Parkinson's Disease Cases Research Articles

Neuroanatomical and prognostic associations of depression in Parkinson’s disease

BackgroundDepression is reported as a risk factor, prodromal feature and late consequence of Parkinson’s disease (PD). We aimed to evaluate the timing, neuroanatomy and prognostic implications of depression in PD.MethodsWe...

Parkinson’s disease is associated with clonal hematopoiesis with TET2 mutation

Clonal hematopoiesis of indeterminate potential (CHIP), a premalignant expansion of mutated hematopoietic stem cells, is linked to immune alterations. Given the role of neuroinflammation and immune dysfunction in Parkinson’s disease (PD), we hypothesized a connection between CHIP and PD. We analyzed peripheral blood DNA from 341 PD, 92 isolated REM sleep behavior disorder (iRBD) patients, and 5003 controls using targeted sequencing of 24 genes associated with hematologic neoplasms. PD cases were classified by clinical progression mode: fast, slow, and typical. Using multivariable logistic regression models, CHIP prevalence was assessed against controls with a 1.0% variant allele fraction threshold. CHIP with TET2 mutations was more prevalent in PD than controls (aOR 1.75, 95% CI 1.11–2.77, p = 0.017), particularly in the fast motor progression subgroup (aOR 3.19, p = 0.004). No distinct associations were observed with iRBD. PD is linked to increased odds of CHIP with TET2 mutations, suggesting immune dysregulation in PD pathophysiology.

Advanced MRI-based evaluation of gray and white matter changes in Parkinson’s disease

BackgroundParkinson’s disease (PD) is the most common movement disorder and the second most common neurodegenerative disease. The aim of our study was to compare gray–white matter changes (GWC) between Parkinson's disease (PD) patients and age-matched healthy control group as well as comparing GWC between different stages of PD (early and complicated). Our study was prospective cross-sectional case–control observational study with analytic component conducted on twenty patients and ten controls without any signs or symptoms of PD or any history of PD in first-degree relatives. All patients and controls were tested for history taking with stress on resting tremors, rigidity, gait abnormalities, postural instability and any symptoms of cognitive impairment, clinical examination including general examination and neurological examination. Also diffusion tensor imaging (DTI) with fiber tracking (tractography) and susceptibility-weighted MR imaging were performed for all cases.ResultsAs regards DTI and evaluation of fractional anisotropy (FA) and mean diffusivity (MD) values between PD cases and healthy controls, the cases group showed significant decrease in FA values at substantia nigra on both sides and left cingulum as well as significant increase in MD values at substantia nigra on both sides and corpus callosum. Also, there are significant decrease in FA values at substantia nigra on both sides and significant increase in MD values at substantia nigra on both sides and right cingulum in late parkinsonism when compared to early parkinsonism. A cutoff FA value of 0.945 at right substantia nigra and cutoff FA value of 0.585 at left substantia nigra showed significant AUC that could differentiate between cases and controls. Also cutoff MD value of 0.791 at right substantia nigra and cutoff MD value of 0.813 at left substantia nigra showed significant AUC that could differentiate between cases and controls.ConclusionsDiffusion tensor imaging showed valuable role in evaluation of gray–white matter changes in Parkinson's disease. Also, it helps to assess degree of gray–white matter changes when comparing late parkinsonism to early parkinsonism through evaluation of FA and MD values at corpus callosum, substania nigra, and cingulum.

Correlation of psychological resilience with social support and coping style in Parkinson's disease: A cross-sectional study.

To analyse the current status of psychological resilience in Parkinson's disease (PD) patients and its correlation with social support and coping style. A cross-sectional study. PD patients hospitalized in a tertiary-level hospital in Shijiazhuang, Hebei Province, from March 2022 to March 2023 were selected for the study using the convenience sampling method. A general information questionnaire, psychological resilience scale, Medical Coping Modes Questionnaire and Perceived Social Support Scale were used to investigate 111 cases of PD. SPSS 25.0 software was used for statistical analysis. The data were analysed using independent samples t-test, one-way ANOVA, multiple linear regression analysis and the Pearson correlation coefficient. Parkinson's disease patients have a moderate level of psychological resilience. The results of the Pearson correlation analyses showed that the level of psychological resilience was positively correlated with social support and confrontation and was negatively correlated with avoidance and acceptance-resignation. The results of multiple linear regression analysis showed that social support and acceptance-resignation were the influencing factors of psychological resilience in PD patients. The psychological resilience of PD patients is at a moderate level. Social support and acceptance-resignation are the factors influencing the psychological resilience of PD patients. This study analysed the level of psychological resilience in PD patients and its correlation with social support and coping style from the perspective of positive psychology to provide some reference for targeted clinical interventions. Our study found that social support and acceptance-resignation are influential factors in psychological resilience in PD patients. Medical staff should encourage patients to face the disease positively and their social support should be increased in order to improve their level of psychological resilience. No patient or public contribution.

Iron-sulfur cluster loss in mitochondrial CISD1 mediates PINK1 loss-of-function phenotypes.

Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra of the midbrain. Familial cases of PD are often caused by mutations of PTEN-induced kinase 1 (PINK1) and the ubiquitin ligase Parkin, both pivotal in maintaining mitochondrial quality control. CISD1, a homodimeric mitochondrial iron-sulfur-binding protein, is a major target of Parkin-mediated ubiquitination. We here discovered a heightened propensity of CISD1 to form dimers in Pink1 mutant flies and in dopaminergic neurons from PINK1 mutation patients. The dimer consists of two monomers that are covalently linked by a disulfide bridge. In this conformation CISD1 cannot coordinate the iron-sulfur cofactor. Overexpressing Cisd, the Drosophila orthologue of CISD1, and a mutant Cisd incapable of binding the iron-sulfur cluster in Drosophila reduced climbing ability and lifespan. This was more pronounced with mutant Cisd and aggravated in Pink1 mutant flies. Complete loss of Cisd, in contrast, rescued all detrimental effects of Pink1 mutation on climbing ability, wing posture, dopamine levels, lifespan, and mitochondrial ultrastructure. Our results suggest that Cisd, probably iron-depleted Cisd, operates downstream of Pink1 shedding light on PD pathophysiology and implicating CISD1 as a potential therapeutic target.

Loss-of-function variants in ITSN1 confer high risk of Parkinson’s disease

Parkinson’s disease (PD) is a debilitating neurodegenerative disorder and its rising global incidence highlights the need for the identification of modifiable risk factors. In a gene-based burden test of rare variants (8647 PD cases and 777,693 controls) we discovered a novel association between loss-of-function variants in ITSN1 and PD. This association was further supported with burden data from the Neurodegenerative Disease Knowledge Portal and the Accelerating Medicines Partnership Parkinson’s Disease Knowledge Platform. Our findings show that Rho GTPases and disruptions in synaptic vesicle transport may be involved in the pathogenesis of PD, pointing to the possibility of novel therapeutic approaches.

Daily steps are a predictor of, but perhaps not a modifiable risk factor for Parkinson's Disease: findings from the UK Biobank.

Higher physical activity levels have been suggested as a potential modifiable risk factor for lowering the risk of incident Parkinson's disease (PD). This study uses objective measures of physical activity to investigate the role of reverse causation in the observed association. To investigate the association between accelerometer-derived daily step count and incident PD, and to assess the impact of reverse causation on this association. This prospective cohort study involved a follow-up period with a median duration of 7.9 years, with participants who wore wrist-worn accelerometers for up to 7 days. The study was conducted within the UK Biobank, a large, population-based cohort. The analysis included 94,696 participants aged 43-78 years (56% female) from the UK Biobank who provided valid accelerometer data and did not have prevalent PD. Daily step counts were derived using machine learning models to determine the median daily step count over the monitoring period. The primary outcome was incident PD, identified through hospital admission and death records. Cox proportional hazards regression models estimated hazard ratios (HR) and 95% confidence intervals (CI) for the association between daily step count and incident PD, with adjustments for various covariates and evaluation of reverse causation by splitting follow-up periods. During a median follow-up of 7.9 years (IQR: 7.4-8.4), 407 incident PD cases were identified. An inverse linear association was observed between daily step count and incident PD. Participants in the highest quintile of daily steps (>12,369 steps) had an HR of 0.41 (95% CI 0.31-0.54) compared to the lowest quintile (<6,276 steps; HR 1.00; 95% CI 0.84-1.19). A per 1,000 step increase was associated with an HR of 0.92 (95% CI 0.89-0.94). However, after excluding the first six years of follow-up, the association was not significant (HR 0.96, 95% CI 0.92-1.01). The observed association between higher daily step count and lower incident PD is likely influenced by reverse causation, suggesting changes in physical activity levels occur years before PD diagnosis. While step counts may serve as a predictor for PD, they may not represent a modifiable risk factor. Further research with extended follow-up periods is warranted to better understand this relationship and account for reverse causation.

Regulation of TIR-1/SARM-1 by miR-71 Protects Dopaminergic Neurons in a C. elegans Model of LRRK2-Induced Parkinson's Disease.

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by symptoms such as bradykinesia, resting tremor, and rigidity, primarily driven by the degradation of dopaminergic (DA) neurons in the substantia nigra. A significant contributor to familial autosomal dominant PD cases is mutations in the LRRK2 gene, making it a primary therapeutic target. This study explores the role of microRNAs (miRNAs) in regulating the proteomic stress responses associated with neurodegeneration in PD using C. elegans models. Our focus is on miR-71, a miRNA known to affect stress resistance and act as a pro-longevity factor in C. elegans. We investigated miR-71's function in C. elegans models of PD, where mutant LRRK2 expression correlates with dopaminergic neuronal death. Our findings reveal that miR-71 overexpression rescues motility defects and slows dopaminergic neurodegeneration in these models, suggesting its critical role in mitigating the proteotoxic effects of mutant LRRK2. Conversely, miR-71 knockout exacerbates neuronal death caused by mutant LRRK2. Additionally, our data indicate that miR-71's neuroprotective effect involves downregulating the toll receptor domain protein tir-1, implicating miR-71 repression of tir-1 as vital in the response to LRRK2-induced proteotoxicity. These insights into miR-71's role in C. elegans models of PD not only enhance our understanding of molecular mechanisms in neurodegeneration but also pave the way for potential research into human neurodegenerative diseases, leveraging the conservation of miRNAs and their targets across species.

Wavelet-based selection-and-recalibration network for Parkinson’s disease screening in OCT images

Background and Objective:Parkinson’s disease (PD) is one of the most prevalent neurodegenerative brain diseases worldwide. Therefore, accurate PD screening is crucial for early clinical intervention and treatment. Recent clinical research indicates that changes in pathology, such as the texture and thickness of the retinal layers, can serve as biomarkers for clinical PD diagnosis based on optical coherence tomography (OCT) images. However, the pathological manifestations of PD in the retinal layers are subtle compared to the more salient lesions associated with retinal diseases. Methods:Inspired by textural edge feature extraction in frequency domain learning, we aim to explore a potential approach to enhance the distinction between the feature distributions in retinal layers of PD cases and healthy controls. In this paper, we introduce a simple yet novel wavelet-based selection and recalibration module to effectively enhance the feature representations of the deep neural network by aggregating the unique clinical properties, such as the retinal layers in each frequency band. We combine this module with the residual block to form a deep network named Wavelet-based Selection and Recalibration Network (WaveSRNet) for automatic PD screening. Results:The extensive experiments on a clinical PD-OCT dataset and two publicly available datasets demonstrate that our approach outperforms state-of-the-art methods. Visualization analysis and ablation studies are conducted to enhance the explainability of WaveSRNet in the decision-making process. Conclusions:Our results suggest the potential role of the retina as an assessment tool for PD. Visual analysis shows that PD-related elements include not only certain retinal layers but also the location of the fovea in OCT images.

Relationship Between Melatonin Receptor Agonists and Parkinson's Disease.

Parkinson's disease affects millions of people worldwide, and without significant progress in disease prevention and treatment, its incidence and prevalence could increase by more than 30% by 2030. Researchers have focused on targeting sleep and the circadian system as a novel treatment strategy for Parkinson's disease. This study investigated the association between melatonin receptor agonists and Parkinson's disease, using the Food and Drug Administration (FDA) Adverse Events Reporting System (FAERS). The target drugs were melatonin receptor agonists including ramelteon, tasimelteon, and agomelatine. Parkinson's disease cases were defined according to the Medical Dictionary for Regulatory Activities (MedDRA) 25.0; Standardized MedDRA Query (SMQ) using both the "narrow" and "broad" preferred terms (PTs) associated with Parkinson's disease. The association between melatonin receptor agonists (ramelteon, tasimelteon, and agomelatine) and Parkinson's disease was evaluated by the reporting odds ratio. Upon analyzing the data from all patients registered in the FAERS, ramelteon (ROR: 0.66, 95% confidence interval [95% CI]: 0.51-0.84) and tasimelteon (ROR: 0.49, 95% CI: 0.38-0.62) showed negative correlations with Parkinson's disease. Conversely, only agomelatine was positively correlated with Parkinson's disease (ROR: 2.63, 95% CI: 2.04-3.40). These results suggest that among the melatonin receptor agonists, ramelteon and tasimelteon are negatively correlated with Parkinson's disease. In contrast, agomelatine was shown to be positively correlated with Parkinson's disease. These results should be used in research to develop drugs for the treatment of Parkinson's disease, fully considering the limitations of the spontaneous reporting system.

Associations between different coffee types, neurodegenerative diseases, and related mortality: findings from a large prospective cohort study

BackgroundObservational studies have suggested associations between amount of coffee consumption and decreased risk of neurodegenerative diseases. However, these studies do not consider differences among coffee types, including sweetened, unsweetened, caffeinated, and decaffeinated varieties. ObjectivesThis study aims to identify associations between the consumption of various coffee types (sugar-sweetened, artificially sweetened, unsweetened, caffeinated, and decaffeinated) and risks of Alzheimer’s disease and related dementias (ADRD) and Parkinson’s disease (PD), along with related mortality. MethodsThis prospective study included 204,847 participants (44.7% males) from the UK Biobank. Cox proportional hazards models were used to assess the associations of coffee type with neurodegenerative outcome. On the basis of coffee consumption, participants were divided into 5 groups: non-coffee consumers, >0–1 cup/d, ≥1–2 cups/d, ≥2–3 cups/d, and ≥3 cups/d. ResultsOver a median follow-up of 9 y, the study documented 1696 cases of ADRD, 1093 cases of PD, and 419 neurodegenerative-related deaths. In the multivariate analysis, compared with non-coffee consumers, those with the highest intake of unsweetened and caffeinated coffee (≥3 cups/d) showed hazard ratios (95% confidence intervals) of 0.75 (0.62, 0.91) for ADRD, 0.71 (0.56, 0.91) for PD, and 0.67 (0.44, 1.01) for neurodegenerative-related death. However, no significant associations were noted in either decaffeinated or sugar/artificially sweetened coffee groups (P > 0.05). ConclusionsHigher intake of caffeinated coffee, particularly the unsweetened variety, was associated with reduced risks of ADRD and PD. No such associations were observed for sugar-sweetened or artificially sweetened coffee.

Effects of antimicrobial exposure on the risk of Parkinson's disease

BackgroundWe aimed to assess how antimicrobial exposure affects Parkinson's disease (PD) risk. MethodsA nested case-control study was performed to examine the association between antimicrobial exposure and newly diagnosed PD using the Clinical Practice Research Datalink (CPRD). Each PD case was matched by age, sex, and year of diagnosis (index date) to up to 15 controls. Number of prescribed antimicrobial courses was assessed 1–5, 6–10, and 11–15 years prior to the index date. Logistic regression with generalized estimating equations (GEE) was used to estimate odds ratios (ORs) and false discovery rate-adjusted p-values between antimicrobial exposure and risk of PD. ResultsWe compared 12,557 PD cases with 80,804 matched controls. We found an inverse dose-response relationship between number of penicillin courses and PD risk across multiple time periods (5+ courses, 1–5 years prior: OR 0.85, 95 % CI 0.76–0.95, p = 0.043; 6–10 years prior: OR 0.84, 95 % CI: 0.73–0.95, p = 0.059; 11–15 years prior: OR 0.87, 95 % CI 0.74–1.02, p = 0.291). The number of macrolide courses was inversely but not significantly associated with PD risk 1–5 years prior to the index date (OR 0.89–0.91, 95 % CI: 0.79–0.99, adjusted p = 0.140–0.167). Exposure to ≥2 courses of antifungals 1–5 years prior was associated with an increased risk of PD (OR 1.16, 95 % CI: 1.06–1.27, p = 0.020). ConclusionsIn a large UK-representative population, the risk of PD was modestly lower among adults who had previously received multiple courses of penicillins in the last 15 years and modestly higher among those exposed to antifungal medicines in recent years.

Longitudinal evaluation of polyneuropathy in Parkinson’s disease

BackgroundIncreasing evidence indicates a higher prevalence of polyneuropathy (PNP) in Parkinson’s disease (PD). However, the involvement of large fiber neuropathy in PD still remains poorly understood. Given the lack of longitudinal data, we investigated the course of PNP associated with PD.MethodsIn total, 41 PD patients underwent comprehensive clinical evaluation including motor and non-motor assessments as well as nerve conduction studies at baseline and at 2 years of follow-up. The definition of PNP was based on electrophysiological standard criteria. Common causes of PNP were excluded.ResultsAt baseline, PNP was diagnosed in 65.85% of PD patients via electroneurography. Patients with PNP presented with higher age (p = 0.019) and PD motor symptom severity (UPDRS III; p < 0.001). Over the course of 2 years, PNP deteriorated in 21.95% of cases, and 26.83% remained without PNP. Deterioration of nerve amplitude was most prevalent in the median sensory nerve affecting 57.58% of all PD cases with an overall reduction of median sensory nerve amplitude of 45.0%. With regard to PD phenotype, PNP progression was observed in 33.33% of the tremor dominant and 23.81% of the postural instability/gait difficulties subtype. Decrease of sural nerve amplitude correlated with lower quality of life (PDQ-39, p = 0.037) and worse cognitive status at baseline (MoCA, p = 0.042).ConclusionThe study confirms the high PNP rate in PD, and demonstrates a significant electrophysiological progression also involving nerves of the upper extremities. Longitudinal studies with larger cohorts are urgently needed and should elucidate the link between PD and PNP with the underlying pathomechanisms.

Characterizing a complex CT-rich haplotype in intron 4 of SNCA using large-scale targeted amplicon long-read sequencing

Parkinson’s disease (PD) is a common neurodegenerative disorder with a significant risk proportion driven by genetics. While much progress has been made, most of the heritability remains unknown. This is in-part because previous genetic studies have focused on the contribution of single nucleotide variants. More complex forms of variation, such as structural variants and tandem repeats, are already associated with several synucleinopathies. However, because more sophisticated sequencing methods are usually required to detect these regions, little is understood regarding their contribution to PD. One example is a polymorphic CT-rich region in intron 4 of the SNCA gene. This haplotype has been suggested to be associated with risk of Lewy Body (LB) pathology in Alzheimer’s Disease and SNCA gene expression, but is yet to be investigated in PD. Here, we attempt to resolve this CT-rich haplotype and investigate its role in PD. We performed targeted PacBio HiFi sequencing of the region in 1375 PD cases and 959 controls. We replicate the previously reported associations and a novel association between two PD risk SNVs (rs356182 and rs5019538) and haplotype 4, the largest haplotype. Through quantitative trait locus analyzes we identify a significant haplotype 4 association with alternative CAGE transcriptional start site usage, not leading to significant differential SNCA gene expression in post-mortem frontal cortex brain tissue. Therefore, disease association in this locus might not be biologically driven by this CT-rich repeat region. Our data demonstrates the complexity of this SNCA region and highlights that further follow up functional studies are warranted.

Ultrasensitive detection of aggregated α-synuclein using quiescent seed amplification assay for the diagnosis of Parkinson’s disease

BackgroundSeed amplification assays (SAA) enable the amplification of pathological misfolded proteins, including α-synuclein (αSyn), in both tissue homogenates and body fluids of Parkinson’s disease (PD) patients. SAA involves repeated cycles of shaking or sonication coupled with incubation periods. However, this amplification scheme has limitations in tracking protein propagation due to repeated fragmentation.MethodsWe introduced a modified form of SAA, known as Quiescent SAA (QSAA), and evaluated biopsy and autopsy samples from individuals clinically diagnosed with PD and those without synucleinopathies (control group). Brain biopsy samples were obtained from 14 PD patients and 6 controls without synucleinopathies. Additionally, skin samples were collected from 214 PD patients and 208 control subjects. Data were analyzed from April 2019 to May 2023.ResultsQSAA successfully amplified αSyn aggregates in brain tissue sections from mice inoculated with pre-formed fibrils. In the skin samples from 214 PD cases and 208 non-PD cases, QSAA demonstrated high sensitivity (90.2%) and specificity (91.4%) in differentiating between PD and non-PD cases. Notably, more αSyn aggregates were detected by QSAA compared to immunofluorescence with the pS129-αSyn antibody in consecutive slices of both brain and skin samples.ConclusionWe introduced the new QSAA method tailored for in situ amplification of αSyn aggregates in brain and skin samples while maintaining tissue integrity, providing a streamlined approach to diagnosing PD with individual variability. The integration of seeding activities with the location of deposition of αSyn seeds advances our understanding of the mechanism underlying αSyn misfolding in PD.

Multidisciplinary care in Parkinson’s disease

Parkinson’s Disease (PD) is a multifaceted and progressive disorder characterized by a diverse range of motor and non-motor symptoms. The complexity of PD necessitates a multidisciplinary approach to manage both motor symptoms, such as bradykinesia, gait disturbances and falls, and non-motor symptoms, including cognitive dysfunction, sleep disturbances, and mood disorders, which significantly affect patients’ quality of life. Pharmacotherapy, particularly dopaminergic replacement therapy, has advanced to alleviate many symptoms. However, these medications can also induce side effects or aggravate symptoms like hallucinations or orthostatic dysfunction, highlighting the need for comprehensive patient management. The optimal care for PD patients involves a team of specialists, including neurologists, physical and occupational therapists, speech-language pathologists, psychologists, and other medical professionals, to address the complex and individualized needs of each patient. Here, we illustrate the necessity of such a multidisciplinary approach in four illustrative PD cases with different disease stages and motor and non-motor complications. The patients were treated in different treatment settings (specialized outpatient clinic, day clinic, inpatient care including neurorehabilitation). The biggest challenge lies in organizing and implementing such comprehensive care effectively across different clinical settings.

Association between Physical Activity and Parkinson's Disease: A Prospective Cohort Study.

The burden of Parkinson's disease (PD) is still increasing, and physical activity is a modifiable factor for health benefits. The benefits of physical activity in PD are not well established. Therefore, this study aimed to investigate the association between various types of physical activity and the risk of developing PD. Data from 432,497 participants in UK Biobank, who were free of PD at baseline, were analyzed. Physical activity levels were assessed by measuring the duration of walking for pleasure, light and heavy do-it-yourself (DIY) activities, strenuous sports, and other exercises. Physical activity was categorized into daily living activities (walking for pleasure, light DIY, and heavy DIY) and structured exercises (strenuous sports and other exercises). Association between different types of physical activity and PD risk was examined using multivariable adjusted restricted cubic splines and Cox proportional risk models. Over a median follow-up of 13.7 years, 2,350 PD cases were identified. Cubic spline analyses revealed negative linear associations between PD risk and total physical activity, daily living activities, and structured exercise. After multivariable adjustment, the hazard ratios and 95% confidence intervals for incident PD associated with the highest quartile of total physical activity, daily living activities, and structured exercise were 0.72 (0.64-0.81), 0.75 (0.67-0.84), and 0.78 (0.67-0.90), respectively, compared to those in the lowest quartile. Sensitivity analysis confirmed these findings. Higher levels of both daily living activities and structured exercise were associated with a reduced incidence of PD, underscoring the importance of maintaining physical activity to prevent PD.

Genetic background of cognitive decline in Parkinson's disease

Parkinson's disease (PD) is a complex disorder that is influenced by multiple genetic risk factors. There is a significant heterogeneity in PD presentation, both pathologically and clinically. Some of the most common and important symptoms affecting the patient are cognitive impairment and dementia. However, the genetic and biological basis underlying the differences in cognitive profiles, including the development of dementia in PD, is not yet well understood. Understanding the role of genes in cognitive outcomes is crucial for effective patient counseling and treatment. Research on familial PD has discovered more than 20 genes that can cause the disease. The identified genes responsible for familial cases of PD are LRRK2, PARK7, PINK1, PRKN, or SNCA gene, although there may be other genes that also contribute. Additionally, some of these genes may also play a role in cases that were previously thought to be sporadic. Currently, numerous well-described genes increase the risk of cognitive decline in PD, each with varying levels of penetrance. The aim of this review is to identify the relevant genetic factors that contribute to differences in cognition. We discuss the genes that may affect cognition and the challenges in establishing a clear genetic diagnostic and prognostic assessment. This article aims to demonstrate the complexity of the genetic background of cognition in PD and to present the different types of genotype changes that can impact cognition through various neurobiological mechanisms.

Parkinson's disease-associated shifts between DNA methylation and DNA hydroxymethylation in human brain in PD-related genes, including PARK19 (DNAJC6) and PTPRN2 (IA-2β).

The majority of Parkinson's disease (PD) cases are due to a complex interaction between aging, genetics, and environmental factors; epigenetic mechanisms are thought to act as important mediators of these risk factors. While multiple studies to date have explored the role of DNA modifications in PD, few focus on 5-hydroxymethylcytosine (5hmC). Because 5hmC occurs at its highest levels in the brain and is thought to be particularly important in the central nervous system, particularly in the response to neurotoxicants, it is important to explore the potential role of 5hmC in PD. This study expands on our previously published epigenome-wide association study (EWAS) performed on DNA isolated from neuron-enriched nuclei from human postmortem parietal cortex from the Banner Sun Health Research Institute Brain Bank. The study aimed to identify paired changes in 5hmC and 5mC in PD in enriched neuronal nuclei isolated from PD post-mortem parietal cortex and age- and sex-matched controls. We performed oxidative bisulfite (oxBS) conversion and paired it with our previously published bisulfite (BS)-based EWAS on the same samples to identify cytosines with significant shifts between these two related epigenetic marks. Interaction differentially modified cytosines (iDMCs) were identified using our recently published mixed-effects model for co-analyzing βmC and βhmC data. We identified 1,030 iDMCs with paired changes in 5mC and 5hmC (FDR < 0.05) that map to 695 genes, including PARK19 (DNAJC6), a familial PD gene, and PTPRN2 (IA-2), which has been previously implicated in PD in both epigenetic and mechanistic studies. The majority of iDMC-containing genes have not previously been implicated in PD and were not identified in our previous BS-based EWAS. These data potentially link epigenetic regulation of the PARK19 and PTPRN2 loci in the pathogenesis of idiopathic PD. In addition, iDMC-containing genes have known functions in synaptic formation and function, cell cycle and senescence, neuroinflammation, and epigenetic regulation. These data suggest that there are significant shifts between 5mC and 5hmC associated with PD in genes relevant to PD pathogenesis that are not captured by analyzing BS-based data alone or by analyzing each mark as a distinct dataset.

Association between Parkinson’s disease and cardiovascular disease mortality: a prospective population-based study from NHANES

Background and aimConflicting results have been reported on the association between Parkinson's disease (PD) and cardiovascular disease (CVD) mortality in different populations. Therefore, studying the relationship between PD and CVD mortality is crucial to reduce mortality caused by the former.MethodsIn this cohort investigation, we enrolled 28,242 participants from the National Health and Nutrition Examination Survey spanning from 2003 to 2018. The 380 cases of PD in the cohort were identified by documenting ‘ANTIPARKINSON AGENTS’ in their reported prescription medications. Mortality outcomes were ascertained by cross-referencing the cohort database with the National Death Index, which was last updated on 31 December 2019. Cardiovascular disease mortality was categorised according to the 10th revision of the International Classification of Diseases by using a spectrum of diagnostic codes. Weighted multivariable Cox regression analysis was used to examine the association between PD and the risk of CVD mortality.ResultsA total of 28,242 adults were included in the study [mean age, 60.156 (12.55) years, 13,766 men (48.74%)], and the median follow-up period was 89 months. Individuals with PD had an adjusted HR of 1.82 (95% CI, 1.24–2.69; p = 0.002) for CVD mortality and 1.84 (95% CI, 1.44–2.33; p < 0.001) for all-cause mortality compared with those without PD. The association between PD and CVD mortality was robust in sensitivity analyses, after excluding participants who died within 2 years of follow-up and those with a history of cancer at baseline [HR,1.82 (95% CI, 1.20–2.75; p = 0.005)].ConclusionsPD was associated with a high long-term CVD mortality rate in the US population.