form of superoxide dismutase, glutathione peroxidase, catalase, ceruloplasmin and non enzymatic antioxidant vitamins e.g. vitamin E and C in either serum or plasma or erythrocyte in 40 patients of Parkinson's disease in the age group 40-80 years. Trace elements e.g. copper, zinc and selenium were also estimated. Plasma thiobarbituric acid reactive substances and nitric oxide levels were Significantly high but superoxide dismutase, glutathione peroxidase, catalase, ceruloplasmin, vitamin-E, vitamin-C, copper, zinc and selenium levels were significantly low in Parkinson's disease when compared with control subjects. Present study showed that elevated oxidative stress may be playing a role in dopaminergic neuronal loss in substentia nigra pars compacta and involved in pathogenesis of the Parkinson's disease.
Wearden, J. H.; Smith-Spark, J. H.; Cousins, Rosanna; Edelstyn, N. M. J.; Cody, F. W. J.; O'Boyle, D. J.
Previous literature suggests that Parkinson's disease is marked by deficits in timed behaviour. However, the majority of studies of central timing mechanisms in patients with Parkinson's disease have used timing tasks with a motor component. Since the motor abnormalities are a defining feature of the condition, the status of timing in Parkinson's…
Prakash, Ajay; Chopra, Kanwaljit; Medhi, Bikash
Introduction: The present study was designed to evaluate the effect of granulocyte-colony stimulating factor (G-CSF) in the treatment of Parkinson's disease (PD), the second most common neurodegenerative disease characterized by muscle and movement disorder, often associated with depression. PD is very difficult to treat. Hence, the present study was aimed to evaluate the effect of G-CSF in PD associated with depression. Materials and Methods: Adult Wistar male rats weighing about 180-250 g were selected and divided into five groups in parallel designed method namely; control group (n = 5); sham operated group (n = 5); Vehicle group (n = 5); G-CSF group (70 μg/kg, s.c.) (n = 5) and L-DOPA group (n = 5). The rats were treated with 6-hydroxydopamine (6-OHDA) on day 0 and then treatment was continued for 14 day of L-DOPA/carbidopa, whereas G-CSF (70 μg/kg, s.c.) was given from day 1 to 6. Thereafter, adhesive removal and forced swim tests were conducted to evaluate the behavioral outcome of G-CSF treatment. The finding was correlated and analyzed with Nissl staining findings for the final conclusion. Results: The behavioral parameters were assessed and found to be ameliorate the symptoms of Parkinson's and reduced the depression like behavior in PD. The histological findings were supported the behavioral findings and showed pathological improvement. Conclusion: As a preliminary work, the present study first time suggested that G-CSF have a potential role in PD and associated depression. PMID:24347771
... spent, browse our financial information. Learn More Gambling, Sex, and…Parkinson's Disease? By Laura Marsh, M.D. ... and, in people with Parkinson's, most typically involve sex, gambling and abuse of anti-parkinsonian medications. Pathological ...
Fujioka, Shinsuke; Curry, Sadie E; Kennelly, Kathleen D; Tacik, Pawel; Heckman, Michael G; Tsuboi, Yoshio; Strongosky, Audrey J; van Gerpen, Jay A; Uitti, Ryan J; Ross, Owen A; Ikezu, Tsuneya; Wszolek, Zbigniew K
We retrospectively investigated the co-occurrence of Crohn's disease in a cohort of 876 patients with Parkinson's disease, based on the observation that LRRK2 is a shared genetic risk factor. We identified 2 patients with Crohn's disease; this number was consistent with the number of cases expected in the general population.
Aarsland, Dag; Creese, Byron; Politis, Marios; Chaudhuri, K Ray; Ffytche, Dominic H; Weintraub, Daniel; Ballard, Clive
Dementia is a frequent problem encountered in advanced stages of Parkinson disease (PD). In recent years, research has focused on the pre-dementia stages of cognitive impairment in PD, including mild cognitive impairment (MCI). Several longitudinal studies have shown that MCI is a harbinger of dementia in PD, although the course is variable, and stabilization of cognition - or even reversal to normal cognition - is not uncommon. In addition to limbic and cortical spread of Lewy pathology, several other mechanisms are likely to contribute to cognitive decline in PD, and a variety of biomarker studies, some using novel structural and functional imaging techniques, have documented in vivo brain changes associated with cognitive impairment. The evidence consistently suggests that low cerebrospinal fluid levels of amyloid-β42, a marker of comorbid Alzheimer disease (AD), predict future cognitive decline and dementia in PD. Emerging genetic evidence indicates that in addition to the APOE*ε4 allele (an established risk factor for AD), GBA mutations and SCNA mutations and triplications are associated with cognitive decline in PD, whereas the findings are mixed for MAPT polymorphisms. Cognitive enhancing medications have some effect in PD dementia, but no convincing evidence that progression from MCI to dementia can be delayed or prevented is available, although cognitive training has shown promising results.
Stafa, Klodjan; Tsika, Elpida; Moser, Roger; Musso, Alessandra; Glauser, Liliane; Jones, Amy; Biskup, Saskia; Xiong, Yulan; Bandopadhyay, Rina; Dawson, Valina L.; Dawson, Ted M.; Moore, Darren J.
Mutations in LRRK2 cause autosomal dominant Parkinson's disease (PD). LRRK2 encodes a multi-domain protein containing GTPase and kinase domains, and putative protein–protein interaction domains. Familial PD mutations alter the GTPase and kinase activity of LRRK2 in vitro. LRRK2 is suggested to regulate a number of cellular pathways although the underlying mechanisms are poorly understood. To explore such mechanisms, it has proved informative to identify LRRK2-interacting proteins, some of which serve as LRRK2 kinase substrates. Here, we identify common interactions of LRRK2 with members of the dynamin GTPase superfamily. LRRK2 interacts with dynamin 1–3 that mediate membrane scission in clathrin-mediated endocytosis and with dynamin-related proteins that mediate mitochondrial fission (Drp1) and fusion (mitofusins and OPA1). LRRK2 partially co-localizes with endosomal dynamin-1 or with mitofusins and OPA1 at mitochondrial membranes. The subcellular distribution and oligomeric complexes of dynamin GTPases are not altered by modulating LRRK2 in mouse brain, whereas mature OPA1 levels are reduced in G2019S PD brains. LRRK2 enhances mitofusin-1 GTP binding, whereas dynamin-1 and OPA1 serve as modest substrates of LRRK2-mediated phosphorylation in vitro. While dynamin GTPase orthologs are not required for LRRK2-induced toxicity in yeast, LRRK2 functionally interacts with dynamin-1 and mitofusin-1 in cultured neurons. LRRK2 attenuates neurite shortening induced by dynamin-1 by reducing its levels, whereas LRRK2 rescues impaired neurite outgrowth induced by mitofusin-1 potentially by reversing excessive mitochondrial fusion. Our study elucidates novel functional interactions of LRRK2 with dynamin-superfamily GTPases that implicate LRRK2 in the regulation of membrane dynamics important for endocytosis and mitochondrial morphology. PMID:24282027
Vreeling, F W; Verhey, F R; Houx, P J; Jolles, J
A standardised protocol for the examination of 15 primitive reflexes in which the amplitude and the persistence were scored separately, was applied to 25 patients with Parkinson's disease and an equal number of healthy matched control subjects. Most reflexes were found considerably more often in the patients than in the control subjects, especially the snout, the glabellar tap, and its variant, the nasopalpebral reflex. Only the mouth open finger spread reflex was present more often in the control subjects. For all reflexes except this last, the scores for amplitude and persistence of the reflexes for the control group never exceeded the scores for the patient group. Reflexes persisted more often in the patients than in the control subjects. Parkinsonism alone can explain a large number of primitive reflexes, irrespective of the severity or duration of the disease. In contrast, the number of reflexes was related more closely to cognitive scales. It is concluded that such reflexes may be helpful in diagnosing Parkinson's disease. In addition, a standardised protocol for eliciting and scoring is essential for the study of these reflexes in parkinsonism and other neuropsychiatric conditions. PMID:8270937
Kincses, Péter; Kovács, Norbert; Karádi, Kázmér; Feldmann, Ádám; Dorn, Krisztina; Aschermann, Zsuzsanna; Komoly, Sámuel; Szolcsányi, Tibor; Csathó, Árpád; Kállai, János
Introduction. In the genesis of Parkinson's disease (PD) clinical phenomenology the exact nature of the association between bradykinesia and affective variables is unclear. In the present study, we analyzed the gait characteristics and level of depression in PD and healthy volunteers. Methods. Patients with PD (n = 48) and healthy controls (n = 52) were recruited for the present study. Walking speed, stride length, and cadence were compared between groups while participants completed a goal-directed locomotion task under visually controlled (VC) and visually noncontrolled conditions (VnC). Results. Significantly higher depression scores were found in PD comparing to healthy control groups. In PD, depression was associated with gait components in the VC wherein the place of the target was visible. In contrast, in healthy subjects the depression was associated with gait components in VnC wherein the location and image of the target were memorized and recalled. In patients with PD and depression, the visually deprived multitask augments the rate of cadence and diminishes stride length, while velocity remains relatively unchanged. The depression associated with gait characteristics as a comorbid affective factor in PD, and that impairs the coherence of gait pattern. Conclusion. The relationship between depression and gait parameters appears to indicate that PD not only is a neurological disease but also incorporates affective disturbances that associate with the regulation of gait characteristics.
Kincses, Péter; Karádi, Kázmér; Feldmann, Ádám; Dorn, Krisztina; Aschermann, Zsuzsanna; Szolcsányi, Tibor; Csathó, Árpád
Introduction. In the genesis of Parkinson's disease (PD) clinical phenomenology the exact nature of the association between bradykinesia and affective variables is unclear. In the present study, we analyzed the gait characteristics and level of depression in PD and healthy volunteers. Methods. Patients with PD (n = 48) and healthy controls (n = 52) were recruited for the present study. Walking speed, stride length, and cadence were compared between groups while participants completed a goal-directed locomotion task under visually controlled (VC) and visually noncontrolled conditions (VnC). Results. Significantly higher depression scores were found in PD comparing to healthy control groups. In PD, depression was associated with gait components in the VC wherein the place of the target was visible. In contrast, in healthy subjects the depression was associated with gait components in VnC wherein the location and image of the target were memorized and recalled. In patients with PD and depression, the visually deprived multitask augments the rate of cadence and diminishes stride length, while velocity remains relatively unchanged. The depression associated with gait characteristics as a comorbid affective factor in PD, and that impairs the coherence of gait pattern. Conclusion. The relationship between depression and gait parameters appears to indicate that PD not only is a neurological disease but also incorporates affective disturbances that associate with the regulation of gait characteristics. PMID:28293444
Fénelon, Gilles; Césaro, Pierre
Psychological and behavioral disorders associated with Parkinson's disease can have a major impact on patients' and caregivers' quality of life. Depression, anxiety, psychotic symptoms (e.g hallucinations), apathy and impulse-control disorders raise questions as to the respective roles of premorbid vulnerability, disease-related factors, and drug adverse effects. These disorders are often difficult to manage, and there is an unmet need for controlled trials in this field.
Sääksjärvi, Katri; Knekt, Paul; Männistö, Satu; Lyytinen, Jukka; Jääskeläinen, Tuija; Kanerva, Noora; Heliövaara, Markku
The risk factors for Parkinson's disease (PD) are not well established. We therefore examined the prediction of various lifestyle factors on the incidence of PD in a cohort drawn from the Finnish Mobile Clinic Health Examination Survey, conducted in 1973-1976. The study population comprised 6,715 men and women aged 50-79 years and free of PD at the baseline. All of the subjects completed a baseline health examination (including height and weight measurements) and a questionnaire providing information on leisure-time physical activity, smoking, and alcohol consumption. During a 22-year follow-up, 101 incident cases of PD occurred. The statistical analyses were based on Cox's model including age, sex, education, community density, occupation, coffee consumption, body mass index (BMI), leisure-time physical activity, smoking and alcohol consumption as independent variables. At first, BMI was not associated with PD risk, but after exclusion of the first 15 years of follow-up, an elevated risk appeared at higher BMI levels (P for trend 0.02). Furthermore, subjects with heavy leisure-time physical activity had a lower PD risk than those with no activity [relative risk (RR) 0.27, 95 % confidence interval (CI) 0.08-0.90]. In variance with findings for other chronic diseases, current smokers had a lower PD risk than those who had never smoked (RR 0.23, 95 % CI 0.08-0.67), and individuals with moderate alcohol intake (at the level of <5 g/day) had an elevated PD risk compared to non-drinkers. The results support the hypothesis that lifestyle factors predict the occurrence of Parkinson's disease, but more research is needed.
Perlmutter, Joel S.
Parkinson disease (PD) is a progressive neurologic condition that causes motor and non-motor manifestations. Treatment provides symptomatic benefit but no current treatment has been proven to slow disease progression. Research studies of PD require a means of rating the severity of disease by measurement of motor manifestations, assessment of ability to perform daily functional activities, and symptomatic response to medication. The most common rating scales are the Unified Parkinson Disease Rating Scale (UPDRS), Hoehn and Yahr staging, and the Schwab and England rating of activities of daily living. Each of these rating scales are described, including detailed instructions on how to implement these ratings. Although these are the most widely applied rating scales of PD, there are still substantial limitations to these scales that must be considered when using them for research. Finally, some common applications of these scales are described. PMID:19802812
Willis, Allison W
Parkinson disease is the second most neurodegenerative disease, after Alzheimer disease, that affects up to two million Americans, the overwhelming majority of whom are aged 60 and older. The changing demographics of the country place more Americans at risk for Parkinson disease (PD) than ever before. Primary care physicians treat the majority of PD patients in the United States. Here I review diagnosis and treatment strategies for idiopathic Parkinson disease in the elderly adult.
Brooks, David J; Pavese, Nicola
Parkinson's disease (PD) is characterized by a progressive loss of nigrostriatal dopaminergic neurons associated with intracellular Lewy inclusion bodies. The result is poverty of movement, increased muscle rigidity, and tremor at rest and on posture. Midbrain/nigral structural abnormalities can be demonstrated in vivo with both transcranial sonography (TCS) and diffusion tensor magnetic resonance imaging (DTI) while positron emission tomography (PET) and single photon emission computed tomography (SPECT) ligands exist to demonstrate dopamine terminal dysfunction. These radiotracers are markers of dopamine storage capacity, vesicular monoamine and dopamine transporter availability. While loss of putamen dopaminergic function leads to motor disability, Lewy bodies not only target dopamine neurons but have also been observed in serotoninergic, noradrenergic, and cholinergic neurons. As a consequence, non-dopaminergic neurotransmission is also impaired resulting in non-motor symptoms including sleep disturbance, fatigue, depression, dementia, and autonomic dysfunction. PET and SPECT ligands exist to interrogate the function of monoaminergic and cholinergic neurons. Cortical and limbic Lewy body disease is seen in more advanced PD and this can be detected with FDG PET as abnormal covariance between levels of resting brain metabolism in these regions. Additionally, widespread microglial activation can be detected in PD with PET. This review discusses the role of structural and functional imaging for understanding parkinsonian syndromes and aiding in their diagnosis and management.
Allam, Mohamed Farouk; Campbell, Michael J; Del Castillo, Amparo Serrano; Fernández-Crehuet Navajas, Rafael
Our aim was to estimate the pooled risk of current and former smoking for Parkinson's disease (PD). We have reviewed all observational studies that evaluated the association between PD risk and smoking habit. Twenty six studies were identified: 21 case-control, 4 cohort and 1 cross-sectional. The cross-sectional study did not compare former with never smokers. These studies were carried out between 1968 and 2000. There was an obvious protective effect of current smoking in the pooled estimate [risk estimate 0.37 (95% confidence interval 0.33 to 0.41)]. Former versus never smokers had pooled risk estimate of 0.84 (95% confidence interval 0.76 to 0.92). Current and former smoking do not, therefore, exert the same protective effect against PD so that it is unnecessary to postulate a biological mechanism through which smoking protects against PD. The results show that the reverse direction of causation is a more probable explanation, i.e. movement disorders of PD protect against smoking. Another explanation is that failure to develop strong smoking habits in early adult life might be a prodromal symptom of the disease and could perhaps be its first clinical manifestation.
Lu, Yanjun; Liu, Wei; Tan, Kun; Peng, Jing; Zhu, Yaowu; Wang, Xiong
Recent studies investigating the association of the Ras-like without CAAX 2 (RIT2) polymorphism, rs12456492, with Parkinson's disease (PD) are controversial. We performed a meta-analysis to study the association between rs12456492 and PD susceptibility in Asian populations. Literature searches of PubMed and Embase were performed up to June 3, 2015, and the strength of the association between rs12456492 and PD was evaluated by odds ratios (OR) and 95% confidence intervals (CI). Four studies conducted between 2013 and 2015, comprising 2017 PD cases and 2010 controls, were included in the meta-analysis. Significant association of rs12456492 with PD was found in the dominant (GG + AG vs. AA: OR = 1.26, 95% CI = 1.20-1.44, P = 0.00) and additive models (GG vs. AA: OR = 1.38, 95% CI = 1.03-1.83, P = 0.030). Although sensitivity analysis found that the overall result was stable only in the dominant genetic model, a publication bias was also detected. Therefore, the results should be treated with caution. The current meta-analysis suggested that rs12456492 might be associated with increased PD risk in Asian populations, but studies using larger sample sizes and different ethnic populations will be needed to further confirm this association.
Ma, Ze-Gang; He, Feng; Xu, Jian
The aim of this meta-analysis was to evaluate the association between cyclin G-associated kinase (GAK) rs1564282 C/T polymorphism and Parkinson's disease (PD) susceptibility. GAK modifies α-synuclein expression levels and affects susceptibility to PD. Genetic variation in GAK may influence the risk of occurrence and progression of PD. Many studies have evaluated the association between GAK rs1564282 C/T polymorphism and the risk of PD. However, published data are still controversial. Nine case-control studies with a total of 8159 PD patients and 12,747 controls were included in the meta-analysis. The summary odds ratio with 95% confidence interval was calculated to estimate this association. Both the minor allele frequencies and the genotype distributions of rs1564282 within GAK were different between the two groups when all studies were pooled. Subgroup analysis by ethnicity showed GAK rs1564282 C/T polymorphism was significantly associated with increased risk in both Asian and Caucasian populations. This meta-analysis suggests that GAK rs1564282 C/T polymorphism is associated with increased susceptibility to PD.
Caudle, W Michael; Bammler, Theo K; Lin, Yvonne; Pan, Sheng; Zhang, Jing
Although great effort has been put forth to uncover the complex molecular mechanisms exploited in the pathogenesis of Parkinson's disease, a satisfactory explanation remains to be discovered. The emergence of several -omics techniques, transcriptomics, proteomics and metabolomics, have been integral in confirming previously identified pathways that are associated with dopaminergic neurodegeneration and subsequently Parkinson's disease, including mitochondrial and proteasomal function and synaptic neurotransmission. Additionally, these unbiased techniques, particularly in the brain regions uniquely associated with the disease, have greatly enhanced our ability to identify novel pathways, such as axon-guidance, that are potentially involved in Parkinson's pathogenesis. A comprehensive appraisal of the results obtained by different -omics has also reconfirmed the increase in oxidative stress as a common pathway likely to be critical in Parkinson's development/progression. It is hoped that further integration of these techniques will yield a more comprehensive understanding of Parkinson's disease etiology and the biological pathways that mediate neurodegeneration.
Parkinson's disease is a complex neurologic and progressive incapacitating disease. Parkinson's disease severely threatens the quality of live and the number of patients worldwide is expected to rise considerably in the coming decade due to aging of the population. Even with optimal medical management using drugs or neurosurgery, patients are faced with progressively increasing impairments (e.g. in speech, mental and movement related functions), and restrictions in participation (e.g. domestic life and social activities). Physical therapy is often prescribed next to medical treatment but there is a lack of uniform treatment. A systematic literature search for guidelines, systematic reviews, trials, and expert opinions lead to a better understanding. The key question: Is physiotherapy able to optimally treat the Parkinson's disease symptoms? In which way, how and on which scientific bases can the physiotherapist participate to improve autonomy and to help them living independently and avoid, as long as possible, institutionalization? This article has integrated clinical research findings to provide clinicians with an overview to physical therapist management of disorders in people with Parkinson's disease. An Evidence-Based Physical Therapy Guideline providing practice recommendations was developed by the Royal Dutch Society for Physical Therapy (KNGF). Evidence from research was supplemented with clinical expertise and patients values. Randomized clinical trials reflect specific core areas of physical therapy, that is, transfer, posture, balance, reaching and grasping, gait and physical condition. Another aspect is that of educating patients (as well as their partners and family) about the disease process and the benefits of exercise therapy. Alternative therapies can be helpful like Tai Chi, virtual games, dancing, yoga, ball games for example.
Tan, Eng King; Cheng, Lan; Zhang, Jin Hong; Mao, Xue Ye; Chang, Xue Li; Zhao, Dong Mei; Liao, Qiao; Peng, Rong
Background The manganese superoxide dismutase (MnSOD) gene, which encodes a chief reactive oxygen species (ROS) scavenging enzyme, has been reported to be associated with the risk of developing sporadic Parkinson's disease (PD) in some Asian races and the synapsin III (SYN3) gene with some neuropsychiatric diseases. Objective: To explore the associations between the MnSOD and SYN III variations and PD in two Chinese populations from mainland China and Singapore. Methods We recruited 2342 subjects including 1200 sporadic PD patients and 1142 healthy controls from two independent Asian countries. Using a case-control methodology, we genotyped the single nucleotide polymorphisms (SNP) in MnSOD (rs4880) and SYN III (rs3788470, rs3827336, rs5998557) to explore the associations with risk of PD. Results The results showed the genotype distributions and minor allele frequencies (MAF) of MnSOD (rs4880) and SYN III (rs3788470, rs3827336, rs5998557) were not significantly different between PD patients and healthy controls in mainland China and Singapore, as well as in merged populations. Conclusions The variations of MnSOD (rs4880) and SYN III (rs3788470, rs3827336, rs5998557) were not major risk factors for PD among Chinese, at least in our study populations. PMID:24586301
Calderón-Fajardo, Humberto; Cervantes-Arriaga, Amin; Llorens-Arenas, Rodrigo; Ramírez-Bermudez, Jesús; Ruiz-Chow, Ángel; Rodríguez-Violante, Mayela
Purpose To analyze the effectiveness of electroconvulsive therapy for the management of depression and/or psychosis refractory to drug therapy in patients with Parkinson disease.Methods A retrospective study was carried out including patients treated with electroconvulsive therapy during the period between 2002 and 2013. A review of the literature was performed.Results A total of 27 patients were included. In regards to the neuropsychiatric diagnosis, 14 patients had major depression, 12 patients had both psychosis and depression, and only one patient had isolated psychosis. The mean number of electroconvulsive therapy sessions was 12 ± 2.8. After electroconvulsive therapy, all patients showed a statistically significant improvement in the Brief Psychiatric Rating scale (reduction of 52% points) and Hamilton Depression Rating Scale (reduction of 50% points) independent of the presence of psychosis, depression or both.Conclusion Electroconvulsive therapy is effective for the treatment of refractory neuropsychiatric symptoms in Parkinson's disease.
Dai, Limeng; Wang, Dongmei; Meng, Hui; Zhang, Kun; Fu, Liyuan; Wu, Yuanyuan; Bai, Yun
Epidemiological studies have evaluated the associations between brain-derived neurotrophic factor (BDNF) polymorphisms and Parkinson's disease (PD) risk. However, the results remain inconsistent. Therefore, we conducted a meta-analysis of published case-control studies to better understand these results. Systematic searches of electronic databases Embase, PubMed and Web of Science, as well as hand searching of the references of identified articles were performed. The pooled odds ratio (OR) with 95% confidence interval (CI) were calculated. All the statistical tests were performed using Review Manager 5.1 and Stata 11.0. A total of 13 case-control studies were included, involving two polymorphisms (G196A and C270T) of BDNF gene and covering 3333 PD cases and 3418 controls. No significant associations were found on the overall analysis both G196A and C270T polymorphisms. In the subgroup analysis by ethnicity (Caucasian, Asian and Mixed population), there were still no detectable associations. In conclusion, there is no enough evidence for associations between BDNF polymorphisms (G196A and C270T) and PD risk at present. Larger sample-size and multiethnicity studies with homogeneous PD patients and well-matched controls are needed in the future study.
Geissler, Julia M; Romanos, Marcel; Gerlach, Manfred; Berg, Daniela; Schulte, Claudia
Attention-deficit/hyperactivity disorder (ADHD) and Parkinson's disease (PD) involve pathological changes in brain structures such as the basal ganglia, which are essential for the control of motor and cognitive behavior and impulsivity. The cause of ADHD and PD remains unknown, but there is increasing evidence that both seem to result from a complicated interplay of genetic and environmental factors affecting numerous cellular processes and brain regions. To explore the possibility of common genetic pathways within the respective pathophysiologies, nine ADHD candidate single nucleotide polymorphisms (SNPs) in seven genes were tested for association with PD in 5333 cases and 12,019 healthy controls: one variant, respectively, in the genes coding for synaptosomal-associated protein 25 k (SNAP25), the dopamine (DA) transporter (SLC6A3; DAT1), DA receptor D4 (DRD4), serotonin receptor 1B (HTR1B), tryptophan hydroxylase 2 (TPH2), the norepinephrine transporter SLC6A2 and three SNPs in cadherin 13 (CDH13). Information was extracted from a recent meta-analysis of five genome-wide association studies, in which 7,689,524 SNPs in European samples were successfully imputed. No significant association was observed after correction for multiple testing. Therefore, it is reasonable to conclude that candidate variants implicated in the pathogenesis of ADHD do not play a substantial role in PD.
Tekin, Izel; Carkaci-Salli, Nurgul; Lewis, Mechelle M.; Mailman, Richard B.; Huang, Xuemei; Vrana, Kent E.
Introduction Many of the symptoms and signs of Parkinson's disease (PD) arise from the death of midbrain dopamine neurons that utilize tyrosine hydroxylase (TH) as the rate-limiting enzyme in catecholamine biosynthesis. Methods We investigated whether the presence of a common TH polymorphism affects the clinical outcomes in 101 PD subjects. We further examined the effect of this polymorphism on the purified recombinant enzyme. Results PD subjects homozygous for the common V81M polymorphism, have higher overall freezing of gait scores after controlling for disease duration, although this polymorphism does not associate with the occurrence of PD or FOG. In vitro functional assays on pure recombinant wild type TH and V81M TH revealed that the Km of the mutant enzyme for tyrosine was twice that of the wild-type. This polymorphism, however, did not change the stability of the enzyme, nor did it affect the Vmax or Km for the co-substrate BH4. Conclusion The data suggest that presence of a homozygous V81M polymorphism is associated with more severe FOG, possibly due to lower catecholamine synthetic capacity. Further studies are warranted to investigate the role of subtle changes in catecholamine availability in the development of FOG. PMID:26732803
Marotta, Nicholas P.; Lin, Yu Hsuan; Lewis, Yuka E.; Ambroso, Mark R.; Zaro, Balyn W.; Roth, Maxwell T.; Arnold, Don B.; Langen, Ralf; Pratt, Matthew R.
Several aggregation-prone proteins associated with neurodegenerative diseases can be modified by O-linked N-acetyl-glucosamine (O-GlcNAc) in vivo. One of these proteins, α-synuclein, is a toxic aggregating protein associated with synucleinopathies, including Parkinson's disease. However, the effect of O-GlcNAcylation on α-synuclein is not clear. Here, we use synthetic protein chemistry to generate both unmodified α-synuclein and α-synuclein bearing a site-specific O-GlcNAc modification at the physiologically relevant threonine residue 72. We show that this single modification has a notable and substoichiometric inhibitory effect on α-synuclein aggregation, while not affecting the membrane binding or bending properties of α-synuclein. O-GlcNAcylation is also shown to affect the phosphorylation of α-synuclein in vitro and block the toxicity of α-synuclein that was exogenously added to cells in culture. These results suggest that increasing O-GlcNAcylation may slow the progression of synucleinopathies and further support a general function for O-GlcNAc in preventing protein aggregation.
Walton, Courtney C; Naismith, Sharon L; Lampit, Amit; Mowszowski, Loren; Lewis, Simon J G
Cognitive impairment is now widely accepted as a fundamental aspect of Parkinson's disease (PD). Given the prevalence of cognitive impairment and the associated impact on well-being, evidence-based interventions are needed. However, while research is continually accumulating in order to better understand the pathology and trajectory of cognitive changes, treatment options lag behind. Nonpharmacological approaches are of particular interest in this group, given the typical polypharmacy already present in PD patients. In this regard, cognitive training (CT) is a relatively new and prominent therapeutic option with accumulating scientific support and increasing public awareness. Research has now established benefits across many different populations, and trials investigating the use of CT specifically in PD are becoming more common. We offer a brief summary of CT and its efficacy in PD samples to date, as well as discuss areas requiring further exploration in this group. Crucially, we suggest that CT should be supported as a research priority in PD, given both proven and potential benefits as a noninvasive and well-tolerated behavioral intervention for cognitive impairment.
Trinh, Joanne; Farrer, Matt
Parkinson disease (PD) is a multifactorial neurodegenerative disease that was long considered the result of environmental factors. In the past 15 years, however, a genetic aetiology for PD has begun to emerge. Here, we review results from linkage and next-generation sequencing studies of familial parkinsonism, as well as candidate gene and genome-wide association findings in sporadic PD. In these studies, many of the genetic findings overlap, despite different designs and study populations, highlighting novel therapeutic targets. The molecular results delineate a sequence of pathological events whereby deficits in synaptic exocytosis and endocytosis, endosomal trafficking, lysosome-mediated autophagy and mitochondrial maintenance increase susceptibility to PD. These discoveries provide the rationale, molecular insight and research tools to develop neuroprotective and disease-modifying therapies.
Shulman, Lisa M
Because estrogen has numerous effects on dopamine neurotransmission, many researchers are interested in its possible use to either slow the progression or reduce the risk of Parkinson's disease (PD). The incidence of PD is greater in men than in women. Gender differences in neurotoxicity have been observed, and basic research in experimental animals indicates that estrogen protects neurons from various forms of injury. However, the results of retrospective surveys of the neuroprotective effects of estrogen replacement in PD have been mixed, with some showing no effect on risk and others showing a reduction in risk. A mildly significant gender difference in disability and quality-of-life reporting has been noted, with women citing greater disability and reduced quality of life. Gender differences have been shown in response to treatment of PD, for example, in how levodopa is metabolized--women have greater levodopa bioavailability. In the Parkinson's Disease on Estrogen Therapy Replacement in the Menopause Years (POETRY) study, participants were found to have improved scores on the Unified Parkinson Disease Rating Scale. Based on the POETRY results, it is hypothesized that estrogen replacement therapy (ERT) may lead to improvement in PD symptoms and provide an opportunity to reduce the dosage of antiparkinsonian medication in women.
Nanhoe-Mahabier, Wandana; de Laat, Karlijn F; Visser, Jasper E; Zijlmans, Jan; de Leeuw, Frank-Erik; Bloem, Bastiaan R
Optimal management of chronic diseases not only requires tackling of the primary disease processes, but also necessitates timely recognition and treatment of comorbid conditions. In this article, we illustrate this two-pronged approach for two common age-related disorders: Parkinson disease (PD) and cerebrovascular disease (CVD). We first discuss the pathophysiological mechanisms that could provide a link between PD and CVD. Patients with PD have a series of risk factors that could promote development of CVD, but also have several protective factors. We then review the available clinical, radiological and neuropathological evidence to support an association between these two conditions. We conclude by discussing the potential implications for clinical practice, highlighting how comorbid CVD could alter the clinical presentation of PD and reviewing the possibilities for prevention and secondary prophylaxis. Additional research will be needed to fully evaluate the prevalence and clinical relevance of comorbid CVD in PD. Pending further evidence, we recommend that cerebral neuroimaging should be considered if patients with initially uncomplicated PD develop-either acutely or chronically-prominent and/or treatment-resistant gait impairment, postural instability, depression, cognitive decline, or urinary incontinence. Finding comorbid CVD in such patients could have prognostic implications, and could necessitate treatment to arrest further progression of CVD.
Cho, Sang Soo; Aminian, Kelly; Li, Crystal; Lang, Anthony E; Houle, Sylvain; Strafella, Antonio P
Fatigue is a common and disabling non-motor symptom in Parkinson's disease associated with a feeling of overwhelming lack of energy. The aim of this study was to identify the neural substrates that may contribute to the development of fatigue in Parkinson's disease. Twenty-three Parkinson's disease patients meeting UK Brain Bank criteria for the diagnosis of idiopathic Parkinson's disease were recruited and completed the 2-[(18) F]fluoro-2-deoxy-D-glucose (FDG)-PET scan. The metabolic activities of Parkinson's disease patients with fatigue were compared to those without fatigue using statistical parametric mapping analysis. The Parkinson's disease group exhibiting higher level of fatigue showed anti-correlated metabolic changes in cortical regions associated with the salience (i.e., right insular region) and default (i.e., bilateral posterior cingulate cortex) networks. The metabolic abnormalities detected in these brain regions displayed a significant correlation with level of fatigue and were associated with a disruption of the functional correlations with different cortical areas. These observations suggest that fatigue in Parkinson's disease may be the expression of metabolic abnormalities and impaired functional interactions between brain regions linked to the salience network and other neural networks. Hum Brain Mapp 38:283-292, 2017. © 2016 Wiley Periodicals, Inc.
Rittman, Timothy; Rubinov, Mikail; Vértes, Petra E; Patel, Ameera X; Ginestet, Cedric E; Ghosh, Boyd C P; Barker, Roger A; Spillantini, Maria Grazia; Bullmore, Edward T; Rowe, James B
Abnormalities of tau protein are central to the pathogenesis of progressive supranuclear palsy, whereas haplotype variation of the tau gene MAPT influences the risk of Parkinson disease and Parkinson's disease dementia. We assessed whether regional MAPT expression might be associated with selective vulnerability of global brain networks to neurodegenerative pathology. Using task-free functional magnetic resonance imaging in progressive supranuclear palsy, Parkinson disease, and healthy subjects (n = 128), we examined functional brain networks and measured the connection strength between 471 gray matter regions. We obtained MAPT and SNCA microarray expression data in healthy subjects from the Allen brain atlas. Regional connectivity varied according to the normal expression of MAPT. The regional expression of MAPT correlated with the proportionate loss of regional connectivity in Parkinson's disease. Executive cognition was impaired in proportion to the loss of hub connectivity. These effects were not seen with SNCA, suggesting that alpha-synuclein pathology is not mediated through global network properties. The results establish a link between regional MAPT expression and selective vulnerability of functional brain networks to neurodegeneration.
Ghanbari, Mohsen; Darweesh, Sirwan K L; de Looper, Hans W J; van Luijn, Marvin M; Hofman, Albert; Ikram, M Arfan; Franco, Oscar H; Erkeland, Stefan J; Dehghan, Abbas
MicroRNAs (miRNAs) are small noncoding RNAs that serve as key regulators of gene expression. They have been shown to be involved in a wide range of biological processes including neurodegenerative diseases. Genetic variants in miRNAs or miRNA-binding sites on their target genes could affect miRNA function and contribute to disease risk. Here, we investigated the association of miRNA-related genetic variants with Parkinson disease (PD) using data from the largest GWAS on PD. Of 243 miRNA variants, we identified rs897984:T>C in miR-4519 (P value = 1.3×10(-5) and OR = 0.93) and rs11651671:A>G in miR-548at-5p (P value = 1.1×10(-6) and OR = 1.09) to be associated with PD. We showed that the variant's mutant alleles change the secondary structure and decrease expression level of their related miRNAs. Subsequently, we highlighted target genes that might mediate the effects of miR-4519 and miR-548at-5p on PD. Among them, we experimentally showed that NSF is a direct target of miR-4519. Furthermore, among 48,844 miRNA-binding site variants, we found 32 variants (within 13 genes) that are associated with PD. Four of the host genes, CTSB, STX1B, IGSF9B, and HSD3B7, had not previously been reported to be associated with PD. We provide evidence supporting the potential impact of the identified miRNA-binding site variants on miRNA-mediated regulation of their host genes.
Rasheed, Mohd Sami Ur; Tripathi, Sonam; Mishra, Saumya; Singh, Mahendra Pratap
Unwarranted exposure due to liberal use of metals for maintaining the lavish life and to achieve the food demand for escalating population along with an incredible boost in the average human life span owing to orchestrated progress in rejuvenation therapy have gradually increased the occurrence of Parkinson's disease (PD). Etiology is albeit elusive; association of PD with metal accumulation has never been overlooked due to noteworthy similitude between metal-exposure symptoms and a few cardinal features of disease. Even though metals are entailed in the vital functions, a hysterical shift, primarily augmentation, escorts the stern nigrostriatal dopaminergic neurodegeneration. An increase in the passage of metals through the blood brain barrier and impaired metabolic activity and elimination system could lead to metal accumulation in the brain, which eventually makes dopaminergic neurons quite susceptible. In the present article, an update on implication of metal accumulation in PD/Parkinsonism has been provided. Moreover, encouraging and paradoxical facts and fictions associated with metal accumulation in PD/Parkinsonism have also been compiled. Systematic literature survey of PD is performed to describe updated information if metal accumulation is an epicenter or merely an outcome. Finally, a perspective on the association of metal accumulation with pesticide-induced Parkinsonism has been explained to unveil the likely impact of the former in the latter.
Sweet, Eric S.; Saunier-Rebori, Bernadette
Parkinson's disease (PD) is a major movement disorder characterized by the loss of dopamine neurons and formation of Lewy bodies. Clinical and pathological evidence indicates that multiple brain regions are affected in PD in a spatiotemporal manner and are associated with a variety of motor and nonmotor symptoms, including disturbances in mood, executive function, and memory. The common PD-associated gene for leucine-rich repeat kinase, leucine-rich repeat kinase 2 (LRRK2), is highly expressed in brain regions that are involved with nonmotor functions, including the neocortex and hippocampus, but whether mutant LRRK2 contributes to neuronal dysfunction in these regions is unknown. Here, we use bacterial artificial chromosome transgenic mouse models of LRRK2 to explore potential nonmotor mechanisms of PD. Through electrophysiological analysis of the Schaffer collateral–CA1 synapse in dorsal hippocampus, we find that overexpression of LRRK2-G2019S increases basal synaptic efficiency through a postsynaptic mechanism, and disrupts long-term depression. Furthermore, these effects of the G2019S mutation are age dependent and can be normalized by acute inhibition of LRRK2 kinase activity. In contrast, overexpression of wild-type LRRK2 has no effect under the same conditions, suggesting a specific phenotype for the G2019S mutation. These results identify a pathogenic function of LRRK2 in the hippocampus that may contribute to nonmotor symptoms of PD. SIGNIFICANCE STATEMENT Parkinson's disease (PD) is among the most common neurological diseases and is best known for its adverse effects on brain regions that control motor function, resulting in tremor, rigidity, and gait abnormalities. Less well appreciated are the psychiatric symptoms experienced by many PD patients, including depression and memory loss, which do not respond well to currently available treatments for PD. Here, we describe functional effects of a common PD-linked mutation of leucine-rich repeat kinase 2 in
Skalisz, Luana L; Beijamini, Vanessa; Joca, Samia L; Vital, Maria A B F; Da Cunha, Claudio; Andreatini, Roberto
The aim of the present study was to develop an animal model for the study of depressive symptoms associated with Parkinson's disease (PD). Mice treated intraperitoneally with reserpine (RES), 2.0 and 1.0 mg/kg, or its vehicle (VEHIC) were submitted to the sucrose solution (2%) consumption test (a model employed to mimic the depressive symptoms found in PD) and to the spontaneous locomotor activity test (a model employed to mimic the motor impairment found in PD). All animals were submitted to both tests. Twenty-four hours after treatment, only RES 2.0-treated animals showed a significantly decreased preference for the sucrose solution (mean +/- S.E.M. RES 2.0 = 54.4 +/- 4.1%, RES 1.0 = 68.5 +/- 2.5%, VEHIC = 62.3 +/- 4.1%). There was no significant difference among groups in water, sucrose or total fluid consumption. Locomotor activity was significantly decreased by both RES doses (number of beam interruptions: RES 2.0 = 59.9 +/- 11.4, RES 1.0 = 82.2 +/- 9.7, VEHIC = 116.8 +/- 8.2). Thus, RES 2.0 administration to mice induced depressive (anhedonia) and motor (decreased locomotor activity) symptoms of depression-PD association. This suggests that the RES model shows an important aspect of face validity for the depressive state associated with PD, i.e., phenomenological similarities between the model and the situation being modeled.
Piray, Payam; Zeighami, Yashar; Bahrami, Fariba; Eissa, Abeer M; Hewedi, Doaa H; Moustafa, Ahmed A
A substantial subset of Parkinson's disease (PD) patients suffers from impulse control disorders (ICDs), which are side effects of dopaminergic medication. Dopamine plays a key role in reinforcement learning processes. One class of reinforcement learning models, known as the actor-critic model, suggests that two components are involved in these reinforcement learning processes: a critic, which estimates values of stimuli and calculates prediction errors, and an actor, which estimates values of potential actions. To understand the information processing mechanism underlying impulsive behavior, we investigated stimulus and action value learning from reward and punishment in four groups of participants: on-medication PD patients with ICD, on-medication PD patients without ICD, off-medication PD patients without ICD, and healthy controls. Analysis of responses suggested that participants used an actor-critic learning strategy and computed prediction errors based on stimulus values rather than action values. Quantitative model fits also revealed that an actor-critic model of the basal ganglia with different learning rates for positive and negative prediction errors best matched the choice data. Moreover, whereas ICDs were associated with model parameters related to stimulus valuation (critic), PD was associated with parameters related to action valuation (actor). Specifically, PD patients with ICD exhibited lower learning from negative prediction errors in the critic, resulting in an underestimation of adverse consequences associated with stimuli. These findings offer a specific neurocomputational account of the nature of compulsive behaviors induced by dopaminergic drugs.
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Atadzhanov, M; Zumla, A; Mwaba, P
Objective: The aims of this study were (A) to determine inheritance patterns of familial Parkinson's disease in three different geographical areas (Russia, Uzbekistan, and Zambia); (B) compare clinical characteristics of familial with sporadic Parkinson's disease; and (C) assess whether there were ethnic differences in clinical manifestations of the disease. Methods: Fifty two index cases of familial Parkinson's disease in Moscow, 55 in Tashkent, and 27 in Lusaka were selected on the basis of the typical clinical features of Parkinson's disease with a familial history. The sex ratio, transmission patterns, and segregation ratio were determined by pedigree analysis. Results: Familial Parkinson's disease was found in all three countries (30 families in Russia, 12 in Uzbekistan, and seven in Zambia), and appeared more common in Russia. Both autosomal dominant and autosomal recessive patterns of inheritance were seen, but autosomal dominance was more common in all countries. Conclusions: In all three countries men have a higher risk of developing Parkinson's disease than women and there are ethnic differences in clinical manifestations of the disease. The onset of both familial and sporadic Parkinson's disease in Zambian patients occurs at a younger age and is associated with slow progression and a benign course, and generally responds well to levodopa treatment. PMID:15701745
Xiromerisiou, Georgia; Dardiotis, Efthimios; Tsimourtou, Vaïa; Kountra, Persa Maria; Paterakis, Konstantinos N; Kapsalaki, Eftychia Z; Fountas, Kostas N; Hadjigeorgiou, Georgios M
Over the past few years, considerable progress has been made in understanding the molecular mechanisms of Parkinson disease (PD). Mutations in certain genes are found to cause monogenic forms of the disorder, with autosomal dominant or autosomal recessive inheritance. These genes include alpha-synuclein, parkin, PINK1, DJ-1, LRRK2, and ATP13A2. The monogenic variants are important tools in identifying cellular pathways that shed light on the pathogenesis of this disease. Certain common genetic variants are also likely to modulate the risk of PD. International collaborative studies and meta-analyses have identified common variants as genetic susceptibility risk/protective factors for sporadic PD.
Kumudini, Nadella; Uma, Addepally; Devi, Yalavarthy Prameela; Naushad, Shaik Mohammad; Mridula, Rukmini; Borgohain, Rupam; Kutala, Vijay Kumar
Several epidemiologic studies have suggested an association between the Parkinson's disease (PD) and exposure to heavy metals, such as lead, iron, copper, manganese, etc. A growing body of evidence suggests that heavy metals stimulate free radical formation in the brain and can lead to neurodegeneration. In the present study, we investigated whether such association exists in PD cases from rural and urban areas in our study population. The plasma levels of copper, iron, manganese and lead in PD cases (n = 150) and controls (n = 170) were determined by inductively coupled plasma mass spectrometry (ICP-MS) and correlated with the oxidative stress markers like malondialdehyde (MDA), protein carbonyl and total glutathione. Results indicated significant increase in the levels of copper (17.73 +/- 4.48 vs. 13.0 + 3.22 ng/ml) and iron (554.4 +/- 123.8 vs. 421.7 +/- 126.1 ng/ml) in PD cases compared to controls, whereas no significant differences in the levels of manganese and lead were observed. Further, the data based on urban or rural residence showed that plasma copper, iron, manganese levels were comparatively higher in rural subjects, whereas plasma lead levels were significantly higher in urban subjects. Increased plasma iron showed positive correlation with marker of lipid peroxidation (MDA), suggesting that increased iron levels induced oxidative stress in PD. These results substantiated the earlier observations about the role of environmental exposure and metal-induced oxidative stress in the etiology of PD.
Edwards, Todd L.; Scott, William K.; Almonte, Cherylyn; Burt, Amber; Powell, Eric H.; Beecham, Gary W.; Wang, Liyong; Züchner, Stephan; Konidari, Ioanna; Wang, Gaofeng; Singer, Carlos; Nahab, Fatta; Scott, Burton; Stajich, Jeffrey M.; Pericak-Vance, Margaret; Haines, Jonathan; Vance, Jeffery M.; Martin, Eden R.
SUMMARY Parkinson disease (PD) is a chronic neurodegenerative disorder with a cumulative prevalence of greater than one per thousand. To date three independent genome-wide association studies (GWAS) have investigated the genetic susceptibility to PD. These studies have also implicated several genes as PD risk loci with strong, but not genome-wide significant, associations. In this study, we combined data from two previously published GWAS of Caucasian subjects with our GWAS of 604 cases and 619 controls for a joint analysis with a combined sample size of 1752 cases and 1745 controls. SNPs in SNCA (rs2736990, p-value = 6.7×10−8; genome-wide adjusted p = 0.0109, odds ratio (OR) = 1.29 [95% CI: 1.17–1.42] G vs. A allele, population attributable risk percent (PAR%) = 12%) and the MAPT region (rs11012, p-value = 5.6×10−8; genome-wide adjusted p = 0.0079, OR = 0.70 [95% CI: 0.62–0.79] T vs. C allele, PAR% = 8%) were genome-wide significant. No other SNPs were genome-wide significant in this analysis. This study confirms that SNCA and the MAPT region are major genes whose common variants are influencing risk of PD. PMID:20070850
Delgado-Camprubi, Marta; Esteras, Noemi; Soutar, Marc PM; Plun-Favreau, Helene; Abramov, Andrey Y
The Parkinson's disease (PD)-related protein F-box only protein 7 (Fbxo7) is the substrate-recognition component of the Skp1-Cullin-F-box protein E3 ubiquitin ligase complex. We have recently shown that PD-associated mutations in Fbxo7 disrupt mitochondrial autophagy (mitophagy), suggesting a role for Fbxo7 in modulating mitochondrial homeostasis. Here we report that Fbxo7 deficiency is associated with reduced cellular NAD+ levels, which results in increased mitochondrial NADH redox index and impaired activity of complex I in the electron transport chain. Under these conditions of compromised respiration, mitochondrial membrane potential and ATP contents are reduced, and cytosolic reactive oxygen species (ROS) production is increased. ROS activates poly (ADP-ribose) polymerase (PARP) activity in Fbxo7-deficient cells. PARP inhibitor restores cellular NAD+ content and redox index and ATP pool, suggesting that PARP overactivation is cause of decreased complex I-driven respiration. These findings bring new insight into the mechanism of Fbxo7 deficiency, emphasising the importance of mitochondrial dysfunction in PD. PMID:27689878
Edwards, Todd L; Scott, William K; Almonte, Cherylyn; Burt, Amber; Powell, Eric H; Beecham, Gary W; Wang, Liyong; Züchner, Stephan; Konidari, Ioanna; Wang, Gaofeng; Singer, Carlos; Nahab, Fatta; Scott, Burton; Stajich, Jeffrey M; Pericak-Vance, Margaret; Haines, Jonathan; Vance, Jeffery M; Martin, Eden R
Parkinson disease (PD) is a chronic neurodegenerative disorder with a cumulative prevalence of greater than one per thousand. To date three independent genome-wide association studies (GWAS) have investigated the genetic susceptibility to PD. These studies implicated several genes as PD risk loci with strong, but not genome-wide significant, associations. In this study, we combined data from two previously published GWAS of Caucasian subjects with our GWAS of 604 cases and 619 controls for a joint analysis with a combined sample size of 1752 cases and 1745 controls. SNPs in SNCA (rs2736990, p-value = 6.7 x 10(-8); genome-wide adjusted p = 0.0109, odds ratio (OR) = 1.29 [95% CI: 1.17-1.42] G vs. A allele, population attributable risk percent (PAR%) = 12%) and the MAPT region (rs11012, p-value = 5.6 x 10(-8); genome-wide adjusted p = 0.0079, OR = 0.70 [95% CI: 0.62-0.79] T vs. C allele, PAR%= 8%) were genome-wide significant. No other SNPs were genome-wide significant in this analysis. This study confirms that SNCA and the MAPT region are major genes whose common variants are influencing risk of PD.
Grover, Sandeep; Somaiya, Mansi; Kumar, Santhosh; Avasthi, Ajit
Parkinson's disease (PD) is essentially characterized by the motor symptoms in the form of resting tremor, rigidity and bradykinesia. However, over the years it has been recognized that motor symptoms are just the “tip of the iceberg” of clinical manifestations of PD. Besides motor symptoms, PD characterized by many non-motor symptoms, which include cognitive decline, psychiatric disturbances (depression, psychosis and impulse control), sleep difficulties, autonomic failures (gastrointestinal, cardiovascular, urinary, thermoregulation) and pain syndrome. This review evaluates the various aspects of psychiatric disorders including cognitive decline and sleep disturbances in patients with PD. The prevalence rate of various psychiatric disorders is high in patients with PD. In terms of risk factors, various demographic, clinical and treatment-related variables have been shown to be associated with higher risk of development of psychiatric morbidity. Evidence also suggests that the presence of psychiatric morbidity is associated with poorer outcome. Randomized controlled trials, evaluating the various pharmacological and non-pharmacological treatments for management of psychiatric morbidity in patients with PD are meager. Available evidence suggests that tricyclic antidepressants like desipramine and nortriptyline are efficacious for management of depression. Among the antipsychotics, clozapine is considered to be the best choice for management of psychosis in patients with PD. Among the various cognitive enhancers, evidence suggest efficacy of rivastigmine in management of dementia in patients with PD. To conclude, this review suggests that psychiatric morbidity is highly prevalent in patients with PD. Hence, a multidisciplinary approach must be followed to improve the overall outcome of PD. Further studies are required to evaluate the efficacy of various other measures for management of psychiatric morbidity in patients with PD. PMID:25552854
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Brooks, D J
Positron emission tomography (PET) and single photon emission tomography (SPECT) provide sensitive means for quantifying the loss of nigrostriatal dopaminergic fibres in Parkinson's disease and for detecting the presence of dopaminergic dysfunction in asymptomatic at-risk relatives and patients with isolated tremor. Functional imaging can also be used to follow the rate of disease progression objectively, determine the efficacy of putative neuroprotective agents, and monitor the viability of transplants of fetal tissue. Additionally, in vivo pharmacological changes associated with development of treatment complications (fluctuations, dyskinesias) can be studied. Loss of dopaminergic projections produces profound changes in resting and activated brain metabolism. PET and SPECT activation studies have suggested that the akinesia of Parkinson's disease is associated with failure to activate the supplementary motor and dorsal pre-frontal areas. Activation of these cortical areas is restored towards normal by the use of dopaminergic medication, striatal transplantation with fetal mesencephalic tissue, and pallidotomy. The aim of this chapter is to review the insight which functional imaging has given us into the pathophysiology of parkinsonism.
Sterling, Nicholas W; Lichtenstein, Maya; Lee, Eun-Young; Lewis, Mechelle M; Evans, Alicia; Eslinger, Paul J; Du, Guangwei; Gao, Xiang; Chen, Honglei; Kong, Lan; Huang, Xuemei
Plasma low density lipoprotein (LDL) cholesterol has been associated both with risk of Parkinson's disease (PD) and with age-related changes in cognitive function. This prospective study examined the relationship between baseline plasma LDL-cholesterol and cognitive changes in PD and matched Controls. Fasting plasma LDL-cholesterol levels were obtained at baseline from 64 non-demented PD subjects (62.7 ± 7.9 y) and 64 Controls (61.3 ± 6.8 y). Subjects underwent comprehensive neuropsychological testing at baseline, 18-, and 36-months. Linear mixed-effects modeling was used to assess the relationships between baseline LDL-cholesterol levels and longitudinal cognitive changes. At baseline, PD patients had lower scores of fine motor (p<0.0001), executive set shifting (p=0.018), and mental processing speed (p=0.049) compared to Controls. Longitudinally, Controls demonstrated improved fine motor and memory test scores (p=0.044, and p=0.003), whereas PD patients demonstrated significantly accelerated loss in fine motor skill (p=0.002) compared to Controls. Within the PD group, however, higher LDL-cholesterol levels were associated with improved executive set shifting (β=0.003, p<0.001) and fine motor scores (β=0.002, p=0.030) over time. These associations were absent in Controls (p>0.7). The cholesterol - executive set shifting association differed significantly between PDs and Controls (interaction p=0.005), whereas the cholesterol - fine motor association difference did not reach significance (interaction, p=0.104). In summary, higher plasma LDL-cholesterol levels were associated with better executive function and fine motor performance over time in PD, both of which may reflect an effect on nigrostriatal mediation. Confirmation of these results and elucidation of involved mechanisms are warranted, and might lead to feasible therapeutic strategies.
Chen, Yueh-Sheng; Chen, Meng-Hsiang; Lu, Cheng-Hsien; Chen, Pei-Chin; Chen, Hsiu-Ling; Yang, I-Hsiao; Tsai, Nai-Wen; Lin, Wei-Che
Early-onset Parkinson's disease (EOPD) patients are symptomatic at a relatively young age, and the impacts of the disease on both the patients and their caregivers are dramatic. Few studies have reported on the cognitive impairments seen in EOPD, and the results of these studies have been diverse. Furthermore, it is still unclear what microstructural white matter (WM) changes are present in EOPD patients. As such, we conducted this study to investigate the microstructural WM changes experienced by EOPD patients and their association with cognitive function and plasma DNA levels. We enrolled 24 EOPD patients and 33 sex- and age-matched healthy volunteers who underwent complete neuro-psychological testing (NPT) to evaluate their cognitive function and diffusion tensor imaging (DTI) scanning to determine their fiber integrity. The plasma DNA measurements included measurements of nuclear and mitochondrial DNA levels. Fractional anisotropy (FA) maps were compared using voxel-based statistics to determine differences between the two groups. The differences in DTI indices and NPT scores were correlated after adjusting for age, sex, and education. Our results demonstrate that patients with EOPD have elevated nuclear DNA levels and wide spectrums of impairments in NPT, especially in the executive function and visuospatial function domains. Exploratory group-wise comparisons of the DTI indices revealed that the patients with EOPD exhibited lower DTI parameters in several brain locations. These poorer DTI parameters were associated with worse cognitive performances and elevated plasma nuclear DNA levels, especially in the anterior thalamic radiation region. Our findings suggest that the thalamus and its adjacent anterior thalamic radiation may be important in the pathogenesis of EOPD, as they appear to become involved in the disease process at an early stage. PMID:28174514
Opara, J A; Brola, W; Leonardi, M; Błaszczyk, B
In this review report, current possibilities of evaluation of quality of life in Parkinson's disease have been critically presented. Health Related Quality of Life (-HRQoL) comprises a wide spectrum of consequences of the disease. Measurement of quality of life has become increasingly relevant as an outcome parameter, especially in long-term trials. Most of the available QoL instruments depend on patient self-reports. The data can be collected by written questionnaires. There are universal questionnaires of QoL--for many diseases and the specific ones--specially created for one disease. Among universal questionnaires, the Sickness Impact Profile (SIP) and the Short-Form Health Status Survey (SF-36) are the most popular in Parkinson's disease. As for specific questionnaires: the Parkinson`s Disease Questionnaire (PDQ-39) and the Parkinson's Disease Quality of Life Questionnaire (PDQL) have been described.
Aiello, Marilena; Eleopra, Roberto; Rumiati, Raffella I
Research on eating behaviours has extensively highlighted that cognitive systems interact with the metabolic system in driving food intake and in influencing body weight regulation. Parkinson's disease is a good model for studying these complex interactions since alterations in both body weight and cognitive domains have been frequently reported among these patients. Interestingly, even if different non-motor symptoms may characterize the course of the disease, their contribution to weight and food preference has been poorly investigated. This review describes body weight alterations and eating habits in patients with Parkinson's disease, including those who underwent deep brain stimulation surgery. In particular, the review considers the link between non-motor symptoms, affecting sensory perception, cognition, mood and motivation, and food intake and weight alterations. The take home message is twofold. First, we recommend a comprehensive approach in order to develop effective strategies in the management of patients' weight. Second, we also suggest that investigating this issue in patients with Parkinson's disease may provide some useful information about the mechanisms underlying food and weight regulation in healthy subjects.
Lill, C M; Klein, C
Parkinson's disease (PD) is the second most common neurodegenerative disease and has a growing socioeconomic impact due to demographic changes in the industrial nations. There are several forms of PD, a fraction of which (<5%) are monogenic, i. e. caused by mutations in single genes. At present, six genes have been established for the clinically classical form of parkinsonism including three autosomal dominantly (SNCA, LRRK2, VPS35) and three autosomal recessively inherited ones (Parkin, PINK1, DJ-1). In addition, there are a plethora of genes causing atypical forms of parkinsonism. In contrast, idiopathic PD is of a multifactorial nature. Genome-wide association studies have established a total of 26 genetic loci for this form of the disease; however, for most of these loci the underlying functional genetic variants have not yet been identified and the respective disease mechanisms remain unresolved. Furthermore, there are a number of environmental and life style factors that are associated with idiopathic PD. Exposure to pesticides and possibly a history of head trauma represent genuine risk factors. Other PD-associated factors, such as smoking and intake of coffee and alcohol may not represent risk factors per se and the cause-effect relationship has not yet been elucidated for most of these factors. A patient with a positive family history and/or an early age of disease onset should undergo counseling with respect to a possible monogenic form of the disease. Disease prediction based on genetic, environmental and life style factors is not yet possible for idiopathic PD and potential gene-specific therapies are currently in the development or early testing phase.
Sánchez-Pérez, Ana María; Claramonte-Clausell, Berta; Sánchez-Andrés, Juan Vicente; Herrero, María Trinidad
It is generally accepted that a correlation between neurodegenerative disease and protein aggregation in the brain exists; however, a causal relationship has not been elucidated. In neurons, failure of autophagy may result in the accumulation of aggregate-prone proteins and subsequent neurodegeneration. Thus, pharmacological induction of autophagy to enhance the clearance of intracytoplasmic aggregate-prone proteins has been considered as a therapeutic strategy to ameliorate pathology in cell and animal models of neurodegenerative disorders. However, autophagy has also been found to be a factor in the onset of these diseases, which raises the question of whether autophagy induction is an effective therapeutic strategy, or, on the contrary, can result in cell death. In this paper, we will first describe the autophagic machinery, and we will consider the literature to discuss the neuroprotective effects of autophagy. PMID:23125941
Sánchez-Pérez, Ana María; Claramonte-Clausell, Berta; Sánchez-Andrés, Juan Vicente; Herrero, María Trinidad
It is generally accepted that a correlation between neurodegenerative disease and protein aggregation in the brain exists; however, a causal relationship has not been elucidated. In neurons, failure of autophagy may result in the accumulation of aggregate-prone proteins and subsequent neurodegeneration. Thus, pharmacological induction of autophagy to enhance the clearance of intracytoplasmic aggregate-prone proteins has been considered as a therapeutic strategy to ameliorate pathology in cell and animal models of neurodegenerative disorders. However, autophagy has also been found to be a factor in the onset of these diseases, which raises the question of whether autophagy induction is an effective therapeutic strategy, or, on the contrary, can result in cell death. In this paper, we will first describe the autophagic machinery, and we will consider the literature to discuss the neuroprotective effects of autophagy.
Rajapakse, Senaka; Abeynaike, Lakshan; Wickramarathne, Thanushi
A 43-year-old male patient with idiopathic Parkinson disease, on dopaminergic therapy, was admitted with confusion and agitation, diaphoresis, and hyperkinesia after the commencement of the serotonin-noradrenaline reuptake inhibitor venlafaxine 2 weeks prior for depression. He was found to have severe rhabdomyolysis and developed acute renal failure. The most likely diagnosis was serotonin syndrome induced by venlafaxine, although neuroleptic malignant syndrome was also considered. The differential diagnosis, atypical features in this presentation, and possible mechanisms are discussed.
Braak, Heiko; Bohl, Jürgen R; Müller, Christian M; Rüb, Udo; de Vos, Rob A I; Del Tredici, Kelly
The synucleinopathy known as sporadic Parkinson's disease (PD) is a multisystem disorder that severely damages predisposed nerve cell types in circumscribed regions of the human nervous system. A recent staging procedure for the inclusion body pathology associated with PD proposes that, in the brain, the pathological process (formation of proteinaceous intraneuronal Lewy bodies and Lewy neurites) begins at two sites and continues in a topographically predictable sequence in six stages, during which components of the olfactory, autonomic, limbic, and somatomotor systems become progressively involved. In stages 1 to 2, the Lewy body pathology is confined to the medulla oblongata/pontine tegmentum and anterior olfactory structures. In stages 3 to 4, the substantia nigra and other nuclei of the basal mid- and forebrain become the focus of initially subtle and, then, severe changes. During this phase, the illness probably becomes clinically manifest. In the final stages 5 to 6, the lesions appear in the neocortex. This cross-sectional study originally was performed on 168 autopsy cases using material from 69 incidental cases and 41 clinically diagnosed PD patients as well as 58 age- and gender-matched controls. Here, the staging hypothesis is critically reconsidered and discussed.
Anderson, Grant; Noorian, Ali Reza; Taylor, Georgia; Anitha, Mallappa; Bernhard, Doug; Srinivasan, Shanthi; Greene, James G.
Gastrointestinal (GI) dysfunction is the most common non-motor symptom of Parkinson's disease (PD). Symptoms of GI dysmotility include early satiety and nausea from delayed gastric emptying, bloating from poor small bowel coordination, and constipation and defecatory dysfunction from impaired colonic transit. Understanding the pathophysiology and treatment of these symptoms in PD patients has been hampered by the lack of investigation into GI symptoms and pathology in PD animal models. We report that the prototypical parkinsonian neurotoxin, MPTP (1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine), is a selective dopamine neuron toxin in the enteric nervous system (ENS). When examined 10 days after treatment, there was a 40% reduction of dopamine neurons in the ENS of C57Bl/6 mice administered MPTP (60 mg/kg). There were no differences in the density of cholinergic or nitric oxide neurons. Electrophysiological recording of neural-mediated muscle contraction in isolated colon from MPTP-treated animals confirmed a relaxation defect associated with dopaminergic degeneration. Behaviorally, MPTP induced a transient increase in colon motility, but no changes in gastric emptying or small intestine transit. These results provide the first comprehensive assessment of gastrointestinal pathophysiology in an animal model of PD. They provide insight into the impact of dopaminergic dysfunction on gastrointestinal motility and a benchmark for assessment of other PD model systems. PMID:17586496
Mariscal, A; Medrano, I Hernández; Cánovas, A Alonso; Lobo, E; Loinaz, C; Vela, L; Espiga, P García-Ruiz; Castrillo, J C Martínez
One of the particular characteristics of Parkinson's disease (PD) is the wide clinical variation as regards the treatment that can be found in the same patient. This occurs with specific treatment for PD, as well as with other drug groups that can make motor function worse. For this reason, the perioperative management of PD requires experience and above all appropriate planning. In this article, the peculiarities of PD and its treatment are reviewed, and a strategy is set out for the perioperative management of these patients.
Bandrés, Sara; Durán, Raquel; Barrero, Francisco; Ramírez, Manuel; Vives, Francisco
Parkinson's disease (PD) is a neurodegenerative disorder that affects movement and is caused by the death of the dopaminergic neurons in the compact part of the substantia nigra. Its diagnosis is essentially clinical, but although the signs and symptoms of PD are well known, the rate of diagnostic error is relatively high. It is estimated that 10-30% of patients initially diagnosed with PD are later reclassified. This disease has a high prevalence beyond the age of 60, and one of its biggest problems is that it is diagnosed when the degenerative process is already at a very advanced stage. Therefore, it is necessary to look for other biomarkers that make it possible to carry out an early diagnosis of PD, follow up its development, distinguish it from other related pathologies (parkinsonisms) and help monitor the effect of novel therapies. The fact that there are mutations that lead to PD, as well as polygenetic combinations that can act as risk factors, suggests the possibility of measuring the proteins resulting from the expression of these genes in peripheral tissues. And once their sensitivity and specificity have been proved they could be used as biomarkers for PD, even in the early phases of the disease. The aim of this work is to focus on a detailed review of the main candidate proteomic biomarkers researched to date by discussing the most recent literature.
Srivastav, Saurabh; Singh, Sandeep Kumar; Yadav, Amarish Kumar; Srikrishna, Saripella
parkin loss associated early-onset of Parkinson's disease, involves mitochondrial dysfunction and oxidative stress as the plausible decisive molecular mechanisms in disease pathogenesis. Mitochondrial dysfunction involves several up/down regulation of gene products, one of which being p53 is found to be elevated. Elevated p53 is involved in mitochondrial mediated apoptosis of neuronal cells in Parkinson's patients who are folate deficient as well. The present study therefore attempts to examine the effect of Folic acid (FA) supplementation in alleviation of anomalies associated with parkin knockdown using RNAi approach, specific to Dopaminergic (DA) neurons in Drosophila model system. Here we show that FA supplementation provide protection against parkin RNAi associated discrepancies, thereby improves locomotor ability, reduces mortality and oxidative stress, and partially improves Zn levels. Further, metabolic active cell status and ATP levels were also found to be improved thereby indicating improved mitochondrial function. To corroborate FA supplementation in mitochondrial functioning further, status of p53 and spargel was checked by qRT-PCR. Here we show that folic acid supplementation enrich mitochondrial functioning as depicted from improved spargel level and lowered p53 level, which was originally vice versa in parkin knockdown flies cultured in standard media. Our data thus support the potential of folic acid in alleviating the behavioural defects, oxidative stress, augmentation of zinc and ATP levels in parkin knock down flies. Further, folic acid role in repressing mitochondrial dysfunction is encouraging to further explore its possible mechanistic role to be utilized as potential therapeutics for Parkinson's disease.
Frandsen, Rune; Kjellberg, Jakob; Ibsen, Rikke; Jennum, Poul
Background Nonmotor symptoms are probably present prior to, early on, and following, a diagnosis of Parkinson's disease. Nonmotor symptoms may hold important information about the progression of Parkinson's disease. Objective To evaluated the total early and prediagnostic morbidities in the 3 years before a hospital contact leading to a diagnosis of Parkinson's disease. Methods Retrospective morbidity data from Danish National Patient Registry records (1997–2007) of 10,490 adult patients with a secondary care diagnosis of Parkinson's disease were compared with 42,505 control cases. Results Parkinson's disease was associated with significantly higher morbidity rates associated with conditions in the following categories: mental and psychiatric, nervous system, gastrointestinal, musculoskeletal system and connective tissue, genitourinary, abnormal clinical and laboratory findings, injury, poisoning and certain other external causes, and other factors influencing health status and contact with health services. It was negatively associated with neoplasm, cardiovascular, and respiratory diseases. Conclusions Patients with a diagnosis of Parkinson's disease present significant differences in morbidities early on, following, and prior to, their diagnosis, compared with healthy controls. PMID:24944873
Higgins, D C; Haidri, N H; Wilbourn, A J
The muscle silent period was measured in 11 patients with moderate to severe rigidity associated with Parkinson's disease. The determinations were made under conditions of maximum disability for each patient, since all medications had been withdrawn before testing. The duration of the EMG silence, produced by small and large electrical twitch contractions of the adductor pollicis muscle, fell within a range of values previously determined for normal individuals. Major alleviation of the rigidity and bradykinesia with chronic oral l-dopa therapy was not accompanied by any change in the silent period. It was concluded that in untreated Parkinsonism, and also after its treatment with l-dopa, the functioning of the muscle spindles and local inhibitory reflexes remains normal.
Teixeira, Felipe Roberti; Randle, Suzanne J.; Patel, Shachi P.; Mevissen, Tycho E.T.; Zenkeviciute, Grasilda; Koide, Tie; Komander, David; Laman, Heike
Fbxo7 is a clinically relevant F-box protein, associated with both cancer and Parkinson's disease (PD). Additionally, SNPs within FBXO7 are correlated with alterations in red blood cell parameters. Point mutations within FBXO7 map within specific functional domains, including near its F-box domain and its substrate recruiting domains, suggesting that deficiencies in SCFFbxo7/PARK15 ubiquitin ligase activity are mechanistically linked to early-onset PD. To date, relatively few substrates of the ligase have been identified. These include HURP (hepatoma up-regulated protein), whose ubiquitination results in proteasome-mediated degradation, and c-IAP1 (inhibitor of apoptosis protein 1), TNF receptor-associated factor 2 (TRAF2), and NRAGE, which are not destabilized as a result of ubiquitination. None of these substrates have been linked directly to PD, nor has it been determined whether they would directly engage neuronal cell death pathways. To discover ubiquitinated substrates of SCFFbxo7 implicated more directly in PD aetiology, we conducted a high-throughput screen using protein arrays to identify new candidates. A total of 338 new targets were identified and from these we validated glycogen synthase kinase 3β (Gsk3β), which can phosphorylate α-synuclein, and translocase of outer mitochondrial membrane 20 (Tomm20), a mitochondrial translocase that, when ubiquitinated, promotes mitophagy, as SCFFbxo7 substrates both in vitro and in vivo. Ubiquitin chain restriction analyses revealed that Fbxo7 modified Gsk3β using K63 linkages. Our results indicate that Fbxo7 negatively regulates Gsk3β activity, rather than its levels or localization. In addition, Fbxo7 ubiquitinated Tomm20, and its levels correlated with Fbxo7 expression, indicating a stabilizing effect. None of the PD-associated mutations in Fbxo7 impaired Tomm20 ubiquitination. Our findings demonstrate that SCFFbxo7 has an impact directly on two proteins implicated in pathological processes leading to PD
Chen, Sheng; Le, Weidong
During the past decade, there has been a remarkable progress in our understanding of the biology of Parkinson disease (PD), which has been translated into searching for novel therapy for PD. Much focus is shifted from the development of drugs that only relieve PD symptoms to new generation of remedies that can potentially protect dopaminergic neurons and modify the disease course. Several novel therapeutic approaches have been tested in preclinical experiments and in clinical trials, including molecules targeting on genes involved in the pathogenesis of the disease, neurotrophic factors critical for dopaminergic neuron survival and function, new generation of dopamine receptor agonists that may possess neuroprotective effects, and agents of antioxidation, antiinflammation, and antiapoptosis. The results of these studies will shed new light to our hope that PD can be cured in the future.
Parkes, J D; Marsden, C D; Donaldson, I; Galea-Debono, A; Walters, J; Kennedy, G; Asselman, P
Thirty-one patients with Parkinson's disease were treated with the ergot alkaloid bromocriptine, a drug which stimulates dopamine receptors. Bromocriptine had a slight therapeutic effect in patients on no other treatment and an additional effect in patients on levodopa. The mean optimum dosage of bromocriptine, established over a 12 week period, was 26 mg daily. In 20 patients bromocriptine was compared with placebo in a double-blind controlled trial. Active treatment caused a significant (P less than 0.02) reduction in total disability and akinesia scores. The least disabled patients showed the greatest response. Side-effects of bromocriptine--nausea, vomiting, hallucinations, and abnormal involuntary movements--were similar to nature to those of levodopa. In most normal subjects, bromocriptine causes an increase in plasma growth hormone concentration. This was determined in 20 patients with Parkinson's disease after 1-15 mg bromocriptine. Only a single patient showed an obvious increase up to 120 minutes after dosage. Bromocriptine was not effective treatment in two patients who had not previously responded to levodopa and replacement of this drug by bromocriptine in patients with end-of-dose akinesia after chronic levodopa treatment did not totally abolish response swings. PMID:772175
Xie, Yi; Feng, Hongliang; Peng, Sisi; Xiao, Jinsong; Zhang, Junjian
Hyperhomocysteinemia has been associated with cognitive disorders such as mild cognitive impairment, Alzheimer's disease and vascular dementia. Previous studies showed that levodopa-treated Parkinson's disease (PD) patients were likely to have elevated homocysteine levels. In addition, epidemiological evidence found that cognitive impairment presented in the vast majority of PD patients. However, what role homocysteine played in cognitive function of PD patients remained debated. Therefore, we conducted this meta-analysis to investigate the possible correlations among cognitive function, homocysteine, folate and vitamin B12 levels in PD patients. A structured literature search was carried out on Pubmed, Springer, EMbase, Cochrane library, CNKI, VP and Wanfang database up to April 2016 using strict inclusion criteria. Data on demographic information, levodopa equivalent dosage, homocysteine, folate and vitamin B12 levels and Mini Mental Scale Examination scores were collected and pooled. The mean difference (MD) with 95% confidence intervals (CIs) was used as the effect size. Of 75 articles identified, 15 were eligible for inclusion. The results suggested that PD patients with cognitive dysfunction were likely to have higher homocysteine levels(MD=5.05, 95%CI [4.03, 6.07]), lower folate(MD=-0.21, 95%CI [-0.34, -0.08]) and vitamin B12 levels(MD=-47.58, 95%CI [-72.07, -23.09]). We again verified a close relationship between hyperhomocysteinemia and PD (MD=5.67, 95%CI [4.40, 6.94]). We concluded that hyperhomocysteinemia was related to cognitive impairment of PD patients, and further studies should focus on the intervention to lower homocysteine level, hopefully to provide useful advice for clinical practice.
Planetta, Peggy J; Ofori, Edward; Pasternak, Ofer; Burciu, Roxana G; Shukla, Priyank; DeSimone, Jesse C; Okun, Michael S; McFarland, Nikolaus R; Vaillancourt, David E
Conventional single tensor diffusion analysis models have provided mixed findings in the substantia nigra of Parkinson's disease, but recent work using a bi-tensor analysis model has shown more promising results. Using a bi-tensor model, free-water values were found to be increased in the posterior substantia nigra of Parkinson's disease compared with controls at a single site and in a multi-site cohort. Further, free-water increased longitudinally over 1 year in the posterior substantia nigra of Parkinson's disease. Here, we test the hypothesis that other parkinsonian disorders such as multiple system atrophy and progressive supranuclear palsy have elevated free-water in the substantia nigra. Equally important, however, is whether the bi-tensor diffusion model is able to detect alterations in other brain regions beyond the substantia nigra in Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy and to accurately distinguish between these diseases. Free-water and free-water-corrected fractional anisotropy maps were compared across 72 individuals in the basal ganglia, midbrain, thalamus, dentate nucleus, cerebellar peduncles, cerebellar vermis and lobules V and VI, and corpus callosum. Compared with controls, free-water was increased in the anterior and posterior substantia nigra of Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy. Despite no other changes in Parkinson's disease, we observed elevated free-water in all regions except the dentate nucleus, subthalamic nucleus, and corpus callosum of multiple system atrophy, and in all regions examined for progressive supranuclear palsy. Compared with controls, free-water-corrected fractional anisotropy values were increased for multiple system atrophy in the putamen and caudate, and increased for progressive supranuclear palsy in the putamen, caudate, thalamus, and vermis, and decreased in the superior cerebellar peduncle and corpus callosum. For all disease
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Távora, Daniel Gurgel Fernandes; de Bruin, Veralice Meireles Sales; Lopes Gama, Romulo; Lopes, Emily Mourão Soares; Jorge, Iago Farias; de Bruin, Pedro Felipe Carvalhedo
Objectives Excessive daytime sleepiness (EDS) and sudden sleep onset (SOS) episodes are frequent in Parkinson׳s disease (PD). The objectives are to identify clinical characteristics and factors associated with EDS and SOS episodes. Methods Clinical demographic data were recorded (N=100, mean age=65.0±10.4). EDS was identified by the Epworth Sleepiness Scale (ESS>10) and SOS episodes were registered. Disease severity was evaluated by the Unified Parkinson׳s Disease Rating Scale (UPDRS, I, II, and III), sleep disturbances by the Parkinson׳s Disease Sleep Scale (PDSS<100), depressive symptoms by the Beck Depression Inventory (BDI>10) and rapid eye movement (REM) sleep behavior disorder (RBD) by the REM sleep behavior scale. Levodopa equivalent dose was measured. Results: PD patients with EDS (67%) were predominately male (73.1%) and had worse disease severity (UPDRS II and III p= 0.005); SOS episodes (39%) were associated with disease duration, diabetes, sleep disturbances (PDSS Scale), disease severity (UPDRS I, II, III) and RBD symptoms (p<0.05). Stepwise regression analysis showed that EDS was independently associated with motor-symptoms severity (UPDRS III scale, p=0.003). SOS episodes were independently associated with disease duration (p=0.006) and sleep disturbances (PDSS scale, p=0.03): patients had more uncomfortable immobility at night, tremor on waking and snoring or difficult breathing. Discussion EDS and or SOS episodes are frequent and manifest a differential pattern in PD. SOS episodes are associated with longer disease duration, diabetes, sleep disturbances and RBD symptoms indicating that these “sleep attacks” are of multifactorial origin and probably influenced by brain structural abnormalities. PMID:26483896
Hisahara, Shin; Shimohama, Shun
Parkinson's disease (PD) is a progressive extrapyramidal motor disorder. Pathologically, this disease is characterized by the selective dopaminergic (DAergic) neuronal degeneration in the substantia nigra. Correcting the DA deficiency in PD with levodopa (L-dopa) significantly attenuates the motor symptoms; however, its effectiveness often declines, and L-dopa-related adverse effects emerge after long-term treatment. Nowadays, DA receptor agonists are useful medication even regarded as first choice to delay the starting of L-dopa therapy. In advanced stage of PD, they are also used as adjunct therapy together with L-dopa. DA receptor agonists act by stimulation of presynaptic and postsynaptic DA receptors. Despite the usefulness, they could be causative drugs for valvulopathy and nonmotor complication such as DA dysregulation syndrome (DDS). In this paper, physiological characteristics of DA receptor familyare discussed. We also discuss the validity, benefits, and specific adverse effects of pharmaceutical DA receptor agonist. PMID:25954517
Jones, Jeffrey M
James Parkinson is credited with the first complete clinical description of the syndrome attributed to his name, Parkinson disease. It is recognized as the first syndrome defined after neurology became a specialty. Descriptions of Parkinson features are rare in antiquity, and famous people with this disorder have not been found before the 1800s. During the 20th century, more and more famous people appear to be afflicted with Parkinson, and this article reviews some of those who have withstood the "test of Time magazine," and examines some of the reasons why the syndrome is a relatively recent disorder.
Paillusson, S; Lebouvier, T; Pouclet, H; Coron, E; Bruley des Varannes, S; Damier, P; Neunlist, M; Derkinderen, P
It has become increasingly evident over the last years that Parkinson's disease is a multicentric neurodegenerative disease that affects several neuronal structures outside the substantia nigra, among which is the enteric nervous system. The aims of the present article are to discuss the role of the enteric nervous system lesions in pathology spreading (Braak's hypothesis) and in the gastrointestinal dysfunction encountered in Parkinson's disease. Owing to its accessibility to biopsies, we further discuss the use of the enteric nervous system as an original source of biomarker in Parkinson's disease.
Elstein, Deborah; Alcalay, Roy; Zimran, Ari
In the last decade, several lines of evidence have been presented that document the clinical manifestations, genetic associations, and sub-cellular mechanisms of the inter-relatedness of β-glucocerebrosidase mutations and the emergence of Parkinson disease among carriers and patients with Gaucher disease. This review is an attempt to apprise the reader of the recent literature with the caveat that this is an area of intensive exploration that is constantly being updated because of the immediate clinical ramifications but also because of the impact on our understanding of Parkinson disease, and finally because of the unexpected inter-reactions between these entities on the molecular level. It has been an unexpected happenstance that it has been discovered that a rare monogenetic disease has an interface at many points with a neurological disorder of the elderly that has both familial and sporadic forms: to date there is no cure for either of these disorders.
Advances in the field of stem cell research have raised hopes of creating novel cell replacement therapies for Parkinson disease (PD), although double-blinded clinical trials have met with controversial success in patients implanted with fetal midbrain tissue and autopsy results have shown that some of the grafted fetal neurons displayed pathological changes typical of PD. Dopaminergic neurons have been efficiently derived from stem cells using various methods, and beneficial effects after transplantation have been demonstrated in animal models of PD. Some obstacles remain to be overcome before stem cell therapy can be routinely and safely used to treat PD in humans. A widely used prodrug/suicide gene therapy would be applied to stem cells to reduce risk of tumor formation. Since grafts were transplanted ectopically into the striatum instead of the substantia nigra in most current protocols, surviving dopaminergic neurons would not have to be the same subtype as the nigral cells. If the main mechanism underlying any functional recovery achieved by cell therapies is restoration of dopaminergic neurotransmission, then viral vector-mediated gene delivery of dopamine-synthesizing enzymes represents a more straightforward approach. Future targets for cell therapy should include some types of Parkinsonism with degeneration of striatal neurons.
Katus, Linn; Shtilbans, Alexander
Parkinson's disease is the second most common neurodegenerative disease worldwide, leading to a wide range of disability and medical complications. Managing patients with Parkinson's disease in the perioperative hospital setting can be particularly challenging. Suboptimal management can lead to medical complications, prolonged hospital stays, and delayed recovery. This review aims to address the most important issues related to caring for patients with Parkinson's disease perioperatively who are undergoing emergent or planned general surgery. It also intends to help hospitalists, internists, and other health care providers mitigate potential in-hospital morbidity and prevent prolonged recovery. Challenges in managing patients with Parkinson's disease in the perioperative hospital setting include disruption of medication schedules, "nothing by mouth" status, reduced mobility, and medication interactions and their side effects. Patients with Parkinson's disease are more prone to immobility and developing dysphagia, respiratory dysfunction, urinary retention, and psychiatric symptoms. These issues lead to higher rates of pneumonia, urinary tract infections, deconditioning, and falls compared with patients without Parkinson's disease, as well as prolonged hospital stays and a greater need for post-hospitalization rehabilitation. Steps can be taken to decrease these complications, including minimizing nothing by mouth status duration, using alternative routes of drugs administration when unable to give medications orally, avoiding drug interactions and medications that can worsen parkinsonism, assessing swallowing ability frequently, encouraging incentive spirometry, performing bladder scans, avoiding Foley catheters, and providing aggressive physical therapy. Knowing and anticipating these potential complications allow hospital physicians to mitigate nosocomial morbidity and shorten recovery times and hospital stays.
Fellows, S J; Noth, J; Schwarz, M
In order to investigate sensorimotor processing and force development in Parkinson's disease, 16 patients, four patients with hemiparkinsonism and 12 age-matched normal subjects were assessed during lifting and holding of an object in a precision grip between thumb and forefinger, or holding the object in this grip at a fixed height above a table. In the former case, object loading could be changed between lifts without warning. In the latter case, unexpected step load changes to the object were applied to the object with a torque motor. All procedures could be applied with or without visual control of the hand and the object. Normal subjects lifted an unpredictable load employing the grip force parameters used in the preceding lift. If a load change was encountered, the parameters became adapted to the new conditions during the lift, modulating grip forces to match the loading. Parkinsonian patients retained this strategy and the ability to regulate grip forces according to load. Under all conditions, however, parkinsonian subjects developed abnormally high grip forces in both the lift and the hold phase, although the ratio of these forces remained normal. Lifting height was normal in parkinsonian subjects, but the duration of the lifting task was significantly prolonged, due to a marked slowing in the rate of grip force development in the lead-up to object lift-off and to prolongation of the movement phase. Forewarning of object loading, with or without visual control, did not reduce timing deficits or improve the rate of grip force development. However, it did allow parkinsonian subjects to reduce the safety margin significantly. Responses to step load changes imposed during holding without visual control showed minor abnormalities in the parkinsonian patients: onset latencies and EMG activity in the first dorsal interosseus and thenar muscles were normal up to 140 ms after displacement. Subsequent EMG activity in the first dorsal interosseus remained largely
Penko, Amanda L.; Hirsch, Joshua R.; Voelcker-Rehage, Claudia; Martin, Philip E.; Blackburn, Gordon; Alberts, Jay L.
Background Approximately 1.5 million Americans are affected by Parkinson's disease  which includes the symptoms of postural instability and gait dysfunction. Currently, clinical evaluations of postural instability and gait dysfunction consist of a subjective rater assessment of gait patterns using items from the Unified Parkinson's Disease Rating Scale, and assessments can be insensitive to the effectiveness of medical interventions. Current research suggests the importance of cycling for Parkinson's disease patients, and while Parkinson's gait has been evaluated in previous studies, little is known about lower extremity control during cycling. The purpose of this study is to examine the lower extremity coordination patterns of Parkinson's patients during cycling. Methods Twenty five participants, ages 44-72, with a clinical diagnosis of idiopathic Parkinson's disease participated in an exercise test on a cycle ergometer that was equipped with pedal force measurements. Crank torque, crank angle and power produced by right and left leg were measured throughout the test to calculate Symmetry Index at three stages of exercise (20 Watt, 60 Watt, maximum performance). Findings Decreases in Symmetry Index were observed for average power output in Parkinson's patients as workload increased. Maximum power Symmetry Index showed a significant difference in symmetry between performance at both the 20 Watt and 60 Watt stage and the maximal resistance stage. Minimum power Symmetry Index did not show significant differences across the stages of the test. While lower extremity asymmetries were present in Parkinson's patients during pedaling, these asymmetries did not correlate to postural instability and gait dysfunction Unified Parkinson's Disease Rating Scale scores. Interpretation This pedaling analysis allows for a more sensitive measure of lower extremity function than the Unified Parkinson's Disease Rating Scale and may help to provide unique insight into current and
Bortolanza, Mariza; Bariotto-Dos-Santos, Keila D; Dos-Santos-Pereira, Maurício; da-Silva, Célia Aparecida; Del-Bel, Elaine
Amantadine is the noncompetitive antagonist of N-methyl-D-aspartate, receptor activated by the excitatory neurotransmitter glutamate. It is the only effective medication used to alleviate dyskinesia induced by L-3,4-dihydroxyphenylalanine (L-DOPA) in Parkinson's disease patients. Unfortunately, adverse effects as abnormal involuntary movements (AIMs) known as L-DOPA-induced dyskinesia limit its clinical utility. Combined effective symptomatic treatment modalities may lessen the liability to undesirable events. Likewise drugs known to interfere with nitrergic system reduce AIMs in animal models of Parkinson's disease. We aimed to analyze an interaction between amantadine, neuronal nitric oxide synthase inhibitor (7-nitroindazole, 7NI), and nitric oxide donor (sodium nitroprusside, SNP) in 6-hydroxydopamine-(6-OHDA)-lesioned rats (microinjection in the medial forebrain bundle) presenting L-DOPA-induced dyskinesia (20 mg/kg, gavage, during 21 days). We confirm that 7NI-30 mg/kg, SNP-2/4 mg/kg and amantadine-40 mg/kg, individually reduced AIMs. Our results revealed that co-administration of sub-effective dose of amantadine (10 mg/kg) plus sub-effective dose of 7NI (20 mg/kg) potentiates the effect of reducing AIMs scores when compared to the effect of the drugs individually. No superior benefit on L-DOPA-induced AIMs was observed with the combination of amantadine and SNP. The results revealed that combination of ineffective doses of amantadine and 7NI represents a new strategy to increase antidyskinetic effect in L-DOPA-induced AIMs. It may provide additional therapeutic benefits to Parkinson's disease patients from these disabling complications at lower and thus safer and more tolerable doses than required when either drug is used alone. To close, we discuss the paradox of both nitric oxide synthase inhibitor and/or donor produced AIMs reduction by targeting nitric oxide synthase.
Kim, Young Eun; Jeon, Beom S
REM sleep behavior disorder (RBD) appears to have a predilection for some neurodegenerative disorders, especially synucleinopathies such as Parkinson's disease (PD), dementia with Lewy bodies and multiple system atrophy. The frequency of RBD in PD has been reported to variably range from 20 to 72%. RBD may precede or follow onset of parkinsonism. Idiopathic RBD may foreshadow neurodegenerative diseases, and RBD in patients with PD has several associated clinical factors although their causal or temporal relationships are not known. RBD may be associated with the development of hallucinations and dementia in PD. It has been reported that the male gender, old age, a non-tremor motor subtype, a more severe parkinsonism, fall, longer disease duration, autonomic dysfunction, and higher levodopa doses are factors associated with RBD in PD. This review will address the clinical implications of RBD as a preclinical marker of neurodegenerative diseases and PD phenotypes associated with RBD.
Riederer, P; Youdim, M B H; Mandel, S; Gerlach, M; Grünblatt, E
Parkinson's disease (PD) is thought to be associated with oxidative stress mechanisms, as well as with glutamate receptor abnormalities, ubiquitin-proteasome dysfunction, inflammatory and cytokine activation, dysfunction in neurotrophic factors, damage to mitochondria, cytoskeletal abnormalities, synaptic dysfunction and activation of apoptotic pathways. To investigate these hypotheses, many researchers have applied molecular biology techniques to the study of neuronal cell death in these conditions. In this article, we discuss recent findings of gene expression in PD that may elucidate the usage of specific new biomarkers for sporadic PD and point to novel drug developments.
Sarmiento, Fernanda; Atehortúa, Angélica; Martínez, Fabio; Romero, Eduardo
A reliable diagnosis of the Parkinson Disease lies on the objective evaluation of different motor sub-systems. Discovering specific motor patterns associated to the disease is fundamental for the development of unbiased assessments that facilitate the disease characterization, independently of the particular examiner. This paper proposes a new objective screening of patients with Parkinson, an approach that optimally combines ipsilateral global descriptors. These ipsilateral gait features are simple upper-lower limb relationships in frequency and relative phase spaces. These low level characteristics feed a simple SVM classifier with a polynomial kernel function. The strategy was assessed in a binary classification task, normal against Parkinson, under a leave-one-out scheme in a population of 16 Parkinson patients and 7 healthy control subjects. Results showed an accuracy of 94;6% using relative phase spaces and 82;1% with simple frequency relations.
O'Reilly, Eilis J; Gao, Xiang; Weisskopf, Marc G; Chen, Honglei; Schwarzschild, Michael A; Spiegelman, Donna; Ascherio, Alberto
Plasma urate has been consistently associated with a lower risk of Parkinson's disease in men, but it is less clear if this relation exists in women. Between 1990 and 2004, the authors conducted a nested case-control study among participants of the female-only Nurses' Health Study. In controls (n = 504), plasma urate was positively associated with age, body mass index, alcohol consumption, hypertension, and use of diuretics and was inversely associated with physical activity and postmenopausal hormone use, as expected. Mean urate levels were 5.04 mg/dL for cases (n = 101) and 4.86 mg/dL for controls (P = 0.17). The age-, smoking-, and caffeine-adjusted rate ratio comparing women in the highest (≥5.8 mg/dL) with those in the lowest (<4.0 mg/dL) quartile was 1.33 (95% confidence interval: 0.69, 2.57; P(trend) = 0.4). Further adjustment for body mass index, physical activity, history of hypertension, and postmenopausal hormone use did not change the results. Unlike in men, these findings do not support the hypothesis that urate is strongly associated with lower rates of Parkinson's disease among women.
Frasier, Mark; Chowdhury, Sohini; Eberling, Jamie; Sherer, Todd
Therapeutic development in Parkinson's disease is hampered by the paucity of well-validated biomarkers that can assist with diagnosis and/or tracking the progression of the disease. Since its inception, the Michael J Fox Foundation for Parkinson's Research has invested heavily in biomarker research and continues to prioritize discovery and development efforts. This article summarizes the history and evolution of the Michael J Fox Foundation's role in supporting biomarker research and lays out the current challenges in successfully developing markers that can be used to test therapies, while also providing a vision of future funding efforts in Parkinson's disease biomarkers.
Vilming, S T
The significance of restrictions on protein for patients with Parkinson's disease is reviewed. Large neutral amino acids and levodopa share the same saturated carrier system through the blood-brain-barrier. Fluctuating patients are sensitive to a decreased supply of levodopa from the blood, and clinical studies show that an increased concentration of large neutral amino acids in the blood decreases mobility and reduces "on-time". A reduction of protein intake to 0.75-0.8 g/kg body weight/day has been recommended. A protein redistribution diet implying that less than 10% of the daily protein is taken in daytime and the rest in the evening, gives best results. However, in the elderly, protein restrictions may lead to a lasting negative nitrogen balance, and even in younger patients the supply of certain minerals and vitamins may become too low or marginally adequate. The diet must therefore be used with caution.
Lakie, M; Mutch, W J
Finger tremor was investigated in 20 patients (age range 54-88 yr) diagnosed as suffering from idiopathic Parkinson's disease and six controls of a similar age and no known neurological abnormality. In nine of the patients tremor was not clinically obvious. When the tremor of these patients was recorded immediately after voluntary movement and subjected to instrumental analysis there were consistently observable differences from the controls. Such analysis may have diagnostic potential when there is clinical uncertainty. Surface EMG recordings were obtained from four patients. One patient had a large resting tremor with obvious reciprocating activity in flexors and extensors; in the others who had no symptomatic tremor there was reciprocating activity only after movement, and this died away in a few seconds as the induced tremor disappeared.
Delgado-Alvarado, Manuel; Gago, Belén; Navalpotro-Gomez, Irene; Jiménez-Urbieta, Haritz; Rodriguez-Oroz, María C
Cognitive decline is one of the most frequent and disabling nonmotor features of Parkinson's disease. Around 30% of patients with Parkinson's disease experience mild cognitive impairment, a well-established risk factor for the development of dementia. However, mild cognitive impairment in patients with Parkinson's disease is a heterogeneous entity that involves different types and extents of cognitive deficits. Because it is not currently known which type of mild cognitive impairment confers a higher risk of progression to dementia, it would be useful to define biomarkers that could identify these patients to better study disease progression and possible interventions. In this sense, the identification among patients with Parkinson's disease and mild cognitive impairment of biomarkers associated with dementia would allow the early detection of this process. This review summarizes studies from the past 25 years that have assessed the potential biomarkers of dementia and mild cognitive impairment in Parkinson's disease patients. Despite the potential importance, no biomarker has as yet been validated. However, features such as low levels of epidermal and insulin-like growth factors or uric acid in plasma/serum and of Aß in CSF, reduction of cerebral cholinergic innervation and metabolism measured by PET mainly in posterior areas, and hippocampal atrophy in MRI might be indicative of distinct deficits with a distinct risk of dementia in subgroups of patients. Longitudinal studies combining the existing techniques and new approaches are needed to identify patients at higher risk of dementia. © 2016 International Parkinson and Movement Disorder Society.
Wolters, Erik; Lees, Andrew J; Volkmann, Jens; van Laar, Teus; Hovestadt, Ad
The pathophysiology of Parkinson's disease is marked by the loss of dopaminergic neurons, which leads to striatal dopaminergic deficiency. This causes resting tremor, hypokinesia, rigidity, bradykinesia, and loss of postural reflexes. Most current treatments for Parkinson's disease aim to restore striatal dopamine signaling by increasing the supply of dopamine with oral levodopa (L-dopa), stimulating dopamine receptors directly using dopamine agonists, or inhibiting the reuptake of endogenous dopamine. L-dopa is standard therapy for patients with Parkinson's disease. However, with continued treatment and disease progression, the response to oral dopaminergic drugs becomes unstable and motor fluctuations emerge, including off periods and dyskinesia. Direct duodenal-administered infusible L-dopa/carbidopa is effective for the management of refractory motor fluctuations in some patient populations. However, enteral infusions cannot mimic the function of the normal dopaminergic brain, and around-the-clock constant-rate administration carries the risk of causing refractory off periods associated with severe immobility and hyperpyrexia. Subthalamic nucleus (STN) deep brain stimulation (DBS) is also a promising treatment. DBS passes a high-frequency electrical current into the target area, mimicking the effect of lesioning the stimulated area. However, this treatment requires invasive surgery and is appropriate for a limited segment of the patient population. This supplement provides a rationale for the use of continuous dopaminergic receptor stimulation and offers guidelines on the individualization of treatment decisions, with special focus on continuous L-dopa infusion and STN DBS. Erik Wolters, MD, PhD, offers an introduction to the impact of continuous L-dopa infusion. Andrew J. Lees, MD, FRCP, provides an overview of the physiologic response to L-dopa and reviews clinical pharmacologic studies of intravenous and intraduodenal L-dopa. Jens Volkmann, MD, discusses
Anang, Julius B.M.; Bertrand, Josie-Anne; Romenets, Silvia Rios; Latreille, Veronique; Panisset, Michel; Montplaisir, Jacques
Objective: We investigated an array of possible markers of early dementia in Parkinson disease. Methods: We performed a comprehensive assessment of autonomic, sleep, psychiatric, visual, olfactory, and motor manifestations in 80 patients with Parkinson disease who were dementia-free at baseline. After 4.4 years’ follow-up, patients were evaluated for dementia. Predictive variables were assessed using logistic regression adjusting for disease duration, follow-up duration, age, and sex. Results: Of 80 patients, 27 (34%) developed dementia. Patients destined to develop dementia were older and more often male (odds ratio [OR] = 3.64, p = 0.023). Those with baseline mild cognitive impairment had increased dementia risk (OR = 22.5, p < 0.001). REM sleep behavior disorder at baseline dramatically increased dementia risk (OR = 49.7, p = 0.001); however, neither daytime sleepiness nor insomnia predicted dementia. Higher baseline blood pressure increased dementia risk (OR = 1.37 per 10 mm Hg, p = 0.032). Orthostatic blood pressure drop was strongly associated with dementia risk (OR = 1.84 per 10 mm Hg, p < 0.001); having a systolic drop of >10 mm Hg increased dementia odds 7-fold (OR = 7.3, p = 0.002). Abnormal color vision increased dementia risk (OR = 3.3, p = 0.014), but olfactory dysfunction did not. Among baseline motor variables, proportion of gait involvement (OR = 1.12, p = 0.023), falls (OR = 3.02, p = 0.042), and freezing (OR = 2.63, p = 0.013), as well as the Purdue Pegboard Test (OR = 0.67, p = 0.049) and alternate tap test (OR = 0.97, p = 0.033) predicted dementia. Conclusion: Cardiovascular autonomic dysfunction, REM sleep behavior disorder, color discrimination ability, and gait dysfunction strongly predict development of dementia in Parkinson disease. PMID:25171928
Krüger, Rejko; Sharma, Manu; Riess, Olaf; Gasser, Thomas; Van Broeckhoven, Christine; Theuns, Jessie; Aasly, Jan; Annesi, Grazia; Bentivoglio, Anna Rita; Brice, Alexis; Djarmati, Ana; Elbaz, Alexis; Farrer, Matthew; Ferrarese, Carlo; Gibson, J Mark; Hadjigeorgiou, Georgios M; Hattori, Nobutaka; Ioannidis, John P A; Jasinska-Myga, Barbara; Klein, Christine; Lambert, Jean-Charles; Lesage, Suzanne; Lin, Juei-Jueng; Lynch, Timothy; Mellick, George D; de Nigris, Francesa; Opala, Grzegorz; Prigione, Alessandro; Quattrone, Aldo; Ross, Owen A; Satake, Wataru; Silburn, Peter A; Tan, Eng King; Toda, Tatsushi; Tomiyama, Hiroyuki; Wirdefeldt, Karin; Wszolek, Zbigniew; Xiromerisiou, Georgia; Maraganore, Demetrius M
High-profile studies have provided conflicting results regarding the involvement of the Omi/HtrA2 gene in Parkinson's disease (PD) susceptibility. Therefore, we performed a large-scale analysis of the association of common Omi/HtrA2 variants in the Genetic Epidemiology of Parkinson's disease (GEO-PD) consortium. GEO-PD sites provided clinical and genetic data including affection status, gender, ethnicity, age at study, age at examination (all subjects); age at onset and family history of PD (patients). Genotyping was performed for the five most informative SNPs spanning the Omi/HtrA2 gene in approximately 2-3 kb intervals (rs10779958, rs2231250, rs72470544, rs1183739, rs2241028). Fixed as well as random effect models were used to provide summary risk estimates of Omi/HtrA2 variants. The 20 GEO-PD sites provided data for 6378 cases and 8880 controls. No overall significant associations for the five Omi/HtrA2 SNPs and PD were observed using either fixed effect or random effect models. The summary odds ratios ranged between 0.98 and 1.08 and the estimates of between-study heterogeneity were not large (non-significant Q statistics for all 5 SNPs; I(2) estimates 0-28%). Trends for association were seen for participants of Scandinavian descent for rs2241028 (OR 1.41, p=0.04) and for rs1183739 for age at examination (cut-off 65 years; OR 1.17, p=0.02), but these would not be significant after adjusting for multiple comparisons and their Bayes factors were only modest. This largest association study performed to define the role of any gene in the pathogenesis of Parkinson's disease revealed no overall strong association of Omi/HtrA2 variants with PD in populations worldwide.
Mata, Ignacio F.; Leverenz, James B.; Weintraub, Daniel; Trojanowski, John Q.; Chen-Plotkin, Alice; Van Deerlin, Vivianna M.; Ritz, Beate; Rausch, Rebecca; Factor, Stewart A.; Wood-Siverio, Cathy; Quinn, Joseph F.; Chung, Kathryn A.; Peterson-Hiller, Amie L.; Goldman, Jennifer G.; Stebbins, Glenn T.; Bernard, Bryan; Espay, Alberto J.; Revilla, Fredy J.; Devoto, Johnna; Rosenthal, Liana S.; Dawson, Ted M.; Albert, Marilyn S.; Tsuang, Debby; Huston, Haley; Yearout, Dora; Hu, Shu-Ching; Cholerton, Brenna A.; Montine, Thomas J.; Edwards, Karen L.; Zabetian, Cyrus P.
Background Loss-of-function mutations in the GBA gene are associated with more severe cognitive impairment in PD, but the nature of these deficits is not well understood and whether common GBA polymorphisms influence cognitive performance in PD is not yet known. Objectives/Methods We screened the GBA coding region for mutations and the E326K polymorphism in 1,369 PD patients enrolled at 8 sites from the PD Cognitive Genetics Consortium. Participants underwent assessments of learning and memory (Hopkins Verbal Learning Test–Revised), working memory/executive function (Letter-Number Sequencing and Trail Making A and B), language processing (semantic and phonemic verbal fluency), visuospatial abilities (Benton Judgment of Line Orientation), and global cognitive function (Montreal Cognitive Assessment). We used linear regression to test for association between genotype and cognitive performance with adjustment for important covariates and accounted for multiple testing using Bonferroni corrections. Results Mutation carriers (n=60; 4.4%) and E326K carriers (n=65; 4.7%) had a higher prevalence of dementia (mutations, odds ratio =5.1; p=9.7 × 10−6; E326K, odds ratio =6.4; p=5.7 × 10−7) and lower performance on Letter-Number Sequencing (mutations, corrected p[pc]=9.0 × 10−4; E326K, pc=0.036), Trail Making B-A (mutations, pc=0.018; E326K, pc=0.018), and Benton Judgment of Line Orientation (mutations, pc=0.0045; E326K, pc=0.0013). Conclusions Both GBA mutations and E326K are associated with a distinct cognitive profile characterized by greater impairment in working memory/executive function and visuospatial abilities in PD patients. The discovery that E326K negatively impacts cognitive performance approximately doubles the proportion of PD patients we now recognize are at risk for more severe GBA-related cognitive deficits. PMID:26296077
Oguru, Miyako; Tachibana, Hisao; Toda, Kazuo; Okuda, Bungo; Oka, Nobuyuki
The purpose of this study was to investigate the prevalence and clinical correlates of apathy and depression in Parkinson disease (PD), and to clarify whether apathy can be dissociated from depression. One hundred fifty patients with PD completed the Beck Depression Inventory Second Edition (BDI-II), Starkstein's Apathy Scale (AS), and a quality of life (QOL) battery. Hoehn and Yahr (HY) staging, the Unified Parkinson's Disease Rating Scale (UPDRS), and the Mini-Mental State Examination (MMSE) were performed on the same day. Apathy (AS score > or = 16) was diagnosed in 60% of patients and depression (BDI-II score > or = 14) in 56%. Apathy coexisted with depression in 43% of patients, compared with depression without apathy in 13% and apathy without depression in 17%. Apathy scale score was significantly correlated with UPDRS scores, HY stage, and age, whereas BDI-II score was correlated only with UPDRS scores. Both AS and BDI-II scores were negatively correlated with QOL. However, multiple regression analysis revealed that depression was strongly and negatively associated with emotional well-being and communication, whereas apathy was mainly associated with cognition and stigma. These findings suggest that apathy and depression may be separable in PD, although both are common in patients with PD and are associated with QOL.
Mak, Elijah; Su, Li; Williams, Guy B; Firbank, Michael J; Lawson, Rachael A; Yarnall, Alison J; Duncan, Gordon W; Owen, Adrian M; Khoo, Tien K; Brooks, David J; Rowe, James B; Barker, Roger A; Burn, David J; O'Brien, John T
Mild cognitive impairment in Parkinson's disease is associated with progression to dementia (Parkinson's disease dementia) in a majority of patients. Determining structural imaging biomarkers associated with prodromal Parkinson's disease dementia may allow for the earlier identification of those at risk, and allow for targeted disease modifying therapies. One hundred and five non-demented subjects with newly diagnosed idiopathic Parkinson's disease and 37 healthy matched controls had serial 3 T structural magnetic resonance imaging scans with clinical and neuropsychological assessments at baseline, which were repeated after 18 months. The Movement Disorder Society Task Force criteria were used to classify the Parkinson's disease subjects into Parkinson's disease with mild cognitive impairment (n = 39) and Parkinson's disease with no cognitive impairment (n = 66). Freesurfer image processing software was used to measure cortical thickness and subcortical volumes at baseline and follow-up. We compared regional percentage change of cortical thinning and subcortical atrophy over 18 months. At baseline, cases with Parkinson's disease with mild cognitive impairment demonstrated widespread cortical thinning relative to controls and atrophy of the nucleus accumbens compared to both controls and subjects with Parkinson's disease with no cognitive impairment. Regional cortical thickness at baseline was correlated with global cognition in the combined Parkinson's disease cohort. Over 18 months, patients with Parkinson's disease with mild cognitive impairment demonstrated more severe cortical thinning in frontal and temporo-parietal cortices, including hippocampal atrophy, relative to those with Parkinson's disease and no cognitive impairment and healthy controls, whereas subjects with Parkinson's disease and no cognitive impairment showed more severe frontal cortical thinning compared to healthy controls. At baseline, Parkinson's disease with no cognitive impairment
Lamont, Robyn M; Morris, Meg E; Woollacott, Marjorie H; Brauer, Sandra G
People with Parkinson's disease often have walking difficulty, and this is likely to be exacerbated while walking in places in the community, where people are likely to face greater and more varied challenges. This study aims to understand the facilitators and the barriers to walking in the community perceived by people with Parkinson's disease. This qualitative study involved 5 focus groups (n = 34) of people with Parkinson's disease and their partners residing in metropolitan and rural regions in Queensland, Australia. Results found that people with PD reported to use internal personal strategies as facilitators to community walking, but identified primarily external factors, particularly the environmental factors as barriers. The adoption of strategies or the use of facilitators allows people with Parkinson's disease to cope so that participants often did not report disability.
Watts, R L; Mandir, A S; Ahn, K J; Juncos, J L; Zakers, G O; Freeman, A
We have been interested in the application of quantitative measures of motor performance as a possible means of early detection of Parkinson's disease. To assess motor function, we have measured movement time (the physiologic correlate of bradykinesia) and reaction time (simple and directional choice) with an upper limb motor task, and tremor with accelerometry and electromyographic recordings. In this report we describe preliminary data from a Parkinson's disease patient group with symptoms of fewer than 2 years' average duration (compared with an age- and gender-matched normal control group) which indicate that precise, quantitative tests of motor function can detect the slight deviations from normal that are present in early Parkinson's disease. It appears that tests of bradykinesia are most sensitive, and detection of rest tremor is most specific. These tests may be applicable in screening individuals who are suspected of having or are "at risk for" Parkinson's disease and other related disorders.
Watts, R L; Mandir, A S; Ahn, K J; Juncos, J L; Zakers, G O; Freeman, A
We have been interested in the application of quantitative measures of motor performance as a possible means of early detection of Parkinson's disease. To assess motor function, we have measured movement time (the physiologic correlate of bradykinesia) and reaction time (simple and directional choice) with an upper limb motor task, and tremor with accelerometry and electromyographic recordings. In this report we describe preliminary data from a Parkinson's disease patient group with symptoms of fewer than 2 years' average duration (compared with an age- and gender-matched normal control group) which indicate that precise, quantitative tests of motor function can detect the slight deviations from normal that are present in early Parkinson's disease. It appears that tests of bradykinesia are most sensitive, and detection of rest tremor is most specific. These tests may be applicable in screening individuals who are suspected of having or are "at risk for" Parkinson's disease and other related disorders.
Schapira, A H; Holt, I J; Sweeney, M; Harding, A E; Jenner, P; Marsden, C D
The reduced form of nicotinamide adenine dinucleotide coenzyme Q reductase (complex I) activity has recently been shown to be deficient in the substantia nigra of patients dying with Parkinson's disease. This biochemical defect is identical to that produced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which also produces parkinsonism in humans. Complex I comprises 25 polypeptides, seven of which are encoded by mitochondrial DNA. Restriction fragment analysis of substantia nigra DNA from six patients with Parkinson's disease did not show any major deletion. In two cases, there were different novel polymorphisms that were not observed in control brain (n = 6) or blood (n = 34) samples.
Stoddard, S L
This paper reviews the literature describing the condition of the adrenal medulla in Parkinson's disease. Parkinson's disease is a neurodegenerative disorder that is characterized primarily by the loss of dopaminergic neurons in the substantia nigra. Clinical observations have revealed that Parkinson's disease is also frequently accompanied by a variety of autonomic symptoms. The adrenal medulla is a major component of the autonomic nervous system. However, until recently this organ has not been of particular interest in Parkinson's disease. Early studies found histologic abnormalities in adrenal medullary cells, and several groups measured urinary and plasma catecholamines to determine general autonomic status. In the late 1980s adrenal medullary tissue was first transplanted to the caudate nucleus in an attempt to augment the decreased levels of dopamine, and thus treat the symptoms of Parkinson's disease. At this time the status of the adrenal medulla in this disease became clinically important. We measured the total catecholamine content of the parkinsonian adrenal medulla in tissue collected both at autopsy and in conjunction with adrenal-caudate transplants. Adrenal medullary catecholamines and several neuropeptides were severely depressed in parkinsonian glands. Thus, the adrenal medulla appears to be a target of the peripheral manifestations of Parkinson's disease.
Vilariño-Güell, Carles; Rajput, Alex; Milnerwood, Austen J; Shah, Brinda; Szu-Tu, Chelsea; Trinh, Joanne; Yu, Irene; Encarnacion, Mary; Munsie, Lise N; Tapia, Lucia; Gustavsson, Emil K; Chou, Patrick; Tatarnikov, Igor; Evans, Daniel M; Pishotta, Frederick T; Volta, Mattia; Beccano-Kelly, Dayne; Thompson, Christina; Lin, Michelle K; Sherman, Holly E; Han, Heather J; Guenther, Bruce L; Wasserman, Wyeth W; Bernard, Virginie; Ross, Colin J; Appel-Cresswell, Silke; Stoessl, A Jon; Robinson, Christopher A; Dickson, Dennis W; Ross, Owen A; Wszolek, Zbigniew K; Aasly, Jan O; Wu, Ruey-Meei; Hentati, Faycal; Gibson, Rachel A; McPherson, Peter S; Girard, Martine; Rajput, Michele; Rajput, Ali H; Farrer, Matthew J
A Saskatchewan multi-incident family was clinically characterized with Parkinson disease (PD) and Lewy body pathology. PD segregates as an autosomal-dominant trait, which could not be ascribed to any known mutation. DNA from three affected members was subjected to exome sequencing. Genome alignment, variant annotation and comparative analyses were used to identify shared coding mutations. Sanger sequencing was performed within the extended family and ethnically matched controls. Subsequent genotyping was performed in a multi-ethnic case-control series consisting of 2928 patients and 2676 control subjects from Canada, Norway, Taiwan, Tunisia, and the USA. A novel mutation in receptor-mediated endocytosis 8/RME-8 (DNAJC13 p.Asn855Ser) was found to segregate with disease. Screening of cases and controls identified four additional patients with the mutation, of which two had familial parkinsonism. All carriers shared an ancestral DNAJC13 p.Asn855Ser haplotype and claimed Dutch-German-Russian Mennonite heritage. DNAJC13 regulates the dynamics of clathrin coats on early endosomes. Cellular analysis shows that the mutation confers a toxic gain-of-function and impairs endosomal transport. DNAJC13 immunoreactivity was also noted within Lewy body inclusions. In late-onset disease which is most reminiscent of idiopathic PD subtle deficits in endosomal receptor-sorting/recycling are highlighted by the discovery of pathogenic mutations VPS35, LRRK2 and now DNAJC13. With this latest discovery, and from a neuronal perspective, a temporal and functional ecology is emerging that connects synaptic exo- and endocytosis, vesicular trafficking, endosomal recycling and the endo-lysosomal degradative pathway. Molecular deficits in these processes are genetically linked to the phenotypic spectrum of parkinsonism associated with Lewy body pathology.
1-0001 Brian A Trimble, MD Alaska Native Parkinson’s Disease Registry Principal Investigator A. Introduction Parkinsonism (PS) is a syndrome...characterized by tremor , rigidity, slowness of movement, and problems with walking and balance. Parkinson’s disease is the most common form of PS... parkinsonism cases will be the Indian Health Service (IHS) provider database, called the Resource and Patient Management System (RPMS), but the protocol will
W81XWH-07-1-0001 Brian A Trimble, MD Alaska Native Parkinson’s Disease Registry Principal Investigator A. Introduction Parkinsonism (PS) is a...syndrome characterized by tremor , rigidity, slowness of movement, and problems with walking and balance. Parkinson’s disease is the most common form...protocol. The primary source of parkinsonism cases will be the Indian Health Service (IHS) provider database, called the Resource and Patient Management
Kempster, Peter A
Michael J. Fox was a popular and successful film and television comic actor who developed Parkinson's disease at the age of 29 years. His recently published book, Lucky Man, structured around the story of his Parkinson's disease, is an amusing, briskly paced yet introspective memoir that covers the first 40 years of his life. Although quite anecdotal, it contains interesting observations on the preclinical phase of the disorder, evolution of motor fluctuations, and tactics for pharmacological treatment.
Swick, Todd J.
Parkinson's disease (PD) has traditionally been characterized by its cardinal motor symptoms of bradykinesia, rigidity, resting tremor, and postural instability. However, PD is increasingly being recognized as a multidimensional disease associated with myriad nonmotor symptoms including autonomic dysfunction, mood disorders, cognitive impairment, pain, gastrointestinal disturbance, impaired olfaction, psychosis, and sleep disorders. Sleep disturbances, which include sleep fragmentation, daytime somnolence, sleep-disordered breathing, restless legs syndrome (RLS), nightmares, and rapid eye movement (REM) sleep behavior disorder (RBD), are estimated to occur in 60% to 98% of patients with PD. For years nonmotor symptoms received little attention from clinicians and researchers, but now these symptoms are known to be significant predictors of morbidity in determining quality of life, costs of disease, and rates of institutionalization. A discussion of the clinical aspects, pathophysiology, evaluation techniques, and treatment options for the sleep disorders that are encountered with PD is presented. PMID:23326757
Nonnekes, Jorik; Timmer, Monique H M; de Vries, Nienke M; Rascol, Olivier; Helmich, Rick C; Bloem, Bastiaan R
Some motor and nonmotor features associated with Parkinson's disease (PD) do not seem to respond well to levodopa (or other forms of dopaminergic medication) or appear to become resistant to levodopa treatment with disease progression and longer disease duration. In this narrative review, we elaborate on this issue of levodopa resistance in PD. First, we discuss the possibility of pseudoresistance, which refers to dopamine-sensitive symptoms or signs that falsely appear to be (or have become) resistant to levodopa, when in fact other mechanisms are at play, resulting in suboptimal dopaminergic efficacy. Examples include interindividual differences in pharmacodynamics and pharmacokinetics and underdosing because of dose-limiting side effects or because of levodopa phobia. Moreover, pseudoresistance can emerge as not all features of PD respond adequately to the same dosage of levodopa. Second, we address that for several motor features (eg, freezing of gait or tremor) and several nonmotor features (eg, specific cognitive functions), the response to levodopa is fairly complex, with a combination of levodopa-responsive, levodopa-resistant, and even levodopa-induced characteristics. A possible explanation relates to the mixed presence of underlying dopaminergic and nondopaminergic brain lesions. We suggest that clinicians take these possibilities into account before concluding that symptoms or signs of PD are totally levodopa resistant. © 2016 International Parkinson and Movement Disorder Society.
West, Ryan J. H.; Furmston, Rebecca; Williams, Charles A. C.; Elliott, Christopher J. H.
We provide an insight into the role Drosophila has played in elucidating neurophysiological perturbations associated with Parkinson's disease- (PD-) related genes. Synaptic signalling deficits are observed in motor, central, and sensory systems. Given the neurological impact of disease causing mutations within these same genes in humans the phenotypes observed in fly are of significant interest. As such we observe four unique opportunities provided by fly nervous system models of Parkinson's disease. Firstly, Drosophila models are instrumental in exploring the mechanisms of neurodegeneration, with several PD-related mutations eliciting related phenotypes including sensitivity to energy supply and vesicular deformities. These are leading to the identification of plausible cellular mechanisms, which may be specific to (dopaminergic) neurons and synapses rather than general cellular phenotypes. Secondly, models show noncell autonomous signalling within the nervous system, offering the opportunity to develop our understanding of the way pathogenic signalling propagates, resembling Braak's scheme of spreading pathology in PD. Thirdly, the models link physiological deficits to changes in synaptic structure. While the structure-function relationship is complex, the genetic tractability of Drosophila offers the chance to separate fundamental changes from downstream consequences. Finally, the strong neuronal phenotypes permit relevant first in vivo drug testing. PMID:25960916
Rubinsztein, D.C.; Leggo, J.; Barton, D.E.
The clinical features of Parkinson`s disease, particularly rigidity and bradykinesia and occasionally tremor, are seen in juvenile-onset Huntington`s disease. Therefore, the CAG and CCG repeats in the Huntington`s disease gene were investigated in 45 Parkinson`s disease patients and compared to 40 control individuals. All of the Parkinson`s disease chromosomes fell within the normal size ranges. In addition, the distributions of the two repeats in the Parkinson`s disease patients did not differ significantly from those of the control population. Therefore, abnormalities of these trinucleotide repeats in the Huntington`s disease gene are not likely to contribute to the pathogenesis of Parkinson`s disease. 12 refs., 2 figs.
Foerde, Karin; Braun, Erin Kendall; Higgins, E Tory; Shohamy, Daphna
Learning and motivation are intrinsically related, and both have been linked to dopamine. Parkinson's disease results from a progressive loss of dopaminergic inputs to the striatum and leads to impairments in motivation and learning from feedback. However, the link between motivation and learning in Parkinson's disease is not well understood. To address this gap, we leverage a well-established psychological theory of motivation, regulatory mode theory, which distinguishes between two functionally independent motivational concerns in regulating behavior: a concern with having an effect by initiating and maintaining movement (Locomotion) and a concern with establishing what is correct by critically evaluating goal pursuit means and outcomes (Assessment). We examined Locomotion and Assessment in patients with Parkinson's disease and age-matched controls. Parkinson's disease patients demonstrated a selective decrease in Assessment motivation but no change in Locomotion motivation, suggesting that Parkinson's disease leads to a reduced tendency to evaluate and monitor outcomes. Moreover, weaker Assessment motivation was correlated with poorer performance on a feedback-based learning task previously shown to depend on the striatum. Together, these findings link a questionnaire-based personality inventory with performance on a well-characterized experimental task, advancing our understanding of how Parkinson's disease affects motivation with implications for well-being and treatment outcomes.
Trinh, Joanne; Amouri, Rim; Duda, John E; Morley, James F; Read, Matthew; Donald, Alan; Vilariño-Güell, Carles; Thompson, Christina; Szu Tu, Chelsea; Gustavsson, Emil K; Ben Sassi, Samia; Hentati, Emna; Zouari, Mourad; Farhat, Emna; Nabli, Fatma; Hentati, Faycel; Farrer, Matthew J
Parkinson disease is a progressive neurodegenerative disease for which leucine-rich repeat kinase 2 (LRRK2 carriers) p.G2019S confers substantial genotypic and population attributable risk. With informed consent, we have recruited clinical data from 778 patients from Tunisia (of which 266 have LRRK2 parkinsonism) and 580 unaffected subjects. Motor, autonomic, and cognitive assessments in idiopathic Parkinson disease and LRRK2 patients were compared with regression models. The age-associated cumulative incidence of LRRK2 parkinsonism was also estimated using case-control and family-based designs. LRRK2 parkinsonism patients had slightly less gastrointestinal dysfunction and rapid eye movement sleep disorder. Overall, disease penetrance in LRRK2 carriers was 80% by 70 years but women become affected a median 5 years younger than men. Idiopathic Parkinson disease patients with younger age at diagnosis have slower disease progression. However, age at diagnoses does not predict progression in LRRK2 parkinsonism. LRRK2 p.G2019S mutation is a useful aid to diagnosis and modifiers of disease in LRRK2 parkinsonism may aid in developing therapeutic targets.
Chen, Honglei; O'Reilly, Eilis; McCullough, Marjorie L; Rodriguez, Carmen; Schwarzschild, Michael A; Calle, Eugenia E; Thun, Michael J; Ascherio, Alberto
The authors prospectively investigated the association between intake of dairy products and risk of Parkinson's disease among 57,689 men and 73,175 women from the American Cancer Society's Cancer Prevention Study II Nutrition Cohort. A total of 250 men and 138 women with Parkinson's disease were identified during follow-up (1992-2001). Dairy product consumption was positively associated with risk of Parkinson's disease: Compared with the lowest intake quintile, the corresponding relative risks for quintiles 2-5 were 1.4, 1.4, 1.4, and 1.6 (95 percent confidence interval (CI): 1.1, 2.2; p for trend = 0.05). A higher risk among dairy product consumers was found in both men and women, although the association in women appeared nonlinear. Meta-analysis of all prospective studies confirmed a moderately elevated risk of Parkinson's disease among persons with high dairy product consumption: For extreme intake categories, relative risks were 1.6 (95 percent CI: 1.3, 2.0) for both sexes, 1.8 for men (95 percent CI: 1.4, 2.4), and 1.3 for women (95 percent CI: 0.8, 2.1). These data suggest that dairy consumption may increase the risk of Parkinson's disease, particularly in men. More studies are needed to further examine these findings and to explore underlying mechanisms.
Hovestadt, A; Bogaard, J M; Meerwaldt, J D; van der Meché, F G; Stigt, J
Pulmonary function was investigated in 31 consecutive patients with relatively severe Parkinson's disease. Clinical disability was assessed by Hoehn and Yahr scale, Northwestern University Disability Scale and Websterscore. All patients were on levodopa substitution therapy and used anticholinergics. Pulmonary function was investigated by spirography, determination of a maximal inspiratory and expiratory flow-volume curve and, when possible, maximal static mouth pressures were determined. Peak inspiratory and expiratory flow, maximal expiratory flow at 50% and maximal static mouth pressures were significantly below normal values. Vital capacity, forced inspiratory volume in 1 s and the ratio of forced expiratory volume in 1 s and vital capacity were relatively normal. Nine patients had upper airway obstruction (UAO) as judged by abnormal values for peak inspiratory flow, the ratio of forced expiratory volume in 1 s and peak expiratory flow and the ratio of maximal expiratory and inspiratory flow at 50%. Flow-volume curves were normal in eight patients; four patients demonstrated flow decelerations and accelerations (type A) and 16 had a rounded off flow-volume curve (type B). Type A can be explained by UAO and type B by a combination of decreased effective muscle strength and possible UAO. Overall results of pulmonary function tests in patients without any clinical signs or symptoms of pulmonary disease point to subclinical upper airway obstruction and decreased effective muscle strength in a significant proportion of patients. PMID:2926415
Hovestadt, A; Bogaard, J M; Meerwaldt, J D; van der Meché, F G; Stigt, J
Pulmonary function was investigated in 31 consecutive patients with relatively severe Parkinson's disease. Clinical disability was assessed by Hoehn and Yahr scale, Northwestern University Disability Scale and Websterscore. All patients were on levodopa substitution therapy and used anticholinergics. Pulmonary function was investigated by spirography, determination of a maximal inspiratory and expiratory flow-volume curve and, when possible, maximal static mouth pressures were determined. Peak inspiratory and expiratory flow, maximal expiratory flow at 50% and maximal static mouth pressures were significantly below normal values. Vital capacity, forced inspiratory volume in 1 s and the ratio of forced expiratory volume in 1 s and vital capacity were relatively normal. Nine patients had upper airway obstruction (UAO) as judged by abnormal values for peak inspiratory flow, the ratio of forced expiratory volume in 1 s and peak expiratory flow and the ratio of maximal expiratory and inspiratory flow at 50%. Flow-volume curves were normal in eight patients; four patients demonstrated flow decelerations and accelerations (type A) and 16 had a rounded off flow-volume curve (type B). Type A can be explained by UAO and type B by a combination of decreased effective muscle strength and possible UAO. Overall results of pulmonary function tests in patients without any clinical signs or symptoms of pulmonary disease point to subclinical upper airway obstruction and decreased effective muscle strength in a significant proportion of patients.
Ascherio, Alberto; Schwarzschild, Michael A
Since 2006, several longitudinal studies have assessed environmental or behavioural factors that seem to modify the risk of developing Parkinson's disease. Increased risk of Parkinson's disease has been associated with exposure to pesticides, consumption of dairy products, history of melanoma, and traumatic brain injury, whereas a reduced risk has been reported in association with smoking, caffeine consumption, higher serum urate concentrations, physical activity, and use of ibuprofen and other common medications. Randomised trials are investigating the possibility that some of the negative risk factors might be neuroprotective and thus beneficial in individuals with early Parkinson's disease, particularly with respect to smoking (nicotine), caffeine, and urate. In the future, it might be possible to identify Parkinson's disease in its prodromal phase and to promote neuroprotective interventions before the onset of motor symptoms. At this time, however, the only intervention that seems justifiable for the primary prevention of Parkinson's disease is the promotion of physical activity, which is likely to be beneficial for the prevention of several chronic diseases.
Estupinan, Danny; Nathoo, Sunina; Okun, Michael S
In 1961, David C. Poskanzer and Robert S. Schwab presented a paper, "Studies in the epidemiology of Parkinson's disease predicting its disappearance as a major clinical entity by 1980." This paper introduced the hypothesis that Parkinson's disease was derived from a single aetiology, the influenza virus. We review the original Poskanzer and Schwab hypothesis that Parkinson's disease was based on the association between the 1918-19 influenza epidemic and the later observation of Parkinsonism in some influenza sufferers. We also further explore the prediction that Parkinson's disease would totally disappear as an entity once original influenza victims were all deceased. Current research has revealed that there are many potential causes and factors important in the occurrence of Parkinson's disease, postencephalitic Parkinsonism, and encephalitis lethargica. Poskanzer and Schwab presented a novel hypothesis; however, it was proven false by a combination of research and time.
Arnulf, Isabelle; Neutel, Dulce; Herlin, Bastien; Golmard, Jean-Louis; Leu-Semenescu, Smaranda; Cochen de Cock, Valérie; Vidailhet, Marie
Objective: To determine whether patients with idiopathic and symptomatic RBD were sleepier than controls, and if sleepiness in idiopathic RBD predicted earlier conversion to Parkinson disease. Methods: The Epworth Sleepiness Scale (ESS) and its determinants were compared at the time of a video-polysomnography for an RBD diagnosis in patients with idiopathic RBD, in patients with Parkinson disease, and in controls. Whether sleepiness at time of RBD diagnosis predicted an earlier conversion to neurodegenerative diseases was retrospectively analyzed in the followed-up patients. Results: The 75 patients with idiopathic RBD were sleepier (ESS: 7.8 ± 4.6) at the time of RBD diagnosis than 74 age- and sex-matched controls (ESS: 5.0 ± 3.6, P < 0.0001). They reached the levels of 114 patients with Parkinson disease (ESS: 8.7 ± 4.8), whether they had (n = 78) or did not have (n = 36) concomitant RBD. The severity of sleepiness in idiopathic RBD correlated with younger age, but not with sleep measures. Among the 69 patients with idiopathic RBD who were followed up for a median 3 years (1–15 years), 16 (23.2%) developed parkinsonism (n = 6), dementia (n = 6), dementia plus parkinsonism (n = 2), and multiple system atrophy (n = 2). An ESS greater than 8 at time of RBD diagnosis predicted a shorter time to phenoconversion to parkinsonism and dementia, from RBD onset, and from RBD diagnosis (when adjusted for age and time between RBD onset and diagnosis). Conclusions: Sleepiness is associated with idiopathic REM sleep behavior disorder and predicts more rapid conversion to parkinsonism and dementia, suggesting it is an early marker of neuronal loss in brainstem arousal systems. Citation: Arnulf I, Neutel D, Herlin B, Golmard JL, Leu-Semenescu S, Cochen de Cock V, Vidailhet M. Sleepiness in idiopathic REM sleep behavior disorder and Parkinson disease. SLEEP 2015;38(10):1529–1535. PMID:26085299
Heikkila, V; Turkka, J; Korpelainen, J; Kallanranta, T; Summala, H
BACKGROUND—Driving is a complex form of activity involving especially cognitive and psychomotor functions. These functions may be impaired by Parkinson's disease. The relation between Parkinson's disease and driving ability is still obscure and clinicians have to make decisions concerning the driving ability of their patients based on insufficent information. Until now no studies have compared different methods for evaluating the driving ability of patients with Parkinson's disease. METHODS—The driving ability of 20 patients with idiopathic Parkinson's disease and 20 age and sex matched healthy control subjects was evaluated by a neurologist, psychologist, vocational rehabilitation counsellor, and driving instructor using a standard 10 point scale. The patients and controls also evaluated their own driving ability. Cognitive and psychomotor laboratory tests and a structured on road driving test were used for evaluating the subjects' driving ability. RESULTS—The patients with Parkinson's disease performed worse than the controls both in the laboratory tests and in the driving test. There was a high correlation between the laboratory tests and driving test both in the patient group and in the control group. Disease indices were not associated with the driving test. The neurologist overestimated the ability of patients with Parkinson's disease to drive compared with the driving ability evaluated by the structured on road driving test and with the driving related laboratory tests. Patients themselves were not capable of evaluating their own ability reliably. CONCLUSION—Driving ability is greatly decreased in patients with even mild to moderate Parkinson's disease. The evaluation of patients' driving ability is very difficult to carry out without psychological and psychomotor tests and/or a driving test. PMID:9527142
Cano-de la Cuerda, Roberto; Vela-Desojo, Lydia; Miangolarra-Page, Juan C; Macías-Macías, Yolanda; Muñoz-Hellin, Elena
Parkinson's disease is a disabling and progressive neurological condition characterized by multiple motor and non motor symptoms that contribute to deterioration in quality of life. The diversity of symptoms associated with the disease and its management affect the patients on their physical, social and mental quality of life. The aim of this study was to identify key dimensions of health related quality of life (HRQOL) in a population affected with Parkinson's disease with a degree of mild-moderate impairment. Thirty six patients with Parkinson were recruited. The Hoehn and Yarh scale, the Unified Parkinson's Disease Rate Scale, the scale of activities of daily life and Schwab & England Get Up & Go Test were applied. HRQOL was assessed with the EuroQol-5D and the specific questionnaire Parkinson's Disease Questionnaire-39 items. The dimensions of the PDQ-39, except the PDQ-39 Pain domain and the EuroQol-5D correlated significantly with the severity of the disease. HRQOL was correlated with the functional status of patients. Only the PDQ-39 pain domain correlated with the risk of falls. Our results suggest that the HRQOL of patients with PD, in a state of mild-moderate impairment, is strongly influenced by disease severity and functional status.
Kalia, S K; Kalia, L V; McLean, P J
Parkinson's disease is a neurodegenerative movement disorder that is caused, in part, by the loss of dopaminergic neurons within the substantia nigra pars compacta of the basal ganglia. The presence of intracellular protein aggregates, known as Lewy bodies and Lewy neurites, within the surviving nigral neurons is the defining neuropathological feature of the disease. Accordingly, the identification of specific genes mutated in families with Parkinson's disease and of genetic susceptibility variants for idiopathic Parkinson's disease has implicated abnormalities in proteostasis, or the handling and elimination of misfolded proteins, in the pathogenesis of this neurodegenerative disorder. Protein folding and the refolding of misfolded proteins are regulated by a network of interactive molecules, known as the chaperone system, which is composed of molecular chaperones and co-chaperones. The chaperone system is intimately associated with the ubiquitin-proteasome system and the autophagy-lysosomal pathway which are responsible for elimination of misfolded proteins and protein quality control. In addition to their role in proteostasis, some chaperone molecules are involved in the regulation of cell death pathways. Here we review the role of the molecular chaperones Hsp70 and Hsp90, and the cochaperones Hsp40, BAG family members such as BAG5, CHIP and Hip in modulating neuronal death with a focus on dopaminergic neurodegeneration in Parkinson's disease. We also review current progress in preclinical studies aimed at targetting the chaperone system to prevent neurodegeneration. Finally, we discuss potential future chaperone-based therapeutics for the symptomatic treatment and possible disease modification of Parkinson's disease.
Alcalay, Roy N; Levy, Oren A; Waters, Cheryl C; Fahn, Stanley; Ford, Blair; Kuo, Sheng-Han; Mazzoni, Pietro; Pauciulo, Michael W; Nichols, William C; Gan-Or, Ziv; Rouleau, Guy A; Chung, Wendy K; Wolf, Pavlina; Oliva, Petra; Keutzer, Joan; Marder, Karen; Zhang, Xiaokui
Glucocerebrosidase (GBA) mutations have been associated with Parkinson's disease in numerous studies. However, it is unknown whether the increased risk of Parkinson's disease in GBA carriers is due to a loss of glucocerebrosidase enzymatic activity. We measured glucocerebrosidase enzymatic activity in dried blood spots in patients with Parkinson's disease (n = 517) and controls (n = 252) with and without GBA mutations. Participants were recruited from Columbia University, New York, and fully sequenced for GBA mutations and genotyped for the LRRK2 G2019S mutation, the most common autosomal dominant mutation in the Ashkenazi Jewish population. Glucocerebrosidase enzymatic activity in dried blood spots was measured by a mass spectrometry-based assay and compared among participants categorized by GBA mutation status and Parkinson's disease diagnosis. Parkinson's disease patients were more likely than controls to carry the LRRK2 G2019S mutation (n = 39, 7.5% versus n = 2, 0.8%, P < 0.001) and GBA mutations or variants (seven homozygotes and compound heterozygotes and 81 heterozygotes, 17.0% versus 17 heterozygotes, 6.7%, P < 0.001). GBA homozygotes/compound heterozygotes had lower enzymatic activity than GBA heterozygotes (0.85 µmol/l/h versus 7.88 µmol/l/h, P < 0.001), and GBA heterozygotes had lower enzymatic activity than GBA and LRRK2 non-carriers (7.88 µmol/l/h versus 11.93 µmol/l/h, P < 0.001). Glucocerebrosidase activity was reduced in heterozygotes compared to non-carriers when each mutation was compared independently (N370S, P < 0.001; L444P, P < 0.001; 84GG, P = 0.003; R496H, P = 0.018) and also reduced in GBA variants associated with Parkinson's risk but not with Gaucher disease (E326K, P = 0.009; T369M, P < 0.001). When all patients with Parkinson's disease were considered, they had lower mean glucocerebrosidase enzymatic activity than controls (11.14 µmol/l/h versus 11.85 µmol/l/h, P = 0.011). Difference compared to controls persisted in patients with
Darweesh, Sirwan K L; Verlinden, Vincentius J A; Stricker, Bruno H; Hofman, Albert; Koudstaal, Peter J; Ikram, M Arfan
SEE BREEN AND LANG DOI101093/AWW321 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: At the time of clinical diagnosis, patients with Parkinson's disease already have a wide range of motor and non-motor features that affect their daily functioning. However, the temporal sequence of occurrence of these features remains largely unknown. We studied trajectories of daily functioning and motor and non-motor features in the 23 years preceding Parkinson's disease diagnosis by performing a nested case-control study within the prospective Rotterdam study. Between 1990 and 2013, we repeatedly performed standardized assessments of daily functioning (Stanford Health Assessment Questionnaire, Lawton Instrumental Activities of Daily Living Scale), potential prediagnostic motor (hypo- and bradykinesia, tremor, rigidity, postural imbalance, postural abnormalities) and non-motor features of Parkinson's disease, including cognition (Mini-Mental State Examination, Stroop Test, Letter-Digit-Substitution Test, Word Fluency Test), mood (Center for Epidemiological Studies-Depression Scale, Hamilton Anxiety and Depression Scale), and autonomic function (blood pressure, laxative use). In addition, the cohort was followed-up for the onset of clinical Parkinson's disease using several overlapping modalities, including repeated in-person examinations, as well as complete access to medical records and specialist letters of study participants. During follow-up, 109 individuals were diagnosed with Parkinson's disease, and each case was matched to 10 controls based on age and sex (total n = 1199). Subsequently, we compared prediagnostic trajectories of daily functioning and other features between Parkinson's disease cases and controls. From 7 years before diagnosis onwards, prediagnostic Parkinson's disease cases more commonly had problems in instrumental activities of daily functioning, and more frequently showed signs of movement poverty and slowness, tremor and subtle cognitive deficits. In the
Beuter, Anne; Vasilakos, Konstantinon
Experimental evidence has shown a plethora of short-term fluctuations in patients with Parkinson's disease. We investigate these transitory events using the concept of dynamical disease. Several examples of short-term fluctuations in tremor are analyzed, and in two cases, other systemic variables (i.e., respiration and blood pressure) are examined as well. A model for tremor, based on negative feedback with delays is proposed, and the transient events are simulated. The theoretical implications of the model suggest that interactions between the central and peripheral loops, as well as interactions between the control loops and other systemic signals, can give rise to transitory events in tremor, both in the pathological and in the normal case.
Muñoz, Yorka; Carrasco, Carlos M; Campos, Joaquín D; Aguirre, Pabla; Núñez, Marco T
Mitochondrial dysfunction, iron accumulation, and oxidative damage are conditions often found in damaged brain areas of Parkinson's disease. We propose that a causal link exists between these three events. Mitochondrial dysfunction results not only in increased reactive oxygen species production but also in decreased iron-sulfur cluster synthesis and unorthodox activation of Iron Regulatory Protein 1 (IRP1), a key regulator of cell iron homeostasis. In turn, IRP1 activation results in iron accumulation and hydroxyl radical-mediated damage. These three occurrences-mitochondrial dysfunction, iron accumulation, and oxidative damage-generate a positive feedback loop of increased iron accumulation and oxidative stress. Here, we review the evidence that points to a link between mitochondrial dysfunction and iron accumulation as early events in the development of sporadic and genetic cases of Parkinson's disease. Finally, an attempt is done to contextualize the possible relationship between mitochondria dysfunction and iron dyshomeostasis. Based on published evidence, we propose that iron chelation-by decreasing iron-associated oxidative damage and by inducing cell survival and cell-rescue pathways-is a viable therapy for retarding this cycle.
Carrasco, Carlos M.; Núñez, Marco T.
Mitochondrial dysfunction, iron accumulation, and oxidative damage are conditions often found in damaged brain areas of Parkinson's disease. We propose that a causal link exists between these three events. Mitochondrial dysfunction results not only in increased reactive oxygen species production but also in decreased iron-sulfur cluster synthesis and unorthodox activation of Iron Regulatory Protein 1 (IRP1), a key regulator of cell iron homeostasis. In turn, IRP1 activation results in iron accumulation and hydroxyl radical-mediated damage. These three occurrences—mitochondrial dysfunction, iron accumulation, and oxidative damage—generate a positive feedback loop of increased iron accumulation and oxidative stress. Here, we review the evidence that points to a link between mitochondrial dysfunction and iron accumulation as early events in the development of sporadic and genetic cases of Parkinson's disease. Finally, an attempt is done to contextualize the possible relationship between mitochondria dysfunction and iron dyshomeostasis. Based on published evidence, we propose that iron chelation—by decreasing iron-associated oxidative damage and by inducing cell survival and cell-rescue pathways—is a viable therapy for retarding this cycle. PMID:27293957
Brooks, D.J. )
Putamen 18F-dopa uptake of patients with Parkinson's disease (PD) is reduced by at least 35% at onset of symptoms; therefore, positron-emission tomography (PET) can be used to detect preclinical disease in clinically unaffected twins and relatives of patients with PD. Three out of 6 monozygotic and 2 out of 3 dizygotic unaffected PD co-twins have shown reduced putamen 18F-dopa uptake to date. In addition, an intact sibling and a daughter of 1 of 4 siblings with PD both had low putamen 18F-dopa uptake. These preliminary findings suggest there may be a familial component to the etiology of PD. PET can also be used to detect underlying nigral pathology in patients with isolated tremor and patients who become rigid taking dopamine-receptor blocking agents (DRBAs). Patients with familial essential tremor have normal, and those with isolated rest tremor have consistently low, putamen 18F-dopa uptake. Drug-induced parkinsonism is infrequently associated with underlying nigral pathology.
Brooks, D.J. )
Putamen 18F-dopa uptake of patients with Parkinson's disease (PD) is reduced by at least 35% at onset of symptoms; therefore, positron-emission tomography (PET) can be used to detect preclinical disease in clinically unaffected twins and relatives of patients with PD. Three out of 6 monozygotic and 2 out of 3 dizygotic unaffected PD co-twins have shown reduced putamen 18F-dopa uptake to date. In addition, an intact sibling and a daughter of 1 of 4 siblings with PD both had low putamen 18F-dopa uptake. These preliminary findings suggest there may be a familial component to the etiology of PD. PET can also be used to detect underlying nigral pathology in patients with isolated tremor and patients who become rigid taking dopamine-receptor blocking agents (DRBAs). Patients with familial essential tremor have normal, and those with isolated rest tremor have consistently low, putamen 18F-dopa uptake. Drug-induced parkinsonism is infrequently associated with underlying nigral pathology.
Ferencz, Beata; Scholtissen, Bart; Bogorodskaya, Milana; Okun, Michael S; Bowers, Dawn
Apathy is one of the primary neuropsychiatric signatures in Parkinson's disease, yet little research has addressed the construct validity of two commonly used apathy measures, the Apathy Scale and the Lille Apathy Rating Scale. The authors tested the hypothesis that apathy is associated with reduced initiative/engaged behaviors on a laboratory-based measure of apathy. Support was found for the hypothesis that apathy, as indexed by the Apathy Scale and the Lille Apathy Rating Scale, is associated with reduced initiative/engagement on an experimental measure of apathy in Parkinson's disease patients. These findings provide independent evidence for the construct validity of self-report apathy scales, beyond clinician judgment.
Idiopathic Parkinson's Disease; Parkinson's Disease; Basal Ganglia Disease; Brain Diseases; Central Nervous System Diseases; Movement Disorders; Nervous System Diseases; Neurodegenerative Diseases; Parkinsonian Disorders
Lazarus, A; Stelmach, G E
This study examined the degree to which Parkinson's disease (PD) patients could "spatially link" the upper limbs to facilitate the performance of bimanual simultaneous movements. Six right-handed PD patients, and seven normal age- and sex-matched controls performed three different tasks: (a) an isotonic elbow flexion as rapidly as possible through an angle of 30 degrees; (b) an isometric contraction of the flexor muscles at the elbow joint to 40% and 60% of maximal volitional force (MVF) for a period of 5 s; (c) an isometric contraction for 2.5 s with one limb, then simultaneously performing an isotonic flexion with the contralateral limb while maintaining the isometric contraction for 2.5 s more. As expected, PD patients were significantly slower in performing the isotonic movement and produced lower peak velocities than the controls. More importantly, the two groups were differentially affected during the bimanual condition. In normals, movement time decreased and peak velocity increased in the bimanual condition. In contrast, PD patients showed increased movement times and sometimes decreased peak velocities in the bimanual condition. The results suggest that normal subjects utilize bilateral outflow to symmetrical muscle groups to synchronize the two limbs in the bimanual task, whereas PD patients dissociate the two limbs.
Rye, D B; Bliwise, D L; Dihenia, B; Gurecki, P
We describe multiple sleep latency test (MSLT) results in 27 adult patients with idiopathic Parkinson's disease (PD). Pathological sleepiness (i.e. mean sleep latency =5 min) was common (40 of 134 nap opportunities), and sleep-onset REM periods were also observed (13 of 134 nap opportunities). These findings bore little relationship to disease specific variables (e.g. level of disability, medication use), or sleep architecture measures (e.g. total sleep time, sleep stage percentage's). Our findings speak against a simple association of excessive sleepiness and the quality and quantity of prior night's sleep, but rather, argue for primary impairments of waking arousal and REM-sleep expression in a sizeable subpopulation of PD patients.
Kieburtz, Karl; Wunderle, Kathryn B
Parkinson's disease (PD) has no known cause. Although recent research has focused particularly on genetic causes of PD, environmental causes also play a role in developing the disease. This article reviews environmental factors that may increase the risk of PD, as well as the evidence behind those factors. Enough evidence exists to suggest that age has a causal relationship to PD. Significant evidence exists that gender, tobacco use, and caffeine consumption are also associated with the development of PD. Other environmental factors (pesticide exposure, occupation, blood urate levels, NSAID use, brain injury, and exercise) have limited or conflicting evidence of a relationship to PD. Future research must not neglect the impact of these environmental factors on the development of PD, especially with respect to potential gene-environment interactions.
Ragland, Margaret; Hutter, Carolyn; Zabetian, Cyrus; Edwards, Karen
The ubiquitin carboxyl-terminal esterase L1 gene, UCHL1, located on chromosome 4p14, has been studied as a potential candidate gene for Parkinson's disease risk. The authors conducted a Human Genome Epidemiology review and meta-analysis of published case-control studies of the UCHL1 S18Y variant and Parkinson's disease in Asian and Caucasian samples. The meta-analysis of studies in populations of Asian ancestry showed a statistically significant association between the Y allele and reduced risk of Parkinson's disease under a recessive model (odds ratio (OR) for YY vs. SY + SS = 0.79, 95% confidence interval (CI): 0.67, 0.94; P = 0.006). For a dominant model, the association was not significant in Asian populations (OR for YY + SY vs. SS = 0.88, 95% CI: 0.68, 1.14; P = 0.33). For populations of European ancestry, the meta-analysis showed a significant association between the Y allele and decreased risk of Parkinson's disease under a dominant model (OR = 0.89, 95% CI: 0.81, 0.98; P = 0.02) but not under a recessive model (OR = 0.92, 95% CI: 0.66, 1.30; P = 0.65). Using the Venice criteria, developed by the Human Genome Epidemiology Network Working Group on the assessment of cumulative evidence, the authors concluded that moderate evidence exists for an association between the S18Y variant and Parkinson's disease.
Fraiwan, Luay; Khnouf, Ruba; Mashagbeh, Abdel Razaq
Parkinson's disease currently affects millions of people worldwide and is steadily increasing. Many symptoms are associated with this disease, including rest tremor, bradykinesia, stiffness or rigidity of the extremities and postural instability. No cure is currently available for Parkinson's disease patients; instead most medications are for treatment of symptoms. This treatment depends on the quantification of these symptoms such as hand tremor. This work proposes a new system for mobile phone applications. The system is based on measuring the acceleration from the Parkinson's disease patient's hand using a mobile cell phone accelerometer. Recordings from 21 Parkinson's disease patients and 21 healthy subjects were used. These recordings were analysed using a two level wavelet packet analysis and features were extracted forming a feature vector of 12 elements. The features extracted from the 42 subjects were classified using a neural networks classifier. The results obtained showed an accuracy of 95% and a Kappa coefficient of 90%. These results indicate that a cell phone accelerometer can accurately detect and record rest tremor in Parkinson's disease patients.
Supranuclear Palsy . These studies showed that there is significant increase in lipid peroxidation in the subthalamic nucleus. We developed a novel column...of Parkinson’s Disease and the MPTP model of Parkinsonism. We carried out initial studies in the Parkinsonian Syndrome known as Progressive ...neuroprotective against MPTP neurotoxicity. The studies to date, have made significant progress on the original aims of the proposal.
Dickson, Dennis W.
Parkinsonism, the clinical term for a disorder with prominent bradykinesia and variable associated extrapyramidal signs and symptoms, is accompanied by degeneration of the nigrostriatal dopaminergic system, with neuronal loss and reactive gliosis in the substantia nigra found at autopsy. Parkinsonism is pathologically heterogeneous, with the most common pathologic substrates related to abnormalities in the presynaptic protein α-synuclein or the microtubule binding protein tau. In idiopathic Parkinson’s disease (PD), α-synuclein accumulates in neuronal perikarya (Lewy bodies) and neuronal processes (Lewy neurites). The disease process is multifocal and involves select central nervous system neurons and peripheral autonomic nervous system neurons. The particular set of neurons affected determines nonmotor clinical presentations. Multiple system atrophy (MSA) is the other major α-synucleinopathy. It is also associated with autonomic dysfunction and in some cases with cerebellar signs. The hallmark histopathologic feature of MSA is accumulation of α-synuclein within glial cytoplasmic inclusions (GCI). The most common of the Parkinsonian tauopathies is progressive supranuclear palsy (PSP), which is clinically associated with severe postural instability leading to early falls. The tau pathology of PSP also affects both neurons and glia. Given the population frequency of PD, α-synuclein pathology similar to that in PD, but not accompanied by neuronal loss, is relatively common (10% of people over 65 years of age) in neurologically normal individuals, leading to proposed staging schemes for PD progression. Although MSA-like and PSP-like pathology can be detected in neurologically normal individuals, such cases are too infrequent to permit assessment of patterns of disease progression. PMID:22908195
Camicioli, Richard; Sabino, Jennifer; Gee, Myrlene; Bouchard, Thomas; Fisher, Nancy; Hanstock, Chris; Emery, Derek; Martin, W R Wayne
Age-related ventricular enlargement is accelerated in Alzheimer's disease, but its relationship to cognitive decline in Parkinson's disease is less clear, even though dementia is common in Parkinson's disease. Our goals were to determine if greater enlargement of the ventricles and gray or white matter atrophy occurred in Parkinson's disease patients developing cognitive decline. Older nondemented patients with Parkinson's disease (33) and age- and sex-matched controls (39) were recruited and prospectively assessed for the development of significant cognitive decline over 36 months. Magnetic resonance imaging was obtained every 18 months, and ventricular volume and total brain gray and white matter volumes were measured using reliable segmentation of T1-weighted volumetric scans. Subjects with incidental intracranial abnormalities, an atypical course, and stroke as well as dropouts were excluded from a cohort of 52 patients and 50 controls. Among 33 patients and 39 controls, 10 patients and 3 controls developed significant cognitive impairment or dementia. Ventricular change and Parkinson's disease status were significantly associated with dementia. Ventricular change was significantly correlated with change in Mini-Mental Status Examination in the Parkinson's disease with dementia group (r = 0.87, P = .001). Gray matter atrophy was greater in Parkinson's disease with dementia, with similar change over time in both Parkinson's disease and Parkinson's disease with dementia. White matter volumes were not significantly different between Parkinson's disease and Parkinson's disease with dementia; however, the decrease over time might be greater in Parkinson's disease with dementia. Ventricular dilatation occurs early in the course of significant cognitive decline in patients with Parkinson's disease, possibly reflecting both cortical gray and white matter loss.
Uitti, Ryan J
Driving a motor vehicle represents an important activity associated with personal independence and freedom. Being told that one can no longer drive is itself associated with loss of independence, depression, low self-esteem and reduced activities [1,2]. Patients with Parkinson's disease (PD), therefore, understandably wish to continue to be able to maintain their ability to drive automobiles, motorcycles, airplanes, and boats, etc. The ability to determine if and when a PD patient is no longer fit to drive a motor vehicle is important for maintaining safety for the PD patient and the public. There are numerous requirements for being able to drive a motor vehicle safely. When any of these capacities deteriorate, the ability to drive safely may be lost. This review will concentrate upon common issues that would be peculiar to patients with PD.
Breen, David P; Evans, Jonathan R; Farrell, Krista; Brayne, Carol; Barker, Roger A
The early and accurate diagnosis of Parkinson's disease (PD) is the first step towards optimal patient management. The aim of this study was to investigate the major determinants of delayed diagnosis in PD. We recruited a population-representative cohort of 239 newly-diagnosed PD patients who underwent clinical and neuropsychological evaluation. Non-parametric methods were used to define the factors associated with diagnostic delay. The median time from motor symptom onset to primary care physician (PCP) presentation was considerably longer than the time from PCP presentation to PD diagnosis (11 vs. 1 months). Male sex and presenting motor phenotype were independently associated with delayed PCP presentation on Cox regression analysis. Patients presenting with gait disturbance experienced the longest delay, whilst those presenting with tremor had the shortest. In summary, male sex and presenting motor phenotype are key determinants of delayed diagnosis in PD.
Bravo-San Pedro, José M.; Gómez-Sánchez, Rubén; Pizarro-Estrella, Elisa; Niso-Santano, Mireia; González-Polo, Rosa A.; Fuentes Rodríguez, José M.
Parkinson's disease is the second common neurodegenerative disorder, after Alzheimer's disease. It is a clinical syndrome characterized by loss of dopamine-generating cells in the substancia nigra, a region of the midbrain. The etiology of Parkinson's disease has long been through to involve both genetic and environmental factors. Mutations in the leucine-rich repeat kinase 2 gene cause late-onset Parkinson's disease with a clinical appearance indistinguishable from Parkinson's disease idiopathic. Autophagy is an intracellular catabolic mechanism whereby a cell recycles or degrades damage proteins and cytoplasmic organelles. This degradative process has been associated with cellular dysfunction in neurodegenerative processes including Parkinson's disease. We discuss the role of leucine-rich repeat kinase 2 in autophagy, and how the deregulations of this degradative mechanism in cells can be implicated in the Parkinson's disease etiology. PMID:22970411
Bravo-San Pedro, José M; Gómez-Sánchez, Rubén; Pizarro-Estrella, Elisa; Niso-Santano, Mireia; González-Polo, Rosa A; Fuentes Rodríguez, José M
Parkinson's disease is the second common neurodegenerative disorder, after Alzheimer's disease. It is a clinical syndrome characterized by loss of dopamine-generating cells in the substancia nigra, a region of the midbrain. The etiology of Parkinson's disease has long been through to involve both genetic and environmental factors. Mutations in the leucine-rich repeat kinase 2 gene cause late-onset Parkinson's disease with a clinical appearance indistinguishable from Parkinson's disease idiopathic. Autophagy is an intracellular catabolic mechanism whereby a cell recycles or degrades damage proteins and cytoplasmic organelles. This degradative process has been associated with cellular dysfunction in neurodegenerative processes including Parkinson's disease. We discuss the role of leucine-rich repeat kinase 2 in autophagy, and how the deregulations of this degradative mechanism in cells can be implicated in the Parkinson's disease etiology.
Evatt, Marian L
Advise patients with Parkinson's disease (PD) to consume a balanced diet, with special attention to adequate intake of dietary fiber, fluids, and macro- and micronutrients. Regularly reassess patients' nutritional history and anthropomorphic measures (height and weight), particularly in patients with advanced disease. PD-related psychosocial as well as physical and cognitive limitations increase susceptibility to subacute and chronic malnutrition. Nutritional requirements may change with PD progression or after surgical therapy for PD. Patients and caregivers may benefit from counseling by a dietician who is knowledgeable about the nutritional risks and needs of PD. Regularly inquire about dysphagia symptoms, and consider speech therapy consultation for clinical and modified barium-swallowing evaluations and management recommendations. Although non-oral delivery options of dopaminergic therapy are increasing, severe dysphagia may warrant percutaneous endoscopic gastrostomy tube placement for nutritional support and more reliable PD medication dosing. Analyze vitamin B(12) and D concentrations at regular intervals. Both vitamins are frequently deficient in elderly persons but may not be routinely checked by primary care physicians. Record over-the-counter and nutritional supplement medications at each visit, and assist patients in periodically re-evaluating their potential benefits, side effects, drug interactions, and costs. To date, clinical trials of antioxidant vitamins and nutritional supplements have provided insufficient evidence to support routine use for PD in the clinic. Data from several clinical trials of antioxidant vitamins/nutritional supplements are expected in the near future. Consider altering medication dosing in relation to meals to help with mild to moderate motor fluctuations. Patients with severe motor fluctuations may benefit from adapting the 5:1 carbohydrate-to-protein ratio in their daily meals and snacks. Following a "protein
Neurol, 1996. 53(6): p. 538-42. 13. Bayles, K.A., et al., Change in cognitive function in idiopathic Parkinson disease . Arch Neurol, 1996. 53(11): p...empirical evidence that the Parkinson ’s disease (PD) ANAM battery is sensitive to neurocognitive change independently identified by traditional...diagnosed patients are under the age 40[American Parkinson Disease Association, 1995 in the text I have]. A cognitive impairment rate of 19% of a group of
Altered Expression Patterns of Inflammation-Associated and Trophic Molecules in Substantia Nigra and Striatum Brain Samples from Parkinson's Disease, Incidental Lewy Body Disease and Normal Control Cases
Walker, Douglas G.; Lue, Lih-Fen; Serrano, Geidy; Adler, Charles H.; Caviness, John N.; Sue, Lucia I.; Beach, Thomas G.
Evidence of inflammation has been consistently associated with pathology in Parkinson's disease (PD)-affected brains, and has been suggested as a causative factor. Dopaminergic neurons in the substantia nigra (SN) pars compacta, whose loss results in the clinical symptoms associated with PD, are particularly susceptible to inflammatory damage and oxidative stress. Inflammation in the striatum, where SN dopaminergic neurons project, is also a feature of PD brains. It is not known whether inflammatory changes occur first in striatum or SN. Many animal models of PD have implicated certain inflammatory molecules with dopaminergic cell neuronal loss; however, there have been few studies to validate these findings by measuring the levels of these and other inflammatory factors in human PD brain samples. This study also included samples from incidental Lewy body disease (ILBD) cases, since ILBD is considered a non-symptomatic precursor to PD, with subjects having significant loss of tyrosine hydroxylase-producing neurons. We hypothesized that there may be a progressive change in key inflammatory factors in ILBD samples intermediate between neurologically normal and PD. To address this, we used a quantitative antibody-array platform (Raybiotech-Quantibody arrays) to measure the levels of 160 different inflammation-associated cytokines, chemokines, growth factors, and related molecules in extracts of SN and striatum from clinically and neuropathologically characterized PD, ILBD, and normal control cases. Patterns of changes in inflammation and related molecules were distinctly different between SN and striatum. Our results showed significantly different levels of interleukin (IL)-5, IL-15, monokine induced by gamma interferon, and IL-6 soluble receptor in SN between disease groups. A different panel of 13 proteins with significant changes in striatum, with IL-15 as the common feature, was identified. Although the ability to detect some proteins was limited by sensitivity
Saarela, Marika S; Lehtimaki, Terho; Rinne, Juha O; Huhtala, Heini; Rontu, Riika; Hervonen, Antti; Roytta, Matias; Ahonen, Jukka-Pekka; Mattila, Kari M
The brain-derived neurotrophic factor (BDNF) promotes survival, differentiation and maintenance of neurons in the central nervous system. BDNF 196 G>A and 270 C>T polymorphisms have previously been associated with Alzheimer's disease (AD) and with Parkinson's disease (PD). To study the role of BDNF 196 G>A and 270 C>T polymorphisms in Finnish AD and PD patients we genotyped BDNF 196 G>A and 270 C>T polymorphisms in 97 sporadic AD patients, 52 PD patients and 101 control subjects with polymerase chain reaction. No associations were found between the genotypes studied and AD or PD in Finnish patients. Moreover, no interaction between either BDNF polymorphism and the epsilon 4 allele of apolipoprotein E was found. In conclusion, it seems that the BDNF gene does not contribute significantly to the risk of AD or PD in Finnish patients.
Schöndorf, David C; Aureli, Massimo; McAllister, Fiona E; Hindley, Christopher J; Mayer, Florian; Schmid, Benjamin; Sardi, S Pablo; Valsecchi, Manuela; Hoffmann, Susanna; Schwarz, Lukas Kristoffer; Hedrich, Ulrike; Berg, Daniela; Shihabuddin, Lamya S; Hu, Jing; Pruszak, Jan; Gygi, Steven P; Sonnino, Sandro; Gasser, Thomas; Deleidi, Michela
Mutations in the acid β-glucocerebrosidase (GBA1) gene, responsible for the lysosomal storage disorder Gaucher's disease (GD), are the strongest genetic risk factor for Parkinson's disease (PD) known to date. Here we generate induced pluripotent stem cells from subjects with GD and PD harbouring GBA1 mutations, and differentiate them into midbrain dopaminergic neurons followed by enrichment using fluorescence-activated cell sorting. Neurons show a reduction in glucocerebrosidase activity and protein levels, increase in glucosylceramide and α-synuclein levels as well as autophagic and lysosomal defects. Quantitative proteomic profiling reveals an increase of the neuronal calcium-binding protein 2 (NECAB2) in diseased neurons. Mutant neurons show a dysregulation of calcium homeostasis and increased vulnerability to stress responses involving elevation of cytosolic calcium. Importantly, correction of the mutations rescues such pathological phenotypes. These findings provide evidence for a link between GBA1 mutations and complex changes in the autophagic/lysosomal system and intracellular calcium homeostasis, which underlie vulnerability to neurodegeneration.
Bu, Lu-Lu; Yang, Ke; Xiong, Wei-Xi; Liu, Feng-Tao; Anderson, Boyd; Wang, Ye; Wang, Jian
Precision medicine refers to an innovative approach selected for disease prevention and health promotion according to the individual characteristics of each patient. The goal of precision medicine is to formulate prevention and treatment strategies based on each individual with novel physiological and pathological insights into a certain disease. A multidimensional data-driven approach is about to upgrade "precision medicine" to a higher level of greater individualization in healthcare, a shift towards the treatment of individual patients rather than treating a certain disease including Parkinson's disease (PD). As one of the most common neurodegenerative diseases, PD is a lifelong chronic disease with clinical and pathophysiologic complexity, currently it is treatable but neither preventable nor curable. At its advanced stage, PD is associated with devastating chronic complications including both motor dysfunction and non-motor symptoms which impose an immense burden on the life quality of patients. Advances in computational approaches provide opportunity to establish the patient's personalized disease data at the multidimensional levels, which finally meeting the need for the current concept of precision medicine via achieving the minimal side effects and maximal benefits individually. Hence, in this review, we focus on highlighting the perspectives of precision medicine in PD based on multi-dimensional information about OMICS, molecular imaging, deep brain stimulation (DBS) and wearable sensors. Precision medicine in PD is expected to integrate the best evidence-based knowledge to individualize optimal management in future health care for those with PD.
Chiasserini, Davide; Tozzi, Alessandro; de Iure, Antonio; Tantucci, Michela; Susta, Federica; Orvietani, Pier Luigi; Koya, Keizo; Binaglia, Luciano; Calabresi, Paolo
Among heat shock proteins, mortalin has been linked to the pathogenesis of Parkinson's disease. In the present work a rat model of Parkinson's disease was used to analyze the expression of striatal proteins and, more specifically, mortalin expression. The possible involvement of mortalin in Parkinson's disease pathogenesis was further investigated by utilizing an electrophysiological approach and pharmacological inhibition of mortalin in both the physiological and the parkinsonian states. Proteomic analysis was used to investigate changes in striatal protein expression in the 6-hydroxydopamine rat model of Parkinson's disease. The electrophysiological effects of MKT-077, a rhodamine-123 analogue acting as an inhibitor of mortalin, were measured by field potential recordings from corticostriatal brain slices obtained from control, sham-operated, and 6-hydroxydopamine-denervated animals. Slices in the presence of rotenone, an inhibitor of mitochondrial complex I, were also analyzed. Proteomic analysis revealed downregulation of mortalin in the striata of 6-hydroxydopamine-treated rats in comparison with sham-operated animals. MKT-077 reduced corticostriatal field potential amplitude in physiological conditions, inducing membrane depolarization and inward current in striatal medium spiny neurons. In addition, we observed that concentrations of MKT-077 not inducing any electrophysiological effect in physiological conditions caused significant changes in striatal slices from parkinsonian animals as well as in slices treated with a submaximal concentration of rotenone. These findings suggest a critical link between mortalin function and mitochondrial activity in both physiological and pathological conditions mimicking Parkinson's disease.
Batista, Leonardo M; Portela de Oliveira, Millena Teles; Magalhaes, Wilrama B; Bastos, Poliana Lima
Parkinson's disease is a chronic progressive neurodegenerative disorder with a multifactorial etiology. The symptoms are characterized by motor disorders - tremor, rigidity, bradykinesia and postural instability, which hinder oral hygiene. Oral and dental health in Parkinson's disease has been under-documented and findings are conflicting. Moreover, a number of dentists have limited experience regarding the management of these patients. This article reviews literature published within the last fifteen years, to better understand the impact of this disease in oral health. A literature search (MEDLINE and PUBMED), using keywords Parkinson Disease and Oral Hygiene, yielded 27 articles, from which 20 were selected. All of the articles were published in English in the last 15 years.
Arena, Julieta E; Stoessl, A Jon
Parkinson's disease (PD) and other disorders characterized by basal ganglia dysfunction are often associated with limited structural imaging changes that might assist in the clinical or research setting. Radionuclide imaging has been used to assess characteristic functional changes. Presynaptic dopaminergic dysfunction in PD can be revealed through the imaging of different steps in the process of dopamine synthesis and storage: L-aromatic amino acid decarboxylase (AADC) activity, Vesicular Monoamine Transporter type 2 (VMAT2) binding or its reuptake via the dopamine transporter (DAT). Postsynaptic dopamine dysfunction can also be studied with a variety of different tracers that primarily assess D2-like dopamine receptor availability. The function of other neurotransmitters such as norepinephrine, serotonin and acetylcholine can be imaged as well, giving important information about the underlying pathophysiologic process of PD and its complications. The imaging of metabolic activity and pathologic changes has also provided great advances in the field. Together, these techniques have allowed for a better understanding of PD, may be of aid for differentiating PD from other forms of parkinsonism and will undoubtedly be useful for the establishment of new therapeutic targets.
Sorrell, Jeanne M
Parkinson's disease is one of the most common chronically disabling disorders of the nervous system. The disorder affects predominately older adults; only 4% of individuals are diagnosed before age 50. Receiving a diagnosis of Parkinson's disease can be overwhelming for someone who is active and feels healthy, but new research shows that patients who take charge of their illness by adopting healthful habits of mind and body can slow the development of the disease and have a better quality of life. [Journal of Psychosocial Nursing and Mental Health Services, 55(4), 15-18.].
Contreras, Ana; Grandas, Francisco
Falls are a major source of disability in Parkinson's disease. Risk factors for falling in Parkinson's disease remain unclear. To determine the relevant risk factors for falling in Parkinson's disease, we screened 160 consecutive patients with Parkinson's disease for falls and assessed 40 variables. A comparison between fallers and nonfallers was performed using statistical univariate analyses, followed by bivariate and multivariate logistic regression, receiver-operating characteristics analysis, and Kaplan-Meier curves. 38.8% of patients experienced falls since the onset of Parkinson's disease (recurrent in 67%). Tinetti Balance score and Hoehn and Yahr staging were the best independent variables associated with falls. The Tinetti Balance test predicted falls with 71% sensitivity and 79% specificity and Hoehn and Yahr staging with 77% sensitivity and 71% specificity. The risk of falls increased exponentially with age, especially from 70 years onward. Patients aged >70 years at the onset of Parkinson's disease experienced falls significantly earlier than younger patients.
Draijer, Willem; Eizenga, Wietze H; Sluiter, Alja; Opstelten, Wim; Goudswaard, A N Lex
Parkinson's disease is characterised by bradykinesia in combination with one or more of the following symptoms: rigidity, resting tremor and disorders of posture and balance. Refer a patient with suspected Parkinson's disease (or parkinsonism) for diagnosis and treatment preferably to a neurologist with expertise in movement disorders. The treatment of Parkinson's disease is symptomatic; to date, there is no treatment that slows disease progression. The treatment of patients with Parkinson's disease and its related disorders involves collaboration of the neurologist, Parkinson's disease nurse and general practitioner. In addition to recognizing the hypokinetic-rigid syndrome, the general practitioner has a role in diagnosing and treating associated symptoms and disorders, and in supporting and counseling the patient and their partner or caregiver.
Babayeva, Mariana; Assefa, Haregewein; Basu, Paramita; Chumki, Sanjeda; Loewy, Zvi
Parkinson's disease (PD), a neurodegenerative disorder, is the second most common neurological illness in United States. Neurologically, it is characterized by the selective degeneration of a unique population of cells, the nigrostriatal dopamine neurons. The current treatment is symptomatic and mainly involves replacement of dopamine deficiency. This therapy improves only motor symptoms of Parkinson's disease and is associated with a number of adverse effects including dyskinesia. Therefore, there is unmet need for more comprehensive approach in the management of PD. Cannabis and related compounds have created significant research interest as a promising therapy in neurodegenerative and movement disorders. In this review we examine the potential benefits of medical marijuana and related compounds in the treatment of both motor and nonmotor symptoms as well as in slowing the progression of the disease. The potential for cannabis to enhance the quality of life of Parkinson's patients is explored.
Assefa, Haregewein; Basu, Paramita; Chumki, Sanjeda; Loewy, Zvi
Parkinson's disease (PD), a neurodegenerative disorder, is the second most common neurological illness in United States. Neurologically, it is characterized by the selective degeneration of a unique population of cells, the nigrostriatal dopamine neurons. The current treatment is symptomatic and mainly involves replacement of dopamine deficiency. This therapy improves only motor symptoms of Parkinson's disease and is associated with a number of adverse effects including dyskinesia. Therefore, there is unmet need for more comprehensive approach in the management of PD. Cannabis and related compounds have created significant research interest as a promising therapy in neurodegenerative and movement disorders. In this review we examine the potential benefits of medical marijuana and related compounds in the treatment of both motor and nonmotor symptoms as well as in slowing the progression of the disease. The potential for cannabis to enhance the quality of life of Parkinson's patients is explored. PMID:28050308
Tartaglione, A; Pizio, N; Bino, G; Spadavecchia, L; Favale, E
Two stimulus configurations (gratings and checkerboards) have been presented to a series of consecutive patients with the aim of exploring VEP changes in Parkinson's disease. The outcome turned out to be quite different according to the stimulus employed. Specifically, grating pattern produced a high diagnostic yield as opposite to checkerboard, which did not reveal substantial modifications of the latency of the VEP major positive peak with respect to a control group. This finding raises problems as to the characteristics of visual changes associated with Parkinson's disease. PMID:6707679
Tokisato, Kaori; Fukunaga, Kimiko; Tokunaga, Makoto; Watanabe, Susumu; Nakanishi, Ryoji; Yamanaga, Hiroaki
We herein report three cases of Parkinson's disease associated with difficulty in eyelid opening, referred to as apraxia of eyelid opening (AEO), which improved after aripiprazole treatment. In case 1, aripiprazole was administered as a psychiatric treatment. It proved to be effective in AEO with blepharospasm. In case 2 and case 3, the patients experienced AEO without blepharospasm, and a significant improvement was observed after aripiprazole treatment. In this study, the aripiprazole dosage ranged between 3 and 9 mg/day. This is the first report of aripiprazole as a potentially effective treatment for AEO in Parkinson's disease.
Wilcox, Sarah K
Patients with Parkinson's disease have an illness which shortens their life and involves a heavy symptom burden for patient and carer. This article discusses some common palliative care issues pertinent to patients with Parkinson's disease.
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Galati, Salvatore; Salvadè, Agnese; Pace, Marta; Sarasso, Simone; Baracchi, Francesca; Bassetti, Claudio L; Kaelin-Lang, Alain; Städler, Claudio; Stanzione, Paolo; Möller, Jens C
Levodopa-induced dyskinesia (LID) represents a major challenge for clinicians treating patients affected by Parkinson's disease (PD). Although levodopa is the most effective treatment for PD, the remodeling effects induced by disease progression and the pharmacologic treatment itself cause a narrowing of the therapeutic window because of the development of LID. Although animal models of PD provide strong evidence that striatal plasticity underlies the development of dyskinetic movements, the pathogenesis of LID is not entirely understood. In recent years, slow homeostatic adjustment of intrinsic excitability occurring during sleep has been considered fundamental for network stabilization by gradually modifying plasticity thresholds. So far, how sleep affects on LID has not been investigated. Therefore, we measured synaptic downscaling across sleep episodes in a parkinsonian animal model showing dyskinetic movements similar to LID. Our electrophysiological, molecular, and behavioral results are consistent with an impaired synaptic homeostasis during sleep in animals showing dyskinesia. Accordingly, sleep deprivation causes an anticipation and worsening of LID supporting a link between sleep and the development of LID.
Pedrosa, David J; Reck, Christiane; Florin, Esther; Pauls, K Amande M; Maarouf, Mohammad; Wojtecki, Lars; Dafsari, Haidar Salimi; Sturm, Volker; Schnitzler, Alfons; Fink, Gereon R; Timmermann, Lars
Different tremor entities such as Essential Tremor (ET) or tremor in Parkinson's disease (PD) can be ameliorated by the implantation of electrodes in the ventral thalamus for Deep Brain Stimulation (DBS). The exact neural mechanisms underlying this treatment, as well as the specific pathophysiology of the tremor in both diseases to date remain elusive. Since tremor-related local field potentials (LFP) have been shown to cluster with a somatotopic representation in the subthalamic nucleus, we here investigated the neurophysiological correlates of tremor in the ventral thalamus in ET and PD using power and coherence analysis. Local field potentials (LFPs) at different recording depths and surface electromyographic signals (EMGs) from the extensor and flexor muscles of the contralateral forearm were recorded simultaneously in twelve ET and five PD patients. Data analysis revealed individual electrophysiological patterns of LFP-EMG coherence at single and double tremor frequency for each patient. Patterns observed varied in their spatial distribution within the Ventral lateral posterior nucleus of the thalamus (VLp), revealing a specific topography of 'tremor clusters' for PD and ET. The data strongly suggest that within VLp individual tremor-related electrophysiological signatures exist in ET and PD tremor.
Fiesel, Fabienne C; Caulfield, Thomas R; Moussaud-Lamodière, Elisabeth L; Ogaki, Kotaro; Dourado, Daniel F A R; Flores, Samuel C; Ross, Owen A; Springer, Wolfdieter
Mutations in the PARKIN/PARK2 gene that result in loss-of-function of the encoded, neuroprotective E3 ubiquitin ligase Parkin cause recessive, familial early-onset Parkinson disease. As an increasing number of rare Parkin sequence variants with unclear pathogenicity are identified, structure-function analyses will be critical to determine their disease relevance. Depending on the specific amino acids affected, several distinct pathomechanisms can result in loss of Parkin function. These include disruption of overall Parkin folding, decreased solubility, and protein aggregation. However pathogenic effects can also result from misregulation of Parkin autoinhibition and of its enzymatic functions. In addition, interference of binding to coenzymes, substrates, and adaptor proteins can affect its catalytic activity too. Herein, we have performed a comprehensive structural and functional analysis of 21 PARK2 missense mutations distributed across the individual protein domains. Using this combined approach, we were able to pinpoint some of the pathogenic mechanisms of individual sequence variants. Similar analyses will be critical in gaining a complete understanding of the complex regulations and enzymatic functions of Parkin. These studies will not only highlight the important residues, but will also help to develop novel therapeutics aimed at activating and preserving an active, neuroprotective form of Parkin.
Vaou, Okeanis; Saint-Hilaire, Marie; Friedman, Joseph
Visual hallucinations are reported in 16-37% of drug-treated patients with Parkinson's disease (PD) and are the most common hallucinations in PD. We report two patients with PD with symptoms that uniquely integrate visual hallucinations and delusions. We report two cases of patients with PD with visual hallucinations who saw the persistence of these hallucinations in photographs. These pictures were taken to prove the absence of these hallucinations. We believe this is the first description of this peculiar phenomenon, in which hallucinations or illusions could be replicated in photographs. Both patients had delusions associated with the images and we speculate that the images they saw in the photographs represent a further delusion, hence a 'delusional hallucination' or 'delusional illusion.' We believe that delusions fostering hallucinations are rare.
Taetzsch, Thomas; Block, Michelle L
Accumulating evidence indicates that pesticide exposure is associated with an increased risk for developing Parkinson's disease (PD). Several pesticides known to damage dopaminergic (DA) neurons, such as paraquat, rotenone, lindane, and dieldrin also demonstrate the ability to activate microglia, the resident innate immune cell in the brain. While each of these environmental toxicants may impact microglia through unique mechanisms, they all appear to converge on a common final pathway of microglial activation: NADPH oxidase 2 (NOX2) activation. This review will detail the role of microglia in selective DA neurotoxicity, highlight what is currently known about the mechanism of microglial NOX2 activation in these key pesticides, and describe the importance for DA neuron survival and PD etiology.
Lin, Chin-Hsien; Wu, Ruey-Meei
Cognitive impairment is a frequent and devastating non-motor symptom of Parkinson's disease (PD). Impaired cognition has a major impact on either quality of life or mortality in patients with PD. Notably, the rate of cognitive decline and pattern of early cognitive deficits in PD are highly variable between individuals. Given that the underlying mechanisms of cognitive decline or dementia associated with PD remain unclear, there is currently no mechanism-based treatment available. Identification of biological markers, including neuroimaging, biofluids and common genetic variants, that account for the heterogeneity of PD related cognitive decline could provide important insights into the pathological processes that underlie cognitive impairment in PD. These combined biomarker approaches will enable early diagnosis and provide indicators of cognitive progression in PD patients. This review summarizes recent advances in the development of biomarkers for cognitive impairments in PD.
terminal integrity, will provide a quantitative biomarker of Parkinson’s disease progression in subjects with early Parkinson’s disease during a rime...dopa on the rate of progression of Parkinson’s disease . All subjects have been and will be recruited and clinically evaluated through their participation...in early Parkinson’s disease , whether the rate of neuronal degeneration is affected by L-dopa, a potential neurotoxin, and whether the changes in
Shi, Min; Huber, Bertrand R.; Zhang, Jing
Cognitive impairment, including dementia, is commonly seen in those afflicted with Parkinson disease (PD), particularly at advanced disease stages. Pathologically, PD with dementia (PD-D) is most often associated with the presence of cortical Lewy bodies, as is the closely related dementia with Lewy bodies (DLB). Both PD-D and DLB are also frequently complicated by the presence of neurofibrillary tangles and amyloid plaques, features most often attributed to Alzheimer disease. Biomarkers are urgently needed to differentiate among these disease processes and predict dementia in PD as well as monitor responses of patients to new therapies. A few clinical assessments, along with structural and functional neuroimaging, have been utilized in the last few years with some success in this area. Additionally, a number of other strategies have been employed to identify biochemical/molecular biomarkers associated with cognitive impairment and dementia in PD, e.g., targeted analysis of candidate proteins known to be important to PD pathogenesis and progression in cerebrospinal fluid or blood. Finally, interesting results are emerging from preliminary studies with unbiased and high throughput genomic, proteomic and metabolomic techniques. The current findings and perspectives of applying these strategies and techniques are reviewed in this article, together with potential areas of advancement. PMID:20522092
Shulman, Lisa M; Gruber-Baldini, Ann L; Anderson, Karen E; Vaughan, Christopher G; Reich, Stephen G; Fishman, Paul S; Weiner, William J
The objectives of this study are to assess the level of disease severity associated with disability in Parkinson disease (PD) and the sequence of loss of independence in basic and instrumental activities of daily living (ADLs and IADLs). Six hundred eighteen patients with PD were evaluated for disease severity with the Unified PD Rating Scale (UPDRS) and for disability with the Older Americans Resource and Services Disability Subscale (OARS). The association between patient-reported disability on ADLs and IADLs and level of disease severity on the total UPDRS was examined cross-sectionally. Disability, with loss of independent function is reported between total UPDRS scores 30 to 40, and HY stages II to III. Difficulty with daily activities, without loss of independent function is reported earlier, at UPDRS <20 and HY I to II. Difficulty with walking is initially reported, followed by problems with a number of gait-dependent activities including housework, dressing, transferring in and out of bed, and traveling in the community. The transition from HY stage II to III marks a pivotal milestone in PD, when gait and balance impairment results in disability in many gait-dependent activities. The onset of disability in PD can be identified by asking patients about their walking, housework, dressing, and traveling. While individual patients vary in progression, the benchmarks of disability in this study provide guidance when counseling patients about prognosis. Better understanding of the stages of disability may facilitate the development of novel outcome measures in clinical trials in PD.
Culbertson, William; Moberg, Paul; Duda, John; Stern, Matthew; Weintraub, Daniel
The aim of the study was to investigate the utility of the Tower of London-Drexel (TOL DX ) in assessing the executive deficits associated with Parkinsons disease (PD). We sought to determine whether the TOL DX would differentiate between (a) patients with PD and healthy control participants (HCP), (b) demented and nondemented patients, and (c)…
Argolo, Natalie; Sampaio, Marília; Pinho, Patrícia; Melo, Ailton; Nóbrega, Ana Caline
Background: Lingual pumping (LP) is a repetitive, involuntary, anteroposterior movement of the tongue on the soft palate that is executed prior to transferring the food bolus to the pharynx, but we also observed LP when multiple swallows were taken. LP may be associated with rigidity and bradykinesia in patients with Parkinson's disease (PD). This…
Jahanshahi, Marjan; Wilkinson, Leonora; Gahir, Harpreet; Dharminda, Angeline; Lagnado, David A.
In Parkinson's disease (PD), it is possible that tonic increase of dopamine associated with levodopa medication overshadows phasic release of dopamine, which is essential for learning. Thus while the motor symptoms of PD are improved with levodopa medication, learning would be disrupted. To test this hypothesis, we investigated the effect of…
Bankiewicz, Krystof; Cunningham, Janet
Methods of delivering viral vectors, particularly recombinant adeno-associated virus (rAAV) virions, to the central nervous system (CNS) using convection enhanced delivery (CED) are provided. The rAAV virions include a nucleic acid sequence encoding a therapeutic polypeptide. The methods can be used for treating CNS disorders such as for treating Parkinson's Disease.
Beauchamp, M. H.; Dagher, A.; Panisset, M.; Doyon, J.
While cognitive skill learning is normally acquired implicitly through frontostrial circuitry in healthy individuals, neuroimaging studies suggest that patients with Parkinson's disease (PD) do so by activating alternate, intact brain areas associated with explicit memory processing. To further test this hypothesis, 10 patients with PD and 12…
Holtgraves, Thomas; McNamara, Patrick; Cappaert, Kevin; Durso, Raymond
Asymmetric motor severity is common in Parkinson's Disease (PD) and provides a method for examining the neurobiologic mechanisms underlying cognitive and linguistic deficits associated with the disorder. In the present research, PD participants (N = 31) were assessed in terms of the asymmetry of their motor symptoms. Interviews with the…
Collado-Vázquez, Susana; Cano-de-la-Cuerda, Roberto; Carrillo, Jesús M
INTRODUCTION. Since James Parkinson published what can be considered the first treaty on the disease that bears his name in 1817, the scientific literature on this pathology has not ceased to grow. But the illness has also been represented in literature, the cinema and on television, where the symptoms, treatment and socio-familial context of the disease have often been examined very closely. AIM. To address the cases in which Parkinson's disease appears in literature, cinema and television, as well as to reflect on the image of the condition presented in those contexts. DEVELOPMENT. We reviewed some of the most important works in the literature dealing with Parkinson's disease from any period of history and many of them were found to offer very faithful portrayals of the disease. Likewise, we also reviewed major films and TV series that sometimes offer the general public a close look at the vision and the impact of the disease on patients or their relatives. CONCLUSIONS. Literature, cinema and television have helped provide a realistic view of both Parkinson's disease and the related healthcare professionals, and there are many examples that portray the actual experiences of the patients themselves, while also highlighting the importance of healthcare and socio-familial care.
Parkinson's disease is characterised by three main symptoms: slowness and paucity of movements, rigidity, and resting tremor. Rapid improvement in these symptoms after levodopa administration supports the diagnosis of Parkinson's disease. It is important to inform the patient tactfully, allowing him or her to control the pace at which information on the diagnosis, symptoms and prognosis is conveyed. Patients with minimal discomfort or mild disability derive little benefit from drug therapy. Physiotherapy and physical exercises are sometimes useful. Previously untreated patients with marked functional impairment should receive medication. The choice is essentially between levodopa and ropinirole, and mainly depends on the patient's age.
Crespo-Burillo, José A; Alarcia-Alejos, Raquel
Autonomic dysfunction is a common manifestation in patients with in Parkinson's disease, which can sometimes precede motor impairment. It can be expressed as orthostatic and postprandial hypotension, supine hypertension, hypersalivation, constipation, delayed gastric emptying, dyshidrosis, bladder and sexual dysfunction. It impairs the quality of life of patients and complicates the management of motor symptoms. Evidence available to treat complications is low. Our aim is to review the pathophysiology and clinical features of autonomic dysfunction in Parkinson's disease and provide a practical approach to handling the available evidence.
Podlesniy, Petar; Vilas, Dolores; Taylor, Peggy; Shaw, Leslie M; Tolosa, Eduard; Trullas, Ramon
Mitochondrial DNA regulates mitochondrial function which is altered in both idiopathic and familial forms of Parkinson's disease. To investigate whether these two disease forms exhibit an altered regulation of mitochondrial DNA we measured cell free mitochondrial DNA content in cerebrospinal fluid (CSF) from idiopathic and LRRK2-related Parkinson's disease patients. The concentration of mitochondrial DNA was measured using a digital droplet polymerase chain reaction technique in a total of 98 CSF samples from a cohort of subjects including: 20 LRRK2(G2019S) mutation carriers with Parkinson's disease, 26 asymptomatic LRRK2(G2019S) mutation carriers, 31 patients with idiopathic Parkinson's disease and 21 first-degree relatives of LRRK2 Parkinson's disease patients without the mutation. Here we report that LRRK2(G2019S) mutation carriers with Parkinson's disease exhibit a high concentration of mitochondrial DNA in CSF compared with asymptomatic LRRK2(G2019S) mutation carriers and with idiopathic Parkinson's disease patients. In addition, idiopathic, but not LRRK2 Parkinson's disease is associated with low CSF concentration of α-synuclein. These results show that high mitochondrial DNA content in CSF distinguishes idiopathic from LRRK2-related Parkinson's disease suggesting that different biochemical pathways underlie neurodegeneration in these two disorders.
Xie, Cheng-Long; Pan, Jia-Lin; Wang, Wen-Wen; Zhang, Yu; Zhang, Su-Fang; Gan, Jing; Liu, Zhen-Guo
Clinical diagnosis of Parkinson's disease (PD) is essential but misdiagnosis of PD-like diseases is quite common. LRRK2 G2385R variants have been extensively examined for the association to the risk of Parkinson's disease. However, results from different studies are inconsistent. The purpose of this meta-analysis was to assess the association between the LRRK2 G2385R variants and the risk of PD. A systematic literature search was performed for 6 databases up to January of 2014 to identify case-control studies involving LRRK2 G2385R variants and the risk of PD. A total of 12,915 cases and 12,451 controls in 23 case-control studies were included in this meta-analysis. The results indicated that the variant A allele carriers (GA + AA) increased risk of PD when compared with the homozygote GG (GA + AA vs. GG: OR = 2.4, 95 % CI = 1.97 to 2.92, P < 0.00001). In the subgroup analysis by ethnicity, increased risks were identified among Chinese (OR = 2.69, 95 % CI = 2.1-3.45, P < 0.00001) as well as in non-Chinese (OR = 2.17, 95 % CI 1.75-2.69, P < 0.00001). In the subgroup analysis by age of onset, significant associations were found in both later-onset PD (LOPD) and early-onset PD (EOPD) cases. And there was no significant difference of the allele frequency between patients with LOPD and EOPD (OR = 1.18, 95 % CI = 0.77-1.80, P = 0.45). Our results suggest that the LRRK2 G2385R variants contribute to the susceptibility of PD especially in Chinese PD. Meanwhile, it is possible that age is not the risk factor to facilitate G2385R gene mutation.
Franzén, Erika; Paquette, Caroline; Gurfinkel, Victor S; Cordo, Paul J; Nutt, John G; Horak, Fay B
Rigidity or hypertonicity is a cardinal symptom of Parkinson's disease (PD). We hypothesized that hypertonicity of the body axis affects functional performance of tasks involving balance, walking and turning. The magnitude of axial postural tone in the neck, trunk and hip segments of 15 subjects with PD (both ON and OFF levodopa) and 15 control subjects was quantified during unsupported standing in an axial twisting device in our laboratory as resistance to torsional rotation. Subjects also performed six functional tests (walking in a figure of eight [Figure of Eight], Timed Up & Go, Berg Balance Scale, supine rolling task [rollover], Functional Reach, and standing 360-deg turn-in-place) in the ON and OFF state. Results showed that PD subjects had increased tone throughout the axis compared to control subjects (p=0.008) and that this increase was most prominent in the neck. In PD subjects, axial tone was related to functional performance, but most strongly for tone at the neck and accounted for an especially large portion of the variability in the performance of the Figure of Eight test (rOFF=0.68 and rON=0.74, p<0.05) and the Rollover test (rOFF=0.67and rON=0.55, p<0.05). Our results suggest that neck tone plays a significant role in functional mobility and that abnormally high postural tone may be an important contributor to balance and mobility disorders in individuals with PD. PMID:19573528
Sawada, Yoichi; Nishio, Yoshiyuki; Suzuki, Kyoko; Hirayama, Kazumi; Takeda, Atsushi; Hosokai, Yoshiyuki; Ishioka, Toshiyuki; Itoyama, Yasuto; Takahashi, Shoki; Fukuda, Hiroshi; Mori, Etsuro
The attentional set-shifting deficit that has been observed in Parkinson's disease (PD) has long been considered neuropsychological evidence of the involvement of meso-prefrontal and prefrontal-striatal circuits in cognitive flexibility. However, recent studies have suggested that non-dopaminergic, posterior cortical pathologies may also contribute to this deficit. Although several neuroimaging studies have addressed this issue, the results of these studies were confounded by the use of tasks that required other cognitive processes in addition to set-shifting, such as rule learning and working memory. In this study, we attempted to identify the neural correlates of the attentional set-shifting deficit in PD using a compound letter task and 18F-fluoro-deoxy-glucose (FDG) positron emission tomography during rest. Shift cost, which is a measure of attentional set-shifting ability, was significantly correlated with hypometabolism in the right dorsolateral prefrontal cortex, including the putative human frontal eye field. Our results provide direct evidence that dysfunction in the dorsolateral prefrontal cortex makes a primary contribution to the attentional set-shifting deficit that has been observed in PD patients.
Nenasheva, V V; Novosadova, E V; Makarova, I V; Lebedeva, O S; Grefenshtein, M A; Arsenyeva, E L; Antonov, S A; Grivennikov, I A; Tarantul, V Z
Over the last few years, in vitro models, based on patient-derived induced pluripotent stem cells (iPSCs), have received considerable attention for modeling different neurodegenerative disorders. Using this model, we analyzed transcription of 15 tripartite motif (trim) genes in iPSCs, derived from the different groups: Parkinson's disease (PD) patients bearing mutations in different genes, patient with the sporadic form of PD, and the healthy individuals. The transcription was observed during neuronal differentiation of the cells in vitro into neuronal stem cells and terminally differentiated neurons. The transcription of over 50 % of these genes, belonging to different sub-groups of the TRIM family, varied between PD patients and healthy individuals during the reprogramming of fibroblasts into iPSCs and the following neuronal differentiation. Moreover, the transcription of the trim6 and trim24 genes was different between cells, derived from PD patients, and control cells at all stages. The transcription of the four trim genes (trim5α, 26, 27, 31) remained unchanged during almost all investigated stages, compared with the controls. We suppose that the revealed changes in the transcription of several trim genes reflect their possible role in neurodegenerative processes at the early stages of PD. These genes may act as a gear unit between the PD progression and the deregulation of the immune system.
Song, Saera; Jang, Seoyeon; Park, Jeehye; Bang, Sunhoe; Choi, Sekyu; Kwon, Kyum-Yil; Zhuang, Xiaoxi; Kim, Eunjoon; Chung, Jongkyeong
Mutations in PINK1 (PTEN-induced putative kinase 1) are tightly linked to autosomal recessive Parkinson disease (PD). Although more than 50 mutations in PINK1 have been discovered, the role of these mutations in PD pathogenesis remains poorly understood. Here, we characterized 17 representative PINK1 pathogenic mutations in both mammalian cells and Drosophila. These mutations did not affect the typical cleavage patterns and subcellular localization of PINK1 under both normal and damaged mitochondria conditions in mammalian cells. However, PINK1 mutations in the kinase domain failed to translocate Parkin to mitochondria and to induce mitochondrial aggregation. Consistent with the mammalian data, Drosophila PINK1 mutants with mutations in the kinase domain (G426D and L464P) did not genetically interact with Parkin. Furthermore, PINK1-null flies expressing the transgenic G426D mutant displayed defective phenotypes with increasing age, whereas L464P mutant-expressing flies exhibited the phenotypes at an earlier age. Collectively, these results strongly support the hypothesis that the kinase activity of PINK1 is essential for its function and for regulating downstream Parkin functions in mitochondria. We believe that this study provides the basis for understanding the molecular and physiological functions of various PINK1 mutations and provides insights into the pathogenic mechanisms of PINK1-linked PD.
Monti, Chiara; Colugnat, Ilaria; Lopiano, Leonardo; Chiò, Adriano; Alberio, Tiziana
Neurodegenerative diseases are characterized by the progressive loss of specific neurons in selected regions of the central nervous system. The main clinical manifestation (movement disorders, cognitive impairment, and/or psychiatric disturbances) depends on the neuron population being primarily affected. Parkinson's disease is a common movement disorder, whose etiology remains mostly unknown. Progressive loss of dopaminergic neurons in the substantia nigra causes an impairment of the motor control. Some of the pathogenetic mechanisms causing the progressive deterioration of these neurons are not specific for Parkinson's disease but are shared by other neurodegenerative diseases, like Alzheimer's disease and amyotrophic lateral sclerosis. Here, we performed a meta-analysis of the literature of all the quantitative proteomic investigations of neuronal alterations in different models of Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis to distinguish between general and Parkinson's disease-specific pattern of neurodegeneration. Then, we merged proteomics data with genetics information from the DisGeNET database. The comparison of gene and protein information allowed us to identify 25 proteins involved uniquely in Parkinson's disease and we verified the alteration of one of them, i.e., transaldolase 1 (TALDO1), in the substantia nigra of 5 patients. By using open-source bioinformatics tools, we identified the biological processes specifically affected in Parkinson's disease, i.e., proteolysis, mitochondrion organization, and mitophagy. Eventually, we highlighted four cellular component complexes mostly involved in the pathogenesis: the proteasome complex, the protein phosphatase 2A, the chaperonins CCT complex, and the complex III of the respiratory chain.
Ling, Helen; Massey, Luke A; Lees, Andrew J; Brown, Peter; Day, Brian L
, characterized by slowness with progressive reduction in amplitude and speed and increased variability in speed throughout the tap trial. In Parkinson's disease, smaller amplitude, slower speed and greater speed variability were all associated with a more severe Unified Parkinson's Disease Rating Scale motor score. Analyses of handwriting showed that micrographia, defined as smaller than 50% of the control group's mean script size, was present in 75% of patients with progressive supranuclear palsy and 15% of patients with Parkinson's disease (P = 0.022). Most scripts performed by patients with progressive supranuclear palsy did not exhibit decrements in script size. In conclusion, patients with progressive supranuclear palsy have a specific finger tap pattern of 'hypokinesia without decrement' and they do not have criteria-defined limb bradykinesia. Similarly, 'micrographia' and 'lack of decrement in script size' are also more common in progressive supranuclear palsy than in Parkinson's disease.
Rolinski, Michal; Zokaei, Nahid; Baig, Fahd; Giehl, Kathrin; Quinnell, Timothy; Zaiwalla, Zenobia; Mackay, Clare E; Husain, Masud; Hu, Michele T M
Individuals with REM sleep behaviour disorder are at significantly higher risk of developing Parkinson's disease. Here we examined visual short-term memory deficits--long associated with Parkinson's disease--in patients with REM sleep behaviour disorder without Parkinson's disease using a novel task that measures recall precision. Visual short-term memory for sequentially presented coloured bars of different orientation was assessed in 21 patients with polysomnography-proven idiopathic REM sleep behaviour disorder, 26 cases with early Parkinson's disease and 26 healthy controls. Three tasks using the same stimuli controlled for attentional filtering ability, sensorimotor and temporal decay factors. Both patients with REM sleep behaviour disorder and Parkinson's disease demonstrated a deficit in visual short-term memory, with recall precision significantly worse than in healthy controls with no deficit observed in any of the control tasks. Importantly, the pattern of memory deficit in both patient groups was specifically explained by an increase in random responses. These results demonstrate that it is possible to detect the signature of memory impairment associated with Parkinson's disease in individuals with REM sleep behaviour disorder, a condition associated with a high risk of developing Parkinson's disease. The pattern of visual short-term memory deficit potentially provides a cognitive marker of 'prodromal' Parkinson's disease that might be useful in tracking disease progression and for disease-modifying intervention trials.
Lee, Yunjong; Dawson, Valina L.; Dawson, Ted M.
Parkinson's disease (PD) is a complex genetic disorder that is associated with environmental risk factors and aging. Vertebrate genetic models, especially mice, have aided the study of autosomal-dominant and autosomal-recessive PD. Mice are capable of showing a broad range of phenotypes and, coupled with their conserved genetic and anatomical structures, provide unparalleled molecular and pathological tools to model human disease. These models used in combination with aging and PD-associated toxins have expanded our understanding of PD pathogenesis. Attempts to refine PD animal models using conditional approaches have yielded in vivo nigrostriatal degeneration that is instructive in ordering pathogenic signaling and in developing therapeutic strategies to cure or halt the disease. Here, we provide an overview of the generation and characterization of transgenic and knockout mice used to study PD followed by a review of the molecular insights that have been gleaned from current PD mouse models. Finally, potential approaches to refine and improve current models are discussed. PMID:22960626
Trimmer, Patricia A; Bennett, James P
Parkinson's disease (PD) is the eponym attached to the most prevalent neurodegenerative movement disorder of adults, derived from observations of an early nineteenth century physician and paleontologist, James Parkinson, and is now recognized to encompass much more than a movement disorder clinically or dopamine neuron death pathologically. Most PD ( approximately 90%) is sporadic (sPD), is associated with mitochondrial deficiencies and has been studied in cell and animal models arising from the use of mitochondrial toxins that unfortunately have not predicted clinical efficacy to slow disease progression in humans. We have extensively studied the cytoplasmic hybrid ("cybrid") model of sPD in which donor mtDNAs are introduced into and expressed in neural tumor cells with identical nuclear genetic and environmental backgrounds. sPD cybrids demonstrate many abnormalities in which increased oxidative stress drives downstream antioxidant response and cell death activating signaling pathways. sPD cybrids regulate mitochondrial ETC genes and gene ontology families like sPD brain. sPD cybrids spontaneously form Lewy bodies and Lewy neurites, linking mtDNA expression to neuropathology, and demonstrate impaired organelle transport in processes and reduced mitochondrial respiration. Our recent studies show that near-infrared laser light therapy normalizes mitochondrial movement and can stimulate respiration in sPD cybrid neurons, and mitochondrial gene therapy can restore respiration and stimulate mitochondrial ETC gene and protein expression. sPD cybrids have provided multiple lines of circumstantial evidence linking mtDNA to sPD pathogenesis and can serve as platforms for therapy development. sPD cybrid models can be improved by the use of non-tumor human stem cell-derived neural precursor cells and by an introduction of postmortem brain mtDNA to test its causality directly.
Nilashi, Mehrbakhsh; Ibrahim, Othman; Ahani, Ali
Parkinson's disease (PD) is a member of a larger group of neuromotor diseases marked by the progressive death of dopamineproducing cells in the brain. Providing computational tools for Parkinson disease using a set of data that contains medical information is very desirable for alleviating the symptoms that can help the amount of people who want to discover the risk of disease at an early stage. This paper proposes a new hybrid intelligent system for the prediction of PD progression using noise removal, clustering and prediction methods. Principal Component Analysis (PCA) and Expectation Maximization (EM) are respectively employed to address the multi-collinearity problems in the experimental datasets and clustering the data. We then apply Adaptive Neuro-Fuzzy Inference System (ANFIS) and Support Vector Regression (SVR) for prediction of PD progression. Experimental results on public Parkinson's datasets show that the proposed method remarkably improves the accuracy of prediction of PD progression. The hybrid intelligent system can assist medical practitioners in the healthcare practice for early detection of Parkinson disease.
Fatigue is a common, under recognized, and poorly understood nonmotor symptom in Parkinson's disease (PD). Fatigue frequently presents early in PD, and its prevalence increases with disease progression, affecting up to 60% of patients. Fatigue has a negative impact on quality of life. Fatigue is often associated with other nonmotor symptoms, including sleep disturbance, excessive daytime sleepiness, and depression. Only a few reports have been published on the treatment of fatigue in PD (methylphenidate, levodopa, and pramipexole). Further well-designed studies, including physiotherapy, are necessary to develop more effective treatments for PD-associated fatigue. A number of patients with PD lose weight because of loss of fat. However, the evolution and determinants of weight loss are not well established. Possible determinants of weight loss in PD include loss of appetite, impaired hand-mouth coordination, difficulty in chewing and dysphagia, nausea, intestinal hypomotility, and increased energy requirements because of muscular rigidity and involuntary movements. Noticeable weight gain has repeatedly been reported after subthalamic or pallidal deep brain stimulation. Because low body weight is associated with negative health effects and a poor prognosis, monitoring weight and nutritional status should be part of PD management.
O'Reilly, Eilis J; Chen, Honglei; Gardener, Hannah; Gao, Xiang; Schwarzschild, Michael A; Ascherio, Alberto
In epidemiologic studies and in studies of discordant twins, cigarette smoking has been consistently associated with a lower risk of Parkinson's disease, but whether this association is causal remains controversial. Alternatively, an infectious or toxic exposure in childhood or early adulthood could affect both the reward mechanisms that determine smoking behavior and the future risk of Parkinson's disease. If so, parental smoking, commonly established before the birth of the first child, would be unlikely to be related to Parkinson's disease risk. The authors assessed the association between Parkinson's disease and parental smoking during childhood in the Nurses' Health Study and the Health Professionals Follow-up Study conducted in the United States. During 26 years and 18 years of follow-up, respectively, 455 newly diagnosed Parkinson's disease cases were documented among those who provided information on parental smoking. The age-adjusted, pooled relative rate of Parkinson's disease was 0.73 (95% confidence interval: 0.53, 1.00; P-trend = 0.04) comparing participants who reported that both parents smoked with those who reported that neither did. Adjustment for caffeine and alcohol intake did not materially change the results. If the inverse association between smoking and Parkinson's disease were due to confounding by an environmental factor or were the result of reverse causation, it is unlikely that parental smoking would predict Parkinson's disease.
Lewis, Gwyn N; Byblow, Winston D
Transcranial magnetic stimulation (TMS) was used to investigate sensorimotor integration in the upper limb of 10 patients with Parkinson's disease and 10 age-matched controls. Non-conditioned and subthreshold conditioned (2 ms interstimulus interval) responses were recorded in the flexor and extensor carpi radialis muscles (FCR and ECR) of the more impaired (non-dominant) limb. Stimuli were delivered while the wrist joint was positioned statically at various joint angles as well as during different phases of passive movement of the wrist joint (90 degrees amplitude, 0.2 Hz). The FCR and ECR muscles remained relaxed during all stimulation. In both groups, responses in the static condition were larger when the target muscle was in a shortened position. Responses were also facilitated in the muscle shortening phases of passive movement. In both static and dynamic conditions, the extent of modulations in response amplitude was significantly reduced in the patient group. The level of intracortical inhibition (ICI) was also significantly less in the Parkinson's disease patients in static conditions. During passive movement, control subjects demonstrated a clear reduction in ICI compared with the static trials; however, the level of ICI was unchanged in the Parkinson's disease group in the dynamic condition. The results suggest an abnormal influence of afference on corticomotor excitability in Parkinson's disease. This may be related to abnormal sensory input, a defective integrative unit or an inappropriate motor response.
Fischer, Emily; Goberman, Alexander M.
Research has found that speaking rate has an effect on voice onset time (VOT). Given that Parkinson disease (PD) affects speaking rate, the purpose of this study was to examine VOT with the effect of rate removed (VOT ratio), along with the traditional VOT measure, in individuals with PD. VOT and VOT ratio were examined in 9 individuals with PD…
Cohen, Henri; Gagne, Marie-Helene; Hess, Ursula; Pourcher, Emmanuelle
The neuropsychological literature on the processing of emotions in Parkinson's disease (PD) reveals conflicting evidence about the role of the basal ganglia in the recognition of facial emotions. Hence, the present study had two objectives. One was to determine the extent to which the visual processing of emotions and objects differs in PD. The…
Pontone, Gregory M.; Williams, James R.; Anderson, Karen E.; Chase, Gary; Goldstein, Susanne R.; Grill, Stephen; Hirsch, Elaina S.; Lehmann, Susan; Little, John T.; Margolis, Russell L.; Palanci, Justin; Rabins, Peter V.; Weiss, Howard D.; Marsh, Laura
Objective Neither best practices nor an evidence-base for the pharmacologic treatment of anxiety in Parkinson's disease has been established. This study investigated pharmacologic treatment of anxiety disorders in idiopathic Parkinson's disease and the associated clinical features. Design Cross-sectional. Setting Three community-based movement disorder neurology practices Participants 250 subjects with Parkinson's disease. Measurements Anxiety disorder diagnoses were established by consensus using a panel of six psychiatrists with expertise in geriatric psychiatry and movement disorders. Current medications were provided by the treating neurologists at the time of interview. Results Amongst subjects with anxiety disorders only, 53% were untreated with medications. However, when anxious subjects with comorbid depressive disorders were included, 70.8% were on medications effective for treatment of anxiety. Subjects with anxiety and comorbid depressive disorders were more likely to be treated for their psychiatric disturbances than subjects with anxiety disorders alone (Odds Ratio 8.33) as were subjects with comorbid motor fluctuations (Odds Ratio, 3.65). There were no differences in the types of anti-anxiety medications used in regard to the presence of depression or motor fluctuations. Conclusions These findings suggest that over half of non-depressed Parkinson's disease patients with clinically significant anxiety are untreated with medication. A better understanding of the role of clinical features associated with anxiety in PD, such as depression and motor fluctuations, may improve the recognition and treatment of anxiety disorders in this population. PMID:23567419
... page: https://medlineplus.gov/news/fullstory_164379.html Hepatitis Infection May Raise Risk for Parkinson's Disease New ... 2017 (HealthDay News) -- People with the liver infection hepatitis may be at heightened risk of developing Parkinson's ...
Nagle, Michael W; Latourelle, Jeanne C; Labadorf, Adam; Dumitriu, Alexandra; Hadzi, Tiffany C; Beach, Thomas G; Myers, Richard H
Genome-wide association studies (GWAS) have identified the GAK/DGKQ/IDUA region on 4p16.3 among the top three risk loci for Parkinson's disease (PD), but the specific gene and risk mechanism are unclear. Here, we report transcripts containing the 3' clathrin-binding domain of GAK identified by RNA deep-sequencing in post-mortem human brain tissue as having increased expression in PD. Furthermore, carriers of 4p16.3 PD GWAS risk SNPs show decreased expression of one of these transcripts, GAK25 (Gencode Transcript 009), which correlates with the expression of genes functioning in the synaptic vesicle membrane. Together, these findings provide strong evidence for GAK clathrin-binding- and J-domain transcripts' influence on PD pathogenicity, and for a role for GAK in regulating synaptic function in PD.
Xie, Xin; Luo, Xiaoguang; Xie, Mingliang; Liu, Yang; Wu, Ting
Recently, growing evidence has revealed the significant association between Parkinson's disease (PD) and cancer. However, controversy still exists concerning the association between PD and lung cancer. A comprehensive article search for relevant studies published was performed using the following online databases: PubMed, Web of Science and Embase up to August 31, 2016. The pooled risk ratio (RR) and their 95 % confidence intervals (CI) were calculated using the method of inverse variance with the random-effects model. Fifteen studies comprising 348,780 PD patients were included in this study. The pooled result indicated that patients with PD were significantly associated with a decreased risk of lung cancer (RR: 0.53, 95% CI: 0.41−0.70, P < 0.001). In addition, subgroup analyses performed in Western population also confirmed the significant inverse relationship between PD and risk of lung cancer (RR: 0.48, 95% CI: 0.39−0.60, P < 0.001). In the subgroup analysis, a reduced risk of lung cancer in PD patients from Western population was consistent regardless of study design, gender, or study quality. In conclusion, PD patients were significantly associated with a reduced risk of lung cancer in Western population. The relationship between them in Asian population needs to be confirmed by future studies. PMID:27801674
Ogino, Mako; Ichimura, Mayuko; Nakano, Noriko; Minami, Akari; Kitagishi, Yasuko; Matsuda, Satoru
Oxidative stress is considered to play key roles in aging and pathogenesis of many neurodegenerative diseases such as Parkinson's disease, which could bring DNA damage by cells. The DNA damage may lead to the cell apoptosis, which could contribute to the degeneration of neuronal tissues. Recent evidence suggests that PTEN (phosphatase and tensin homolog on chromosome 10) may be involved in the pathophysiology of the neurodegenerative disorders. Since PTEN expression appears to be one dominant determinant of the neuronal cell death, PTEN should be a potential molecular target of novel therapeutic strategies against Parkinson's disease. In addition, defects in DNA damage response and DNA repair are often associated with modulation of hormone signaling pathways. Especially, many observations imply a role for estrogen in a regulation of the DNA repair action. In the present review, we have attempted to summarize the function of DNA repair molecules at a viewpoint of the PTEN signaling pathway and the hormone related functional modulation of cells, providing a broad interpretation on the molecular mechanisms for treatment of Parkinson's disease. Particular attention will be paid to the mechanisms proposed to explain the health effects of food ingredients against Parkinson's disease related to reduce oxidative stress for an efficient therapeutic intervention.
Kluding, Patricia; McGinnis, Patricia Quinn
The primary impairments associated with Parkinson's disease occur in combination with the secondary, preventable effects of immobility. A community-based fitness program may help increase activity and maintain function in people in the early or middle stages of the disease. This article describes a unique program designed to reduce fall risk and promote independent exercise for people with Parkinson's disease. Two 66-year-old males, both community ambulators and in early or middle stages of Parkinson's disease, participated in 3 months of various physical activities. Group balance classes were held twice weekly during the first month, participants joined a fitness center and self-directed their exercise program during the second month, and group Tai Chi classes were held twice weekly during the third month. At conclusion of the program, participants were given suggestions for continued physical fitness activities. After the 3-month program, improvements were noted for both individuals in functional reach, Timed Up and Go, and Berg Balance scores. Both participants continued to exercise regularly for at least 8 months following the program. Two individuals with Parkinson's disease demonstrated improvement in their balance test performance over a 3-month period. Perhaps most importantly, these participants independently continued exercising after completing this program.
Azmin, Shahrul; Khairul Anuar, Abdul Manaf; Tan, Hui Jan; Nafisah, Wan Yahya; Raymond, Azman Ali; Hanita, Othman; Shah, Shamsul Azhar; Norlinah, Mohamed Ibrahim
Background. The nonmotor symptoms are important determinants of health and quality of life in Parkinson's disease but are not well recognized and addressed in clinical practice. This study was conducted to determine the prevalence of nonmotor symptoms and their impact on quality of life in patients with Parkinson's disease. Methods. This was a cross-sectional study among patients with idiopathic Parkinson's disease. Exclusion criteria were a Mini Mental State Examination score of <21/30. Prevalence of nonmotor symptoms was determined using the NMSQuest. The severity of nonmotor symptoms and the quality of life were assessed using validated disease-specific questionnaires (PDQ-39 and NMSS). Results. A total of 113 patients consisting of 60 males and 53 females were recruited. The median duration of illness was 5.0 (2.0-8.0) years. The prevalence rate of nonmotor symptoms in our cohort was 97.3%. The most common reported nonmotor symptom in our cohort was gastrointestinal (76.1%). We found that the severity of the nonmotor symptoms was associated with poorer quality of life scores (r s : 0.727, P < 0.001). Conclusions. Nonmotor symptoms were highly prevalent in our patients with Parkinson's disease and adversely affected the quality of life of our patients. In contrast to western studies, the most common nonmotor symptom is gastrointestinal. The possibility of an Asian diet playing a role in this observation requires further study.
Mursaleen, Leah R; Stamford, Jonathan A
The term "drug of abuse" is highly contextual. What constitutes a drug of abuse for one population of patients does not for another. It is therefore important to examine the needs of the patient population to properly assess the status of drugs of abuse. The focus of this article is on the bidirectional relationship between patients and drug abuse. In this paper we will introduce the dopaminergic systems of the brain in Parkinson's and the influence of antiparkinsonian drugs upon them before discussing this synergy of condition and medication as fertile ground for drug abuse. We will then examine the relationship between drugs of abuse and Parkinson's, both beneficial and deleterious. In summary we will draw the different strands together and speculate on the future merit of current drugs of abuse as treatments for Parkinson's disease.
López-Pousa, S.; Lombardía-Fernández, C.; Olmo, J. Garre; Monserrat-Vila, S.; Vilalta-Franch, J.; Calvó-Perxas, L.
Background The most frequent behavioral manifestations in Parkinson's disease (PD) are attributed to the dopaminergic dysregulation syndrome (DDS), which is considered to be secondary to the iatrogenic effects of the drugs that replace dopamine. Over the past few years some cases of patients improving their creative abilities after starting treatment with dopaminergic pharmaceuticals have been reported. These effects have not been clearly associated to DDS, but a relationship has been pointed out. Methods Case study of a patient with PD. The evolution of her paintings along medication changes and disease advance has been analyzed. Results The patient showed a compulsive increase of pictorial production after the diagnosis of PD was made. She made her best paintings when treated with cabergolide, and while painting, she reported a feeling of well-being, with loss of awareness of the disease and reduction of physical limitations. Conclusions Dopaminergic antagonists (DA) trigger a dopaminergic dysfunction that alters artistic creativity in patients having a predisposition for it. The development of these skills might be due to the dopaminergic overstimulation due to the therapy with DA, which causes a neurophysiological alteration that globally determines DDS. PMID:23185168
Christiansen, Cory L; Schenkman, Margaret L; McFann, Kim; Wolfe, Pamela; Kohrt, Wendy M
Gait dysfunction is an early problem identified by patients with Parkinson's disease (PD). Alterations in gait may result in an increase in the energy cost of walking (i.e., walking economy). The purpose of this study was to determine whether walking economy is atypical in patients with PD when compared with healthy controls. A secondary purpose was to evaluate the associations of age, sex, and level of disease severity with walking economy in patients with PD. The rate of oxygen consumption (VO2) and other responses to treadmill walking were compared in 90 patients (64.4±10.3 yr) and 44 controls (64.6±7.3 yr) at several walking speeds. Pearson correlation coefficients (r) were calculated to determine relationships of age, sex, and disease state with walking economy in PD patients. Walking economy was significantly worse in PD patients than in controls at all speeds above 1.0 mph. Across all speeds, VO2 was 6 to 10% higher in PD patients. Heart rate, minute ventilation, respiratory exchange ratio, and rating of perceived exertion were correspondingly elevated. No significant relationship of age, sex, or UPDRS score with VO2 was found for patients with PD. The findings suggest that the physiologic stress of daily physical activities is increased in patients with early to mid-stage PD, and this may contribute to the elevated level of fatigue that is characteristic of PD. PMID:19441128
Braak, Heiko; Del Tredici, Kelly
The proteinopathy sporadic Parkinson's disease (sPD) is the second most frequent degenerative disorder of the human nervous system after Alzheimer's disease. The alpha-synuclein inclusion body pathology (Lewy pathology) associated with sPD is distributed throughout the central, peripheral, and enteric nervous systems. The resulting nonrandom neuronal dysfunction and, in some regions, neuronal loss is reflected in a topographic distribution pattern of the Lewy pathology that, in the brain, can be staged. Except for olfactory structures and spinal cord constituents of the pain system, sensory components of the nervous system remain uninvolved or virtually intact. The most disease-related damage revolves around motor areas--particularly around superordinate centers of the limbic and visceromotor systems as well as portions of the somatomotor system. Vulnerable regions are interconnected anatomically and susceptible nerve cell types are not neurotransmitter-dependent. Not all clinical symptoms emerging in the course of sPD can be explained by a lack of dopamine in the nigrostriatal system. These include autonomic dysfunction, pain, hyposmia or anosmia, excessive daytime sleepiness, rapid eye movement (REM) sleep behavioral disorder, depression, anxiety, cognitive decline, and dementia. Against the background of the normal morphology and anatomy, the authors analyze the pathoanatomy of sPD in the nervous system at various neuropathological stages and summarize the potential functional consequences of the lesions.
Geraci-Erck, Maria; Rabin, Marcie L.; Adler, Charles H.; Serrano, Geidy; Beach, Thomas G.; Kurlan, Roger
Objective: To quantify the loss of pigmented neurons in the substantia nigra (SN) of autopsy-confirmed Parkinson disease (PD) and incidental Lewy body disease (ILBD) vs age-matched controls (C). Methods: Unbiased stereology methods were used to rigorously count number and measure volumes of nigral pigmented neurons in PD, ILBD, and C brains. The obtained stereologic results were correlated with Lewy body (LB), amyloid plaque (AP), neurofibrillary tangle (NFT), and vascular pathology loads assessed in nigral and extranigral regions of each PD, ILBD, and C brain. The stereologic measurements were also correlated to predeath motor and cognitive scores as available for each participant. Results: A marked nigral neuronal loss (NNL) in PD (−82%) and ILBD (−40%) compared to C (p < 0.0001) was found. While there was significant correlation between NNL and LB in some cortical areas of PD (i.e., olfactory bulb), there were no correlations between NNL and LB, AP, or NFT loads or cerebral infarct volumes in any other examined regions for PD and ILBD brains. Conclusions: Using unbiased stereology methods, we show that there is a significant loss and absence of hypertrophic changes in nigral pigmented neurons of ILBD in comparison to C brains. Intriguingly, no significant correlations were found between NNL and LB loads in the SN of both PD and ILBD brains. These autopsy-verified stereologically based findings are novel and support ILBD as a pathologic condition. These results suggest possible new and alternative pathophysiologic hypotheses on the actual relationship between NNL and LB pathology. PMID:26468408
Neumann, Juliane; Bras, Jose; Deas, Emma; O'Sullivan, Sean S.; Parkkinen, Laura; Lachmann, Robin H.; Li, Abi; Holton, Janice; Guerreiro, Rita; Paudel, Reema; Segarane, Badmavady; Singleton, Andrew; Lees, Andrew; Hardy, John; Houlden, Henry; Revesz, Tamas; Wood, Nicholas W.
Mutations in the glucocerebrosidase gene (GBA) are associated with Gaucher's disease, the most common lysosomal storage disorder. Parkinsonism is an established feature of Gaucher's disease and an increased frequency of mutations in GBA has been reported in several different ethnic series with sporadic Parkinson's disease. In this study, we evaluated the frequency of GBA mutations in British patients affected by Parkinson's disease. We utilized the DNA of 790 patients and 257 controls, matched for age and ethnicity, to screen for mutations within the GBA gene. Clinical data on all identified GBA mutation carriers was reviewed and analysed. Additionally, in all cases where brain material was available, a neuropathological evaluation was performed and compared to sporadic Parkinson's disease without GBA mutations. The frequency of GBA mutations among the British patients (33/790 = 4.18%) was significantly higher (P = 0.01; odds ratio = 3.7; 95% confidence interval = 1.12–12.14) when compared to the control group (3/257 = 1.17%). Fourteen different GBA mutations were identified, including three previously undescribed mutations, K7E, D443N and G193E. Pathological examination revealed widespread and abundant α-synuclein pathology in all 17 GBA mutation carriers, which were graded as Braak stage of 5–6, and had McKeith's limbic or diffuse neocortical Lewy body-type pathology. Diffuse neocortical Lewy body-type pathology tended to occur more frequently in the group with GBA mutations compared to matched Parkinson's disease controls. Clinical features comprised an early onset of the disease, the presence of hallucinations in 45% (14/31) and symptoms of cognitive decline or dementia in 48% (15/31) of patients. This study demonstrates that GBA mutations are found in British subjects at a higher frequency than any other known Parkinson's disease gene. This is the largest study to date on a non-Jewish patient sample with a detailed genotype/phenotype/pathological analyses
The appearance of levodopa-induced dyskinesia (LID) and ongoing degeneration of nigrostriatal dopaminergic neurons are two key features of Parkinson's disease (PD) that current treatments fail to address. Increased glutamate transmission contributes to the motor symptoms in PD, to the striatal plasticity that underpins LID and to the progression of neurodegeneration through excitotoxic mechanisms. Glutamate receptors have therefore long been considered as potential targets for pharmacological intervention in PD, with emphasis on either blocking activation of 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid (AMPA), N-methyl-D-aspartate (NMDA) or excitatory metabotropic glutamate (mGlu) 5 receptors or promoting the activation of group II/III mGlu receptors. Following a brief summary of the role of glutamate in PD and LID, this article explores the current status of pharmacological studies in pre-clinical rodent and primate models through to clinical trials, where applicable, that support the potential of glutamate-based therapeutic interventions. To date, AMPA antagonists have shown good efficacy against LID in rat and primate models, but the failure of perampanel to lessen LID in clinical trials casts doubt on the translational potential of this approach. In contrast, antagonists selective for NR2B-containing NMDA receptors were effective against LID in animal models and in small-scale clinical trials, though observed adverse cognitive effects need addressing. So far, mGlu5 antagonists or negative allosteric modulators (NAMs) look set to become the first introduced for tackling LID, with AFQ-056 reported to exhibit good efficacy in phase II clinical trials. NR2B antagonists and mGlu5 NAMs may subsequently prove to also be effective disease-modifying agents if their protective effects in rat and primate models of PD, respectively, are replicated in the next stages of investigation. Finally, group III mGlu4 agonists or positive allosteric modulators (PAMs
Morgan, John C; Currie, Lillian J; Harrison, Madaline B; Bennett, James P; Trugman, Joel M; Wooten, G Frederick
Parkinson's disease (PD) is associated with increased mortality despite many advances in treatment. Following the introduction of levodopa in the late 1960's, many studies reported improved or normalized mortality rates in PD. Despite the remarkable symptomatic benefits provided by levodopa, multiple recent studies have demonstrated that PD patients continue to die at a rate in excess of their peers. We undertook this retrospective study of 211 deceased PD patients to determine the factors associated with mortality in levodopa-treated PD. Our findings confirm that PD is associated with increased mortality in both men and women. Unlike the majority of other mortality studies, we found that women have a greater reduction in lifespan compared to men. We also found that patients with early onset PD (onset at the age of 50 or before) have reduced survival relative to PD patients with later ages of onset. A final important finding is that survival is equal in PD patients treated with levodopa early (within 2 years or less of PD onset) versus later.
Hauser, Robert A.
Motor symptoms in Parkinson's disease (PD) are caused by a severe loss of pigmented dopamine-producing nigro-striatal neurons. Symptomatic therapies provide benefit for motor features by restoring dopamine receptor stimulation. Studies have demonstrated that delaying the introduction of dopaminergic medical therapy is associated with a rapid decline in quality of life. Nonmotor symptoms, such as depression, are common in early PD and also affect quality of life. Therefore, dopaminergic therapy should typically be initiated at, or shortly following, diagnosis. Monamine oxidase-B inhibitors provide mild symptomatic benefit, have excellent side effect profiles, and may improve long-term outcomes, making them an important first-line treatment option. Dopamine agonists (DAs) provide moderate symptomatic benefit but are associated with more side effects than levodopa. However, they delay the development of motor complications by delaying the need for levodopa. Levodopa (LD) is the most efficacious medication, but its chronic use is associated with the development of motor complications that can be difficult to resolve. Younger patients are more likely to develop levodopa-induced motor complications and they are therefore often treated with a DA before levodopa is added. For older patients, levodopa provides good motor benefit with a relatively low-risk of motor complications. Using levodopa with a dopa-decarboxylase inhibitor lessens adverse effects, and further adding a catechol-O-methyl transferase inhibitor can improve symptom control. PMID:21180628
Alonso-Navarro, Hortensia; Jimenez-Jimenez, Felix Javier; Garcia-Martin, Elena; Agundez, Jose A G
The relative role of genetic and environmental factors in the pathogenesis of Parkinson's disease (PD) has been the matter of investigation and debate, especially in the last 30 years. The possible interaction between genetic and environmental factors led to a great number of association studies between single nucleotide polymorphisms (SNPs) of many candidate genes and PD risk. In this study we summarized and critically reviewed the results of studies published on this issue, with especial reference to those reported in the last 5 years. Many studies provided conflicting findings and, when positive associations were identified, associations were weak. Polymorphisms related with activation or detoxification of drugs and xenobiotics, such as CYP1A1, CYP1A2, CYP19A1, CYP1B1, CYP2C9, CYP2C19, CYP2E1, CYP2D6, NAT2, GSTM1, GSTM3, GSTO1, GSTP1, PON1, PON2, ABCB1 and ADH genes have not been demonstrated convincingly a definitive association with the risk of developing PD. Nor did polymorphisms in genes related to dopamine or serotonin DRD, DAT, TH, DDC, DBH, MAO, COMT, SLC6A4, MTR, MTHFR, oxidative stress NOQ1, NOQ2, mEPHX, HFE, GPX, CAT, mnSOD, HFE, HO-1, HO-2, NFE2L2, KEAP1, inflammatory processes, ILs, TNF, ACT, NOS, HNMT, ABP1, HRHs, trophic and growth factors BDNF, FGF, or mitochondrial metabolism and function. In addition we analyzed other putative relations and genes associated with monogenic familial PD.Taking together the results of candidate gene association studies and genome wide association studies, only some SNPs of the MAPT, SNCA, HLA and GBA genes seem to be the most likely associated with PD risk.
Bayard, Sophie; Cochen De Cock, Valérie; Dauvillers, Yves
Dopamine replacement therapy in Parkinson's disease (PD) improves the motor symptoms. However, it has recently been shown that a small sub-group of patients suffers from motor and behavioral disturbances associated with the use of dopamine agonists (DAs). The behavioral disorders are incentive- or reward-based repetitive symptoms regrouped under the term « dopamine dysregulation syndrome » (DDS). They include pathological gambling, hypersexuality, compulsive shopping, compulsive eating, punding, and compulsive medication use. Whether these behaviors are related to the dopaminergic medications interacting with an underlying individual vulnerability or whether the primary pathological features of Parkinson's disease play a role is not entirely understood. This review is devoted to the phenomenology of the DDS and factors influencing its susceptibility. We further review the literature studies that investigated the decision-making profile using the Iowa Gambling Task in Parkinson's disease, and the recent literature devoted to these abnormal behaviors in the restless legs syndrome (RLS). Given the potential substantial impact of the DDS on personal, familial, social, and financial well-being, patients with PD or RLS should be informed that DAs use may lead to the development of impulsive and compulsive disorders, and clinicians should include the investigation of these disorders as part of routine clinical care. The refinement of clinical strategies to predict, identify and manage DDS will help the future care of motor and non-motor symptoms of Parkinson's disease.
Xu, Lingjia; Pu, Jiali
Parkinson's disease is a neurodegenerative disease/synucleinopathy that develops slowly; however, there is no efficient method of early diagnosis, nor is there a cure. Progressive dopaminergic neuronal cell loss in the substantia nigra pars compacta and widespread aggregation of the α-synuclein protein (encoded by the SNCA gene) in the form of Lewy bodies and Lewy neurites are the neuropathological hallmarks of Parkinson's disease. The SNCA gene has undergone gene duplications, triplications, and point mutations. However, the specific mechanism of α-synuclein in Parkinson's disease remains obscure. Recent research showed that various α-synuclein oligomers, pathological aggregation, and propagation appear to be harmful in certain areas in Parkinson's disease patients. This review summarizes our current knowledge of the pathogenetic dysfunction of α-synuclein associated with Parkinson's disease and highlights current approaches that seek to develop this protein as a possible diagnostic biomarker and therapeutic target.
Kashihara, Kenichi; Ohno, Manabu; Tomita, Susumu
We determined the frequency of dropped head syndrome in Parkinson's disease (PD) in Japan and evaluated its clinical correlates. A total of 252 consecutive patients with PD who visited our hospital were studied. Dropped head syndrome was found in 15 patients (6.0%) (3 men, 12 women; mean age at onset of PD, 62.8 +/- 11.5 years). The interval before emergence of dropped head after disease onset was 5.4 +/- 4.3 years (-0.5 to 15 years). The Hoehn-Yahr score at the on stage was 3.2 +/- 0.7; at the off stage 3.5 +/- 0.8. Of those 15 patients, 8 had major symptoms of rigidity and akinesia. In 2 patients, administration of a dopamine agonist appeared to evoke dropped head syndrome. An increase in and/or the addition of antiparkinsonian drugs alleviated head drop in 4 patients and reduced head drop in 7 patients. Any medication was not effective for 4 patients. Dropped head syndrome in PD is not rare in Japan. It is more often observed in women and is associated with patients who primarily suffer rigidity and akinesia. Dropped head syndrome in these patients appears to be produced by disproportionate tonus of the neck muscles. It is modulated by antiparkinsonian drugs and is considered to be a type of dystonia.
Martignoni, E; Tassorelli, C; Nappi, G; Zangaglia, R; Pacchetti, C; Blandini, F
Homocysteine, a sulphur-containing amino acid formed by demethylation of methionine, is involved in numerous processes of methyl group transfer, all playing pivotal roles in the biochemistry of the human body. Increased levels of plasma homocysteine (hyperhomocysteinemia) - which may result from a deficiency of folate, vitamin B6 or B12 or mutations in enzymes regulating the catabolism of homocysteine - are associated with a wide range of clinical manifestations, mostly affecting the central nervous system (e.g., mental retardation, cerebral atrophy and epileptic seizures). Recent evidence suggests that changes in the metabolic fate of homocysteine, leading to hyperhomocysteinemia, may also play a role in the pathophysiology of neurodegenerative disorders, particularly Parkinson's disease (PD). The nervous system might be particularly sensitive to homocysteine, due to the excitotoxic-like properties of the amino acid. However, experimental findings have shown that homocysteine does not seem to posses direct, cytotoxic activity, while the amino acid has proven able to synergize with more specific neurotoxic insults. Hyperhomocysteinemia has been repeatedly reported in PD patients; the increase, however, seems mostly related to the methylated catabolism of l-Dopa, the main pharmacological treatment of PD. Therefore, hyperhomocysteinemia may not be specific to movement disorders or other neurological diseases, the condition being, in fact, rather the result of the combinations of different factors, mainly metabolic, but also genetic and pharmacological, intervening in the neurodegenerative process.
Bortolanza, Mariza; Cavalcanti-Kiwiatkoski, Roberta; Padovan-Neto, Fernando E; da-Silva, Célia Aparecida; Mitkovski, Miso; Raisman-Vozari, Rita; Del-Bel, Elaine
l-3, 4-dihydroxyphenylalanine (L-DOPA) is the most effective treatment for Parkinson's disease but can induce debilitating abnormal involuntary movements (dyskinesia). Here we show that the development of L-DOPA-induced dyskinesia in the rat is accompanied by upregulation of an inflammatory cascade involving nitric oxide. Male Wistar rats sustained unilateral injections of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle. After three weeks animals started to receive daily treatment with L-DOPA (30 mg/kg plus benserazide 7.5 mg/kg, for 21 days), combined with an inhibitor of neuronal NOS (7-nitroindazole, 7-NI, 30 mg/kg/day) or vehicle (saline-PEG 50%). All animals treated with L-DOPA and vehicle developed abnormal involuntary movements, and this effect was prevented by 7-NI. L-DOPA-treated dyskinetic animals exhibited an increased striatal and pallidal expression of glial fibrillary acidic protein (GFAP) in reactive astrocytes, an increased number of CD11b-positive microglial cells with activated morphology, and the rise of cells positive for inducible nitric oxide-synthase immunoreactivity (iNOS). All these indexes of glial activation were prevented by 7-NI co-administration. These findings provide evidence that the development of L-DOPA-induced dyskinesia in the rat is associated with activation of glial cells that promote inflammatory responses. The dramatic effect of 7-NI in preventing this glial response points to an involvement of nitric oxide. Moreover, the results suggest that the NOS inhibitor prevents dyskinesia at least in part via inhibition of glial cell activation and iNOS expression. Our observations indicate nitric oxide synthase inhibitors as a therapeutic strategy for preventing neuroinflammatory and glial components of dyskinesia pathogenesis in Parkinson's disease.
Pellecchia, Maria Teresa; Savastano, Riccardo; Moccia, Marcello; Picillo, Marina; Siano, Pietro; Erro, Roberto; Vallelunga, Annamaria; Amboni, Marianna; Vitale, Carmine; Santangelo, Gabriella; Barone, Paolo
Cognitive deficits are common in Parkinson's disease (PD) and many patients eventually develop dementia; however, its occurrence is unpredictable. Serum uric acid (UA) has been proposed as a biomarker of PD, both in the preclinical and clinical phase of the disease. The aim of this pilot study was to evaluate relationships between baseline serum UA levels and occurrence of mild cognitive impairment (MCI) at 4-year follow-up in a cohort of early PD patients. Early PD patients, not presenting concomitant diseases, cognitive impairment or treatment possibly interfering with UA levels, underwent neuropsychological testing at baseline and 4-year follow-up. UA levels were determined in serum at baseline. MCI was found in 23 out of 42 PD patients completing 4-year follow-up. Patients presenting MCI had significantly higher age at onset and lower Frontal Assessment Battery scores at baseline as compared with patients cognitively intact. Logistic regression analysis showed that both serum UA levels (OR = 0.54, p = 0.044) and age (OR = 1.16, p = 0.009) contribute to the occurrence of MCI at 4-year follow-up. Our pilot study suggests that lower levels of serum UA in the early disease stages are associated to the later occurrence of MCI. These results need to be confirmed by further studies on larger samples.
Miller, Diane B; O'Callaghan, James P
Sporadic or idiopathic Parkinson's disease (PD) is an age-related neurodegenerative disorder of unknown origin that ranks only second behind Alzheimer's disease (AD) in prevalence and its consequent social and economic burden. PD neuropathology is characterized by a selective loss of dopaminergic neurons in the substantia nigra pars compacta; however, more widespread involvement of other CNS structures and peripheral tissues now is widely documented. The onset of molecular and cellular neuropathology of PD likely occurs decades before the onset of the motor symptoms characteristic of PD. The hallmark symptoms of PD, resting tremors, rigidity and postural disabilities, are related to dopamine (DA) deficiency. Current therapies treat these symptoms by replacing or boosting existing DA. All current interventions have limited therapeutic benefit for disease progression because damage likely has progressed over an estimated period of ~5 to 15years to a loss of 60%-80% of the nigral DA neurons, before symptoms emerge. There is no accepted definitive biomarker of PD. An urgent need exists to develop early diagnostic biomarkers for two reasons: (1) to intervene at the onset of disease and (2) to monitor the progress of therapeutic interventions that may slow or stop the course of the disease. In the context of disease development, one of the promises of personalized medicine is the ability to predict, on an individual basis, factors contributing to the susceptibility for the development of a given disease. Recent advances in our understanding of genetic factors underlying or contributing to PD offer the potential for monitoring susceptibility biomarkers that can be used to identify at-risk individuals and possibly prevent the onset of disease through treatment. Finally, the exposome concept is new in the biomarker discovery arena and it is suggested as a way to move forward in identifying biomarkers of neurological diseases. It is a two-stage scheme involving a first stage
Magalingam, Kasthuri Bai; Radhakrishnan, Ammu Kutty; Haleagrahara, Nagaraja
Parkinson's disease is a chronic, debilitating neurodegenerative movement disorder characterized by progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta region in human midbrain. To date, oxidative stress is the well accepted concept in the etiology and progression of Parkinson's disease. Hence, the therapeutic agent is targeted against suppressing and alleviating the oxidative stress-induced cellular damage. Within the past decades, an explosion of research discoveries has reported on the protective mechanisms of flavonoids, which are plant-based polyphenols, in the treatment of neurodegenerative disease using both in vitro and in vivo models. In this paper, we have reviewed the literature on the neuroprotective mechanisms of flavonoids in protecting the dopaminergic neurons hence reducing the symptoms of this movement disorder. The mechanism reviewed includes effect of flavonoids in activation of endogenous antioxidant enzymes, suppressing the lipid peroxidation, inhibition of inflammatory mediators, flavonoids as a mitochondrial target therapy, and modulation of gene expression in neuronal cells. PMID:26576219
Parker, W D; Swerdlow, R H
Disordered mitochondrial metabolism may play an important role in a number of idiopathic neurodegenerative disorders. The question of mitochondrial dysfunction is particularly attractive in the case of idiopathic Parkinson disease (PD), since Vyas et al. recognized in the 1980s that the parkinsonism-inducing compound N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine is a mitochondrial toxin. The unique genetic properties of mitochondria also make them worthy of consideration for a pathogenic role in PD, as well as in other late-onset, sporadic neurodegenerative disorders. Although affected persons occasionally do provide family histories that suggest Mendelian inheritance, the vast majority of the time these diseases appear sporadically. Because of unique features such as heteroplasmy, replicative segregation, and threshold effects, mitochondrial inheritance can allow for the apparent sporadic nature of these diseases.
Yang, Xinglong; Liu, Chuanxin; Zhang, Jinxiang; Han, Hongying; Wang, Xiuyan; Liu, Zhoulin; Xu, Yanming
Parkinson's disease (PD) and schizophrenia (SCZ) are frequent central nervous disorders that have unclear etiologies but that show similarities in their pathogenesis. Since elevated histamine levels in the brain have been associated with PD and SCZ, we wanted to explore whether the Thr105Ile substitution in the histamine N-methyltransferase gene (HNMT-Thr105Ile), which impairs histamine degradation, is associated with either disease. We used the ligase detection reaction to genotype a case-control cohort of Han Chinese patients with PD or SCZ and healthy controls at the HNMT-Thr105Ile locus. The Ile allele was associated with reduced risk of PD (OR 0.516, 95% CI 0.318 to 0.838, p = 0.007) and of SCZ (OR 0.499, 95% CI 0.288 to 0.865, p = 0.011). Genotype frequencies and minor allele frequencies were similar between patients and controls when we compared males with females or early-onset patients with late-onset ones. Genotype and allele frequencies were not significantly different between PD patients with dyskinesia and PD patients without dyskinesia. Our results suggest that the heterozygous Thr/Ile genotype at the HNMT-Thr105Ile locus and the minor Ile105 allele protect against PD and SCZ in Han Chinese.
Cabrini, Silvia; Baratti, Mario; Bonfà, Flavio; Cabri, Giulio; Uber, Elena; Avanzi, Maurizio
Dopaminergic medications could increase the occurrence of a set of dysregulated behaviours in Parkinson's disease (PD), including reward-seeking behaviours (pathological gambling, hypersexuality, compulsive shopping, binge eating, reckless driving), punding and compulsive medication use. We report a preliminary evaluation of a questionnaire to assess the presence of these impulsive-compulsive behaviours associated to dopamine replacement therapy in PD. We screened 38 patients and their caregivers, comparing dopamine dysregulation syndrome (DDS) patients and non-DDS patients. The questionnaire was well accepted and demonstrated a preliminary good discriminant validity (p = 0.000). In addition, clinically relevant dysregulated condition is associated with a younger age (p = 0.006), younger age at disease onset (p = 0.001), levodopa-equivalent daily dose (p = 0.029), UPDRS III (p = 0.021), increased global psychopathology (interpersonal sensitivity and psychoticism), and differences in our inventory (p = 0.000). These preliminary results suggest that the DDS-PC inventory could help to identify patients experiencing impulsive-compulsive behaviours associated to DDS.
Fernández-Moriano, Carlos; González-Burgos, Elena; Gómez-Serranillos, M. Pilar
Mitochondria are cytoplasmic organelles that regulate both metabolic and apoptotic signaling pathways; their most highlighted functions include cellular energy generation in the form of adenosine triphosphate (ATP), regulation of cellular calcium homeostasis, balance between ROS production and detoxification, mediation of apoptosis cell death, and synthesis and metabolism of various key molecules. Consistent evidence suggests that mitochondrial failure is associated with early events in the pathogenesis of ageing-related neurodegenerative disorders including Parkinson's disease and Alzheimer's disease. Mitochondria-targeted protective compounds that prevent or minimize mitochondrial dysfunction constitute potential therapeutic strategies in the prevention and treatment of these central nervous system diseases. This paper provides an overview of the involvement of mitochondrial dysfunction in Parkinson's and Alzheimer's diseases, with particular attention to in vitro and in vivo studies on promising endogenous and exogenous mitochondria-targeted protective compounds. PMID:26064418
Ma, Ze-Gang; Xu, Jian; Liu, Tian-Wei
Fibroblast growth factor 20 (FGF20) is a neurotrophic factor which enhances the survival of rat midbrain dopamine neurons. Genetic variation in FGF20 may influence the risk of occurrence and development in Parkinson's diseases (PD). Many studies have evaluated the association between FGF20 rs1721100 C/G polymorphism and the risk of sporadic PD; however, published data are still controversial. The aim of the present meta-analysis was to evaluate the association of FGF20 rs1721100 C/G polymorphism with susceptibility of PD. The summary odds ratio (OR) with its 95 % confidence interval (CI) was calculated to estimate the association. Five case-control studies with a total of 3,463 sporadic PD cases and 4,606 controls were finally included into this meta-analysis. Neither the basic allele frequencies nor the genotypic distributions of rs1721100 C/G within FGF20 were different between two groups when all studies were pooled into the meta-analysis. Subgroup analysis by ethnicity showed FGF20 rs1721100 C/G polymorphism was significantly associated with increased risk in the heterozygote comparison model (CG versus GG: OR = 0.83, 95 % CI, 0.72-0.95, P = 0.009) in Asians but not in Caucasians. Overall, this meta-analysis suggests that FGF20 rs1721100 C/G polymorphism is associated with sporadic PD in Asians.
Weiss, Aner; Herman, Talia; Giladi, Nir; Hausdorff, Jeffrey M.
Background. Cognitive function is generally evaluated based on testing in the clinic, but this may not always reflect real-life function. We tested whether parameters derived from long-term, continuous monitoring of gait are associated with cognitive function in patients with Parkinson's disease (PD). Methods. 107 patients with PD (age: 64.9 ± 9.3 yrs; UPDRS motor sum “off”: 40.4 ± 13.2; 25.23% women) wore a 3D accelerometer on their lower back for 3 days. Computerized measures of global cognitive function, executive function, attention, and nonverbal memory were assessed. Three-day acceleration derived measures included cadence, variability, bilateral coordination, and dynamic postural control. Associations between the acceleration derived measures and cognitive function were determined. Results. Linear regression showed associations between vertical gait variability and cadence and between global cognitive score, attention, and executive function (p ≤ 0.048). Dynamic postural control was associated with global cognitive score and attention (p ≤ 0.027). Nonverbal memory was not associated with the acceleration-derived measures. Conclusions. These findings suggest that metrics derived from a 3-day worn body-fixed sensor reflect cognitive function, further supporting the idea that the gait pattern may be altered as cognition declines and that gait provides a window into cognitive function in patients with PD. PMID:26605103
Weiss, Aner; Herman, Talia; Giladi, Nir; Hausdorff, Jeffrey M
Background. Cognitive function is generally evaluated based on testing in the clinic, but this may not always reflect real-life function. We tested whether parameters derived from long-term, continuous monitoring of gait are associated with cognitive function in patients with Parkinson's disease (PD). Methods. 107 patients with PD (age: 64.9 ± 9.3 yrs; UPDRS motor sum "off": 40.4 ± 13.2; 25.23% women) wore a 3D accelerometer on their lower back for 3 days. Computerized measures of global cognitive function, executive function, attention, and nonverbal memory were assessed. Three-day acceleration derived measures included cadence, variability, bilateral coordination, and dynamic postural control. Associations between the acceleration derived measures and cognitive function were determined. Results. Linear regression showed associations between vertical gait variability and cadence and between global cognitive score, attention, and executive function (p ≤ 0.048). Dynamic postural control was associated with global cognitive score and attention (p ≤ 0.027). Nonverbal memory was not associated with the acceleration-derived measures. Conclusions. These findings suggest that metrics derived from a 3-day worn body-fixed sensor reflect cognitive function, further supporting the idea that the gait pattern may be altered as cognition declines and that gait provides a window into cognitive function in patients with PD.
Gad ELhak, Seham A.; Ghanem, Abdel Aziz A.; AbdelGhaffar, Hassan; El Dakroury, Sahar; Salama, Mohamed M.
Parkinson's disease (PD) is one of the neurodegenerative diseases which we can by certainty identify its pathology, however, this confidence disappeares when talking about the cause. A long history of trials, suggestions, and theories tried linking PD to a specific causation. In this paper, a new suggestion is trying to find its way, could it be toxicology? Can we—in the future—look to PD as an occupational disease, in fact, many clues point to the possible toxic responsibility—either total or partial—in causing this disease. Searching for possible toxic causes for PD would help in designing perfect toxic models in animals. PMID:21152209
Svenningsson, Per; Westman, Eric; Ballard, Clive; Aarsland, Dag
Dementia is one of the most common and important aspects of Parkinson's disease and has consequences for patients and caregivers, and has health-related costs. Mild cognitive impairment is also common and frequently progresses to dementia. The underlying mechanisms of dementia associated with Parkinson's disease are only partly known and no mechanism-based treatments are available. Both dysmetabolism of α-synuclein and amyloid-protein and cholinergic deficits contribute to cognitive impairment in Parkinson's disease, and preliminary findings show that imaging and neurophysiological and peripheral biomarkers could be useful in diagnosis and prognosis. Rivastigmine is the only licensed treatment for dementia in Parkinson's disease, but emerging evidence suggests that memantine might also be useful. Whether these or other treatments can delay the progression from mild cognitive impairment to dementia in Parkinson's disease is a key research question.
Hwang, Sujin; Song, Chiang-Soon
[Purpose] The purpose of this study was to examine the relationships between manual dexterity and the Unified Parkinson's Disease Rating Scale-Motor Exam as a clinical tool for quantifying upper extremity function in persons with Parkinson's disease. [Subjects and Methods] Thirty-two persons with idiopathic Parkinson's disease participated in this study. This study measured two clinical outcomes, the box-and-block test and the Unified Parkinson's Disease Rating Scale-Motor Exam, to investigate the relationships between manual dexterity and the Unified Parkinson's Disease Rating Scale-Motor Exam. [Results] The box-and-block test on the more affected side was positive relationship with the box-and-block test on the less affected side. The Unified Parkinson's Disease Rating Scale-motor exam score had a negative correlation with the box-and-block test results for both sides. [Conclusion] A positive association was noted between manual dexterity and motor function in patients with idiopathic Parkinson disease. The results of this study suggest that the box-and-block test and the Unified Parkinson's Disease Rating Scale-Motor Exam are good clinical measures that quantify upper extremity function and are necessary for the accurate evaluation of patients and to plan intervention strategies.
Katyayan, Preeti Agarwal; Katyayan, Manish Khan; Nugala, Babitha
Parkinson's disease is an idiopathic, slowly progressive disorder of the central nervous system characterized by resting tremor, muscular rigidity, slow and decreased movement (bradykinesia), and postural instability. Oral healthcare providers can expect to be called upon to care for patients with this progressively debilitating disease. To provide competent care to patients with Parkinson's disease, clinicians must understand the disease, its treatment and its impact on the patient's ability to undergo and respond to dental care. The successful prosthodontic management of a 74-year-old completely edentulous Parkinson's disease patient is presented, with the conclusion that a prosthodontic intervention may contribute to improvement in the quality of life of a Parkinson's disease patient.
Purpose: Motor speech abnormalities are highly common and debilitating in individuals with idiopathic Parkinson's disease (IPD). These abnormalities, collectively termed hypokinetic dysarthria (HKD), have been traditionally attributed to hypokinesia and bradykinesia secondary to muscle rigidity and dopamine deficits. However, the role of…
Celardo, I; Martins, L M; Gandhi, S
Mitochondria are essential for cellular function due to their role in ATP production, calcium homeostasis and apoptotic signalling. Neurons are heavily reliant on mitochondrial integrity for their complex signalling, plasticity and excitability properties, and to ensure cell survival over decades. The maintenance of a pool of healthy mitochondria that can meet the bioenergetic demands of a neuron, is therefore of critical importance; this is achieved by maintaining a careful balance between mitochondrial biogenesis, mitochondrial trafficking, mitochondrial dynamics and mitophagy. The molecular mechanisms that underlie these processes are gradually being elucidated. It is widely recognized that mitochondrial dysfunction occurs in many neurodegenerative diseases, including Parkinson's disease. Mitochondrial dysfunction in the form of reduced bioenergetic capacity, increased oxidative stress and reduced resistance to stress, is observed in several Parkinson's disease models. However, identification of the recessive genes implicated in Parkinson's disease has revealed a common pathway involving mitochondrial dynamics, transport, turnover and mitophagy. This body of work has led to the hypothesis that the homeostatic mechanisms that ensure a healthy mitochondrial pool are key to neuronal function and integrity. In this paradigm, impaired mitochondrial dynamics and clearance result in the accumulation of damaged and dysfunctional mitochondria, which may directly induce neuronal dysfunction and death. In this review, we consider the mechanisms by which mitochondrial dysfunction may lead to neurodegeneration. In particular, we focus on the mechanisms that underlie mitochondrial homeostasis, and discuss their importance in neuronal integrity and neurodegeneration in Parkinson's disease. LINKED ARTICLES This article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph
terminal integrity, will provide a quantitative biomarker of Parkinson’s disease progression in subjects with early Parkison’s disease during a nine month...the r te of progression of Parkinson’s disease . All subjects have been and will be recruited and clinically evaluated through their participation in...will directly evaluate in vivo the rate of ongoing dopaminergic ne ronal degeneration in early Parkinson’s disease , whether the rate of ongoing
Radder, Danique L M; Sturkenboom, Ingrid H; van Nimwegen, Marlies; Keus, Samyra H; Bloem, Bastiaan R; de Vries, Nienke M
Current medical management is only partially effective in controlling the symptoms of Parkinson's disease. As part of comprehensive multidisciplinary care, physical therapy and occupational therapy aim to support people with Parkinson's disease in dealing with the consequences of their disease in daily activities. In this narrative review, we address the limitations that people with Parkinson's disease may encounter despite optimal medical management, and we clarify both the unique and shared approaches that physical therapists and occupational therapists can apply in treating these limitations.
Barth, F; Baum, B; Bremen, D; Meuser, T; Jost, W H
The economic impact of parkinsonism has been getting more significant due to the increasing prevalence of Parkinson's disease and the modern therapies available nowadays. The present study is supposed to update the existing databases and to provide a sound foundation for rational decision-making in the health care sector. It does not only focus on the direct costs of this disease incurred by 75 patients over a longer period, but also and for the first time, takes a look on the indirect cost as well. The study shows that the expenses for PD-related house rebuilding and early retirement make up for a substantial share among the indirect costs. In the overall analysis, the ratio between both, direct and indirect costs appear to be relatively balanced with slight domination of the direct costs.