Risk Factor For Parkinson's Disease Research Articles

Obesity and the development of Parkinson’s disease within the Framingham Heart study cohort

ObjectiveTo determine the role of obesity in the development of Parkinson’s disease (PD). BackgroundObesity has been reported to be both a risk factor for PD, as well as potentially protective. The Framingham Heart Study (FHS) is a multigenerational longitudinal cohort study that was started in 1948, which is well-known for its cardiovascular health studies. In this study, we utilized the extensive cardiovascular and neurological data to determine if obesity contributes to the risk of the development of PD. MethodsParticipants in the FHS Original and Offspring cohorts were included in this study. Controls were selected based on sex and age at baseline examination, 1:10. Cox proportional hazard regression models were used, adjusting for age and sex. PD case status was determined utilizing prior medical and neurological examination data, Framingham Heart Study examinations, and self-report data by a panel of movement disorders neurologists using the UK Brain Bank Criteria (UKBB) and other supporting clinical details after being flagged for review by FHS neurologists. We used p < 0.05 for significance. ResultsAccounting for missing covariate data, this study included 117 participants with PD, with 1170 controls. We found that higher BMI was associated with lower PD risk, with participants with BMI 25 kg/m2 to 30 kg/m2 having HR of 0.66 (CI 0.44–0.98; p = 0.04) and BMI >= 30 kg/m2 having HR 0.47 (CI 0.27–0.84; p = 0.01). When the overweight and obese BMI groups were combined, we noted a more robust association, with combined HR of 0.67 (0.41–0.86; p = 0.01). ConclusionsObesity during mid-life potentially reduces the risk of developing PD; however, additional studies are needed to further explore this association.

Environmental Risk Factors for Parkinson's Disease: A Critical Review and Policy Implications.

The age-standardized prevalence of Parkinson's disease (PD) has increased substantially over the years and is expected to increase further. This emphasizes the need to identify modifiable risk factors of PD, which could form a logical entry point for the prevention of PD. The World Health Organization (WHO) has recommended reducing exposure to specific environmental factors that have been reported to be associated with PD, in particular pesticides, trichloroethylene (TCE), and air pollution. In this review we critically evaluate the epidemiological and biological evidence on the associations of these factors with PD and review evidence on whether these putative associations are causal. We conclude that when considered in isolation, it is difficult to determine whether these associations are causal, in large part because of the decades-long lag between relevant exposures and the incidence of manifest PD. However, when considered in tandem with evidence from complementary research lines (such as animal models), it is increasingly likely that these associations reflect harmful causal effects. Fundamentally, whilst we highlight some evidence gaps that require further attention, we believe the current evidence base is sufficiently strong enough to support our call for stronger policy action. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

GBA1 T369M and Parkinson's disease - Further evidence of a lack of association in the Swedish population

Variants in GBA1 are important genetic risk factors in Parkinson's disease (PD). GBA1 T369M has been linked to an ∼80 % increased PD risk but the reports are conflicting and the relevance of GBA1 variants in different populations varies. A lack of association between T369M and PD in the Swedish population was recently reported but needs further validation. We therefore investigated T369M in 1,808 PD patients and 2,183 controls and our results support that T369M is not a risk factor for PD in the Swedish population.

Peripheral biomarkers of Parkinson’s disease and its correlation with clinical symptoms: a case-control study

BackgroundInflammation significantly impacts Parkinson’s disease (PD), yet the intricate relationship between inflammatory markers and PD remains elusive.ObjectiveTo identify the peripheral biomarkers of PD and its correlation with the motor and non-motor symptoms of PD.Methods79 PD patients and 65 controls were included in this study. Clinical information and the serum levels of IL-8, IL-27, IL-33, β-NGF, AgRP, and TRAILR2 in the participants were collected. Appropriate scales were used to assess the symptoms of PD. For the factors with significant differences in the two groups, multivariable logistic regression was used to determine its relationship with PD. Moreover, spearman correlation was conducted to explore the correlation between the factors and PD related symptoms. The IL-27 level was compared between the cognitively healthy PD group and the mild cognitive impairment in PD (PD-MCI). The serum level of TRAILR2 was positively correlated with age and was not associated with other clinical characteristics related to PD.ResultsCompared to controls, the serum levels of IL-27(P = 0.013) were increased whereas the levels of TRAILR2(P = 0.008) were decreased in PD patients. IL-8, IL-33, β-NGF, and AgRP showed no significant differences between the two groups. After controlling for the other variables, IL-27 was considered as an independent risk factor for PD in the multivariable logistic regression model. The receiver operating characteristic (ROC) curve for diagnosing PD with IL-27 yielded an area under the curve (AUC) of 0.621. Additionally, IL-27 level in PD patients was positively correlated with age, the disease duration, LEDD and negatively correlated with the MoCA scores. However, no significant difference was found in IL-27 levels between cognitively healthy PD and PD-MCI groups.ConclusionElevated serum IL-27 was a risk factor for PD and positively correlated with the cognitive decline in PD.

Behavioral disorders in Parkinson disease: current view.

Patients with Parkinson disease (PD) frequently experience several behavioral symptoms, such as anxiety, apathy, irritability, agitation, impulsive control and obsessive-compulsive or REM sleep behavior disorders, which can cause severe psychosocial problems and impair quality of life. Occurring in 30-70% of PD patients, these symptoms can manifest at early stages of the disease, sometimes even before the appearance of classic motor symptoms, while others can develop later. Behavioral changes in PD show distinct patterns of brain atrophy, dopaminergic and serotonergic deterioration, altered neuronal connectivity in frontostriatal, corticolimbic, default mode and other networks due to a cascade linking molecular pathologies and deficits in multiple behavior domains. The changes suggest a multi-system neurodegenerative process in the context of a specific α-synucleinopathy inducing a variety of biochemical and functional changes, the neurobiological basis and clinical relevance of which await further elucidation. This paper is intended to review the recent literature with focus on the main behavioral disturbances in PD patients, their epidemiology, clinical features, risk factors, animal models, neuroimaging findings, pathophysiological backgrounds, and treatment options of these deleterious lesions.

Family History in Parkinson's Disease: A National Cross-Sectional Study.

Family history of Parkinson's disease (PD) is a common finding in PD patients. However, a few studies have systematically examined this aspect. We investigated the family history of PD patients, comparing demographic and clinical features between familial PD (fPD) and sporadic PD (sPD). A cross-sectional study enrolling 2035 PD patients was conducted in 28 Italian centers. Clinical data and family history up to the third degree of kinship were collected. Family history of PD was determined in 21.9% of patients. fPD patients had earlier age at onset than sporadic patients. No relevant differences in the prevalence of motor and nonmotor symptoms were detected. Family history of mood disorders resulted more prevalently in the fPD group. fPD was found to recur more frequently than previously reported. Family history collection beyond the core family is essential to discover disease clusters and identify novel risk factors for PD.

Midnolin, a Genetic Risk Factor for Parkinson's Disease, Promotes Neurite Outgrowth Accompanied by Early Growth Response 1 Activation in PC12 Cells.

Parkinson's disease (PD) is an age-related progressive neurodegenerative disease. Previously, we identified midnolin (MIDN) as a genetic risk factor for PD. Although MIDN copy number loss increases the risk of PD, the molecular function of MIDN remains unclear. To investigate the role of MIDN in PD, we established monoclonal Midn knockout (KO) PC12 cell models. Midn KO inhibited neurite outgrowth and neurofilament light chain (Nefl) gene expression. Although MIDN is mainly localized in the nucleus, it does not encode DNA-binding domains. We therefore hypothesized that MIDN might bind to certain transcription factors and regulate gene expression. Of the candidate transcription factors, we focused on early growth response 1 (EGR1) because it is required for neurite outgrowth and its target genes are downregulated by Midn KO. An interaction between MIDN and EGR1 was confirmed by immunoprecipitation. Surprisingly, although EGR1 protein levels were significantly increased in Midn KO cells, the binding of EGR1 to the Nefl promoter and resulting transcriptional activity were downregulated as measured by luciferase assay and chromatin immunoprecipitation quantitative real-time polymerase chain reaction. Overall, we identified the MIDN-dependent regulation of EGR1 function. This mechanism may be an underlying reason for the neurite outgrowth defects of Midn KO PC12 cells.

Identifying potential causal effects of Parkinson’s disease: A polygenic risk score-based phenome-wide association and mendelian randomization study in UK Biobank

There is considerable uncertainty regarding the associations between various risk factors and Parkinson’s Disease (PD). This study systematically screened and validated a wide range of potential PD risk factors from 502,364 participants in the UK Biobank. Baseline data for 1851 factors across 11 categories were analyzed through a phenome-wide association study (PheWAS). Polygenic risk scores (PRS) for PD were used to diagnose Parkinson’s Disease and identify factors associated with PD diagnosis through PheWAS. Two-sample Mendelian randomization (MR) analysis was employed to assess causal relationships. PheWAS results revealed 267 risk factors significantly associated with PD-PRS among the 1851 factors, and of these, 27 factors showed causal evidence from MR analysis. Compelling evidence suggests that fluid intelligence score, age at first sexual intercourse, cereal intake, dried fruit intake, and average total household income before tax have emerged as newly identified risk factors for PD. Conversely, maternal smoking around birth, playing computer games, salt added to food, and time spent watching television have been identified as novel protective factors against PD. The integration of phenotypic and genomic data may help to identify risk factors and prevention targets for PD.

Post-Traumatic Stress Disorder and Risk of Parkinson's Disease in a Veteran Cohort.

Post-traumatic stress disorder (PTSD) may be a risk factor for Parkinson's disease (PD). We examined the relation between PTSD and PD in a cohort of 158,122 Veterans who had any Veterans Health Administration (VHA) or Medicare health care utilization between 10/1/1999- 2/17/2021. Using a nested case-control design we matched 10 controls to each Veteran with PD by sex, race, and rank. In conditional logistic regression models adjusted for camp and smoking, a PTSD diagnosis was significantly associated with PD (OR = 1.35; p = 0.0002); odds were higher if PTSD was coded before PD (OR = 1.53, p < 0.0001). PTSD may be a risk factor for PD.

Resistance to high-fat diet-induced weight gain in transgenic mice overexpressing human wild-type α-synuclein: A model for metabolic dysfunction in Parkinson's disease.

Unintentional weight loss, primarily due to the loss of fat mass rather than muscle mass, is common among patients with Parkinson's disease (PD) and is associated with poor quality of life and accelerated disease progression. Since transgenic mice overexpressing human wild-type α-synuclein (α-Syn mice) are modestly leaner than control mice, and since diabetes, a metabolic disorder, is a major risk factor for PD, we reasoned that high-fat diet-induced diabetes/metabolic dysregulation in α-Syn mice may serve as a robust tool for exploring how early α-synuclein pathology contributes to metabolic dysregulation, leading to weight loss in PD. Thus, α-Syn and age-matched controls were fed a high-fat diet (HFD) chow (60% fat calories) ad libitum for four months. Compared with controls on HFD (control-HFD), α-Syn mice on HFD (α-Syn-HFD) were dramatically leaner. The resistance to gaining weight in α-Syn-HFD mice was accompanied by improved glucose tolerance, a dramatic decrease in fat mass, and an increase in energy expenditure. Despite this leaner phenotype and better glucose tolerance, the mortality was much higher in male α-Syn-HFD mice than in all controls, but was unaffected in females, suggesting protective effects of female sex hormones, as well as lower α-synuclein levels. Immunoblot analysis of insulin signaling in the olfactory bulb, the proposed initial seeding site of α-synuclein pathology, revealed a decrease of IGF-IRβ, p GSK, and p mTOR in α-Syn-HFD mice. Since GSK-3β and mTOR regulate synaptic plasticity, we assessed levels of PSD-95 and synaptophysin in the olfactory bulb. As anticipated, we observed a significant decrease in the levels of PSD-95, along with a potentially compensatory increase in synaptophysin levels. Our results show that α-Syn mice, when challenged with diet-induced diabetes/metabolic dysregulation, clearly reveal a profile of robust metabolic dysfunction, thus providing a sensitive tool for assessing the underlying mechanism of metabolic dysfunction and its impact on weight loss and disease progression in PD. We propose a role for olfactory dysfunction in PD-related unintentional weight loss and suggest that strategies aimed at increasing body weight/BMI will improve the quality of life and prognosis for people living with PD.

Advancing age and the rs6265 BDNF SNP are permissive to graft-induced dyskinesias in parkinsonian rats

The rs6265 single nucleotide polymorphism (SNP) in the gene for brain-derived neurotrophic factor is a common variant that alters therapeutic outcomes for individuals with Parkinson’s disease (PD). We previously investigated the effects of this SNP on the experimental therapeutic approach of neural grafting, demonstrating that young adult parkinsonian rats carrying the variant Met allele exhibited enhanced graft function compared to wild-type rats and also exclusively developed aberrant graft-induced dyskinesias (GID). Aging is the primary risk factor for PD and reduces graft efficacy. Here we investigated whether aging interacts with this SNP to further alter cell transplantation outcomes. We hypothesized that aging would reduce enhancement of graft function associated with this genetic variant and exacerbate GID in all grafted subjects. Unexpectedly, beneficial graft function was maintained in aged rs6265 subjects. However, aging was permissive to GID induction, regardless of genotype, with the greatest incidence and severity found in rs6265-expressing animals.

Exposure to household pesticides and Parkinson's disease in the Parkinson's Progression Markers Initiative cohort.

In the last decades, the association of household pesticide usage with Parkinson's disease (PD) has been poorly explored, with discordant results. Based on the Parkinson's Progression Markers Initiative (PPMI) cohort study, we analyzed (1) the association of household pesticide exposure with the development of PD and (2) the effect of household pesticides on progression of PD. Data from participants of the "FOllow Up persons with Neurologic Disease" (FOUND study) included in the PPMI cohort database were analyzed. The PPMI FOUND study applied the Parkinson's Disease Risk Factor Questionnaire to collect information regarding the use of pesticides in non-work settings during periods of life, and the lifetime pesticide exposure for each participant was estimated. We defined a high use of pesticides if the exposure estimate had a z-score higher than one standard deviation from the mean. Also, we evaluated longitudinal data of people with PD to analyze the effect of high use of household pesticides on disease progression according to motor impairment, cognitive dysfunction, depressive symptoms, and modification of motor clinical phenotype. We analyzed data from 206 people with PD and 64 healthy controls, almost all from the USA. High use of household pesticides was not associated with the odds of developing PD. Regarding PD progression, only cognitive dysfunction was associated with the high use of household fungicides (HR 5.64 per standard deviation increase in exposure estimate, 95% CI 1.41-22.6). Chronic exposure to household pesticides may impact the clinical progression of PD, especially cognitive symptoms.

Lipids and α-Synuclein: adding further variables to the equation.

Aggregation of alpha-Synuclein (αSyn) has been connected to several neurodegenerative diseases, such as Parkinson's disease (PD), dementia with Lewy Bodies (DLB), and multiple system atrophy (MSA), that are collected under the umbrella term synucleinopathies. The membrane binding abilities of αSyn to negatively charged phospholipids have been well described and are connected to putative physiological functions of αSyn. Consequently, αSyn-related neurodegeneration has been increasingly connected to changes in lipid metabolism and membrane lipid composition. Indeed, αSyn aggregation has been shown to be triggered by the presence of membranes in vitro, and some genetic risk factors for PD and DLB are associated with genes coding for proteins directly involved in lipid metabolism. At the same time, αSyn aggregation itself can cause alterations of cellular lipid composition and brain samples of patients also show altered lipid compositions. Thus, it is likely that there is a reciprocal influence between cellular lipid composition and αSyn aggregation, which can be further affected by environmental or genetic factors and ageing. Little is known about lipid changes during physiological ageing and regional differences of the lipid composition of the aged brain. In this review, we aim to summarise our current understanding of lipid changes in connection to αSyn and discuss open questions that need to be answered to further our knowledge of αSyn related neurodegeneration.

The association between cytomegalovirus infection and neurodegenerative diseases: a prospective cohort using UK Biobank data

Certain viral infections have been linked to the development of neurodegenerative diseases. This study aimed to investigate the association between cytomegalovirus (CMV) infection and five neurodegenerative diseases, spinal muscular atrophy (SMA) and related syndromes, Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), and disorders of the autonomic nervous system (DANS). This prospective cohort included white British individuals who underwent CMV testing in the UK Biobank from January 1, 2006 to December 31, 2021. A Cox proportional hazard model was utilized to estimate the future risk of developing five neurodegenerative diseases in individuals with or without CMV infection, adjusted for batch effect, age, sex, and Townsend deprivation index in Model 1, and additionally for type 2 diabetes, cancer, osteoporosis, vitamin D, monocyte count and leukocyte count in Model 2. Bidirectional Mendelian randomization was employed to validate the potential causal relationship between CMV infection and PD. A total of 8346 individuals, consisting of 4620 females (55.4%) and 3726 males (44.6%) who were white British at an average age of 56.74 (8.11), were included in this study. The results showed that CMV infection did not affect the risk of developing AD (model 1: HR [95% CI]=1.01 [0.57, 1.81], P=0.965; model 2: HR=1.00 [0.56, 1.79], P=0.999), SMA and related syndromes (model 1: HR=3.57 [0.64, 19.80], P=0.146; model 2: HR=3.52 [0.63, 19.61], P=0.152), MS (model 1: HR=1.16 [0.45, 2.97], P=0.756; model 2: HR=1.16 [0.45, 2.97], P=0.761) and DANS (model 1: HR=0.65 [0.16, 2.66], P=0.552; model 2: HR=0.65 [0.16, 2.64], P=0.543). Interestingly, it was found that participants who were CMV seronegative had a higher risk of developing PD compared to those who were seropositive (model 1: HR=2.37 [1.25, 4.51], P=0.009; model 2: HR=2.39 [1.25, 4.54], P=0.008) after excluding deceased individuals. This association was notably stronger in males (model 1: HR=3.16 [1.42, 7.07], P=0.005; model 2: HR=3.41 [1.50, 7.71], P=0.003), but no significant difference was observed in the female subgroup (model 1: HR=1.28 [0.40, 4.07], P=0.679; model 2: HR=1.27 [0.40, 4.06], P=0.684). However, a bidirectional Mendelian randomization analysis did not find a genetic association between CMV infection and PD. The study found that males who did not have a CMV infection were at a higher risk of developing PD. The findings provided a new viewpoint on the risk factors for PD and may potentially influence public health approaches for the disease. National Natural Science Foundation of China (81873776), Natural Science Foundation of Guangdong Province, China (2021A1515011681, 2023A1515010495).

Lipid accumulation drives cellular senescence in dopaminergic neurons.

Parkinson's disease (PD) is an age-related movement disorder caused by the loss of dopaminergic (DA) neurons of the substantia nigra pars compacta (SNpc) of the midbrain, however, the underlying cause(s) of this DA neuron loss in PD is unknown and there are currently no effective treatment options to prevent or slow neuronal loss or the progression of related symptoms. It has been shown that both environmental factors as well as genetic predispositions underpin PD development and recent research has revealed that lysosomal dysfunction and lipid accumulation are contributors to disease progression, where an age-related aggregation of alpha-synuclein as well as lipids have been found in PD patients. Interestingly, the most common genetic risk factor for PD is Glucosylceramidase Beta 1 (GBA), which encodes a lysosomal glucocerebrosidase (GCase) that cleaves the beta-glucosidic linkage of lipids known as glucocerebrosides (GluCer). We have recently discovered that artificial induction of GluCer accumulation leads to cellular senescence of DA neurons, suggesting that lipid aggregation plays a crucial role in the pathology of PD by driving senescence in these vulnerable DA neurons. Here, we discuss the relevance of the age-related aggregation of lipids as well as the direct functional link between general lipid aggregation, cellular senescence, and inflammaging of DA neurons. We propose that the expression of a cellular senescence phenotype in the most vulnerable neurons in PD can be triggered by lysosomal impairment and lipid aggregation. Importantly, we highlight additional data that perilipin (PLIN2) is significantly upregulated in senescent DA neurons, suggesting an overall enrichment of lipid droplets (LDs) in these cells. These findings align with our previous results in dopaminergic neurons in highlighting a central role for lipid accumulation in the senescence of DA neurons. Importantly, general lipid droplet aggregation and global lysosomal impairment have been implicated in many neurodegenerative diseases including PD. Taken together, our data suggest a connection between age-related lysosomal impairment, lipid accumulation, and cellular senescence in DA neurons that in turn drives inflammaging in the midbrain and ultimately leads to neurodegeneration and PD.

Sodium-glucose cotransporter 1/2 inhibition and risk of neurodegenerative disorders: A Mendelian randomization study.

This study aims to evaluate the effects of sodium-glucose cotransporter 1 inhibitors (SGLT1i) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) on neurodegenerative disorders and to investigate the role of hemoglobin A1c (HbA1c) levels. Utilizing drug target Mendelian randomization, we employed single nucleotide polymorphisms (SNPs) proximal to the SLC5A1 and SLC5A2 genes to analyze the influence of SGLT1i and SGLT2i on Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), frontotemporal dementia (FTD), Lewy body dementia (LBD), and amyotrophic lateral sclerosis (ALS), with type 2 diabetes (T2D) as a positive control. An additional analysis examined the impact of HbA1c levels on the same disorders. SGLT1i exhibited a significant association with decreased risk for ALS and MS. Conversely, SGLT2i were linked to an increased risk of AD, PD, and MS. Elevated HbA1c levels, independent of SGLT1 and SGLT2 effects, were associated with an increased risk of PD. Sensitivity analyses supported the robustness of these findings. Our study suggests that SGLT1i may confer protection against ALS and MS, whereas SGLT2i could elevate the risk of AD, PD, and MS. Additionally, elevated HbA1c levels emerged as a risk factor for PD. These findings underscore the importance of personalized approaches in the utilization of SGLT inhibitors, considering their varying impacts on the risks of neurodegenerative diseases.

Association between serum insulin-like growth factor 1 and osteoporosis risk in Parkinson's disease: a cross-sectional study.

To examine the correlation between serum insulin-like growth factor 1 (IGF-1) and osteoporosis (OP) in Parkinson's disease (PD). We retrospectively analyzed clinical data from 105 PD patients (PD group) and 78 individuals in the health examination group (HC group). We compared general clinical data and serum IGF-1 levels between the two groups. PD patients were further categorized into PD with OP (50 cases) and PD without OP (55 cases) based on dual-energy X-ray absorptiometry (DXA) results for bone density. We compared general clinical data and serum IGF-1 levels between these two subgroups. Pearson correlation coefficient analysis was conducted to assess the relationship between serum IGF-1 levels and bone density at the lumbar spine and left femoral neck. Multifactorial logistic regression analysis was performed to identify risk factors for PD with OP. Serum IGF-1 levels were significantly lower in the PD group compared to the HC group (P < 0.05). Pearson correlation analysis revealed a positive association between serum IGF-1 levels and both lumbar spine and left femoral neck bone densities (r = 0.653, P < 0.001; r = 0.625, P < 0.001). Multivariate logistic regression analysis identified decreased serum IGF-1 levels, lower uric acid levels, and higher H-Y stage as risk factors for PD with OP (P < 0.05). Reduced levels of serum IGF-1, uric acid, and an increased H-Y stage are closely linked to osteoporosis in PD. Elevating serum levels of IGF-1 and uric acid may potentially offer therapeutic avenues for PD with osteoporosis.

Causal relationship between PCSK9 inhibitor and common neurodegenerative diseases: A drug target Mendelian randomization study.

In addition to lowering cholesterol levels, the proprotein convertase subtilis kexin 9 (PCSK9) inhibitor has a variety of effects, including anti-neuroapoptosis. However, the effects of PCSK9 inhibitors on neurodegenerative diseases are controversial. Therefore, we used drug-targeted Mendelian randomization (MR) analysis to investigate the effects of PCSK9 inhibitors on different neurodegenerative diseases. We collected single nucleotide polymorphisms (SNPs) of PCSK9 from published statistics of genome-wide association studies and performed drug target MR analyses to detect a causal relationship between PCSK9 inhibitors and the risk of neurodegenerative diseases. We utilized the effects of 3-Hydroxy -3- methylglutaryl-assisted enzyme A reductase (HMGCR) inhibitors (statin targets) for comparison with PCSK9 inhibitors. Coronary heart disease risk was used as a positive control, and primary outcomes included amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Alzheimer's disease (AD). PCSK9 inhibitors marginally reduced the risk of ALS (OR [95%]=0.89 [0.77 to 1.00], p=0.048), while they increased the risk of PD (OR [95%]=1.417 [1.178 to 1.657], p=0.004). However, HMGCR inhibitors increased the risk of PD (OR [95%]=1.907 [1.502 to 2.312], p=0.001). PCSK9 inhibitors significantly reduce the risk of ALS but increase the risk of PD. HMGCR inhibitors may be the risk factor for PD.

Prevention of Parkinson's Disease: From Risk Factors to Early Interventions.

Parkinson's disease (PD) is a debilitating neurological disorder characterized by progressively worsening motor dysfunction. Currently, available therapies merely alleviate symptoms, and there are no cures. Consequently, some researchers have now shifted their attention to identifying the modifiable risk factors of PD, with the intention of possibly implementing early interventions to prevent the development of PD. Four primary risk factors for PD are discussed including environmental factors (pesticides and heavy metals), lifestyle (physical activity and dietary intake), drug abuse, and individual comorbidities. Additionally, clinical biomarkers, neuroimaging, biochemical biomarkers, and genetic biomarkers could also help to detect prodromal PD. This review compiled available evidence that illustrates the relationship between modifiable risk factors, biomarkers, and PD. In summary, we raise the distinct possibility of preventing PD via early interventions of the modifiable risk factors and early diagnosis.

P.L1795F LRRK2 variant is a common cause of Parkinson's disease in Central Europe.

Pathogenic variants in LRRK2 are one of the most common genetic risk factors for Parkinson's disease (PD). Recently, the lesser-known p.L1795F variant was proposed as a strong genetic risk factor for PD, however, further families are currently lacking in literature. A multicentre young onset and familial PD cohort (n = 220) from 9 movement disorder centres across Central Europe within the CEGEMOD consortium was screened for rare LRRK2 variants using whole exome sequencing data. We identified 4 PD cases with heterozygous p.L1795F variant. All 4 cases were characterised by akinetic-rigid PD phenotype with early onset of severe motor fluctuations, 2 receiving LCIG therapy and 2 implanted with STN DBS; all 4 cases showed unsatisfactory effect of advanced therapies on motor fluctuations. Our data also suggest that p.L1795F may represent the most common currently known pathogenic LRRK2 variant in Central Europe compared to the more studied p.G2019S, being present in 1.81% of PD cases within the Central European cohort and 3.23% of familial PD cases. Together with the ongoing clinical trials for LRRK2 inhibitors, this finding emphasises the urgent need for more ethnic diversity in PD genetic research.