BackgroundGastrointestinal symptoms are frequent in Parkinson's disease (PD) and may precede diagnosis by decades, suggesting a possible role in its pathogenesis. Patients with PD have higher rates of Helicobacter pylori (H. pylori) infection than the general population, although its potential contribution to PD development remains unclear. Similarly, evidence linking gastritis and peptic ulcer to PD risk is limited.MethodsUsing the nationwide ESPRESSO cohort, we investigated associations between H. pylori infection, peptic ulcer, gastritis, and future risk of PD. Individuals diagnosed with these conditions between 1987 or 1990 and 2017 were matched to ≤5 referents from the general population by age, sex, calendar year, and county of residence. Stratified Cox models estimated hazard ratios (HRs), adjusting for country of birth, education, chronic obstructive pulmonary disease, and number of healthcare visits. Incident PD was identified from the National Patient Register.ResultsThe H. pylori cohort included 48,258 exposed individuals and 231,805 referents; the peptic ulcer cohort included 52,761 exposed individuals and 274,313 referents, while the gastritis cohort included 242,325 exposed individuals and 1,053,688 referents. H. pylori infection (HR: 1.14, 95% CI: 1.02-1.28) and gastritis (HR: 1.14, 95% CI: 1.09-1.19) were associated with a marginally increased PD risk, but we found no significant association in peptic ulcer (HR: 1.08, 95% CI: 0.98-1.19). We observed increased PD risk up to ten years after gastritis diagnosis and no time-varying association for H. pylori and peptic ulcer.ConclusionsH. pylori and gastritis may have some relevance for PD development but are unlikely to be major contributors to its pathogenesis.Plain language summary titleUsing gastrointestinal biopsies to explore the link between Helicobacter pylori infection, peptic ulcer, gastritis and Parkinson's disease: findings from a nationwide Swedish cohort study.

To investigate whether antidiabetic drugs have a biological basis to be repurposed in PD prevention, we applied a drug target Mendelian randomization framework to assess associations between genetic variation in antidiabetic drug targets and PD risk or age at onset (AAO). Instrumental variables (IVs) were derived from GWAS summary statistics on fasting glucose (FG), glycated hemoglobin (HbA1c), and gene expression data from GTEx. Apart from SGLT2 inhibitors, all other antidiabetic drugs of interest could be instrumented through our methods. Positive and negative control analyses were carried out to validate 20 IVs in the FG arm and 23 IVs in the HbA1c arm. DPP-4 inhibitors failed the positive control. GWAS summary statistics for PD risk and AAO data were sourced from the IPDGC and COURAGE-PD consortia, resulting in 42 083 cases/457 090 controls for risk and 37 103 PD cases for AAO. MR analyses showed no significant associations across consortia or in meta-analysis. These findings do not support a causal role of genetic variation in antidiabetic drug targets in PD risk or AAO.

Background Gastrointestinal symptoms are frequent in Parkinson's disease (PD) and may precede diagnosis by decades, suggesting a possible role in its pathogenesis. Patients with PD have higher rates of Helicobacter pylori ( H. pylori ) infection than the general population, although its potential contribution to PD development remains unclear. Similarly, evidence linking gastritis and peptic ulcer to PD risk is limited. Methods Using the nationwide ESPRESSO cohort, we investigated associations between H. pylori infection, peptic ulcer, gastritis, and future risk of PD. Individuals diagnosed with these conditions between 1987 or 1990 and 2017 were matched to ≤5 referents from the general population by age, sex, calendar year, and county of residence. Stratified Cox models estimated hazard ratios (HRs), adjusting for country of birth, education, chronic obstructive pulmonary disease, and number of healthcare visits. Incident PD was identified from the National Patient Register. Results The H. pylori cohort included 48,258 exposed individuals and 231,805 referents; the peptic ulcer cohort included 52,761 exposed individuals and 274,313 referents, while the gastritis cohort included 242,325 exposed individuals and 1,053,688 referents. H. pylori infection (HR: 1.14, 95% CI: 1.02–1.28) and gastritis (HR: 1.14, 95% CI: 1.09–1.19) were associated with a marginally increased PD risk, but we found no significant association in peptic ulcer (HR: 1.08, 95% CI: 0.98–1.19). We observed increased PD risk up to ten years after gastritis diagnosis and no time-varying association for H. pylori and peptic ulcer. Conclusions H. pylori and gastritis may have some relevance for PD development but are unlikely to be major contributors to its pathogenesis. Plain language summary title Using gastrointestinal biopsies to explore the link between Helicobacter pylori infection, peptic ulcer, gastritis and Parkinson's disease: findings from a nationwide Swedish cohort study

We investigated the role of copy number variations (CNVs) in Parkinson's disease (PD) using genotyping data from 10,815 patients (2731 early-onset PD, EOPD) and 8901 controls from the COURAGE-PD consortium. CNVs were analyzed using a sliding window genome-wide association and burden approach. No genome-wide significant CNVs were detected in the overall cohort, but a robust deletion spanning exons 2-6 of PRKN was identified in EOPD cases, validated by MLPA, and replicated in the GP2 dataset (23,089 cases, 18,824 controls). CNV burden was significantly enriched in PD-related genes, primarily driven by PRKN, with the strongest effect observed in EOPD. PRKN CNV carriers showed earlier age at onset, confirmed by survival analysis. No association was observed for genome-wide or large CNV burden. Our findings reinforce the pivotal role of PRKN deletions in early-onset PD and highlight the need for high-resolution CNV analysis in large cohorts to uncover additional rare contributors to PD risk.

BACKGROUND AND OBJECTIVES:The prevalence of Parkinson disease (PD), multiple sclerosis (MS), and motor neuron diseases (MNDs) is rising globally. However, it is unclear to what degree this is related to an increase in incidence or to improved survival after diagnosis. METHODS:We performed 2 nationwide, population-based, retrospective cohort studies, including all individuals living in Sweden between 2001 and 2016 and living in France between 2009 and 2022, respectively. Pooled mixed-effects regression models, with country as a random effect, were used to determine temporal trends in prevalence, crude and age-standardized and sex-standardized incidence, and age and life expectancy at diagnosis. RESULTS:Annualized prevalence of PD, MS, and MNDs increased significantly between 2003 and 2022 in the pooled model (PD: prevalence ratio [PR] per year = 1.014, p < 0.001; MS: PR = 1.029, p < 0.001; MND: PR = 1.028, p < 0.001). While the crude incidence of both PD and MS remained nearly stable over time (PD: incidence rate ratio [IRR] per year = 0.998, p < 0.001; MS: IRR = 0.992, p < 0.001), the standardized incidence showed a more marked decrease for PD (IRR = 0.986, p < 0.001) while remaining almost unchanged for MS (IRR = 0.995, p < 0.001). For MNDs, both the crude and standardized incidence increased over time (crude IRR = 1.018, p < 0.001; standardized IRR = 1.008, p < 0.001). Life expectancy at diagnosis of PD increased between 2003 and 2013 (+0.95 months per calendar year, p < 0.001) and then decreased between 2013 and 2022 (-1.20 months, p = 0.002), while it increased significantly over the entire study period for MS (+2.35 months, p < 0.001) and MNDs (+0.34 months, p = 0.01). DISCUSSION:These findings indicate that the rising MS prevalence is largely survival-driven and the rising MND prevalence reflects a true increase in incidence, whereas PD prevalence grows modestly, largely independent of incidence. Depending on the mechanism that drives prevalence, whether increased incidence reflecting changing risk factor exposures, improved survival due to therapeutic advances, or demographic aging of the population, inferences about underlying causes differ substantially between PD, MS, and MNDs, with direct implications for health care planning and etiologic research.

BACKGROUND:The microbiota-gut-brain axis has been implicated in dementia. Yet whether dementia is associated with microscopic colitis (MC), an age-related inflammatory colonic disease involving gut dysbiosis, remains unknown. METHODS:Using the nationwide ESPRESSO cohort in Sweden, we compared MC patients histologically diagnosed 1990-2017 and aged ≥30 years to their population-based comparators and siblings, separately. MC association with incident and prevalent dementia diagnosis, respectively, was investigated in a matched cohort and a matched case-control design. FINDINGS:Following 13,037 MC patients and 61,710 population comparators for a median of ∼10 years, we observed 4674 incident dementia cases (46% were Alzheimer's disease [AD]). During the first 5 years since biopsy, MC was associated with a 19% higher dementia risk (adjusted hazard ratio [aHR]: 1.19; 95% confidence interval [CI]: 1.07-1.32). This short-term association applied to both AD and vascular dementia and appeared stronger as compared to siblings (aHR: 1.55; 95% CI: 1.22-1.97). After 5 years, it attenuated to null in both comparisons, regardless of dementia subtype. Prior dementia was less prevalent in MC (adjusted odds ratio [aOR]: 0.73; 95% CI: 0.65-0.82). This inverse association was independent from medications commonly prescribed in MC but was not supported by sibling findings (aOR: 1.11; 95% CI: 0.81-1.51). CONCLUSIONS:MC patients may be more vulnerable to dementia diagnosis in early disease course. The intriguing inverse association between MC and preexisting dementia implies a possible underdiagnosis of MC in demented population and warrants further investigation.

BACKGROUND AND OBJECTIVES:Myelitis is a relatively common clinical entity for neurologists, with diverse underlying causes. The aim of this study was to describe the incidence of myelitis, its causes, clinical presentation, and factors predicting functional outcomes and relapses. METHODS:Using the Swedish National Patient Registry, we identified all adult patients in Stockholm County between 2008 and 2018 using International Classification of Diseases, 10th Edition (ICD-10) codes likely to include myelitis. We collected medical records and classified patients using a modification of the 2002 Transverse Myelitis Consortium Group criteria. Long-term follow-up data were collected for patients not diagnosed with multiple sclerosis (MS) or neuromyelitis optica spectrum disorder as a result of the initial myelitis. RESULTS:We identified 2,321 individuals, of whom 461 were patients with myelitis. The crude mean incidence of all-cause myelitis was 24.9 (95% CI 16.7-33.9) cases per million person-years, of which idiopathic myelitis had an incidence of 8.0 (95% CI 3.8-12.1) cases per million person-years. Partial myelitis was found in 80% of patients. Poor functional outcome was found in 11% of the cohort and correlated, in a multivariate logistic model, with age older than 50 years (OR 4.26, 95% CI 1.75-10.40), transverse spinal cord lesions (odds ratio [OR] 6.85, 95% CI 2.68-17.52), elevated CSF count of polymorphonuclear cells (OR 6.09, 95% CI 1.56-23.72), and elevated CSF/serum albumin ratio (OR 3.17, 95% CI 1.23-8.17). The median follow-up time was 5.4 years. Relapses occurred in 27% of patients with idiopathic myelitis and 72% of patients with unspecified demyelinating disease of the CNS. An increased relapse rate after idiopathic myelitis was found to be associated, in a multivariate model, with the presence of oligoclonal bands (incidence rate ratio [IRR] 4.47, 95% CI 1.70-11.73), transverse spinal cord lesions (IRR 2.81, 95% CI 1.11-7.12), and multifocal spinal cord lesions (IRR 2.82, 95% CI 1.03-7.69). Around half (48%) of all patients with myelitis received MS diagnosis during the study period. DISCUSSION:This large population-wide study describes a relatively high incidence of myelitis and low risk of relapses after idiopathic myelitis. A complete diagnostic workup of myelitis, including MRI of the entire CNS and collection of CSF, is essential in evaluating underlying causes and prognosis.

Background and ObjectivesMyelitis is a relatively common clinical entity for neurologists, with diverse underlying causes. The aim of this study was to describe the incidence of myelitis, its causes, clinical presentation, and factors predicting functional outcomes and relapses.MethodsUsing the Swedish National Patient Registry, we identified all adult patients in Stockholm County between 2008 and 2018 using International Classification of Diseases, 10th Edition (ICD-10) codes likely to include myelitis. We collected medical records and classified patients using a modification of the 2002 Transverse Myelitis Consortium Group criteria. Long-term follow-up data were collected for patients not diagnosed with multiple sclerosis (MS) or neuromyelitis optica spectrum disorder as a result of the initial myelitis.ResultsWe identified 2,321 individuals, of whom 461 were patients with myelitis. The crude mean incidence of all-cause myelitis was 24.9 (95% CI 16.7-33.9) cases per million person-years, of which idiopathic myelitis had an incidence of 8.0 (95% CI 3.8-12.1) cases per million person-years. Partial myelitis was found in 80% of patients. Poor functional outcome was found in 11% of the cohort and correlated, in a multivariate logistic model, with age older than 50 years (OR 4.26, 95% CI 1.75-10.40), transverse spinal cord lesions (odds ratio [OR] 6.85, 95% CI 2.68-17.52), elevated CSF count of polymorphonuclear cells (OR 6.09, 95% CI 1.56-23.72), and elevated CSF/serum albumin ratio (OR 3.17, 95% CI 1.23-8.17). The median follow-up time was 5.4 years. Relapses occurred in 27% of patients with idiopathic myelitis and 72% of patients with unspecified demyelinating disease of the CNS. An increased relapse rate after idiopathic myelitis was found to be associated, in a multivariate model, with the presence of oligoclonal bands (incidence rate ratio [IRR] 4.47, 95% CI 1.70-11.73), transverse spinal cord lesions (IRR 2.81, 95% CI 1.11-7.12), and multifocal spinal cord lesions (IRR 2.82, 95% CI 1.03-7.69). Around half (48%) of all patients with myelitis received MS diagnosis during the study period.DiscussionThis large population-wide study describes a relatively high incidence of myelitis and low risk of relapses after idiopathic myelitis. A complete diagnostic workup of myelitis, including MRI of the entire CNS and collection of CSF, is essential in evaluating underlying causes and prognosis.

BACKGROUND:Levodopa-induced dyskinesia (LID) in Parkinson's disease (PD) is associated with 'false neurotransmitter' release of dopamine from serotonin (5-HT) neurons. NLX-112 is a first-in-class, highly selective 5-HT1A receptor agonist which counteracts LIDs in experimental PD models. OBJECTIVES:The primary objective was to evaluate the safety and tolerability of NLX-112 compared with placebo in people with PD. The secondary objective was to assess the preliminary efficacy of NLX-112 in reducing LID and its effects on PD symptoms. METHODS:Participants received NLX-112 or placebo (2:1 ratio) alongside stable Parkinson's medications, with 22 participants completing the study. Dosing was up-titrated over 28 days to 2 mg/day (1 mg twice daily), stabilized for 14 days (to day 42), and down-titrated for 14 days. Efficacy was measured using the Unified Dyskinesia Rating Scale (UDysRS), Unified Parkinson's Disease Rating Scale (UPDRS), and Clinical Global Impression of Change (CGI-C) following a levodopa challenge (150% of usual dose). RESULTS:Adverse events (AEs) were mainly central nervous system (CNS)-related and mostly occurred during up-titration, with no serious AEs in the NLX-112 group. There were no treatment-induced clinically significant changes in vital signs, electrocardiogram, or laboratory parameters. NLX-112 reduced LID from baseline levels: at day 42, UDysRS total score decreased by 6.3 points, whereas placebo group changes were not significant (-2.4). NLX-112 also reduced parkinsonism from baseline values: UPDRS Part 3 scores decreased by 3.7 points, whereas placebo group changes were non-significant (+0.1). In CGI-C assessment, the NLX-112 group showed greater improvement than the placebo group (53% vs. 29%). CONCLUSION:These results support further clinical investigation of NLX-112 for treatment of PD LID. © 2025 Neurolixis SAS. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Objective:To investigate the impact of copy number variations (CNVs) on Parkinson's disease (PD) pathogenesis using genome-wide data and explore their role in sporadic PD. Methods:We analyzed CNV data from 11,035 PD patients (including 2,731 early-onset PD (EOPD)) and 8,901 controls from the COURAGE-PD consortium using a sliding window CNV-GWAS and genome-wide burden analysis. The independent dataset from the Global Parkinson Genetics Program (GP2) consisted of 23,089 cases and 18,824 controls were used to validate our initial findings. Results:The exploratory dataset identifies multiple CNV regions associated with PD risk. The nominated CNV loci were not confirmed in an independent dataset, except that only a deletion in the PRKN gene, a well-established EOPD locus, remained genome-wide significant and robustly supported. CNV burden analysis showed a higher prevalence of CNVs in PD-related genes in patients compared to controls (OR=1.56 [1.18-2.09], p=0.0013), with PRKN showing the highest burden (OR=1.47 [1.10-1.98], p=0.026). Patients with CNVs in PRKN had an earlier disease onset. Burden analysis with controls and EOPD patients showed similar results. Interpretation:The largest CNV-based GWAS on PD highlights both the promise and pitfalls of array-based CNV detection in PD and underscores the relevance of whole-genome sequencing approaches in resolving the role of CNV in PD. The array-based findings are prone towards false positive findings that might arise either from platform limitations and/or cohort biases. Future studies require improved genotyping resolution and rigorous cross-cohort validation to reliably assess CNV contributions to PD risk.

Infectious diseases are known to trigger acute seizures, but their long-term impact on epilepsy, especially in later life, is unclear. We conducted nested case-control studies of newly diagnosed epilepsy after age 50 in the UK Biobank (2,486 cases; 12,430 controls) and Swedish registers (56,266 cases; 281,330 controls), including a sibling comparison. Previous hospital-treated infections were associated with a persistently elevated epilepsy risk (for example, >10 years after infection: odds ratio (OR) 1.68, 95% confidence interval: 1.39-2.04 in UK Biobank; 1.46, 1.41-1.51 in Sweden). Associations were robust in sibling analyses and across infection types and sites. We further found that infections, together with a high cardiovascular genetic risk (OR 2.62, 2.22-3.08), a high cardiovascular risk score (OR 3.14, 2.68-3.68) or cardiovascular disease history (OR 4.77, 4.64-4.91), were associated with the highest epilepsy risk. Hospital-treated infections exert prolonged impact on epilepsy risk in older age, especially when in combination with cardiovascular risk factors.

Mediterranean dietary patterns (MDP) may be neuroprotective. Using a large population-based cohort of 42,582 Swedish women, this study examined the association between MDP adherence and the risk of Parkinson’s disease (PD), Alzheimer’s disease (AD), and amyotrophic lateral sclerosis (ALS). During 1991–1992, women in the Women’s Lifestyle and Health Study reported dietary intake, and MDP adherence was calculated. Incident neurodegenerative diseases were identified using the Swedish National Patient Register through 2022. Women who reported high MDP adherence had a lower risk of PD (HR: 0.69, 95% CI: 0.49–0.95), primarily over age 60 (HR: 0.68, 95% CI: 0.47–0.97). A moderate-high MDP adherence was associated with a lower risk of ALS before age 60 (HR: 0.44, 95% CI: 0.19–0.99), but not overall. We observed no association between MDP adherence and AD. Our findings suggest higher adherence to a MDP may be protective against PD above age 60, and ALS before age 60.

BackgroundHigher socioeconomic status (SES) among people with migraine has been associated with an increased use of triptans, but it is undetermined whether high SES is also associated with dispensation of monoclonal antibodies against calcitonin gene-related peptide (CGRPi), a prophylactic treatment against migraine episodes. Our hypothesis was that higher SES is associated with CGRPi dispensation, although the association is expected to be attenuated in a country that generally allows for reimbursement of CGRPi costs.MethodsIn this register-based nested case-control study, the association between SES, categorized into three levels (low, middle and high) and the outcome of a first dispensation of a CGRPi was assessed among people with a migraine diagnosis in Region Stockholm, using univariable and multivariable logistic regression models.ResultsOf 52,996 individuals in the study population, 3.2% (n = 1674) were dispensed CGRPi. Individuals with high or middle SES had an increased probability of being dispensed CGRPi, compared to individuals with low SES (adjusted odds ratio = 1.68; 95% confidence interval = 1.46-1.92 and adjusted odds ratio = 1.41; 95% confidence interval = 1.24-1.61, respectively).ConclusionsHigher SES was associated with dispensation of CGRPi, which suggests unequal access to CGRPi.

OBJECTIVE:Persons with epilepsy have a higher risk of suicide compared to the general population, but limited data makes it unclear how extensive this risk is and who is most vulnerable. Our study aimed to explore the incidence of suicide among persons with epilepsy in Sweden, and compare to the general population. To facilitate prevention, we also wanted to examine methods and circumstances of suicide. METHODS:We identified all individuals with a diagnosis of epilepsy (ICD G40) in the Swedish Patient Register between 1998 and 2005 who were alive in 2006 (n = 60,952). Among them, 190 cases of suicide were recorded in the National Cause of Death Register during follow-up 2006 to 2011. We reviewed their medical records, death certificates, and autopsy records to validate the cause of death and epilepsy diagnosis, as well as collect information on suicide method and circumstances. After validation we calculated the incidence rates by age and sex and standardized mortality ratios (SMRs) with 95 % confidence intervals (CI). RESULTS:Overall suicide incidence was 40.0/100,000 person-years (95 % CI 33.0-47.9). Incidence was highest in age 45 to 64 years (61.3, 95 % CI 46.4-79.1) and appeared higher in men than in women with epilepsy. Compared to the general population, individuals with epilepsy had twice the risk of suicide (SMR 2.03 CI 1.67-2.45) and the excess risk appeared more pronounced in women (SMR 2.70 CI 1.92-3.68) than in men (SMR 1.80 CI 1.40-2.26). Intoxication (50 %) was the most common method, followed by hanging, cutting weapons and guns (25 % combined). SIGNIFICANCE:Our results confirm that suicide is overrepresented in individuals with epilepsy, especially in middle age. Incidence was higher in men but the SMR was higher among women, suggesting that the effect of epilepsy on suicide risk is greater for women than for men. Identifying subgroups that are particularly vulnerable is important for suicide prevention.

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/m(2) [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.

BACKGROUND:Little is known regarding the association between clonal hematopoiesis of indeterminate potential (CHIP) and risk of neurodegenerative diseases. OBJECTIVE:To estimate the risk of neurodegenerative diseases among individuals with CHIP. METHODS:We conducted a community-based cohort study based on UK Biobank and used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of any neurodegenerative disease, subtypes of neurodegenerative diseases (including primary neurodegenerative diseases, vascular neurodegenerative diseases, and other neurodegenerative diseases), and specific diagnoses of neurodegenerative diseases (i.e., amyotrophic lateral sclerosis [ALS], Alzheimer's disease [AD], and Parkinson's disease [PD]) associated with CHIP. RESULTS:We identified 14,440 individuals with CHIP and 450,907 individuals without CHIP. Individuals with CHIP had an increased risk of any neurodegenerative disease (HR 1.10, 95% CI: 1.01-1.19). We also observed a statistically significantly increased risk for vascular neurodegenerative diseases (HR 1.31, 95% CI 1.05-1.63) and ALS (HR 1.50, 95% CI 1.05-2.15). An increased risk was also noted for other neurodegenerative diseases (HR 1.13, 95% CI 0.97-1.32), although not statistically significant. Null association was noted for primary neurodegenerative diseases (HR 1.06, 95% CI 0.96-1.17), AD (HR 1.04, 95% CI 0.88-1.23), and PD (HR 1.02, 95% CI 0.86-1.21). The risk increase in any neurodegenerative disease was mainly observed for DNMT3A-mutant CHIP, ASXL1-mutant CHIP, or SRSF2-mutant CHIP. CONCLUSION:Individuals with CHIP were at an increased risk of neurodegenerative diseases, primarily vascular neurodegenerative diseases and ALS, but potentially also other neurodegenerative diseases. These findings suggest potential shared mechanisms between CHIP and neurodegenerative diseases.

Introduction Parkinson’s disease (PD) patients are prone to fall and fall-related injuries (FI). Vascular disease is common in PD and is positively associated with falls in elderly. We aimed to evaluate the association of vascular disease with FI risk in PD. Methods A nationwide cohort study of patients with primary PD diagnosis in Sweden was performed using Swedish national registers. Patients with and without vascular disease were followed from PD diagnosis until subsequent FI or 2013-12-31. The association of vascular disease with FI risk was estimated as hazard ratio (HR) and 95% confidence interval (CI) by Cox regression using attained age as underlying timescale. Results We identified 2,734 and 6,979 incident FI from 8,025 PD patients with and 20,543 without vascular disease, respectively. Overall, vascular disease associated positively with subsequent FI, which was mainly driven by the significant risk elevation within the first 6 months following vascular disease (HR<0.5year [95% CI] for PD diagnosed ≤75 years is 1.61 [1.39-1.87] and for PD diagnosed >75 years is 1.48 [1.32-1.65]). Thereafter, the association attenuated to null before it rebounded five years after exposure in PD diagnosed ≤75 years (HR>5year =1.26, 95% CI: 1.10-1.45); whereas for PD diagnosed >75 years, it dropped remarkably and remained non-significant 6 months after exposure. When vascular disease was restricted to stroke, we saw a similar temporal pattern except that the short-term HRs among younger patients were stronger, lasted longer, and declined continuously without rebound. Conclusions Fall prevention is crucial to PD patients immediately after a vascular event.

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.