Chiu, Shannon

Abstract Background Diabetes mellitus elevates Parkinson’s disease (PD) risk, via hypothesized cerebrovascular mediation. Whether the diabetes/prediabetes vascular-risk phenotype concentrates in cardiometabolic risk or macrovascular events across prodromal and clinically diagnosed PD remains unresolved. Objectives To quantify the vascular-risk burden associated with diabetes/prediabetes across the PPMI diagnostic cohorts to test whether this association differs by cohort. Methods Cross-sectional analysis of 413 PPMI participants (76 healthy controls, 145 prodromal PD, 192 clinically diagnosed PD) examined diabetes/prediabetes (n = 73) and seven vascular risk factors. The Vascular Burden Score (0 to 7) was a priori partitioned into microvascular and macrovascular sub-scores. Modified Poisson regression estimated adjusted prevalence ratios (aPR), adjusted for age, sex, and body mass index. A cohort-by-diabetes interaction tested cross-cohort consistency. Sensitivity analyses incorporated nigral diffusion tensor imaging (PD-risk biomarker) and FreeSurfer white matter hypointensity volume (cerebrovascular marker). Results Diabetes/prediabetes elevated Vascular Burden Score (β = 0.53, 95% CI 0.29 to 0.77, p < 0.001) versus non-diabetic participants, with a non-significant cohort-by-diabetes interaction (F = 0.29, p = 0.747). Three microvascular factors survived false discovery rate correction: obesity (aPR 2.28), hypertension (aPR 1.60), and hyperlipidemia (aPR 1.45). Macrovascular events showed no diabetic amplification (β = −0.06, p = 0.25). In the imaging-phenotyped subset, Vascular Burden Score components contributed classifier variance distinct from nigral microstructure. Conclusions Diabetes/prediabetes operationalize a microvascular cluster stable across prodromal and idiopathic PD. Cardiometabolic phenotyping may complement established PD-risk biomarkers (dopamine transporter SPECT, nigral diffusion), pending longitudinal validation linking vascular phenotype to dopaminergic markers.

Objective Positive α‐synuclein seed amplification assay (SAA) is a biomarker found in most people with Parkinson's disease (PD). We explored if free‐water (FW) imaging detects microstructural differences in the brains of patients with early PD with SAA+ or SAA– status. Methods We studied patients with PD with baseline diffusion imaging and α‐synuclein SAA data from the Parkinson's Progression Markers Initiative (PPMI). We compared FW, FW corrected fractional anisotropy (FA T ), and clinical characteristics between SAA+ and SAA– groups. We also applied the Automated Imaging Differentiation for Parkinsonism (AIDP) at baseline to classify PD versus atypical parkinsonism, stratified by SAA status. Results Among 462 participants (41 SAA– and 421 SAA+), individuals with SAA+ had hyposmia and shorter motor symptom duration before baseline magnetic resonance imaging (MRI). AIDP identified PD in 92.4% (n = 427, 91.6% had SAA+) and classified 7.6% as atypical parkinsonism (n = 35, 85.7% had SAA+). At baseline, SAA+ individuals had lower FW in the superior cerebellar peduncle, compared to SAA– (pFDR < 0.05). No significant differences in FA T were found between groups. Interpretation Positive α‐synuclein SAA was associated with focal microstructural differences but did not distinguish broader diffusion MRI (dMRI) changes across FW and FA T metrics. These findings indicate that molecular confirmation of synuclein aggregation (via SAA) provides limited stratification of neurodegeneration detected by FW imaging in early PD. ANN NEUROL 2026;100:295–304

AbstractINTRODUCTIONMales are disproportionately represented in dementia with Lewy bodies (DLB). Little is known regarding sex differences in cognitive, neuropsychiatric, and motor features of the prodromal stage of DLB.METHODSWe used National Alzheimer's Coordinating Center longitudinal data to examine cognitive, neuropsychiatric, and motor features in 120 males and 23 females 2 years prior to a clinical diagnosis of DLB.RESULTSMales were more likely than females to present with two or more core DLB clinical features 2 years prior to obtaining a diagnosis of dementia. Rapid eye movement sleep behavior disorder, cognitive fluctuations, bradykinesia, and rigidity were more common in males than females. Neuropsychological test performance was similar between groups.DISCUSSIONIn prodromal DLB, males exhibit a greater number of core features than females. Core DLB features may fall short in identifying females at risk. Additional work is needed to better understand the clinical profile of prodromal DLB in females.Highlights There are sex differences in the presentation and course of neurodegenerative disease. Findings from the National Alzheimer's Coordinating Center Uniform Data Set suggest there are sex differences in prodromal DLB symptoms. Females were less likely to demonstrate core clinical features of DLB prior to dementia diagnosis. This information can help inform clinical diagnostic criteria for prodromal DLB.