W.D.J. van de Berg

Reduced α‐synuclein levels in cerebrospinal fluid in Parkinson's disease are unrelated to clinical and imaging measures of disease severity

The cerebrospinal fluid (CSF) concentration of α‐synuclein may reflect the aggregation of α‐synuclein in brain tissue that neuropathologically characterizes Parkinsons disease (PD). Although most studies in large cohorts report reduced CSF α‐synuclein levels in PD, the available data to date are not consistent due to variation in group sizes, pre‐analytical confounding factors and assay characteristics. Furthermore, it remains unclear whether CSF α‐synuclein concentrations correlate with measures of disease severity. Acknowledging the methodological issues that emerged from previous studies, we evaluated whether CSF α‐synuclein levels differ between patients with PD and controls, and relate to disease duration or severity.

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

To gain a better understanding of the significance of α‐synuclein pathological conditions during disease progression in Parkinsons disease, we investigated whether 1) nigral neuronal loss in incidental Lewy body disease and Parkinsons 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 Parkinsons 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 Parkinsons 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 Parkinsons disease.

Pedunculopontine cholinergic cell loss in hallucinating Parkinson disease patients but not in dementia with Lewy bodies patients

There is a cholinergic deficit in Parkinson disease (PD) and in dementia with Lewy bodies (DLB) that plays a role in a variety of clinical symptoms, including visual hallucinations (VH). The aim of this study was to assess cholinergic neuronal loss and PD and Alzheimer disease pathology in the pedunculopontine nucleus pars compacta (PPNc) of PD and DLB patients with VH. Postmortem brainstem tissue samples of 9 clinically diagnosed and pathologically confirmed PD patients with VH, 9 DLB patients with VH, and 9 age- and sex-matched nondemented controls were obtained from the Netherlands Brain Bank. Using a morphometric approach, we estimated the density of cholinergic neurons in the PPNc and determined the local load of α-synuclein-immunoreactive Lewy pathology, neurofibrillary tangles, and β-amyloid plaques. Cholinergic cell density in the PPNc was significantly lower in PD compared with DLB patients with VH (-39%, p < 0.001) and controls (-41%, p < 0.001). Alpha-synuclein load was higher in PD, whereas β-amyloid plaque pathology was more pronounced in DLB patients. The mean cell density in DLB patients was not significantly reduced compared with that in controls. These results may indicate different patterns of degeneration of cholinergic output structures in PD and DLB.

Differential insular cortex subregional vulnerability to α-synuclein pathology in Parkinson's disease and dementia with Lewy bodies

The insular cortex consists of a heterogenous cytoarchitecture and diverse connections and is thought to integrate autonomic, cognitive, emotional and interoceptive functions to guide behaviour. In Parkinsons disease (PD) and dementia with Lewy bodies (DLB), it reveals α‐synuclein pathology in advanced stages. The aim of this study is to assess the insular cortex cellular and subregional vulnerability to α‐synuclein pathology in well‐characterized PD and DLB subjects.