Stage‐dependent nigral neuronal loss in incidental Lewy body and Parkinson's disease

Abstract

To gain a better understanding of the significance of α-synuclein pathological conditions during disease progression in Parkinson's disease, we investigated whether 1) nigral neuronal loss in incidental Lewy body disease and Parkinson's disease donors is associated with the local burden α-synuclein pathological conditions during progression of pathological conditions; 2) the burden and distribution of α-synuclein pathological conditions are related to clinical measures of disease progression. Post-mortem tissue and medical records of 24 Parkinson's disease patients, 20 incidental Lewy body disease donors, and 12 age-matched controls were obtained from the Netherlands Brain Bank for morphometric analysis. We observed a 20% decrease in nigral neuronal cell density in incidental Lewy body disease compared with controls. Nigral neuronal loss (12%) was already observed before the appearance α-synuclein aggregates. The progression from Braak α-synuclein stage 3 to 4 was associated with a significant decline in neuronal cell density (46%). Nigral neuronal loss increased with later Braak α-synuclein stages but did not vary across consecutive Braak α-synuclein stages. We observed a negative correlation between neuronal density and local α-synuclein burden in the substantia nigra of Parkinson's disease patients (ρ = -0.54), but no relationship with Hoehn & Yahr stage or disease duration. In conclusion, our findings cast doubt on the pathogenic role of α-synuclein aggregates in elderly, but do suggest that the severity of neurodegeneration and local burden of α-synuclein pathological conditions are closely coupled during disease progression in Parkinson's disease.

Selective neuronal vulnerability in Parkinson disease

“…Recent studies have investigated whether there is neuronal death in the brains of asymptomatic (probably presymptomatic) individuals in whom LP was restricted to the medulla and pons (that is, in Braak stages 1–2). Indeed, in these brains, there was a substantial (10–20%) loss of SNc DA neurons in the ventral tier of the SNc, but not elsewhere, including regions with LP 4,44 . Later, in the early symptomatic stages of cPD, nearly all DA neurons in the ventral tier of the SNc are dead 45,46 .…”

“…Another important piece of information from this latter data set is that LP is not randomly distributed — neither in patients with late-stage cPD nor in asymptomatic individuals 4,7 . In patients with late-stage cPD, LP appears within a few circumscribed nuclei in the caudal medulla (the DMV and the intermediate reticular zone).…”

“…Most notably, Lewy pathology (LP) is commonly observed in some brain regions of patients with cPD, particularly within the brainstem 3 . However, LP also occurs in other ageing-related neurodegenerative diseases, even in the absence of cPD, making it alone an unsuitable diagnostic criterion 4 .…”

“…Most importantly, because none of the data was longitudinal in nature, the proposition that LP retrogradely spread sequentially from one structure to another was inferred from comparisons of the severity of the pathology in the brains of patients with symptomatic PD and asymptomatic individuals with LP — the latter of whom may or may not have ever developed PD had they lived long enough. In this regard, it is important to remember that LP is found in several other clinically defined ageing-related neurological diseases that do not have the main features of cPD 4 .…”

Calcium, mitochondrial dysfunction and slowing the progression of Parkinson's disease

“…For example, neuronal loss in the SNc precedes any discernible LP. Moreover, some patients with cPD have no discernible LP, whereas others who do, fail to manifest cPD symptoms (Dijkstra et al, 2014). The question is not whether aSYN fibrils or monomers in sufficient quantities can kill neurons; they clearly can.…”