Genetics and Pathology Data Highlight Diagnostic Complexity in Parkinsonian Disorders

Clinical diagnosis of parkinsonian movement disorders remains complicated by overlapping features, frequent copathology, and genetic heterogeneity, according to findings from a multicenter autopsy-confirmed brain bank study published in JAMA Neurology. Investigators reported that integrating genetic and neuropathologic data may improve diagnostic accuracy and support more biologically informed approaches to clinical trial design.

The cross-sectional study included 3353 eligible brain donors with available genetic data from 11 academic brain banks in the United Kingdom, United States, and Australia. Donors were enrolled between 1985 and 2024 and included individuals with clinical diagnoses of Parkinson disease (PD), Parkinson disease dementia (PDD), dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP), corticobasal syndrome, multiple system atrophy (MSA), or neurologically normal controls. The mean age at death was 76.8 years, and 61.8% of donors were male.

Clinicopathologic and Genetic Findings

• When clinical diagnoses were compared with autopsy findings, approximately 10% to 20% of movement disorder diagnoses were discordant with the primary pathology.
• Lewy body pathology was more consistently confirmed at autopsy in donors with PDD or DLB than in those diagnosed with PD without dementia (odds ratio [OR], 1.96; 95% CI, 1.30 to 3.04; P=7.2 × 10−4).
• Among neurologically normal controls, 4.4% had Lewy pathology at autopsy.
• Mixed pathology was common: Alzheimer disease copathology was found in 40.0% of Lewy body disease cases.
• GBA1 variant carriers had a more extensive Lewy body pathology burden than both noncarriers (OR, 1.94; 95% CI, 1.24 to 3.03; P=.01) and carriers (OR, 7.44; 95% CI, 2.16 to 25.64; P=.01) of LRRK2 variants.
• In survival analyses, LRRK2 variant carriers had longer survival than individuals without identified pathogenic variants.

The study also identified ancestry-associated differences in pathology. South Asian donors were more likely to have PSP pathology, whereas Ashkenazi Jewish donors were more likely to have Lewy body disease, independent of GBA1 and LRRK2 variant status. The authors noted that sample sizes for non-European ancestry groups were limited and that these findings may reflect recruitment bias rather than true biologic variation.

Among clinically diagnosed movement disorders, corticobasal syndrome showed the lowest positive predictive value for corticobasal degeneration pathology, reflecting the heterogeneous causes of the clinical syndrome. Alzheimer disease and PSP pathology were also identified among clinically diagnosed corticobasal syndrome cases.

Limitations included referral and sampling bias inherent to brain bank research, variability in neuropathologic staging across centers and time periods, incomplete documentation of some copathologies, and limited representation of non-European ancestry groups. The investigators stated that larger, systematically annotated brain bank datasets with broader ancestry representation may help support pathology-targeted diagnostics and genotype-informed therapies.

Source

Wu LY, du Toit T, Georgiades T, et al. Pathology and Genetics in a Global Cohort of Parkinsonian Disorders. JAMA Neurol. Published online June 08, 2026. doi:10.1001/jamaneurol.2026.1634