Common variants in PARK loci and related genes and Parkinson's disease

Rare mutations in PARK loci genes cause Parkinson's disease (PD) in some families and isolated populations. We investigated the association of common variants in PARK loci and related genes with PD susceptibility and age at onset in an outbred population. A total of 1,103 PD cases from the upper Midwest, USA, were individually matched to unaffected siblings (n = 654) or unrelated controls (n = 449) from the same region. Using a sequencing approach in 25 cases and 25 controls, single nucleotide polymorphisms (SNPs) in species‐conserved regions of PARK loci and related genes were detected. We selected additional tag SNPs from the HapMap. We genotyped a total of 235 SNPs and two variable number tandem repeats in the ATP13A2, DJ1, LRRK1, LRRK2, MAPT, Omi/HtrA2, PARK2, PINK1, SNCA, SNCB, SNCG, SPR, and UCHL1 genes in all 2,206 subjects. Case‐control analyses were performed to study association with PD susceptibility, while cases‐only analyses were used to study association with age at onset. Only MAPT SNP rs2435200 was associated with PD susceptibility after correction for multiple testing (OR = 0.74, 95% CI = 0.64–0.86, uncorrected P < 0.0001, log additive model); however, 16 additional MAPT variants, seven SNCA variants, and one LRRK2, PARK2, and UCHL1 variants each had significant uncorrected P‐values. There were no significant associations for age at onset after correction for multiple testing. Our results confirm the association of MAPT and SNCA genes with PD susceptibility but show limited association of other PARK loci and related genes with PD. © 2010 Movement Disorder Society     

Perceived imbalance and risk of Parkinson's disease

We prospectively examined associations between perceived imbalance and Parkinson's disease (PD) risk in the Health Professional Follow‐up Study (HPFS), and Nurses' Health Study (NHS). We included 39,087 men and 82,299 women free of PD at baseline (1990) in the current analyses. We documented 449 incident PD cases during 12 years follow‐up. Subjects who reported difficulty with balance before 1990 (baseline) were 1.8 more times likely to develop PD, relative to those who reported no balance difficulty (pooled multivariate RR = 1.8; 95% CI: 1.3, 2.5; P < 0.0001). When we further examined associations between perceived imbalance at baseline and PD onset during different time periods, we found a significant elevation of PD risk only during the first 4 years of follow‐up. This result suggests that the imbalance may in some cases be an early sign of PD, and may represent the onset of motor symptoms although they have not been clinically recognized. © 2008 Movement Disorder Society     

Coffee and tea consumption and the risk of Parkinson's disease.

Several prospective studies have assessed the association between coffee consumption and Parkinson's disease (PD) risk, but the results are inconsistent. We examined the association of coffee and tea consumption with the risk of incident PD among 29,335 Finnish subjects aged 25 to 74 years without a history of PD at baseline. During a mean follow-up of 12.9 years, 102 men and 98 women developed an incident PD. The multivariate-adjusted (age, body mass index, systolic blood pressure, total cholesterol, education, leisure-time physical activity, smoking, alcohol and tea consumption, and history of diabetes) hazard ratios (HRs) of PD associated with the amount of coffee consumed daily (0, 1-4, and > or = 5 cups) were 1.00, 0.55, and 0.41 (P for trend = 0.063) in men, 1.00, 0.50, and 0.39 (P for trend = 0.073) in women, and 1.00, 0.53, and 0.40 (P for trend = 0.005) in men and women combined (adjusted also for sex), respectively. In both sexes combined, the multivariate-adjusted HRs of PD for subjects drinking > or = 3 cups of tea daily compared with tea nondrinkers was 0.41 (95% CI 0.20-0.83). These results suggest that coffee drinking is associated with a lower risk of PD. More tea drinking is associated with a lower risk of PD.     

Variants in estrogen‐related genes and risk of Parkinson's disease

Incidence rates of Parkinson's disease are higher in men than in women at all ages, and these differences may be a result of the neuroprotective effects of estrogen on the nigrostriatal pathway. We investigated the association of common variants in 4 estrogen‐related genes with Parkinson's disease. Tagging single‐nucleotide polymorphisms in the CYP19A1, ESR1, ESR2, and PRDM2 genes were selected from the International Haplotype Map and genotyped in 1103 Parkinson's disease cases from the upper Midwest of the United States and in 1103 individually matched controls (654 unaffected siblings, and 449 unrelated controls from the same region). Of 137 informative single‐nucleotide polymorphisms, 2 PRDM2 single‐nucleotide polymorphisms were significantly associated with an increased risk of Parkinson's disease at the Bonferroni‐corrected significance level of 0.0004 (rs2744690: OR, 1.54; SE(logOR), .109; 99.96% CI, 1.05–2.26; uncorrected P = .0001; rs2744687: OR, 1.53; SE(logOR), .113; 99.96% CI, 1.03–2.29, uncorrected P = .0002); the association was significant in the women‐only stratum but not in the men‐only stratum. An additional 6 single‐nucleotide polymorphisms in PRDM2, 2 in ESR1, 1 in ESR2, and 1 in CYP19A1 had significant P values in the overall sample before Bonferroni correction. None of the single‐nucleotide polymorphisms were significantly associated with age at onset of Parkinson's disease after Bonferroni correction. Our results confirm the association of PRDM2 variants with Parkinson's disease susceptibility, especially in women. © 2011 Movement Disorder Society     

Major life events and risk of Parkinson's disease

Major life events such as divorce, death of a spouse or a child, or long‐term unemployment are stressful to most people and animal models have suggested a link between stress and onset of parkinsonian symptoms. In a large case‐control study based on nationwide registries, we aim to address whether major life events are risk factors for Parkinson's disease. Between 1986 and 2006, we identified 13,695 patients with a (PD) primary diagnosis of PD in the Danish National Hospital Register. Each case was frequency matched by age and gender to five population controls. Information on major life events before onset of PD was ascertained from national registries. Among men, number of life events was associated with risk of Parkinson's disease in an inverse dose‐response manner (P < 0.0001). Compared to no events, three or more events were associated with a 42% lower risk of PD (OR = 0.58; 95 % CI: 0.34–0.99). Life events were not associated with PD in women. In contrast, a higher risk of PD was observed among women who had never been married (1.16; 1.04–1.29) and among men (1.47; 1.18–1.82) and women (1.30; 1.05–1.61) who have never been employees. The lower risk of Parkinson's disease among men who had experienced life events was unexpected but might suggest a general “risk avoidance behavior” in Parkinson's patients. © 2010 Movement Disorder Society     

Calcium channel blocker use and risk of Parkinson's disease

We investigated whether the use of calcium channel blockers (CCBs) was associated with a reduced risk of Parkinson's disease (PD) in two large prospective cohorts: the Nurses' Health Study (NHS) and Health Professionals' Follow‐Up Study (HPFS). Cox proportional hazards models were used to estimate relative risks (RRs) and 95% confidence intervals (CIs) to assess the association between use of CCBs and risk of PD adjusting for potential confounders. We identified 514 incident cases of PD during follow‐up. No association between baseline use of CCBs (RR = 1.18, 95% CI: 0.73–1.92), frequency of use or duration of use of CCBs and PD risk was observed (P > 0.2 for all). These findings do not support a role for CCBs in providing neuroprotection against development of PD. © 2010 Movement Disorder Society     

Integrated Multi-Cohort Analysis of the Parkinson's Disease Gut Metagenome

Background

The gut microbiome is altered in several neurologic disorders, including Parkinson's disease (PD).

Objectives

The aim is to profile the fecal gut metagenome in PD for alterations in microbial composition, taxon abundance, metabolic pathways, and microbial gene products, and their relationship with disease progression.

Methods

Shotgun metagenomic sequencing was conducted on 244 stool donors from two independent cohorts in the United States, including individuals with PD (n = 48, n = 47, respectively), environmental household controls (HC, n = 29, n = 30), and community population controls (PC, n = 41, n = 49). Microbial features consistently altered in PD compared to HC and PC subjects were identified. Data were cross-referenced to public metagenomic data sets from two previous studies in Germany and China to determine generalizable microbiome features.

Results

We find several significantly altered taxa between PD and controls within the two cohorts sequenced in this study. Analysis across global cohorts returns consistent changes only in Intestinimonas butyriciproducens. Pathway enrichment analysis reveals disruptions in microbial carbohydrate and lipid metabolism and increased amino acid and nucleotide metabolism in PD. Global gene-level signatures indicate an increased response to oxidative stress, decreased cellular growth and microbial motility, and disrupted intercommunity signaling.

Conclusions

A metagenomic meta-analysis of PD shows consistent and novel alterations in functional metabolic potential and microbial gene abundance across four independent studies from three continents. These data reveal that stereotypic changes in the functional potential of the gut microbiome are a consistent feature of PD, highlighting potential diagnostic and therapeutic avenues for future research. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.     

Visual symptoms in Parkinson's disease and Parkinson's disease dementia

Visual symptoms are common in PD and PD dementia and include difficulty reading, double vision, illusions, feelings of presence and passage, and complex visual hallucinations. Despite the established prognostic implications of complex visual hallucinations, the interaction between cognitive decline, visual impairment, and other visual symptoms remains poorly understood. Our aim was to characterize the spectrum of visual symptomatology in PD and examine clinical predictors for their occurrence. Sixty-four subjects with PD, 26 with PD dementia, and 32 age-matched controls were assessed for visual symptoms, cognitive impairment, and ocular pathology. Complex visual hallucinations were common in PD (17%) and PD dementia (89%). Dementia subjects reported illusions (65%) and presence (62%) more frequently than PD or control subjects, but the frequency of passage hallucinations in PD and PD dementia groups was equivalent (48% versus 69%, respectively; P = 0.102). Visual acuity and contrast sensitivity was impaired in parkinsonian subjects, with disease severity and age emerging as the key predictors. Regression analysis identified a variety of factors independently predictive of complex visual hallucinations (e.g., dementia, visual acuity, and depression), illusions (e.g., excessive daytime somnolence and disease severity), and presence (e.g., rapid eye movement sleep behavior disorder and excessive daytime somnolence). Our results demonstrate that different "hallucinatory" experiences in PD do not necessarily share common disease predictors and may, therefore, be driven by different pathophysiological mechanisms. If confirmed, such a finding will have important implications for future studies of visual symptoms and cognitive decline in PD and PD dementia.     

STN-DBS does not change emotion recognition in advanced Parkinson's disease

Deep brain stimulation of the subthalamic nuclei (STN-DBS) for the treatment of levodopa-induced motor complications in advanced Parkinson's disease (APD) has been associated with neuropsychiatric disorders. It has been suggested that a postoperative decline in visual emotion recognition is responsible for those adverse events, although there is also evidence that emotional processing deficits can be present before surgery.The aim of the present study is to compare the ability to recognize emotions before and one year after surgery in APD. Methods: Consecutively operated APD patients were tested pre-operatively and one year after STN-DBS by the Comprehensive Affect Testing System (CATS), which evaluates visual recognition of 7 basic emotions (happiness, sadness, anger, fear, surprise, disgust and neutral) on facial expressions and 4 emotions on prosody (happiness, sadness, anger and fear).ResultsIn a sample of 30 patients 6 had depression or apathy at baseline that significantly increased to 14 post-surgery. There were no significant changes in the tests of identity discrimination, discrimination of emotional faces, naming of emotional faces, recognition of emotional prosody, and naming of emotional prosody after STN-DBS. The results of emotion tests could not predict the development of the neuropsychiatric symptoms.DiscussionThis study does not support the hypothesis of an acquired change in emotion recognition, either in faces or in prosody, after STN-DBS in APD patients. Neuropsychiatric symptoms appearing after STN-DBS should not be attributed to new deficits in emotional recognition.     

The emerging science of precision medicine and pharmacogenomics for Parkinson's disease

Current therapies for Parkinson's disease are problematic because they are symptomatic and have adverse effects. New drugs have failed in clinical trials because of inadequate efficacy. At the core of the problem is trying to make one drug work for all Parkinson's disease patients, when we know this premise is wrong because (1) Parkinson's disease is not a single disease, and (2) no two individuals have the same biological makeup. Precision medicine is the goal to strive for, but we are only at the beginning stages of building the infrastructure for one of the most complex projects in the history of science, and it will be a long time before Parkinson's disease reaps the benefits. Pharmacogenomics, a cornerstone of precision medicine, has already proven successful for many conditions and could also propel drug discovery and improve treatment for Parkinson's disease. To make progress in the pharmacogenomics of Parkinson's disease, we need to change course from small inconclusive candidate gene studies to large‐scale rigorously planned genome‐wide studies that capture the nuclear genome and the microbiome. Pharmacogenomic studies must use homogenous subtypes of Parkinson's disease or apply the brute force of statistical power to overcome heterogeneity, which will require large sample sizes achievable only via internet‐based methods and electronic databases. Large‐scale pharmacogenomic studies, together with biomarker discovery efforts, will yield the knowledge necessary to design clinical trials with precision to alleviate confounding by disease heterogeneity and interindividual variability in drug response, two of the major impediments to successful drug discovery and effective treatment. © 2017 International Parkinson and Movement Disorder Society     

Dietary fat intake and risk for Parkinson's disease

Previous epidemiological studies have generated inconsistent results regarding the associations between dietary fat intakes and risk for Parkinson's disease (PD). We therefore prospectively examined these associations in the National Institutes of Health–American Association of Retired Persons (NIH‐AARP) Diet and Health Study. A 124‐item food frequency questionnaire was administered at baseline in1995 to 1996, and PD diagnosis was self‐reported at the follow‐up survey in 2004 to 2006. A total of 1,087 cases with a PD diagnosis between 2000 and 2006 and 299,617 controls were included in the analyses. Overall, intakes of fats and other macronutrients were not associated with PD risk. However, we found a weak positive association between n‐6 polyunsaturated fatty acids (PUFA) and the risk for PD. After adjusting for potential confounders, the odds ratio (OR) and 95% confidence interval (CI) between extreme quintiles of n‐6 PUFA intake was 1.23 (95% CI = 1.02‐1.49, P for trend = 0.02). A similar association was observed for the intake of linoleic acid. Results were similar among men and among women. Our study suggests that fat intake in general is not related to the risk for PD. The weak positive association between intake of n‐6 PUFA and PD risk needs further investigation. © 2014 International Parkinson and Movement Disorder Society     

Smokeless tobacco use and the risk of Parkinson's disease mortality.

We examined the association between smokeless tobacco use and Parkinson's disease (PD) mortality as assessed by death certificate in a prospective cohort of 95,981 never-smoking men. In this cohort, smokeless tobacco use is inversely associated with PD mortality, with an age-adjusted risk of 0.22 (0.07-0.67) among current users compared to never users.     

Cognitive profile of Parkinson's disease patients: a comparative study between early-onset and late-onset Parkinson's disease

Aim: To investigate the influence of onset age on the occurrence and progression of cognitive dysfunction using neuropsychological tests and the electrophysiological component P300 in both early-onset Parkinson's disease (EOPD) and late-onset Parkinson's disease (LOPD) patients. Methods: A cohort of 76 EOPD patients and 166 LOPD patients was recruited for this study. Demographic information and clinical features, including age, disease duration, education level, family history, the Unified Parkinson's Disease Rating Scale, the Hoehn and Yahr stage, and depression scores were documented for each patient. The Mini-Mental State Examination, Montreal Cognitive Assessment (MoCA), Wechsler Adult Intelligence Scale – Revised, Chinese version (WAIS-RC) and Wechsler Memory Scale – Revised, Chinese version (WMS-RC) were used. In addition, P300 was also examined to assess cognitive function. Results: Although EOPD patients had longer disease duration, their cognitive dysfunction progressed more slowly. The MoCA tests revealed that EOPD patients had higher scores in visuospatial function, attention, delayed recall, and orientation than the LOPD patients. The difference between the two groups on the WMS-RC test did not reach significance, whereas the scores in executive function, visuospatial function and attention as measured on the WAIS-RC test were significantly lower in the LOPD group. In addition, P300 latencies were markedly delayed and P300 amplitudes were reduced in the LOPD group. Conclusions: The current findings demonstrated that cognitive dysfunction progressed more slowly in the EOPD group. Although the LOPD patients exhibited shorter disease durations, their cognitive abilities, including executive function, visuospatial function and attention, may have been impaired.     

Association between Parkinson's disease and risk of colorectal cancer

BackgroundGrowing evidence has reported that gut microbiota is involved in pathogenesis of Parkinson's disease (PD) and colorectal cancer (CRC), and the association between PD and CRC does not reach a consensus. In order to explore their correlation, herein we summarize the epidemiological evidence and included relevant studies to perform a meta-analysis.MethodsA comprehensive literature search for relevant articles published was performed in Medline, Web of Science and Embase up to June 30, 2016. The pooled risk ratio (RR) with 95% confidence intervals (CI) was used to estimate the effects and calculated using the method of generic inverse variance with the Random-effects model.ResultsThirteen studies were included and analyzed in this meta-analysis. The pooled result of 11 cohort studies and 2 case-control studies comprising 343,226 PD patients showed that patients with PD had a decreased risk of CRC (RR: 0.79, 95% CI: 0.66–0.93, P = 0.006). Further subgroup analyses performed in Western population revealed that the significant inverse association between PD and risk of CRC was not undermined by many factors, including study design, tumor location, gender and quality of the study.ConclusionPatients with PD was significantly associated with a decreased risk of CRC in Western population. Future studies are warranted to further clarify this association in Asian population.     

Applause sign in advanced Parkinson's disease

BackgroundThe ‘applause sign’ a tendency to continue applauding in response to instructions to clap three times was described in 1995 and was considered specific to degenerative disease, especially to atypical parkinsonian disorders. In early phase Parkinson's disease (PD) the sign has been reported positive as well. In late stage PD it is unknown whether and to what extent the sign may be elicited and it remains unknown if and to what degree the sign correlates to cognitive impairment and PD related dementia.MethodsNursing home residents with PD (MMSE >17) were included. All patients underwent the clapping test and were tested for cognitive disturbance by making use of accepted clinimetrics (MMSE and Scopa-cog). T-testing was performed with the hypothesis that patients expressing the applause sign would score lower on the MMSE or Scopa-cog.ResultsSeventy three nursing home residents (mainly Hoehn and Yahr 4/5) with a mean disease duration of 10 years and a mean age of 78.7 years were included. The applause sign was found positive in 15 of 73 residents (20.5%). Residents expressing the applause sign had significantly lower mean scores on the MMSE (25.1 vs 22.9 points, p < 0.006) and Scopa-cog (14.8 vs 12.0 points, p < 0.039).ConclusionsThe applause sign is present in late stage PD and correlates with a higher degree of cognitive impairment as established with accepted clinimetric tests. A higher degree of frontal lobe involvement explains the presence of the applause sign.     

Is there seasonal variation in risk of Parkinson's disease?

Recent studies suggest that, for many adult‐onset neurological diseases, persons born at a certain time of year are at higher risk of the disease. Small‐scale studies have suggested that persons born in the spring may be at higher risk of developing Parkinson's disease (PD) late in life. There have also been suggestions that there are clusters of PD birth dates in the years of major influenza pandemics. To determine whether there is any seasonal variation in the birth dates of PD patients, we examined birth dates of 8,168 PD patients collected from subspecialty movement disorder clinics across Canada. Patterns of seasonality of birth were examined and compared with the general Canadian population. In addition, we compared counts of patients born in the years of major influenza pandemics with the number born in the surrounding years. We found no evidence of systematic seasonal variation in PD incidence by birth date, or of clustering of birth dates during influenza pandemic years in PD patients. © 2006 Movement Disorder Society     

Different iron deposition patterns in early- and middle-late-onset Parkinson's disease

BackgroundIron deposition may contribute to the clinical symptoms in Parkinson's disease (PD). With partial different clinical manifestations, the iron deposition patterns between patients with early-onset Parkinson's disease (EOPD) and middle-late-onset Parkinson's disease (M-LOPD) are still unclear. This study was designed to investigate the patterns of iron deposition and their clinical relevance in EOPD and M-LOPD patients, using quantitative susceptibility mapping technique.Materials and methodsThirty-five EOPD patients and 24 matched young controls, 33 M-LOPD patients and 22 matched older controls were recruited in the study. The iron content in the deep grey matter nuclei in the basal ganglia and midbrain were measured, and compared between patients and their corresponding controls. The correlations of regional iron content and clinical features were explored in patient groups.ResultsBoth M-LOPD and EOPD patients showed increased iron content in the substantia nigra (SN) pars compacta and SN pars reticulata. Increased iron content in the putamen was only observed in M-LOPD patients. The relationship between the increased iron content and disease severity (H&Y stages, UPDRS II scores and UPDRS III scores) was observed in M-LOPD patients, but not in EOPD patients.ConclusionOur study suggested that the iron deposition pattern was greatly influenced by the age of PD onset, which increases our understanding of the different pathological underpinnings of EOPD and M-LOPD patients.     

Glycation in Parkinson's disease and Alzheimer's disease

Glycation is a spontaneous age‐dependent posttranslational modification that can impact the structure and function of several proteins. Interestingly, glycation can be detected at the periphery of Lewy bodies in the brain in Parkinson's disease. Moreover, α‐synuclein can be glycated, at least under experimental conditions. In Alzheimer's disease, glycation of amyloid β peptide exacerbates its toxicity and contributes to neurodegeneration. Recent studies establish diabetes mellitus as a risk factor for several neurodegenerative disorders, including Parkinson's and Alzheimer's diseases. However, the mechanisms underlying this connection remain unclear. We hypothesize that hyperglycemia might play an important role in the development of these disorders, possibly by also inducing protein glycation and thereby dysfunction, aggregation, and deposition. Here, we explore protein glycation as a common player in Parkinson's and Alzheimer's diseases and propose it may constitute a novel target for the development of strategies for neuroprotective therapeutic interventions. © 2016 International Parkinson and Movement Disorder Society