Spot the differences: Neuropathological heterogeneity in sporadic and familial Parkinson's disease and dementia with Lewy bodies

Parkinson’s disease (PD) is a neurodegenerative disease that is characterized by bradykinesia together with rest tremor and/or rigidity, a symptom complex known as parkinsonism. There is a large heterogeneity in the rate of clinical decline and the severity of motor and non-motor symptoms between PD patients. This may hamper the clinical distinction with other neurological disorders that are also characterized by parkinsonism. The neuropathological hallmarks of PD and dementia with Lewy bodies (DLB) are loss of dopaminergic neurons in the substantia nigra, in combination with Lewy bodies and Lewy neurites (i.e. Lewy pathology (LP)). In addition, amyloid-β plaques and tau tangles, pathological hallmarks of Alzheimer’s disease (AD), are often observed as concomitant pathology in PD and DLB. However, in the load and spread of LP and AD copathology over the brain may vary between patients. The general aim of this thesis is to broaden our understanding of the neuropathological features and molecular profiles underlying clinical heterogeneity in sporadic and familial PD and DLB. In chapter 2, we examined the pathological correlates of clinical PD and atypical parkinsonian disorders in 293 brain donors from the Netherlands Brain Bank (NBB), collected in period 1985-2016. In 85% of cases with clinical PD, the diagnosis was neuropathologically confirmed. Also, neuropathological criteria for PD were met in 10% of cases without a clinical diagnosis of PD during life, which illustrates the difficulty of the clinical diagnosis. In chapter 3, we investigated the role of AD copathology in DLB. In chapter 3.1, we studied pathological hallmarks in brains of 16 DLB cases clinically mimicking Creutzfeldt-Jakob’s disease with a rapid clinical decline and short survival. The level of AD copathology was intermediate-to-high in 50% (n = 8), which was related to a higher neocortical LP load. Therefore, other factors besides AD copathology and a high burden of neocortical LP may contribute to clinical decline in rapidly progressive DLB. In chapter 3.2, we examined the brains of 50 DLB donors from the NBB, and found that AD copathology was related to a higher load of neocortical LP, more astroglial α-synuclein and a higher frequency of the APOE-ε4 allele. We concluded that astroglial α-synuclein and its relation to AD copathology may play a role in disease progression in DLB, and should be further studied. In chapter 4, we examined neuropathological features in six brain donors with rare variants of the LRP10 gene, which has been related to familial PD and DLB. Four cases showed severe Lewy body disease, one case showed mixed AD/Lewy body disease and one case showed AD pathology without LP. Interestingly, all six cases in these studies showed intermediate-to-high AD (co)pathology, suggesting that LRP10 may exert its pathogenic role by enhancing this type of pathology. In chapter 5, we studied GBA-related PD and DLB, and the associated decreased activity of the glucocerebrosidase (GCase) enzyme. In post-mortem brain tissue of 9 GBA-related PD/DLB cases, 20 sporadic PD/DLB cases and 15 controls, we aimed to identify molecular mechanisms underlying the relation between decreased GCase enzyme activity and α-synuclein pathology using proteomics analysis, biochemical techniques and immunohistochemistry. Lower GCase activity levels and higher levels of insoluble α-synuclein were associated with deregulation of retromer complex proteins, including retromer core components VPS35, VPS26a and VPS29, and the retromer cargo protein SORL1/SorLA. Super-resolution imaging of SorLA immunostainings in dopaminergic neurons in the SN revealed decreased levels of SorLA in α-synuclein-positive neurons, combined with an aberrant subcellular localization. These findings support a role for deregulated retromer trafficking, including SorLA loss of function, downstream of GCase dysfunction in GBA-related and sporadic PD and DLB.