For the millions living with movement disorders—and the clinicians guiding their care—accurate diagnosis is foundational to treatment decisions, prognosis, and trial eligibility. A large-scale autopsy-confirmed study now quantifies precisely how often that foundation cracks, and which genetic and ancestry-related factors correlate with misclassification and pathological variation.
Drawing on 3,353 brain donors enrolled between 1985 and 2024 across 11 academic brain banks in the United States, United Kingdom, and Australia, this multicenter retrospective analysis confirmed clinical diagnoses against neuropathological findings for seven movement disorder categories: Parkinson disease, Parkinson disease dementia, dementia with Lewy bodies, progressive supranuclear palsy, corticobasal syndrome, multiple system atrophy, and neurologically normal controls. Misdiagnosis rates ranged approximately from 10% upward depending on disorder type, with corticobasal syndrome and progressive supranuclear palsy historically among the most diagnostically challenging. The cohort also examined how specific genetic variant carrier status mapped onto pathological burden for both Lewy body and Alzheimer co-pathology, and whether genetically inferred ancestry introduced meaningful differences in these associations.
This study's strength lies in its size and multiancestry scope—rare for brain bank research, which has long been dominated by donors of European ancestry. That design choice matters enormously: ancestry-related differences in genetic risk architecture and pathological expression have been systematically understudied, and their inclusion here is a genuine methodological advance. The persistent misdiagnosis rates, even among highly specialized academic centers, reinforce the urgency of developing reliable in vivo biomarkers—CSF alpha-synuclein seed amplification assays and PET tau tracers are among the most promising candidates in current pipelines. For clinicians, these findings serve as a calibration reminder: clinical phenotyping, however sophisticated, carries meaningful error rates, and genetic context can meaningfully shift the pathological landscape. This is confirmatory of known diagnostic limitations but adds significant scale and ancestral diversity that elevates its practical weight.