Background White matter hyperintensities (WMH) on magnetic resonance imaging may influence clinical presentation in patients with Parkinson's disease (PD), although their significance and pathophysiological origins remain unresolved. Studies examining WMH have identified pathogenic variants in NOTCH3 as an underlying cause of inherited forms of cerebral small vessel disease. Methods We examined NOTCH3 variants, WMH volumes, and clinical correlates in 139 PD patients in the Ontario Neurodegenerative Disease Research Initiative cohort. Results We identified 13 PD patients (~9%) with rare (<1% of general population), nonsynonymous NOTCH3 variants. Bayesian linear modeling demonstrated a doubling of WMH between variant negative and positive patients (3.1 vs. 6.9 mL), with large effect sizes for periventricular WMH (d = 0.8) and lacunes (d = 1.2). Negative correlations were observed between WMH and global cognition (r = −0.2). Conclusion The NOTCH3 rare variants in PD may significantly contribute to increased WMH burden, which in turn may negatively influence cognition. © 2020 International Parkinson and Movement Disorder Society

No abstract

ABSTRACT:Background/Objective:Apolipoprotein E (APOE) E4 is the main genetic risk factor for Alzheimer’s disease (AD). Due to the consistent association, there is interest as to whether E4 influences the risk of other neurodegenerative diseases. Further, there is a constant search for other genetic biomarkers contributing to these phenotypes, such as microtubule-associated protein tau (MAPT) haplotypes. Here, participants from the Ontario Neurodegenerative Disease Research Initiative were genotyped to investigate whether the APOE E4 allele or MAPT H1 haplotype are associated with five neurodegenerative diseases: (1) AD and mild cognitive impairment (MCI), (2) amyotrophic lateral sclerosis, (3) frontotemporal dementia (FTD), (4) Parkinson’s disease, and (5) vascular cognitive impairment.Methods:Genotypes were defined for their respective APOE allele and MAPT haplotype calls for each participant, and logistic regression analyses were performed to identify the associations with the presentations of neurodegenerative diseases.Results:Our work confirmed the association of the E4 allele with a dose-dependent increased presentation of AD, and an association between the E4 allele alone and MCI; however, the other four diseases were not associated with E4. Further, the APOE E2 allele was associated with decreased presentation of both AD and MCI. No associations were identified between MAPT haplotype and the neurodegenerative disease cohorts; but following subtyping of the FTD cohort, the H1 haplotype was significantly associated with progressive supranuclear palsy.Conclusion:This is the first study to concurrently analyze the association of APOE isoforms and MAPT haplotypes with five neurodegenerative diseases using consistent enrollment criteria and broad phenotypic analysis.

Purpose: The natural history and clinical manifestations of dural metastases (DM) in castrate-resistant prostate cancer (CRPC) will change with advances in new hormonal therapy. Here, we characterised the incidence, clinical presentation, and outcomes of patients with DM in a contemporary patient cohort with CRPC. Methods: We retrospectively reviewed our CRPC database from 2012 to 2020. The primary outcome was the diagnosis of DM, defined as metastasis to the dura mater in the brain or spine. We describe the presenting symptoms, biochemistry, radiologic findings, and therapy sequence for all DM patients. Multivariable logistic regression was performed to identify predictors of DM. Results: Six of the 275 patients (2.2%) with CRPC developed DM. The average age of CRPC diagnosis for patients with DM was 65.6 years. Mean patient survival was 4.5 months after the diagnosis of DM. At the time of CRPC diagnosis, patients who developed DM were significantly younger, had lower baseline haemoglobin, higher lactate dehydrogenase (LDH), and elevated alkaline phosphatase (ALP) compared to those without DM. On multivariable analysis, younger age of CRPC diagnosis was found to be a predictor for DM. Conclusion: The presence of neurological symptoms in the context of younger age, anaemia, and elevated baseline LDH and ALP are associated with DM in CRPC. Level of Evidence: 4