Risk Factor For Parkinson's Disease Research Articles

Glial senescence enhances α-synuclein pathology owing to its insufficient clearance caused by autophagy dysfunction

Parkinson’s disease (PD) is characterized by the pathological accumulation of α-synuclein (α-syn) and loss of dopaminergic neurons in the substantia nigra. Aging is a significant risk factor for PD. The accumulation of senescent glial cells in the aged brain contributes to PD progression by inducing chronic neuroinflammatory processes. However, although the insufficient degradation of α-syn aggregates results in PD deterioration, the possible alteration in the ability of α-syn clearance in senescent glia has received little attention. In this study, we investigated how aging and glial senescence affect the capacity of α-syn clearance. We found that following the intra-striatal injection of human α-syn (hu-α-syn) preformed fibril, hu-α-syn pathology persisted more in aged mice compared with younger mice and that aged microglia exhibited greater accumulation of hu-α-syn than younger microglia. Moreover, in vitro assay revealed that the clearance of hu-α-syn was primarily dependent on the autophagy-lysosome system rather than on the ubiquitin-proteasome system and that the capacity of hu-α-syn clearance was diminished in senescent glia because of autophagy-lysosome system dysfunction. Overall, this study provides new insights into the role of senescent glia in PD pathogenesis.

Epigenetic associations of GPNMB rs199347 variant with alcohol consumption in Parkinson's disease.

Alcohol consumption can induce a neuroinflammatory response and contribute to the progression of neurodegeneration. However, its association with Parkinson's disease (PD), the second most common neurodegenerative disorder, remains undetermined. Recent studies suggest that the glycoprotein non-metastatic melanoma protein B (GPNMB) is a potential biomarker for PD. We evaluated the association of rs199347, a variant of the GPNMB gene, with alcohol consumption and methylation upstream of GPNMB. We retrieved genetic and DNA methylation data obtained from participants enrolled in the Taiwan Biobank (TWB) between 2008 and 2016. After excluding individuals with incomplete or missing information about potential PD risk factors, we included 1,357 participants in our final analyses. We used multiple linear regression to assess the association of GPNMB rs199347 and chronic alcohol consumption (and other potential risk factors) with GPNMB cg17274742 methylation. There was no difference between the distribution of GPNMB rs199347 genotypes between chronic alcohol consumers and the other study participants. A significant interaction was observed between the GPNMB rs199347 variant and alcohol consumption (p = 0.0102) concerning cg17274742 methylation. Compared to non-chronic alcohol consumers with the AA genotype, alcohol drinkers with the rs199347 GG genotype had significantly lower levels (hypomethylation) of cg17274742 (p = 0.0187). Alcohol consumption among individuals with the rs199347 GG genotype was associated with lower levels of cg17274742 methylation, which could increase expression of the GPNMB gene, an important neuroinflammatory-related risk gene for PD.

GWAS OF BRAIN ENDOPHENOTYPES: ASSOCIATION OF AUTOPSY-BASED LEWY BODY COUNTS WITH MOVEMENT DISORDER RISK LOCI

Abstract We performed a genome wide association study (GWAS) of neocortical Lewy body density. Case material were 308 autopsies of Japanese-American men (mean age at death 87.5 years; 11% with mild, and 30% with severe cognitive impairment prior to death). Lewy bodies were assessed by manual count of alpha-synuclein stained neocortical sections from the frontal, temporal, parietal, and occipital lobes. Genetic association was tested by linear models controlling for age at death assuming an additive genotypic effect. Top hits include a locus on chromosome 1q32 previously associated with amyotrophic lateral sclerosis (p=5.8e-8), intronic variants on the dopaminergic neuron axonal guidance gene EPHB1 previously associated with Parkinson’s disease (PD) (p=8.4e-6), and a locus containing two independent intron 1 variants on CSMD1, a known risk factor for autosomal dominant PD (p=1.5e-6). Complement inhibitor protein CSMD1 is a type 1 transmembrane cell adhesion molecule implicated in axonal guidance and the development, maintenance, and pruning of synapses in the adult brain. Intermediate hits include genes encoding cell adhesion molecules and a second complement inhibitor implicated in the regulation of synapses (TRAPPC9). This converging evidence points to cell adhesion proteins and complement mediated synaptic regulation in the etiology of Lewy body lesions.

Research on the bidirectional relationships between sleep and parkinsons disease

Parkinsons disease (PD) is the second most prevalent neurodegenerative disease in the world, and among its most common symptoms is sleep disruption. Due to the glymphatic systems role in removing alpha-synuclein and other substances related to PD pathogenesis, glymphatic dysfunction has been established as a risk factor for PD. Though sleep disturbance is often a symptom of PD, its role in increasing glymphatic clearance has led some researchers to believe that sleep disturbance could also be a risk factor for PD. This review will examine the scientific literature that suggests links between sleep disruption, PD pathology, or glymphatic dysfunction, as well as address some of the limitations in affirming such relationships. According to current research, sleep disruption is a common nonmotor symptom of PD but can also lead to reduced glymphatic function, which in turn reduces alpha-synuclein clearance and advances PD pathogenesis. However, PD development could also impair glymphatic clearance by depolarizing AQP4 channels or reducing sleep duration and quality.

6PPD-quinone exposure induces neuronal mitochondrial dysfunction to exacerbate Lewy neurites formation induced by α-synuclein preformed fibrils seeding

The emerging toxicant N-(1,3-dimethylbutyl)-N′-phenyl-p-phenylenediamine quinone (6PPD-Q) is of wide concern due to its ubiquitous occurrence and high toxicity. Despite regular human exposure, limited evidence exists about its presence in the body and potential health risks. Herein, we analyzed cerebrospinal fluid (CSF) samples from Parkinson's disease (PD) patients and controls. The CSF levels of 6PPD-Q were twice as high in PD patients compared to controls. Immunostaining assays performed with primary dopaminergic neurons confirm that 6PPD-Q at environmentally relevant concentrations can exacerbate the formation of Lewy neurites induced by α-synuclein preformed fibrils (α-syn PFF). Assessment of cellular respiration reveals a considerable decrease in neuronal spare respiratory and ATP-linked respiration, potentially due to changes in mitochondrial membrane potential. Moreover, 6PPD-Q-induced mitochondrial impairment correlates with an upsurge in mitochondrial reactive oxygen species (mROS), and Mito-TEMPO-driven scavenging of mROS can lessen the amount of pathologic phospho-serine 129 α-synuclein. Untargeted metabolomics provides supporting evidence for the connection between 6PPD-Q exposure and changes in neuronal metabolite profiles. In-depth targeted metabolomics further unveils an overall reduction in glycolysis metabolite pool and fluctuations in the quantity of TCA cycle intermediates. Given its potentially harmful attributes, the presence of 6PPD-Q in human brain could potentially be a risk factor for PD.

Selenium and selenoproteins role in Parkinson’s disease: Is there a link between selenoproteins and accumulated alpha-synuclein?

BackgroundWhile Parkinson's disease (PD) etiology is not clear yet, accumulated alpha-synuclein is proposed to induce neurodegeneration. Selenium (Se) and its functional proteins play a key role in aggregation of misfolded proteins. However, their implications in neurodegenerative process are unclear. AimDiagnosing Se and selenoprotein P (SelP), selenoprotein S (SelS) proportions in serum of PD patients to compare with healthy controls, whether the changes in their concentration could be a biomarker for PD. MethodsSe concentration was investigated in 30 PD patients and 30 controls using atomic absorption spectrometry. Also, alpha-Synuclein, SelP, and SelS levels were evaluated by ELISA. The parameters were compared in PD patients and controls. Also, the variations within the case group according to their age, disorder stage, and drug administration were evaluated. ResultsPD subjects had higher Se concentration. The mean SelP in PD patients was lower from controls, whilst SelS levels were higher. Also, the concentration of alpha-synuclein was higher in PD patients. However, age, stage (except UPDRS III), and disorder duration had no influence on the Se and selenoproteins level, whilst there was a direct association between alpha-synuclein levels and disorder stage. Also, alpha-synuclein proportions in subjects using levodopa was significantly higher. ConclusionOur results suggest that serum levels of Se and SelP could be a biomarker or risk factor for PD. Although SelS interferes to reduce aggregated proteins, its pathway in PD is not clearly understood. Future studies could focus on how SelS can reduce on alpha-synuclein aggregation. Thus, other studies should be performed on this issue to induce the selenoproteins in PD.

Pesticides and the Microbiome-Gut-Brain Axis: Convergent Pathways in the Pathogenesis of Parkinson's Disease.

The increasing global burden of Parkinson's disease (PD), termed the PD pandemic, is exceeding expectations related purely to population aging and is likely driven in part by lifestyle changes and environmental factors. Pesticides are well recognized risk factors for PD, supported by both epidemiological and experimental evidence, with multiple detrimental effects beyond dopaminergic neuron damage alone. The microbiome-gut-brain axis has gained much attention in recent years and is considered to be a significant contributor and driver of PD pathogenesis. In this narrative review, we first focus on how both pesticides and the microbiome may influence PD initiation and progression independently, describing pesticide-related central and peripheral neurotoxicity and microbiome-related local and systemic effects due to dysbiosis and microbial metabolites. We then depict the bidirectional interplay between pesticides and the microbiome in the context of PD, synthesizing current knowledge about pesticide-induced dysbiosis, microbiome-mediated alterations in pesticide availability, metabolism and toxicity, and complex systemic pesticide-microbiome-host interactions related to inflammatory and metabolic pathways, insulin resistance and other mechanisms. An overview of the unknowns follows, and the role of pesticide-microbiome interactions in the proposed body-/brain-first phenotypes of PD, the complexity of environmental exposures and gene-environment interactions is discussed. The final part deals with possible further steps for translation, consisting of recommendations on future pesticide use and research as well as an outline of promising preventive/therapeutic approaches targeted on strengthening or restoring a healthy gut microbiome, closing with a summary of current gaps and future perspectives in the field.

Study on the Correlation between Blood Urea Nitrogen, Creatinine Level, Proteinuria and Parkinson's Disease.

Parkinson's disease (PD) is related to renal insufficiency. The purpose of this study was to explore the correlation between PD and blood urea nitrogen, creatinine, and proteinuria. The case-control study method was adopted in this study. In total, 200 patients with PD who were hospitalized in the Department of Neurology of the Second Affiliated Hospital of Anhui Medical University were selected as the PD group, and 110 healthy patients during the same period were selected as the control group. The differences in clinical data and laboratory results between the two groups were compared. Logistic regression analysis, ROC curve, and Spearman correlation analysis were used to determine the correlation between PD and blood urea nitrogen, creatinine, and urine protein. The levels of cholesterol (TC), triglycerides (TG), low-density lipoprotein (LDL-C), and apolipoprotein B in the PD group were lower than those in the control group. The levels of creatinine, urea nitrogen, and proteinuria in the PD group were higher than those in the control group. Multivariate logistic regression analysis showed that elevated blood urea nitrogen, creatinine, and urine protein levels were risk factors for PD, and elevated LDL-C levels were protective factors for PD. The blood urea nitrogen level of patients with PD was positively correlated with the course of PD, Hoehn-Yahr staging, and UPDRS exercise score (r = 0.309, 0.434, and 0.540, respectively; P < 0.01). Serum creatinine level was positively correlated with the course of PD, Hoehn-Yahr staging, and UPDRS exercise score (r = 0.139, 0.320, and 0.290, respectively; P < 0.01). Blood urea nitrogen, creatinine levels, and proteinuria can be regarded as the onset of PD and a biomarker of disease progression.

Fine Particulate Matter and Parkinson Disease Risk Among Medicare Beneficiaries.

Numerous studies suggest that environmental exposures play a critical role in Parkinson disease (PD) pathogenesis, and large, population-based studies have the potential to advance substantially the identification of novel PD risk factors. We sought to study the nationwide geographic relationship between PD and air pollution, specifically PM2.5 (particulate matter with a diameter <2.5 micrometers), using population-based US Medicare data. We conducted a population-based geographic study of Medicare beneficiaries aged 66-90 years geocoded to US counties and zip+4. We used integrated nested Laplace approximation to create age, sex, race, smoking, and health care utilization-adjusted relative risk (RR) at the county level for geographic analyses with PM2.5 as the primary exposure of interest. We also performed an individual-level analysis using logistic regression with cases and controls with zip+4 centroid PM2.5. We adjusted a priori for the same covariates and verified no confounding by indicators of socioeconomic status or neurologist density. Among 21,639,190 Medicare beneficiaries, 89,390 had incident PD in 2009. There was a nationwide association between average annual PM2.5 and PD risk whereby the RR of PD was 56% (95% CI 47%-66%) greater for those exposed to the median level of PM2.5 compared with those with the lowest level of PM2.5. This association was linear up to 13 μg/m3 corresponding to a 4.2% (95% CI 3.7%-4.8%) greater risk of PD for each additional μg/m3 of PM2.5 (p trend < 0.0001). We identified a region with high PD risk in the Mississippi-Ohio River Valley, where the risk of PD was 19% greater compared with the rest of the nation. The strongest association between PM2.5 and PD was found in a region with low PD risk in the Rocky Mountains. PM2.5 was also associated with PD in the Mississippi-Ohio River Valley where the association was relatively weaker, due to a possible ceiling effect at average annual PM2.5 levels of ∼13 μg/m3. State-of-the-art geographic analytic techniques revealed an association between PM2.5 and PD that varied in strength by region. A deeper investigation into the specific subfractions of PM2.5 may provide additional insight into regional variability in the PM2.5-PD association.

New horizons in Parkinson's disease in older populations.

Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. Ageing is considered to be the greatest risk factor for PD, with a complex interplay between genetics and the environment. With population ageing, the prevalence of PD is expected to escalate worldwide; thus, it is of utmost importance to reduce the burden of PD. To date, there are no therapies to cure the disease, and current treatment strategies focus on the management of symptoms. Older adults often have multiple chronic diseases and geriatric syndromes, which further complicates the management of PD. Healthcare systems and care models necessary to address the broad needs of older PD patients are largely unavailable. In this New Horizon article, we discuss various aspects of PD from an ageing perspective, including disease management. We highlight recent advancements in PD therapies and discuss new care models with the potential to improve patient's quality of life.

LRRK2 G2019S and Parkinson's disease: insight from Neuroinflammation.

The multiple hypothesis holds that the pathogenesis of Parkinson's disease (PD) requires many factors such as heredity, environment and ageing. Mutations in Leucine-rich repeat kinase 2 (LRRK2) are recognized the risk factors of PD, and closely related to sporadic and familial PD and can regulate a variety of cellular pathways and processes. An Increasing number of studies has shown that glial hyperactivation-mediated neuroinflammation participates in dopaminergic neuron degeneration and pathogenesis of PD. LRRK2 is essential to the regulaton of chronic inflammation, especially for the central nervous system. The review spotlights on the novel development of LRRK2 on microglia and astrocytes, and explore their potential therapeutic targets, in order to provide a new insights in PD. Key messages: What is already known on this topic The G2019S mutation of LRRK2 is now recognised as a pathogenic mutation in PD. Previous studies have focused on the relationship between neurons and LRRK2 G2019S. What this study adds Neuroinflammation mediated by LRRK2 G2019S of glial cells affects the progress and development of PD and attention must be paid to the role of LRRK2 G2019S in glial cells in PD. How this study might affect research, practice or policy Developing anti-inflammatory drugs from the perspective of LRRK2 G2019S of glial cells is a new direction for the treatment of PD.

Parkinson's disease pathology is directly correlated to SIRT3 in human subjects and animal models: Implications for AAV.SIRT3-myc as a disease-modifying therapy

In Parkinson's disease (PD), post-mortem studies in affected brain regions have demonstrated a decline in mitochondrial number and function. This combined with many studies in cell and animal models suggest that mitochondrial dysfunction is central to PD pathology. We and others have shown that the mitochondrial protein deacetylase, SIRT3, has neurorestorative effects in PD models. In this study, to determine whether there is a link between PD pathology and SIRT3, we analysed SIRT3 levels in human subjects with PD, and compared to age-matched controls. In the SNc of PD subjects, SIRT3 was reduced by 56.8 ± 15.5% compared to control, regardless of age (p < 0.05, R = 0.6539). Given that age is the primary risk factor for PD, this finding suggests that reduced SIRT3 may contribute to PD pathology. Next, we measured whether there was a correlation between α-synuclein and SIRT3. In a parallel study, we assessed the disease-modifying potential of SIRT3 over-expression in a seeding model of α-synuclein. In PFF rats, infusion of rAAV1.SIRT3-myc reduced abundance of α-synuclein inclusions by 30.1 ± 18.5%. This was not observed when deacetylation deficient SIRT3H248Y was transduced, demonstrating the importance of SIRT3 deacetylation in reducing α-synuclein aggregation. These studies confirm that there is a clear difference in SIRT3 levels in subjects with PD compared to age-matched controls, suggesting a link between SIRT3 and the progression of PD. We also demonstrate that over-expression of SIRT3 reduces α-synuclein aggregation, further validating AAV.SIRT3-myc as a potential disease-modifying solution for PD.

Fiber deprivation and microbiome-borne curli shift gut bacterial populations and accelerate disease in a mouse model of Parkinson’s disease

Parkinson's disease (PD) is a neurological disorder characterized by motor dysfunction, dopaminergic neuron loss, and alpha-synuclein (αSyn) inclusions. Many PD risk factors are known, but those affecting disease progression are not. Lifestyle and microbial dysbiosis are candidates in this context. Diet-driven gut dysbiosis and reduced barrier function may increase exposure of enteric neurons to toxins. Here, we study whether fiber deprivation and exposure to bacterial curli, a protein cross-seeding with αSyn, individually or together, exacerbate disease in the enteric and central nervous systems of a transgenic PD mouse model. We analyze the gut microbiome, motor behavior, and gastrointestinal and brain pathologies. We find that diet and bacterial curli alter the microbiome and exacerbate motor performance, as well as intestinal and brain pathologies, but to different extents. Our results shed important insights on how diet and microbiome-borne insults modulate PD progression via the gut-brain axis and have implications for lifestyle management of PD.

The exposome in the context of preventive measures for Alzheimer's and Parkinson's diseases

Preventive measures addressing the exposome can counteract neurodegenerative diseases. This article gives an overview on the influence of general and individual exogenous factors (environmental influences and lifestyle changes) as well as endogenous factors (e.g. metabolic alterations) on the development and progression of Alzheimer's disease (AD) and Parkinson's disease (PD). Summary and evaluation of current scientific studies and evidence regarding the exposome and prevention of AD and PD. Numerous studies could demonstrate apotential influence of environmental influences associated with industrialization (general exogenous factors), such as pesticides, solvents or air pollution on the development of AD and PD. Additionally, individually addressable changes of lifestyle (individual exogenous factors, e.g. physical activity, cognitive stimulation, nutrition and sleep) contribute to disease protection and modification and are becoming increasingly more important in light of still limited therapeutic interventions. Moreover, other exogenous factors (medication, noise pollution, head trauma and heavy metals) are discussed as risk factors for AD and/or PD. Endogenous factors (e.g., changes of the enteral microbiome, systemic inflammation and neuroinflammation, metabolic changes) can contribute to disease development by a higher potential for interacting with exogenous factors. Despite the comprehensive scientific evidence confirming the significance of the exposome for the pathogenesis of AD and PD, the great potential of preventive measures has not yet been exploited. A clarification of the high potential of lifestyle changes should be atherapeutic standard not only for individuals with manifest PD/AD but also for individuals with a risk profile or with suspected prodromal disease. Further investigations on the influence of environmental factors and the implementation of preventive strategies to avoid exposure should be the focus of international efforts.

Evaluating the prediction performance of objective physical activity measures for incident Parkinson's disease in the UK Biobank.

Parkinson's disease (PD) is the fastest-growing neurological condition with over 10 million cases worldwide. While age and sex are known predictors of incident PD, there is a need to identify other predictors. This study compares the prediction performance of accelerometry-derived physical activity (PA) measures and traditional risk factors for incident PD in the UK Biobank. The study population consisted of 92,352 UK Biobank participants without PD at baseline (43.8% male, median age 63years with interquartile range 43-69). 245 participants were diagnosed with PD by April 1, 2021 (586,604 person-years of follow-up). The incident PD prediction performances of 10 traditional predictors and 8 objective PA measures were compared using single- and multi-variable Cox models. Prediction performance was assessed using a novel, stable statistic: the repeated cross-validated concordance (rcvC). Sensitivity analyses were conducted where PD cases diagnosed within the first six months, one year, and two years were deleted. Single-predictor Cox regression models indicated that all PA measures were statistically significant (p-values < 0.0001). The highest-performing individual predictors were total acceleration (TA) (rcvC = 0.813) among PA measures, and age (rcvC = 0.757) among traditional predictors. The two-step forward-selection process produced a model containing age, sex, and TA (rcvC = 0.851). Adding TA to the model increased the rcvC by 9.8% (p-value < 0.0001). Results were largely unchanged in sensitivity analyses. Objective PA summaries have better single-predictor model performance than known risk factors and increase the prediction performance substantially when added to models with age and sex.

Is Hearing Loss a Risk Factor for Idiopathic Parkinson's Disease? An English Longitudinal Study of Ageing Analysis.

Observations that hearing loss is a substantial risk factor for dementia may be accounted for by a common pathology. Mitochondrial oxidative stress and alterations in α-synuclein pathology may be common pathology candidates. Crucially, these candidate pathologies are implicated in Parkinson's disease (PD). Consequently, hearing loss may be a risk factor for PD. Subsequently, this prospective cohort study of the English Longitudinal Study of Ageing examines whether hearing loss is a risk factor for PD longitudinally. Participants reporting self-reported hearing capabilities and no PD diagnosis prior to entry (n = 14,340) were used. A joint longitudinal and survival model showed that during a median follow up of 10 years (SD = 4.67 years) increased PD risk (p < 0.001), but not self-reported hearing capability (p = 0.402). Additionally, an exploratory binary logistic regression modelling the influence of hearing loss identified using a screening test (n = 4812) on incident PD indicated that neither moderate (p = 0.794), nor moderately severe/severe hearing loss (p = 0.5210), increased PD risk, compared with normal hearing. Whilst discrepancies with prior literature may suggest a neurological link between hearing loss and PD, further large-scale analyses using clinically derived hearing loss are needed.

Genome-wide Analysis of Motor Progression in Parkinson Disease.

The genetic basis of Parkinson disease (PD) motor progression is largely unknown. Previous studies of the genetics of PD progression have included small cohorts and shown a limited overlap with genetic PD risk factors from case-control studies. Here, we have studied genomic variation associated with PD motor severity and early-stage progression in large longitudinal cohorts to help to define the biology of PD progression and potential new drug targets. We performed a GWAS meta-analysis of early PD motor severity and progression up to 3 years from study entry. We used linear mixed-effect models with additive effects, corrected for age at diagnosis, sex, and the first 5 genetic principal components to assess variability in axial, limb, and total Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) III scores. We included 3,572 unrelated European ancestry patients with PD from 5 observational cohorts and 1 drug trial. The average AAO was 62.6 years (SD = 9.83), and 63% of participants were male. We found an average increase in the total MDS-UPDRS III score of 2.3 points/year. We identified an association between PD axial motor progression and variation at the GJA5 locus at 1q12 (β = -0.25, SE = 0.04, p = 3.4e-10). Exploration of the regulation of gene expression in the region (cis-expression quantitative trait loci [eQTL] analysis) showed that the lead variant was associated with expression of ACP6, a lysophosphatidic acid phosphatase that regulates mitochondrial lipid biosynthesis (cis-eQTL p-values in blood and brain RNA expression data sets: <10-14 in eQTLGen and 10-7 in PsychEncode). Our study highlights the potential role of mitochondrial lipid homeostasis in the progression of PD, which may be important in establishing new drug targets that might modify disease progression.

Lipid Metabolism Disorder in Cerebrospinal Fluid Related to Parkinson's Disease.

Abnormal accumulation of lipids is found in dopamine neurons and resident microglia in the substantia nigra of patients with Parkinson's disease (PD). The accumulation of lipids is an important risk factor for PD. Previous studies have mainly focussed on lipid metabolism in peripheral blood, but little attention has been given to cerebrospinal fluid (CSF). We drew the lipidomic signature in CSF from PD patients and evaluated the role of lipids in CSF as biomarkers for PD diagnosis. Based on lipidomic approaches, we investigated and compared lipid metabolism in CSF from PD patients and healthy controls without dyslipidaemia in peripheral blood and explored the relationship of lipids between CSF and serum by Pearson correlation analysis. A total of 231 lipid species were detected and classified into 13 families in the CSF. The lipid families, including phosphatidylcholine (PC), sphingomyelin (SM) and cholesterol ester (CE), had significantly increased expression compared with the control. Hierarchical clustering was performed to distinguish PD patients based on the significantly changed expression of 34 lipid species. Unsupervised and supervised methods were used to refine this classification. A total of 12 lipid species, including 3-hydroxy-dodecanoyl-carnitine, Cer(d18:1/24:1), CE(20:4), CE(22:6), PC(14:0/18:2), PC(O-18:3/20:2), PC(O-20:2/24:3), SM(d18:0/16:0), SM(d18:2/14:0), SM(d18:2/24:1), SM(d18:1/20:1) and SM(d18:1/12:0), were selected to draw the lipidomic signature of PD. Correlation analysis was performed and showed that the CE family and CE (22:6) in CSF had a positive association with total cholesterol in the peripheral blood from PD patients but not from healthy controls. Our results revealed that the lipidomic signature in CSF may be considered a potential biomarker for PD diagnosis, and increased CE, PC and SM in CSF may reveal pathological changes in PD patients, such as blood-brain barrier leakage.

Increased Serum S100β Concentration is Associated with Depression in Parkinson's Disease.

To explore the relationship between the serum level of S100 calcium-binding protein, beta chain (S100β) and Parkinson's disease (PD) with depression. A total of 145 patients with PD and 60 healthy controls matched for sex, age, and years of education in our hospital were selected. Fluorescence quantitative immunochromatography was used to quantify the level of S100β in serum. Clinical manifestations were assessed by Unified Parkinson's Disease Rating Scale part-III (UPDRS-III), Hoehn & Yahr (H-Y) stage and 17-item Hamilton Rating Scale for Depression (HAMD-17). According to the results of HAMD-17, PD patients were divided into PD with depression group and PD without depression group. The relationship between serum S100β and HAMD-17 scores in PD patients with depression was investigated through correlation analysis and multivariate regression analysis, and receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value of serum S100β. The level of serum S100β in PD with depression group was significantly higher than that in PD without depression group and control group. In PD patients with depression, serum S100β level was positively correlated with UPDRS-III score, H-Y Scale and HAMD-17 score. The HAMD-17 score was positively correlated with the UPDRS-III and H-Y scales, and the increase in the HAMD-17 score was associated with women. Elevated serum S100β level and UPDRS-III score are independent risk factors for PD with depression. Analysis of receiver operating characteristic (ROC) curves showed that the serum S100β level with a cutoff of 0.28 ng/mL distinguished patients with PD with or without depression with an area under the ROC curve (AUC) of 0.742, sensitivity of 0.696, and specificity of 0.779. The serum S100β level could be a biomarker of PD with depression.

Interaction of Mitochondrial Polygenic Score and Lifestyle Factors in LRRK2 p.Gly2019Ser Parkinsonism.

A mitochondrial polygenic score (MGS) is composed of genes related to mitochondrial function and found to be associated with Parkinson's disease (PD) risk. To investigate the impact of the MGS and lifestyle/environment on age at onset (AAO) in LRRK2 p.Gly2019Ser parkinsonism (LRRK2-PD) and idiopathic PD (iPD). We included N = 486 patients with LRRK2-PD and N = 9259 with iPD from the Accelerating Medicines Partnership® Parkinson's Disease Knowledge Platform (AMP-PD), Fox Insight, and a Tunisian Arab-Berber founder population. Genotyping data were used to perform the MGS analysis. Additionally, lifestyle/environmental data were obtained from the PD Risk Factor Questionnaire (PD-RFQ). Linear regression models were used to assess the relationship between MGS, lifestyle/environment, and AAO. Our derived MGS was significantly higher in PD cases compared with controls (P = 1.1 × 10-8 ). We observed that higher MGS was significantly associated with earlier AAO in LRRK2-PD (P = 0.047, β = -1.40) and there was the same trend with a smaller effect size in iPD (P = 0.231, β = 0.22). There was a correlation between MGS and AAO in LRRK2-PD patients of European descent (P = 0.049, r = -0.12) that was visibly less pronounced in Tunisians (P = 0.449, r = -0.05). We found that the MGS interacted with caffeinated soda consumption (P = 0.003, β = -5.65) in LRRK2-PD and with tobacco use (P = 0.010, β = 1.32) in iPD. Thus, patients with a high MGS had an earlier AAO only if they consumed caffeinated soda or were non-smokers. The MGS was more strongly associated with earlier AAO in LRRK2-PD compared with iPD. Caffeinated soda consumption or tobacco use interacted with MGS to predict AAO. Our study suggests gene-environment interactions as modifiers of AAO in LRRK2-PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.