Decades of Parkinson’s disease neuropathology yield a sparse and underpowered map of neuronal vulnerability: a systematic review and meta-analysis

Parkinson’s disease is defined clinically by motor dysfunction, but its pathology is not confined to nigral dopaminergic neurons. Prominent non-motor features including cognitive impairment, autonomic failure and sleep disturbance indicate widespread neurodegeneration that remains incompletely characterised. We pre-registered and conducted a multilevel meta-analysis of 166 case-control post-mortem studies published between 1963 and 2025, mapping neuronal loss across 85 brain regions, 38 cell types and 145 region-cell populations. The evidence base behind this map is thin. Only 4 of 145 populations are adequately powered, and 82% of Allen Brain Atlas regions have never been quantified in Parkinson’s disease. A further 18 populations would reach adequate power with five or fewer additional studies, identifying an efficient route to closing current gaps. Noradrenergic neurons of the locus coeruleus degenerate to a similar extent as substantia nigra dopaminergic neurons, with both populations losing more than 60% of neurons. Cholinergic neurons of the basal nucleus and pedunculopontine tegmental nucleus and dopaminergic neurons of the ventral tegmental area show significant but less severe loss. These findings establish Parkinson’s disease as a multi-system neurodegenerative disorder and expose key gaps and biases in the existing literature.