Associations between Sleep Disorders and Impulsive-Compulsive Behaviors in Parkinson's Disease: A Prospective Cohort Study.

OBJECTIVE: To examine the associations of excessive daytime sleepiness (EDS) and probable rapid eye movement sleep behavior disorder (pRBD), respectively, with impulsive-compulsive behaviors (ICB) over a 5-year follow-up in patients with early Parkinson's disease (PD). METHODS: The Parkinson's Progression Markers Initiative is a multicenter cohort study based on an ongoing and open-ended registry. Longitudinal associations of sleep disorders with ICB over 5-year follow-up visits were estimated using generalized linear mixed-effects models among PD participants. RESULTS: A total of 825 PD participants were enrolled at baseline. The study sample had a median baseline age of 63.1 (interquartile range [IQR]: 55.6-69.3) years and comprised 496 (61.5%) men. Among them, 201 (24.9%) had ICB at baseline. In the generalized mixed-effects models, EDS (odds ratio [OR] =1.09, 95% confidence interval [CI] 1.05, 1.12) and RBD (OR=1.07, 95% CI 1.03, 1.12) were substantially associated with higher odds of developing ICB over time in PD patients, after multivariate adjustment including age, gender, family history, GDS score, STAI-Y score, MDS-UPDRS part III score, LEDD, and disease duration. Consistent results were observed when stratifying by age at baseline, gender, and PD family history. CONCLUSIONS: The study findings suggest a longitudinal association between EDS and pRBD with an increased risk of developing ICB in patients with Parkinson's disease. The findings emphasize the significance of evaluating and addressing sleep disorders in PD patients as a potential approach to managing ICB.

Sex Differences in the Allele Distribution of PGLYRP2 Variant rs892145 in Parkinson's Disease.

Introduction: Parkinson's disease (PD) is a complex multifactorial disease, involving genetic susceptibility, environmental risk factors, and gene-environmental interactions. The microbiota-gut-brain axis is hypothesized to play a role in the pathophysiology of PD, and peptidoglycan recognition proteins (PGLYRPs), which modulate the gut microbiota, are, therefore, relevant candidate genes for PD. Methods: Using quantitative real-time PCR, we genotyped three PGLYRP variants (rs892145, rs959117, and rs10888557) and performed an association analysis in 508 PD patients and 585 control individuals. We further conducted a meta-analysis of rs892145 and analyzed PGLYRP2 gene expression in lymphocytes from patients with PD and controls. Results: Although initial analysis of the three variants rs892145, rs959117, and rs10888557 and a meta-analysis of rs892145 did not reveal any association between the selected variants and PD, we found an interaction between sex and genotype for rs892145, with a marked difference in the allele distribution of rs892145 between male and female patients. As compared to controls, the T allele was less common in female patients (odds ratio = 0.76, P = 0.04) and more common in male patients (odds ratio = 1.29, P = 0.04). No difference was found in PGLYRP2 gene expression between PD patients and controls (P = 0.38), nor between sexes (P = 0.07). Discussion. Overall, this genetic screening in Swedish PD patients does not support previous results demonstrating associations of PGLYRP variants with the risk of PD. Meta-analysis of rs892145 revealed pronounced heterogeneity between previously published studies which is likely to have influenced the results. Taken together, the genetic and gene expression analyses suggest a possible link between genetic variants in PGLYRP2 and sex differences in PD. Because of the limited sample size in our study, these results need to be verified in independent cohorts before concluding.

Risk of Parkinson's Disease in Celiac Disease: A Swedish Population-Based Study.

Using a population-based matched cohort design, we assessed the association of celiac disease (CeD) with risk of PD by comparing patients with biopsy-confirmed CeD in Sweden to a biopsy-free population and their unaffected siblings, separately. No overall association was observed but CeD diagnosed before age 60 associated positively with incident diagnosis of PD (hazard ratio [HR] = 1.29; 95% confidence interval [CI]: 1.02-1.62), which was mainly attributed to the significantly elevated risk detected after 10-15 years since biopsy (HR = 1.68; 95% CI: 1.05-2.68). Our findings imply an increased vulnerability to long-term PD development among patients with CeD diagnosed before 60s. ANN NEUROL 2023;94:911-916.

ß2-Adrenoreceptor Agonists, Montelukast, and Parkinson Disease Risk.

OBJECTIVE: This study was undertaken to examine the association between montelukast use, ß2-adrenoreceptor (ß2AR) agonist use, and later Parkinson disease (PD). METHODS: We ascertained use of ß2AR agonists (430,885 individuals) and montelukast (23,315 individuals) from July 1, 2005 to June 30, 2007, and followed 5,186,886 PD-free individuals from July 1, 2007 to December 31, 2013 for incident PD diagnosis. We estimated hazard ratios and 95% confidence intervals using Cox regressions. RESULTS: We observed 16,383 PD cases during on average 6.1 years of follow-up. Overall, use of ß2AR agonists and montelukast were not related to PD incidence. A 38% lower PD incidence was noted among high-dose montelukast users when restricted to PD registered as the primary diagnosis. INTERPRETATION: Overall, our data do not support inverse associations between ß2AR agonists, montelukast, and PD. The prospect of lower PD incidence with high-dose montelukast exposure warrants further investigation, especially with adjustment for high-quality data on smoking. ANN NEUROL 2023;93:1023-1028.

Genetic overlap between Parkinson's disease and inflammatory bowel disease.

Parkinson's disease and inflammatory bowel disease have been increasingly associated, implying shared pathophysiology. To explore biological explanations for the reported connection, we leveraged summary statistics of updated genome-wide association studies and characterized the genetic overlap between the two diseases. Aggregated genetic association data were available for 37 688 cases versus 981 372 controls for Parkinson's disease and 25 042 cases versus 34 915 controls for inflammatory bowel disease. Genetic correlation was estimated with the high-definition likelihood method. Genetic variants with joint association to both diseases were identified by conditional false discovery rate framework and further annotated to reveal shared loci, genes, and enriched pathways. For both Crohn's disease and ulcerative colitis, the two main subtypes of inflammatory bowel disease, we detected weak but statistically significant genetic correlations with Parkinson's disease (Crohn's disease: rg = 0.06, P = 0.01; ulcerative colitis: rg = 0.06, P = 0.03). A total of 1290 variants in 27 independent genomic loci were detected to associate with Parkinson's disease and Crohn's disease at conjunctional false discovery rate under 0.01 and 1359 variants in 15 loci were pleiotropic to Parkinson's disease and ulcerative colitis. Among the identified pleiotropic loci, 23 are novel and have never been associated with both phenotypes. A mixture of loci conferring either same or opposing genetic effects on two phenotypes was also observed. Positional and expression quantitative trait loci mapping prioritized 296 and 253 genes for Parkinson's disease with Crohn's disease and ulcerative colitis, respectively, among which only <10% are differentially expressed in both colon and substantia nigra. These genes were identified to overrepresent in pathways regulating gene expression and post-translational modification beyond several immune-related pathways enriched by major histocompatibility complex genes. In conclusion, we found robust evidence for a genetic link between Parkinson's disease and inflammatory bowel disease. The identified genetic overlap is complex at the locus and gene levels, indicating the presence of both synergistic and antagonistic pleiotropy. At the functional level, our findings implied a role of immune-centered mechanisms in the reported gut-brain connection.

Gastrointestinal biopsy of normal mucosa or nonspecific inflammation and risk of neurodegenerative disease: Nationwide matched cohort study.

BACKGROUND AND PURPOSE: Evidence has accumulated to support the early involvement of altered gastrointestinal (GI) function in neurodegenerative disease. However, risk of Alzheimer disease (AD) and Parkinson disease (PD) among individuals with a GI biopsy of normal mucosa or nonspecific inflammation is unknown. METHODS: This matched cohort study included all individuals in Sweden with a GI biopsy of normal mucosa (n = 480,346) or nonspecific inflammation (n = 655,937) during 1965-2016 (exposed group) as well as their individually matched population references and unexposed full siblings. A flexible parametric model and stratified Cox model were used to estimate hazard ratio (HR) and its 95% confidence interval (CI). RESULTS: Individuals with normal mucosa or nonspecific inflammation had a higher risk of AD and PD during the 20 years after biopsy. Compared with the population references, individuals with normal mucosa had an increased risk of AD (incidence rate [IR] difference = 13.53 per 100,000 person-years, HR [95% CI] = 1.15 [1.11-1.20]) and PD (IR difference = 6.72, HR [95% CI] = 1.16 [1.10-1.23]). Elevated risk was also observed for nonspecific inflammation regarding AD (IR difference = 13.28, HR [95% CI] = 1.11 [1.08-1.14]) and PD (IR difference = 6.83, HR [95% CI] = 1.10 [1.06-1.14]). Similar results were observed in subgroup and sensitivity analyses and when comparing with their unexposed siblings. CONCLUSIONS: Individuals with a GI biopsy of normal mucosa or nonspecific inflammation had an increased risk of AD and PD. This adds new evidence of the early involvement of GI dysfunction in neurodegenerative disease.

Hospital-treated infections in early- and mid-life and risk of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis: A nationwide nested case-control study in Sweden.

BACKGROUND: Experimental observations have suggested a role of infection in the etiology of neurodegenerative disease. In human studies, however, it is difficult to disentangle whether infection is a risk factor or rather a comorbidity or secondary event of neurodegenerative disease. To this end, we examined the risk of 3 most common neurodegenerative diseases in relation to previous inpatient or outpatient episodes of hospital-treated infections. METHODS AND FINDINGS: We performed a nested case-control study based on several national registers in Sweden. Cases were individuals newly diagnosed with Alzheimer's disease (AD), Parkinson's disease (PD), or amyotrophic lateral sclerosis (ALS) during 1970 to 2016 in Sweden, identified from the National Patient Register. For each case, 5 controls individually matched to the case on sex and year of birth were randomly selected from the general population. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) with adjustment for potential confounders, including sex, year of birth, area of residence, educational attainment, family history of neurodegenerative disease, and Charlson comorbidity index. Infections experienced within 5 years before diagnosis of neurodegenerative disease were excluded to reduce the influence of surveillance bias and reverse causation. The analysis included 291,941 AD cases (median age at diagnosis: 76.2 years; male: 46.6%), 103,919 PD cases (74.3; 55.1%), and 10,161 ALS cases (69.3; 56.8%). A hospital-treated infection 5 or more years earlier was associated with an increased risk of AD (OR = 1.16, 95% CI: 1.15 to 1.18, P < 0.001) and PD (OR = 1.04, 95% CI: 1.02 to 1.06, P < 0.001). Similar results were observed for bacterial, viral, and other infections and among different sites of infection including gastrointestinal and genitourinary infections. Multiple infections before age 40 conveyed the greatest risk of AD (OR = 2.62, 95% CI: 2.52 to 2.72, P < 0.001) and PD (OR = 1.41, 95% CI: 1.29 to 1.53, P < 0.001). The associations were primarily due to AD and PD diagnosed before 60 years (OR = 1.93, 95% CI: 1.89 to 1.98 for AD, P < 0.001; OR = 1.29, 95% CI: 1.22 to 1.36 for PD, P < 0.001), whereas no association was found for those diagnosed at 60 years or older (OR = 1.00, 95% CI: 0.98 to 1.01 for AD, P = 0.508; OR = 1.01, 95% CI: 0.99 to 1.03 for PD, P = 0.382). No association was observed for ALS (OR = 0.97, 95% CI: 0.92 to 1.03, P = 0.384), regardless of age at diagnosis. Excluding infections experienced within 10 years before diagnosis of neurodegenerative disease confirmed these findings. Study limitations include the potential misclassification of hospital-treated infections and neurodegenerative diseases due to incomplete coverage of the National Patient Register, as well as the residual confounding from unmeasured risk or protective factors for neurodegenerative diseases. CONCLUSIONS: Hospital-treated infections, especially in early- and mid-life, were associated with an increased risk of AD and PD, primarily among AD and PD cases diagnosed before 60 years. These findings suggest that infectious events may be a trigger or amplifier of a preexisting disease process, leading to clinical onset of neurodegenerative disease at a relatively early age. However, due to the observational nature of the study, these results do not formally prove a causal link.

Glucocerebrosidase variant T369M is not a risk factor for Parkinson's disease in Sweden.

INTRODUCTION: Genetic variants in the Beta-glucocerebrosidase gene (GBA1) is a known risk factor for Parkinson's disease. The GBA1 mutations L444P, N370S and many other have been shown to associate with the disease in populations with diverse background. Some GBA1 polymorphisms have a less pronounced effect, and their pathogenicity has been debated. We have previously found associations with L444P, N370S and E326K and Parkinson's disease in Sweden. METHOD: In this study we used pyrosequencing to genotype the T369M variant in a large Swedish cohort consisting of 1,131 patients with idiopathic Parkinson's disease, and 1,594 control subjects to evaluate the possibility of this variant conferring an increased risk for Parkinson's disease. RESULTS: The minor allele frequency was 2.15% in patients and 1.76% in controls. Statistical analysis showed that there was no significant difference in allele frequency between patients and control subjects, p-value 0.37, Odds Ratio 1.23 with a 95% confidence interval of 0.82-1.83. CONCLUSION: Our results suggest that T369M is not a risk factor for Parkinson's disease in the Swedish population.

Mendelian randomization study on the causal effects of tumor necrosis factor inhibition on coronary artery disease and ischemic stroke among the general population.

BACKGROUND: Tumor necrosis factor (TNF) is a potent inflammatory cytokine that has been causally associated with coronary artery disease (CAD) and ischemic stroke (IS), implying opportunities for disease prevention by anti-TNF therapeutics. METHODS: Leveraging summary statistics of several genome-wide association studies (GWAS), we assessed the repurposing potential of TNF inhibitors for CAD and IS using drug-target Mendelian randomization (MR) design. Pharmacologic blockade of the pro-inflammatory TNF signalling mediated by TNF receptor 1 (TNFR1) was instrumented by four validated variants. Causal effects of TNF/TNFR1 blockade on CAD (Ncase/control upto 122,733/424,528) and IS (Ncase/control upto 60,341/454,450) were then estimated via various MR estimators using circulating C-reactive protein (CRP; NGWAS=204,402) as downstream biomarker to reflect treatment effect. Associations of a functional variant, rs1800693, with CRP, CAD and IS were also examined. FINDINGS: No protective effect of TNF/TNFR1 inhibition on CAD or IS was observed. For every 10% decrease of circulating CRP achieved by TNF/TNFR1 blockade, odds ratio was 0.98 (95% confidence interval [CI]: 0.60-1.60) for CAD and 0.77 (95% CI: 0.36-1.63) for IS. Findings remained null in all supplement analyses. INTERPRETATION: Our findings do not support TNFR1 as a promising target for CAD or IS prevention among the general population. Future research is warranted to investigate whether the detrimental effect of circulating TNF on CAD and IS might be counteracted by modulating other relevant drug targets. FUNDING: No.

Neuroticism, Smoking, and the Risk of Parkinson's Disease.

BACKGROUND: The relationship among neuroticism, smoking, and Parkinson's disease (PD) is less examined. OBJECTIVE: To examine the causal associations between neuroticism, smoking initiation, and the risk of PD. METHODS: We performed a two-sample Mendelian randomization (MR) design in a network framework. Summary statistics from meta-analyses of genome-wide association studies (GWAS) were based on large cohorts of European ancestry. Study participants were from various cohort studies for neuroticism and smoking initiation, and case-control studies or cohort studies of PD from previously published GWAS meta-analyses. Patients with PD were ascertained from either clinical visit or self-reported. RESULTS: The two-sample MR analysis showed no evidence for a causal association between neuroticism and PD risk (odds ratio [OR] 0.86, 95%confidence intervals [CIs] 0.67 to 1.12). While we did not find a significant association between neuroticism and PD, one SNP, rs58879558 (located in MAPT region), was associated with both neuroticism and PD. We found a significant association of neuroticism on smoking initiation (OR: 1.10, 95%CI: 1.05 to 1.14). Further, our results provided evidence for a protective effect of smoking initiation on the risk of PD (OR: 0.75, 95%CI: 0.62 to 0.91). CONCLUSION: These findings do not support a causal association of neuroticism on PD risk. However, they provide evidence for a causal relationship between neuroticism and smoking initiation and a strong causal effect of smoking initiation on a reduced risk of PD.

Heart rate, intelligence in adolescence, and Parkinson's disease later in life.

To investigate whether physical and cognitive fitness measured in late adolescence was associated with future risk of Parkinson's disease (PD). The cohort included 1,259,485 Swedish men with physical fitness, body mass index (BMI), resting heart rate (RHR), blood pressure, intelligence quotient (IQ), and stress resilience measured at the age of 17-20 in relation to conscription. Incident cases of PD were ascertained from the Swedish Patient Register. Hazard ratios were estimated from Cox models, after controlling for multiple confounders. We further performed Mendelian randomization (MR) analyses to assess the causality of the associations, using GWAS summary statistics with > 800,000 individuals. During follow-up, we identified 1,034 cases of PD (mean age at diagnosis = 53). Men with an RHR > 100 beats per minute had a higher risk of PD compared to men with an RHR of 60-100 beats per minute (HR = 1.47; 95% CI = 1.08-1.99). Men with IQ above the highest tertile had a higher risk of PD compared to men with an IQ below the lowest tertile (HR = 1.46; 95% CI = 1.19-1.79). We found no association for physical fitness, BMI, blood pressure, or stress resilience. A causal relationship was suggested by the MR analysis between IQ and PD, but not between RHR and PD. RHR and IQ in late adolescence were associated with a higher risk of PD diagnosed at relatively young age. The association of IQ with PD is likely causal, whereas the association of RHR with PD suggests that altered cardiac autonomic function might start before 20 years of age in PD.

Association Between Microscopic Colitis and Parkinson's Disease in a Swedish Population.

BACKGROUND: Gastrointestinal inflammation has been linked with Parkinson's disease (PD). Microscopic colitis (MC) is an intestinal inflammatory disease with unknown relationship with PD. OBJECTIVE: This study aimed to examine the association of MC with PD risk. METHODS: In this nationwide matched cohort study in Sweden, PD incidence was compared between 12,609 patients with histologically confirmed MC and a matched population cohort of 58,879 MC-free individuals and a sibling cohort comprising all unaffected siblings of the MC patients (NMC /NSibling  = 6281/12,351). Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression models. RESULTS: During a mean follow-up of ~7 years, we identified 449 incident PD diagnoses among the MC patients and the population cohort. Overall, MC was associated with an adjusted HR of 1.76 for PD, but the association attenuated substantially during follow-up. In the time-varying effects model, PD hazard was 3.45-fold (95% CI: 2.42, 4.93) higher during the first 2 years after biopsy and 1.80-fold (95% CI: 1.23, 2.64) higher during the following 3 years among MC versus MC-free individuals but was not different beyond 5 years after biopsy (HR: 1.03; 95% CI: 0.68, 1.54). This temporal pattern of MC-PD associations persisted when comparing MC patients to their siblings. In a post hoc case-control analysis, we also detected a strong association between MC and preexisting PD (odds ratio: 3.46; 95% CI: 2.91, 4.12). CONCLUSIONS: Our findings suggest that MC may not be a risk factor for PD; instead, it may co-occur with PD as a comorbidity or develop after a diagnosis of PD. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Tumor Necrosis Factor Inhibition and Parkinson Disease: A Mendelian Randomization Study.

OBJECTIVE: To evaluate the effects of long-term tumor necrosis factor (TNF) inhibition on the risk and age at onset of Parkinson disease (PD), we performed a 2-sample Mendelian randomization study using genome-wide association studies (GWAS) summary statistics. METHODS: Genetic variants in the vicinity of TNFRSF1A, the gene encoding TNF receptor 1 (TNFR1), were identified as predictive of pharmacologic blockade of TNFR1 signaling by anti-TNF therapy, based on genetic associations with lower circulating C-reactive protein (CRP; GWAS n = 204,402). The effects of TNF-TNFR1 inhibition were estimated for PD risk (ncases/controls = 37,688/981,372) and age at PD onset (n = 28,568) using GWAS data from the International Parkinson's Disease Genomics Consortium and 23andMe, Inc. To validate variants as proxies of long-term anti-TNF treatment, we also assessed whether variant associations reflected anticipated effects of TNFR1 inhibition on Crohn disease, ulcerative colitis, and multiple sclerosis risk (n = 38,589-45,975). RESULTS: TNF-TNFR1 signaling inhibition was not estimated to affect PD risk (odds ratio [OR] per 10% lower circulating CRP = 0.99; 95% confidence interval [CI] 0.91-1.08) or age at onset (0.13 years later onset; 95% CI -0.66 to 0.92). In contrast, genetically indexed TNF-TNFR1 signaling blockade predicted reduced risk of Crohn disease (OR 0.75; 95% CI 0.65-0.86) and ulcerative colitis (OR 0.84; 95% CI 0.74-0.97) and increased multiple sclerosis risk (OR 1.57; 95% CI 1.36-1.81). Findings were consistent across models using different genetic instruments and Mendelian randomization estimators. CONCLUSIONS: Our findings do not imply that TNF-TNFR1 signaling inhibition will prevent or delay PD onset. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that TNF-TNFR1 signaling inhibition is not associated with the risk or age at onset of PD.

Irritable bowel syndrome and Parkinson's disease risk: register-based studies.

To examine whether irritable bowel syndrome (IBS) was related to the future risk of Parkinson's disease (PD), we conducted a nested case-control study in the Swedish total population including 56,564 PD cases identified from the Swedish Patient Register and 30 controls per case individually matched by sex and year of birth. Odds ratios (ORs) with 95% confidence intervals (CIs) for having a prior diagnosis of IBS were estimated using conditional logistic regression. We furthermore conducted a cohort study using the Swedish Twin Registry following 3046 IBS patients identified by self-reported abdominal symptoms and 41,179 non-IBS individuals. Through Cox proportional hazard models, we estimated hazard ratios (HRs) and 95% CIs for PD risk. In the nested case-control study, 253 (0.4%) PD cases and 5204 (0.3%) controls had a previous IBS diagnosis. IBS diagnosis was associated with a 44% higher risk of PD (OR = 1.44, 95% CI 1.27-1.63). Temporal relationship analyses showed 53% and 38% increased risk of PD more than 5 and 10 years after IBS diagnosis, respectively. In the cohort analysis based on the Swedish Twin Registry, there was no statistically significantly increased risk of PD related to IBS (HR = 1.25, 95% CI = 0.87-1.81). Our results suggest a higher risk of PD diagnosis after IBS. These results provide additional evidence supporting the importance of the gut-brain axis in PD.

Longitudinal Monitoring of Parkinson's Disease in Different Ethnic Cohorts: The DodoNA and LONG-PD Study.

Background: Different factors influence severity, progression, and outcomes in Parkinson's disease (PD). Lack of standardized clinical assessment limits comparison of outcomes and availability of well-characterized cohorts for collaborative studies. Methods: Structured clinical documentation support (SCDS) was developed within the DNA Predictions to Improve Neurological Health (DodoNA) project to standardize clinical assessment and identify molecular predictors of disease progression. The Longitudinal Clinical and Genetic Study of Parkinson's Disease (LONG-PD) was launched within the Genetic Epidemiology of Parkinson's disease (GEoPD) consortium using a Research Electronic Data Capture (REDCap) format mirroring the DodoNA SCDS. Demographics, education, exposures, age at onset (AAO), Unified Parkinson's Disease Rating Scale (UPDRS) parts I-VI or Movement Disorders Society (MDS)-UPDRS, Montreal Cognitive Assessment (MoCA)/Short Test of Mental Status (STMS)/Mini Mental State Examination (MMSE), Geriatric Depression Scale (GDS), Epworth Sleepiness Scale (ESS), dopaminergic therapy, family history, nursing home placement, death and blood samples were collected. DodoNA participants (396) with 6 years of follow-up and 346 LONG-PD participants with up to 3 years of follow-up were analyzed using group-based trajectory modeling (GBTM) focused on: AAO, education, family history, MMSE/MoCA/STMS, UPDRS II-II, UPDRS-III tremor and bradykinesia sub-scores, Hoehn and Yahr staging (H&Y) stage, disease subtype, dopaminergic therapy, and presence of autonomic symptoms. The analysis was performed with either cohort as the training/test set. Results: Patients are classified into slowly and rapidly progressing courses by AAO, MMSE score, H &Y stage, UPDRS-III tremor and bradykinesia sub-scores relatively early in the disease course. Late AAO and male sex assigned patients to the rapidly progressing group, whereas tremor to the slower progressing group. Classification is independent of which cohort serves as the training set. Frequencies of disease-causing variants in LRRK2 and GBA were 1.89 and 2.96%, respectively. Conclusions: Standardized clinical assessment provides accurate phenotypic characterization in pragmatic clinical settings. Trajectory analysis identified two different trajectories of disease progression and determinants of classification. Accurate phenotypic characterization is essential in interpreting genomic information that is generated within consortia, such as the GEoPD, formed to understand the genetic epidemiology of PD. Furthermore, the LONGPD study protocol has served as the prototype for collecting standardized phenotypic information at GEoPD sites. With genomic analysis, this will elucidate disease etiology and lead to targeted therapies that can improve disease outcomes.

Appendectomy, Tonsillectomy and Parkinson's Disease Risk: A Swedish Register-Based Study.

Introduction: The gut-brain hypothesis proposes that Parkinson's disease (PD) pathology may start in the gut and later spread to the brain in a prion-like manner. As PD pathology is redundant in the appendix and tonsils, which are important gut-associated lymphoid tissues, we examined whether appendectomy and tonsillectomy were associated with later PD risk. Methods: The nested case-control study included 78,650 PD patients born in 1900-1980 and with a diagnosis of PD between 1964 and 2010. For each PD patient, we randomly selected 40 non-PD controls individually matched for sex and year of birth at the date of PD diagnosis. Appendectomy and tonsillectomy before PD diagnosis were ascertained from the Swedish Patient Register from 1964 onward. We calculated odds ratios (OR) with 95% confidence intervals (CI) using conditional logistic regression adjusting for country of birth, highest achieved education, COPD, comorbidity index, and number of hospital visits. Results: Overall, we found 16% lower risk of PD linked to previous appendectomy (OR = 0.84, 95% CI: 0.80-0.88) and 8% lower risk of PD linked to previous tonsillectomy, although not statistically significant (OR = 0.92, 95% CI: 0.81-1.04). A 7 and 15% lower risk of PD was also noted ≥20 years after appendectomy and tonsillectomy, respectively. Similar associations were observed for men and women but were stronger for PD diagnosed after age 60. Conclusion: Appendectomy and potentially also tonsillectomy were associated with a lower risk PD. A potential mechanism may involve surgical removal of alpha-synuclein redundancy in the appendix and tonsils.

Vagotomy and subsequent risk of inflammatory bowel disease: a nationwide register-based matched cohort study.

BACKGROUND: The vagus nerve provides essential parasympathetic innervation to the gastrointestinal system and is known to have anti-inflammatory properties. AIMS: To explore the relationship between vagotomy and the risk of inflammatory bowel disease (IBD) and its major categories: Crohn's disease (CD) and ulcerative colitis (UC). METHODS: A matched cohort comprising 15 637 patients undergoing vagotomy was identified through the Swedish Patient Register from 1964 to 2010. Each vagotomised patient was matched for birth year and gender with 40 nonvagotomised individuals on the date of vagotomy. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for IBD using flexible parametric models adjusted for matching variables, year of vagotomy, birth country, chronic obstructive pulmonary disease and comorbidity index. RESULTS: We observed 119 (0.8%) patients with vagotomy developed IBD compared to 3377 (0.5%) IBD cases in nonvagotomised individuals. The crude incidence of IBD (per 1000 person-years) was 0.38 for vagotomised patients and 0.25 for nonvagotomised individuals. We observed a time-dependent elevated risk of IBD associated with vagotomy, for instance, the HR (95% CI) was 1.80 (1.40-2.31) at year 5 and 1.49 (1.14-1.96) at year 10 post-vagotomy. The association appeared to be stronger for truncal than selective vagotomy and limited to CD (HR was 3.63 [1.94-6.80] for truncal and 2.06 [1.49-2.84] for selective vagotomy) but not UC (1.36 [0.71-2.62] for truncal and 1.25 [0.95-1.63] for selective vagotomy). CONCLUSIONS: We found a positive association between vagotomy and later IBD, particularly for CD. The finding indirectly underlines the beneficial role of the vagal tone in IBD.

Association of Stress-Related Disorders With Subsequent Neurodegenerative Diseases.

Importance: Posttraumatic stress disorder (PTSD) has been associated with increased risk for dementia. Less is known, however, about other stress-related disorders and their associations with neurodegenerative diseases. Objective: To examine the association between stress-related disorders and risk for neurodegenerative diseases. Design, Setting, and Participants: This population-matched and sibling cohort study was conducted in Sweden using data from nationwide health registers, including the Swedish National Patient Register. Individuals who received their first diagnosis of stress-related disorders between January 1, 1987, and December 31, 2008, were identified. Individuals who had a history of neurodegenerative diseases, had conflicting or missing information, had no data on family links, or were aged 40 years or younger at the end of the study were excluded. Individuals with stress-related disorders were compared with the general population in a matched cohort design; they were also compared with their siblings in a sibling cohort. Follow-up commenced from the age of 40 years or 5 years after the diagnosis of stress-related disorders, whichever came later, until the first diagnosis of a neurodegenerative disease, death, emigration, or the end of follow-up (December 31, 2013), whichever occurred first. Data analyses were performed from November 2018 to April 2019. Exposures: Diagnosis of stress-related disorders (PTSD, acute stress reaction, adjustment disorder, and other stress reactions). Main Outcomes and Measurements: Neurodegenerative diseases were identified through the National Patient Register and classified as primary or vascular. Alzheimer disease, Parkinson disease, and amyotrophic lateral sclerosis were evaluated separately. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) with 95% CIs after controlling for multiple confounders. Results: The population-matched cohort included 61 748 exposed individuals and 595 335 matched unexposed individuals. A total of 44 839 exposed individuals and their 78 482 unaffected full siblings were included in the sibling cohort analysis. The median (interquartile range) age at the start of follow-up was 47 (41-56) years, and 24 323 (39.4%) of the exposed individuals were male. The median (interquartile range) follow-up was 4.7 (2.1-9.8) years. Compared with unexposed individuals, individuals with a stress-related disorder were at an increased risk of neurodegenerative diseases (HR, 1.57; 95% CI, 1.43-1.73). The risk increase was greater for vascular neurodegenerative diseases (HR, 1.80; 95% CI, 1.40-2.31) than for primary neurodegenerative diseases (HR, 1.31; 95% CI, 1.15-1.48). A statistically significant association was found for Alzheimer disease (HR, 1.36; 95% CI, 1.12-1.67) but not Parkinson disease (HR, 1.20; 95% CI, 0.98-1.47) or amyotrophic lateral sclerosis (HR, 1.20; 95% CI, 0.74-1.96). Results from the sibling cohort corroborated results from the population-matched cohort. Conclusions and Relevance: This study showed an association between stress-related disorders and an increased risk of neurodegenerative diseases. The relative strength of this association for vascular neurodegenerative diseases suggests a potential cerebrovascular pathway.