Association of Body Mass Index and Parkinson Disease: A Bidirectional Mendelian Randomization Study.

BACKGROUND AND OBJECTIVES: The role of body mass index (BMI) in Parkinson disease (PD) is unclear. Based on the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in PD (Courage-PD) consortium, we used 2-sample Mendelian randomization (MR) to replicate a previously reported inverse association of genetically predicted BMI with PD and investigated whether findings were robust in analyses addressing the potential for survival and incidence-prevalence biases. We also examined whether the BMI-PD relation is bidirectional by performing a reverse MR. METHODS: We used summary statistics from a genome-wide association study (GWAS) to extract the association of 501 single-nucleotide polymorphisms (SNPs) with BMI and from the Courage-PD and international Parkinson Disease Genomics Consortium (iPDGC) to estimate their association with PD. Analyses are based on participants of European ancestry. We used the inverse-weighted method to compute odds ratios (ORIVW per 4.8 kg/m2 [95% CI]) of PD and additional pleiotropy robust methods. We performed analyses stratified by age, disease duration, and sex. For reverse MR, we used SNPs associated with PD from 2 iPDGC GWAS to assess the effect of genetic liability toward PD on BMI. RESULTS: Summary statistics for BMI are based on 806,834 participants (54% women). Summary statistics for PD are based on 8,919 (40% women) cases and 7,600 (55% women) controls from Courage-PD, and 19,438 (38% women) cases and 24,388 (51% women) controls from iPDGC. In Courage-PD, we found an inverse association between genetically predicted BMI and PD (ORIVW 0.82 [0.70-0.97], p = 0.012) without evidence for pleiotropy. This association tended to be stronger in younger participants (≤67 years, ORIVW 0.71 [0.55-0.92]) and cases with shorter disease duration (≤7 years, ORIVW 0.75 [0.62-0.91]). In pooled Courage-PD + iPDGC analyses, the association was stronger in women (ORIVW 0.85 [0.74-0.99], p = 0.032) than men (ORIVW 0.92 [0.80-1.04], p = 0.18), but the interaction was not statistically significant (p-interaction = 0.48). In reverse MR, there was evidence for pleiotropy, but pleiotropy robust methods showed a significant inverse association. DISCUSSION: Using an independent data set (Courage-PD), we replicate an inverse association of genetically predicted BMI with PD, not explained by survival or incidence-prevalence biases. Moreover, reverse MR analyses support an inverse association between genetic liability toward PD and BMI, in favor of a bidirectional relation.

Association of elevated cerebrospinal fluid levels of the longevity protein α-Klotho with a delayed onset of cognitive impairment in Parkinson's disease patients.

BACKGROUND AND PURPOSE: Parkinson's disease (PD) is an age-related condition characterized by substantial phenotypic variability. Consequently, pathways and proteins involved in biological aging, such as the central aging pathway comprising insulin-like growth factor 1-α-Klotho-sirtuin 1-forkhead box O3-peroxisome proliferator-activated receptor γ, may potentially influence disease progression. METHODS: Cerebrospinal fluid (CSF) levels of α-Klotho in 471 PD patients were examined. Of the 471 patients, 96 carried a GBA1 variant (PD GBA1), whilst the 375 non-carriers were classified as PD wild-type (PD WT). Each patient was stratified into a CSF α-Klotho tertile group based on the individual level. Kaplan-Meier survival curves and Cox regression analysis stratified by tertile groups were conducted. These longitudinal data were available for 255 patients. Follow-up times reached from 8.4 to 12.4 years. The stratification into PD WT and PD GBA1 was undertaken to evaluate potential continuum patterns, particularly in relation to CSF levels. RESULTS: Higher CSF levels of α-Klotho were associated with a significant later onset of cognitive impairment. Elevated levels of α-Klotho in CSF were linked to higher Montreal Cognitive Assessment scores in male PD patients with GBA1 mutations. CONCLUSIONS: Our results indicate that higher CSF levels of α-Klotho are associated with a delayed cognitive decline in PD. Notably, this correlation is more prominently observed in PD patients with GBA1 mutations, potentially reflecting the accelerated biological aging profile characteristic of individuals harboring GBA1 variants.

Elevated fecal calprotectin is associated with gut microbial dysbiosis, altered serum markers and clinical outcomes in older individuals.

Fecal calprotectin is an established marker of gut inflammation in inflammatory bowel disease (IBD). Elevated levels of fecal calprotectin as well as gut microbial dysbiosis have also been observed in other clinical conditions. However, systemic and multi-omics alterations linked to elevated fecal calprotectin in older individuals remain unclear. This study comprehensively investigated the relationship between fecal calprotectin levels, gut microbiome composition, serum inflammation and targeted metabolomics markers, and relevant lifestyle and medical data in a large sample of older individuals (n = 735; mean age ± SD: 68.7 ± 6.3) from the TREND cohort study. Low (0-50 µg/g; n = 602), moderate (> 50-100 µg/g; n = 64) and high (> 100 µg/g; n = 62) fecal calprotectin groups were stratified. Several pro-inflammatory gut microbial genera were significantly increased and short-chain fatty acid producing genera were decreased in high vs. low calprotectin groups. In serum, IL-17C, CCL19 and the toxic metabolite indoxyl sulfate were increased in high vs. low fecal calprotectin groups. These changes were partially mediated by the gut microbiota. Moreover, the high fecal calprotectin group showed increased BMI and a higher disease prevalence of heart attack and obesity. Our findings contribute to the understanding of fecal calprotectin as a marker of gut dysbiosis and its broader systemic and clinical implications in older individuals.

Aggregation-resistant alpha-synuclein tetramers are reduced in the blood of Parkinson's patients.

Synucleinopathies such as Parkinson's disease (PD) are defined by the accumulation and aggregation of the α-synuclein protein in neurons, glia and other tissues. We have previously shown that destabilization of α-synuclein tetramers is associated with familial PD due to SNCA mutations and demonstrated brain-region specific alterations of α-synuclein multimers in sporadic PD patients following the classical Braak spreading theory. In this study, we assessed relative levels of disordered and higher-ordered multimeric forms of cytosolic α-synuclein in blood from familial PD with G51D mutations and sporadic PD patients. We used an adapted in vitro-cross-linking protocol for human EDTA-whole blood. The relative levels of higher-ordered α-synuclein tetramers were diminished in blood from familial PD and sporadic PD patients compared to controls. Interestingly, the relative amount of α-synuclein tetramers was already decreased in asymptomatic G51D carriers, supporting the hypothesis that α-synuclein multimer destabilization precedes the development of clinical PD. Our data, therefore suggest that measuring α-synuclein tetramers in blood may have potential as a facile biomarker assay for early detection and quantitative tracking of PD progression.

Longitudinal cognitive decline characterizes the profile of non-PD-manifest GBA1 mutation carriers.

With disease-modifying treatment for Parkinson's disease (PD) associated with variants in the glucocerebrosidase gene (GBA1) under way, the challenge to design clinical trials with non-PD-manifest GBA mutation carriers (GBA1NMC) comes within close reach. To delineate trajectories of motor and non-motor markers as well as serum neurofilament light (sNfL) levels and to evaluate clinical endpoints as outcomes for clinical trials in GBA1NMC, longitudinal data of 56 GBA1NMC carriers and 112 age- and sex-matched GBA1 wildtype participants (GBA1wildtype) with up to 9 years of follow-up was analyzed using linear mixed-effects models (LMEM) and Kaplan-Meier survival analysis of clinical endpoints for motor and cognitive function. GBA1NMC showed worse performance in Pegboard, 20 m fast walking, global cognition as well as in executive and memory function at baseline. Longitudinally, LMEM revealed a higher annual increase of the MDS-UPDRS III bradykinesia subscore in GBA1NMC compared to GBA1wildtype, but comparable trajectories of all other motor and non-motor markers as well as sNfL. Kaplan-Meier survival analysis showed a significantly earlier progression to clinical endpoints of cognitive decline in GBA1NMC. Incidence of PD was significantly higher in GBA1NMC. In conclusion, our study extends data on GBA1NMC indicating early cognitive decline as a potentially characteristic feature. Comprehensive longitudinal assessments of cognitive function are crucial to delineate the evolution of early changes in GBA1NMC enabling a more accurate stratification and allow for a more precise definition of trial design and sample size.

Prasinezumab slows motor progression in rapidly progressing early-stage Parkinson's disease.

Prasinezumab, a monoclonal antibody that binds aggregated α-synuclein, is being investigated as a potential disease-modifying therapy in early-stage Parkinson's disease. Although in the PASADENA phase 2 study, the primary endpoint (Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) sum of Parts I + II + III) was not met, prasinezumab-treated individuals exhibited slower progression of motor signs than placebo-treated participants (MDS-UPDRS Part III). We report here an exploratory analysis assessing whether prasinezumab showed greater benefits on motor signs progression in prespecified subgroups with faster motor progression. Prasinezumab's potential effects on disease progression were assessed in four prespecified and six exploratory subpopulations of PASADENA: use of monoamine oxidase B inhibitors at baseline (yes versus no); Hoehn and Yahr stage (2 versus 1); rapid eye movement sleep behavior disorder (yes versus no); data-driven subphenotypes (diffuse malignant versus nondiffuse malignant); age at baseline (≥60 years versus <60 years); sex (male versus female); disease duration (>12 months versus <12 months); age at diagnosis (≥60 years versus <60 years); motor subphenotypes (akinetic-rigid versus tremor-dominant); and motor subphenotypes (postural instability gait dysfunction versus tremor-dominant). In these subpopulations, the effect of prasinezumab on slowing motor signs progression (MDS-UPDRS Part III) was greater in the rapidly progressing subpopulations (for example, participants who were diffuse malignant or taking monoamine oxidase B inhibitors at baseline). This exploratory analysis suggests that, in a trial of 1-year duration, prasinezumab might reduce motor progression to a greater extent in individuals with more rapidly progressing Parkinson's disease. However, because this was a post hoc analysis, additional randomized clinical trials are needed to validate these findings.

Genotype-phenotype correlation in PRKN-associated Parkinson's disease.

Bi-allelic pathogenic variants in PRKN are the most common cause of autosomal recessive Parkinson's disease (PD). 647 patients with PRKN-PD were included in this international study. The pathogenic variants present were characterised and investigated for their effect on phenotype. Clinical features and progression of PRKN-PD was also assessed. Among 133 variants in index cases (n = 582), there were 58 (43.6%) structural variants, 34 (25.6%) missense, 20 (15%) frameshift, 10 splice site (7.5%%), 9 (6.8%) nonsense and 2 (1.5%) indels. The most frequent variant overall was an exon 3 deletion (n = 145, 12.3%), followed by the p.R275W substitution (n = 117, 10%). Exon3, RING0 protein domain and the ubiquitin-like protein domain were mutational hotspots with 31%, 35.4% and 31.7% of index cases presenting mutations in these regions respectively. The presence of a frameshift or structural variant was associated with a 3.4 ± 1.6 years or a 4.7 ± 1.6 years earlier age at onset of PRKN-PD respectively (p < 0.05). Furthermore, variants located in the N-terminus of the protein, a region enriched with frameshift variants, were associated with an earlier age at onset. The phenotype of PRKN-PD was characterised by slow motor progression, preserved cognition, an excellent motor response to levodopa therapy and later development of motor complications compared to early-onset PD. Non-motor symptoms were however common in PRKN-PD. Our findings on the relationship between the type of variant in PRKN and the phenotype of the disease may have implications for both genetic counselling and the design of precision clinical trials.

The comorbidity profiles and medication issues of patients with multiple system atrophy: a systematic cross-sectional analysis.

BACKGROUND: Multiple system atrophy (MSA) is a complex and fatal neurodegenerative movement disorder. Understanding the comorbidities and drug therapy is crucial for MSA patients' safety and management. OBJECTIVES: To investigate the pattern of comorbidities and aspects of drug therapy in MSA patients. METHODS: Cross-sectional data of MSA patients according to Gilman et al. (2008) diagnostic criteria and control patients without neurodegenerative diseases (non-ND) were collected from German, multicenter cohorts. The prevalence of comorbidities according to WHO ICD-10 classification and drugs administered according to WHO ATC system were analyzed. Potential drug-drug interactions were identified using AiDKlinik®. RESULTS: The analysis included 254 MSA and 363 age- and sex-matched non-ND control patients. MSA patients exhibited a significantly higher burden of comorbidities, in particular diseases of the genitourinary system. Also, more medications were prescribed MSA patients, resulting in a higher prevalence of polypharmacy. Importantly, the risk of potential drug-drug interactions, including severe interactions and contraindicated combinations, was elevated in MSA patients. When comparing MSA-P and MSA-C subtypes, MSA-P patients suffered more frequently from diseases of the genitourinary system and diseases of the musculoskeletal system and connective tissue. CONCLUSIONS: MSA patients face a substantial burden of comorbidities, notably in the genitourinary system. This, coupled with increased polypharmacy and potential drug interactions, highlights the complexity of managing MSA patients. Clinicians should carefully consider these factors when devising treatment strategies for MSA patients.

Axonal Lysosomal Assays for Characterizing the Effects of LRRK2 G2019S.

The degeneration of axon terminals before the soma, referred to as "dying back", is a feature of Parkinson's disease (PD). Axonal assays are needed to model early PD pathogenesis as well as identify protective therapeutics. We hypothesized that defects in axon lysosomal trafficking as well as injury repair might be important contributing factors to "dying back" pathology in PD. Since primary human PD neurons are inaccessible, we developed assays to quantify axonal trafficking and injury repair using induced pluripotent stem cell (iPSC)-derived neurons with LRRK2 G2019S, which is one of the most common known PD mutations, and isogenic controls. We observed a subtle axonal trafficking phenotype that was partially rescued by a LRRK2 inhibitor. Mutant LRRK2 neurons showed increased phosphorylated Rab10-positive lysosomes, and lysosomal membrane damage increased LRRK2-dependent Rab10 phosphorylation. Neurons with mutant LRRK2 showed a transient increase in lysosomes at axotomy injury sites. This was a pilot study that used two patient-derived lines to develop its methodology; we observed subtle phenotypes that might correlate with heterogeneity in LRRK2-PD patients. Further analysis using additional iPSC lines is needed. Therefore, our axonal lysosomal assays can potentially be used to characterize early PD pathogenesis and test possible therapeutics.

CSF α-synuclein seed amplification kinetic profiles are associated with cognitive decline in Parkinson's disease.

Seed amplification assays have been implemented in Parkinson's disease to reveal disease-specific misfolded alpha-synuclein aggregates in biospecimens. While the assays' qualitative dichotomous seeding response is valuable to stratify and enrich cohorts for alpha-synuclein pathology in general, more quantitative parameters that are associated with clinical dynamics of disease progression and that might potentially serve as exploratory outcome measures in clinical trials targeting alpha-synuclein would add important information. To evaluate whether the seeding kinetic parameters time required to reach the seeding threshold (LAG phase), the peak of fluorescence response (Imax), and the area under the curve (AUC) are associated with clinical trajectories, we analyzed LAG, Imax, and AUC in relation to the development of cognitive decline in a longitudinal cohort of 199 people with Parkinson's disease with positive CSF alpha-synuclein seeding status. Patients were stratified into tertiles based on their individual CSF alpha-synuclein seeding kinetic properties. The effect of the kinetic parameters on longitudinal development of cognitive impairment defined by MoCA ≤25 was analyzed by Cox-Regression. Patients with a higher number of positive seeding replicates and tertile groups of shorter LAG, higher Imax, and higher AUC showed a higher prevalence of and a shorter duration until cognitive impairment longitudinally (3, 6, and 3 years earlier with p ≤ 0.001, respectively). Results remained similar in separate subgroup analyses of patients with and without GBA mutation. We conclude that a more prominent alpha-synuclein seeding kinetic profile translates into a more rapid development of cognitive decline.

Establishing an online resource to facilitate global collaboration and inclusion of underrepresented populations: Experience from the MJFF Global Genetic Parkinson's Disease Project.

Parkinson's disease (PD) is the fastest-growing neurodegenerative disorder, currently affecting ~7 million people worldwide. PD is clinically and genetically heterogeneous, with at least 10% of all cases explained by a monogenic cause or strong genetic risk factor. However, the vast majority of our present data on monogenic PD is based on the investigation of patients of European White ancestry, leaving a large knowledge gap on monogenic PD in underrepresented populations. Gene-targeted therapies are being developed at a fast pace and have started entering clinical trials. In light of these developments, building a global network of centers working on monogenic PD, fostering collaborative research, and establishing a clinical trial-ready cohort is imperative. Based on a systematic review of the English literature on monogenic PD and a successful team science approach, we have built up a network of 59 sites worldwide and have collected information on the availability of data, biomaterials, and facilities. To enable access to this resource and to foster collaboration across centers, as well as between academia and industry, we have developed an interactive map and online tool allowing for a quick overview of available resources, along with an option to filter for specific items of interest. This initiative is currently being merged with the Global Parkinson's Genetics Program (GP2), which will attract additional centers with a focus on underrepresented sites. This growing resource and tool will facilitate collaborative research and impact the development and testing of new therapies for monogenic and potentially for idiopathic PD patients.

Kinetic parameters of alpha-synuclein seed amplification assay correlate with cognitive impairment in patients with Lewy body disorders.

The alpha-synuclein (aSyn) seed amplification assay (SAA) can identify aSyn aggregates as indicator for Lewy body pathology in biomaterials of living patients and help in diagnosing Parkinson´s disease and dementia syndromes. Our objective was to confirm that qualitative results of aSyn SAA are reproducible across laboratories and to determine whether quantitative findings correlate with patient clinical characteristics. Therefore cerebrospinal fluid samples were re-analysed by aSyn SAA in a second laboratory with four technical replicates for each sample. Kinetic parameters derived from each aggregation curve were summarized and correlated with patient characteristics. We found that qualitative findings were identical between the two laboratories for 54 of 55 patient samples. The number of positive replicates for each sample also showed good agreement between laboratories. Moreover, specific kinetic parameters of the SAA showed a strong correlation with clinical parameters, notably with cognitive performance evaluated by the Montreal Cognitive Assessment. We concluded that SAA findings are highly reproducible across laboratories following the same protocol. SAA reports not only the presence of Lewy pathology but is also associated with clinical characteristics. Thus, aSyn SAA can potentially be used for patient stratification and determining the target engagement of aSyn targeting treatments.

Older adults' coping strategies during the COVID-19 pandemic - a longitudinal mixed-methods study.

Introduction: Older age is a main risk factor for severe COVID-19. In 2020, a broad political debate was initiated as to what extent older adults need special protection and isolation to minimize their risk for SARS-CoV-2 infection. However, isolation might also have indirect negative psychological (e.g., loneliness, stress, fear, anxiety, depression) or physical (e.g., lack of exercise, missing medical visits) consequences depending on individual strategies and personality traits to cope longitudinally with this crisis. Methods: To examine the impact of individuals' coping with the pandemic on mental health, a large sample of 880 older adults of the prospective longitudinal cohort TREND study were surveyed six times about their individual coping strategies in the COVID-19 pandemic between May 2020 (05/2020: Mage = 72.1, SDage = 6.4, Range: 58-91 years) and November 2022 in an open response format. The relevant survey question was: "What was helpful for you to get through the last months despite the COVID-19 pandemic? E.g., phone calls, going for a walk, or others." Results and Discussion: In total, we obtained 4,561 records containing 20,578 text passages that were coded and assigned to 427 distinct categories on seven levels based on qualitative content analysis using MAXQDA. The results allow new insights into the impact of personal prerequisites (e.g., value beliefs, living conditions), the general evaluation of the pandemic (e.g., positive, irrelevant, stressful) as well as the applied coping strategies (e.g., cognitive, emotional- or problem-focused) to deal with the COVID-19 pandemic by using an adapted Lazarus stress model. Throughout the pandemic emotional-focused as well as problem-focused strategies were the main coping strategies, whereas general beliefs, general living conditions and the evaluation were mentioned less frequently.

Glucocerebrosidase is imported into mitochondria and preserves complex I integrity and energy metabolism.

Mutations in GBA1, the gene encoding the lysosomal enzyme ß-glucocerebrosidase (GCase), which cause Gaucher's disease, are the most frequent genetic risk factor for Parkinson's disease (PD). Here, we employ global proteomic and single-cell genomic approaches in stable cell lines as well as induced pluripotent stem cell (iPSC)-derived neurons and midbrain organoids to dissect the mechanisms underlying GCase-related neurodegeneration. We demonstrate that GCase can be imported from the cytosol into the mitochondria via recognition of internal mitochondrial targeting sequence-like signals. In mitochondria, GCase promotes the maintenance of mitochondrial complex I (CI) integrity and function. Furthermore, GCase interacts with the mitochondrial quality control proteins HSP60 and LONP1. Disease-associated mutations impair CI stability and function and enhance the interaction with the mitochondrial quality control machinery. These findings reveal a mitochondrial role of GCase and suggest that defective CI activity and energy metabolism may drive the pathogenesis of GCase-linked neurodegeneration.

Inflammatory CSF profiles and longitudinal development of cognitive decline in sporadic and GBA-associated PD.

Inflammation modifies the incidence and progression of Parkinson's disease (PD). By using 30 inflammatory markers in CSF in 498 people with PD and 67 people with dementia with Lewy bodies (DLB) we show that: (1) levels of ICAM-1, Interleukin-8, MCP-1, MIP-1 beta, SCF and VEGF were associated with clinical scores and neurodegenerative CSF biomarkers (Aß1-42, t-Tau, p181-Tau, NFL and α-synuclein). (2) PD patients with GBA mutations show similar levels of inflammatory markers compared to PD patients without GBA mutations, even when stratified by mutation severity. (3) PD patients who longitudinally developed cognitive impairment during the study had higher levels of TNF-alpha at baseline compared to patients without the development of cognitive impairment. (4) Higher levels of VEGF and MIP-1 beta were associated with a longer duration until the development of cognitive impairment. We conclude that the majority of inflammatory markers is limited in robustly predicting longitudinal trajectories of developing cognitive impairment.

Multidomain cognitive training increases physical activity in people with Parkinson's disease with mild cognitive impairment.

INTRODUCTION: Cognitive impairment in Parkinson's disease (PD), especially in patients with mild cognitive impairment (PD-MCI), coincides with less physical activity. Cognitive trainings (CT) have been found to promote laboratory environment-based movement. Knowledge about their effect in natural home-based environment, reflecting everyday function, is sparse. This explorative study investigated short-term effects of CT on physical activity assessed by home-based accelerometry, and its relation to change of cognitive function over time and non-cognitive outcomes in patients with PD-MCI. Cognitive and non-cognitive correlates of movement parameters at pretest were evaluated as well. METHODS: Eighteen patients with PD-MCI of the TrainParC study were analyzed. Those patients received either a 6-week multidomain group CT or physical training (PT). Physical activity and sedentary behavior were assessed with wearable accelerometers worn up to seven days pre- and post-training. RESULTS: Patients in the CT group displayed significantly greater increases in active periods after training than patients assigned to PT. In the CT group, increases in executive functioning were associated with increases in active periods and decreases in active mean bout length after training. At pretest, reduced working memory correlated with longer sedentary mean bout length, and impairment in activities of daily living (ADL) correlated with a higher number of sedentary periods. CONCLUSION: Study data revealed that CT can increase physical activity in patients with PD-MCI, possibly due to effects on executive functions, which needs further investigation in larger sample sizes. Lower working memory performance and ADL impairment might be associated with a more inactive lifestyle in patients with PD-MCI.

Bayesian network modeling of risk and prodromal markers of Parkinson's disease.

Parkinson's disease (PD) is characterized by a long prodromal phase with a multitude of markers indicating an increased PD risk prior to clinical diagnosis based on motor symptoms. Current PD prediction models do not consider interdependencies of single predictors, lack differentiation by subtypes of prodromal PD, and may be limited and potentially biased by confounding factors, unspecific assessment methods and restricted access to comprehensive marker data of prospective cohorts. We used prospective data of 18 established risk and prodromal markers of PD in 1178 healthy, PD-free individuals and 24 incident PD cases collected longitudinally in the Tübingen evaluation of Risk factors for Early detection of NeuroDegeneration (TREND) study at 4 visits over up to 10 years. We employed artificial intelligence (AI) to learn and quantify PD marker interdependencies via a Bayesian network (BN) with probabilistic confidence estimation using bootstrapping. The BN was employed to generate a synthetic cohort and individual marker profiles. Robust interdependencies were observed for BN edges from age to subthreshold parkinsonism and urinary dysfunction, sex to substantia nigra hyperechogenicity, depression, non-smoking and to constipation; depression to symptomatic hypotension and excessive daytime somnolence; solvent exposure to cognitive deficits and to physical inactivity; and non-smoking to physical inactivity. Conversion to PD was interdependent with prior subthreshold parkinsonism, sex and substantia nigra hyperechogenicity. Several additional interdependencies with lower probabilistic confidence were identified. Synthetic subjects generated via the BN based representation of the TREND study were realistic as assessed through multiple comparison approaches of real and synthetic data. Altogether our work demonstrates the potential of modern AI approaches (specifically BNs) both for modelling and understanding interdependencies between PD risk and prodromal markers, which are so far not accounted for in PD prediction models, as well as for generating realistic synthetic data.

Investigation of Shared Genetic Risk Factors Between Parkinson's Disease and Cancers.

BACKGROUND: Epidemiological studies that examined the association between Parkinson's disease (PD) and cancers led to inconsistent results, but they face a number of methodological difficulties. OBJECTIVE: We used results from genome-wide association studies (GWASs) to study the genetic correlation between PD and different cancers to identify common genetic risk factors. METHODS: We used individual data for participants of European ancestry from the Courage-PD (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease; PD, N = 16,519) and EPITHYR (differentiated thyroid cancer, N = 3527) consortia and summary statistics of GWASs from iPDGC (International Parkinson Disease Genomics Consortium; PD, N = 482,730), Melanoma Meta-Analysis Consortium (MMAC), Breast Cancer Association Consortium (breast cancer), the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (prostate cancer), International Lung Cancer Consortium (lung cancer), and Ovarian Cancer Association Consortium (ovarian cancer) (N comprised between 36,017 and 228,951 for cancer GWASs). We estimated the genetic correlation between PD and cancers using linkage disequilibrium score regression. We studied the association between PD and polymorphisms associated with cancers, and vice versa, using cross-phenotypes polygenic risk score (PRS) analyses. RESULTS: We confirmed a previously reported positive genetic correlation of PD with melanoma (Gcorr = 0.16 [0.04; 0.28]) and reported an additional significant positive correlation of PD with prostate cancer (Gcorr = 0.11 [0.03; 0.19]). There was a significant inverse association between the PRS for ovarian cancer and PD (odds ratio [OR] = 0.89 [0.84; 0.94]). Conversely, the PRS of PD was positively associated with breast cancer (OR = 1.08 [1.06; 1.10]) and inversely associated with ovarian cancer (OR = 0.95 [0.91; 0.99]). The association between PD and ovarian cancer was mostly driven by rs183211 located in an intron of the NSF gene (17q21.31). CONCLUSIONS: We show evidence in favor of a contribution of pleiotropic genes to the association between PD and specific cancers. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.