Nigral pathology and parkinsonian signs in elders without Parkinson disease

Abstract

Objective: Motor symptoms such as mild parkinsonian signs are common in older persons, but little is known about their underlying neuropathology. We tested the hypothesis that nigral pathology is related to parkinsonism in older persons without Parkinson disease (PD).

Methods: More than 2,500 persons participating in the Religious Orders Study or the Memory and Aging Project agreed to annual assessment of parkinsonism with a modified version of the Unified Parkinson Disease Rating Scale and brain donation. Brains from 744 deceased participants without PD were assessed for nigral neuronal loss and α-synuclein immunopositive Lewy bodies.

Results: Mean age at death was 88.5 years. Mean global parkinsonism was 18.6 (standard deviation, 11.90). About ⅓ of cases had mild or more severe nigral neuronal loss, and about 17% had Lewy bodies. In separate regression models that adjusted for age, sex, and education, nigral neuronal loss and Lewy bodies were both related to global parkinsonism (neuronal loss: estimate, 0.231; standard error [SE], 0.068; p < 0.001; Lewy bodies: estimate, 0.291; SE, 0.133; p = 0.029). Employing a similar regression model that included both measures, neuronal loss remained associated with global parkinsonism (neuronal loss: estimate, 0.206; SE, 0.075; p = 0.006). By contrast, the association between Lewy bodies and global parkinsonism was attenuated by >60% and was no longer significant (Lewy bodies: estimate, 0.112; SE, 0.148; p = 0.447), suggesting that neuronal loss may mediate the association of Lewy bodies with global parkinsonism.

Interpretation: Nigral pathology is common in persons without PD and may contribute to loss of motor function in old age.

Figure 1. Spectrum of Nigral Neuronal Degeneration

Substantia nigra showing no neuronal loss (A), mild neuronal loss(B), moderate neuronal loss (C) and severe neuronal loss (D). The inset in panel C shows a neuron containing Lewy bodies. Severe neuronal loss in panel D is associated with atrophy of remaining neurons and astrogliosis (arrowheads). The inset in panel D shows fibrillary astrocytes with immunoreactivity with glial fibrillary acid protein [Novacastra Laboratories Ltd., Newcastle upon Tyne, UK; GFAP 1:1000 antibody dilution]. Scale bar for panels A–D = 200μm; Scale bar for both insets = 12.5 μm