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Background: Two studies that examined the interaction between HLA-DRB1 and smoking in Parkinson's disease (PD) yielded findings in opposite directions., Objective: To perform a large-scale independent replication of the HLA-DRB1 × smoking interaction., Methods: We genotyped 182 single nucleotide polymorphism (SNPs) associated with smoking initiation in 12 424 cases and 9480 controls to perform a Mendelian randomization (MR) analysis in strata defined by HLA-DRB1., Results: At the amino acid level, a valine at position 11 (V11) in HLA-DRB1 displayed the strongest association with PD. MR showed an inverse association between genetically predicted smoking initiation and PD only in absence of V11 (odds ratio, 0.74, 95% confidence interval, 0.59-0.93, P Interaction  = 0.028). In silico predictions of the influence of V11 and smoking-induced modifications of α-synuclein on binding affinity showed findings consistent with this interaction pattern., Conclusions: Despite being one of the most robust findings in PD research, the mechanisms underlying the inverse association between smoking and PD remain unknown. Our findings may help better understand this association. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Biochemical and clinical biomarkers correlate with progression rate and disease severity in Parkinson's disease (PD) but are not sufficiently studied in late PD., Objective: To examine how serum neurofilament light chain (S-NfL) alone or combined with clinical classifications predicts PD outcome in later disease stages., Methods: Eighty-five patients with 7.9±5.1 years of PD duration were included in an observational cohort. Clinical scores were obtained at two separate examinations 8.2±2.0 years apart. S-NfL levels were determined with single molecule array (SiMoA). Five predefined disease progression milestones were assessed. After affirming combination potential of S-NfL and either of two clinical classifications, three combined models were constructed based on these factors and age at onset in different combinations., Results: S-NfL levels showed significant hazard ratios for four out of five disease progression milestones: walking-aid usage (HR 3.5; 95% CI 1.4-8.5), nursing home living (5.1; 2.1-12.5), motor end-stage (6.2; 2.1-17.8), and death (4.1; 1.7-9.7). Higher S-NfL levels were associated with lower ability in activities of daily living and poorer cognition at baseline and/or at follow-up. Combined models showed significantly improved area under receiver operating characteristic curves (0.77-0.91) compared to S-NfL levels alone (0.68-0.71) for predicting the five disease milestones., Conclusion: S-NfL levels stratified patients according to their likelihood to reach clinically relevant progression milestones during this long-term observational study. S-NfL alone reflected motor and social outcomes in later stages of PD. Combining S-NfL with clinical factors was possible and exploratory combined models improved prognostic accuracy.

Parkinson's disease shows a heterogeneous course and different clinical subtyping systems have been described. To compare the capabilities of two clinical classification systems, motor-phenotypes, and a simplified clinical motor-nonmotor subtyping system, a cohort was included at mean 7.9 ± 5.3 years of disease duration, classified using both clinical systems, and reexamined and reclassified at the end of an observation period. Time-points were retrospectively extracted for five major disease milestones: death, dementia, Hoehn and Yahr stage 5, nursing home living, and walking aid use. Eighty-nine patients were observed for 8.1 ± 2.7 years after inclusion. Dementia developed in 32.9% of the patients and 36.0-67.4% reached the other milestones. Motor-phenotypes were unable to stratify risks during this period, but the worst compared with the more favorable groups in the motor-nonmotor system conveyed hazard ratios between 2.6 and 63.6 for all milestones. A clear separation of risks for dying, living at the nursing home, and reaching motor end-stage was also shown when using only postural instability and gait disorder symptoms, without weighing them against the severity of the tremor. At reexamination, 29.4% and 64.7% of patients had changed classification groups in the motor-phenotype and motor-nonmotor systems, respectively. The motor-nonmotor system thus stratified risks of reaching crucial outcomes in mid-late Parkinson's disease far better than the well-studied motor-phenotypes. Removing the tremor aspect of motor-phenotypes clearly improved this system, however. Classifications in both systems became unstable over time. The simplification of the motor-nonmotor system was easily applicable and showed potential as a prognostic marker during a large part of Parkinson's disease., (© 2021. The Author(s).)