The severity of neurodegeneration and local burden of α-synuclein are closely coupled during disease progression in Parkinson’s disease (PD), a post-mortem study has found.
The study also casts doubt on the pathogenetic role of α-synuclein aggregates in elderly patients, since nigral neuronal loss was present before the local appearance of α-synuclein.
α-synuclein is a presynaptic protein that is the principal component of Lewy bodies but little is known about the temporal relationship between occurrence of α-synuclein pathology and neurodegeneration during disease progression.
To investigate, Anke Dijkstra (VU University Medical Center, Amsterdam, the Netherlands) compared pathological features of post-mortem human brain tissue from three groups: 20 people with incidental Lewy body disease (iLBD), 24 patients with PD and 12 age-matched controls.
Among PD patients, the mean age of disease onset was 67.9 years, the mean disease duration was 13.6 years and eight (36%) had dementia. The three groups had a similar mean age at death but mean Braak staging amyloid-β score was higher in PD patients than in the others.
Assessment of serial sections of brain tissue at the level of the oculomotor nerve revealed nigral neuronal loss in patients with iLBD and PD. The mean nigral neuronal density was almost 20% lower in iLBD patients (5015 cells/mm3) and 55% lower (2771 cells/mm3) in PD patients than in healthy controls (mean 6214 cells/mm3).
Neuronal density also differed significantly among Braak α-synuclein stages, the researchers report. There was an overall negative correlation between nigral neuronal density and Braak α-synuclein stages; furthermore, a significant 46% decline occurred during the progression from stage 3 to 4.
The authors observed intracytoplasmic α-synuclein aggregates, extracellular α-synuclein aggregates and Lewy neurites in the substantia nigra of all subjects with Braak α-synuclein stages 3–6, indicating more advanced neurodegenerative disease.
Interestingly, the density of extracellular aggregates and Lewy neurites correlated negatively with the decrease in neuronal density. Also, in patients with Braak α-synuclein stage 3 through 6, the total α-synuclein burden in the substantia nigra was negatively correlated with nigral neuronal density.
Taken together, these findings indicate that nigral neuronal loss is present in the early stages of PD and precedes the presence of α-synuclein aggregates. Furthermore there is a steep decrease in neuronal density between Braak α-synuclein stage 3 and stage 4, whereas differences in other consecutive stages were less pronounced.
This “suggests that the disease progression is not linear but rather negatively exponential, as previously suggested by others”, say the authors in Movement Disorders.
Further, their results “strengthens the idea that iLBD represents the premotor phase of PD.”
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