Neuropathology of incidental Lewy body & prodromal Parkinson’s disease

Abstract

Background Parkinson’s disease (PD) is a progressive neurodegenerative disorder associated with a loss of dopaminergic (DA) neurons. Despite symptomatic therapies, there is currently no disease-modifying treatment to halt neuronal loss in PD. A major hurdle for developing and testing such curative therapies results from the fact that most DA neurons are already lost at the time of the clinical diagnosis, rendering them inaccessible to therapy. Understanding the early pathological changes that precede Lewy body pathology (LBP) and cell loss in PD will likely support the identification of novel diagnostic and therapeutic strategies and help to differentiate LBP-dependent and -independent alterations. Several previous studies identified such specific molecular and cellular changes that occur prior to the appearance of Lewy bodies (LBs) in DA neurons, but a concise map of such early disease events is currently missing. Methods Here, we conducted a literature review to identify and discuss the results of previous studies that investigated cases with incidental Lewy body disease (iLBD), a presumed pathological precursor of PD. Results Collectively, our review demonstrates numerous cellular and molecular neuropathological changes occurring prior to the appearance of LBs in DA neurons. Conclusions Our review provides the reader with a summary of early pathological events in PD that may support the identification of novel therapeutic and diagnostic targets and aid to the development of disease-modifying strategies in PD.

Performance of a seed amplification assay for misfolded alpha-synuclein in cerebrospinal fluid and brain tissue in relation to Lewy body disease stage and pathology burden

“…For example, the percentage of patients with iRBD with coexistent MCI or motor signs was significantly higher in the study reporting an αSyn SAA sensitivity of 90% compared to ours in which the sensitivity was 75%. In summary, the results of the present study, in line with recent imaging findings [ 35 ], strongly suggest that iRBD patients harbor, on average, a Braak stage 3 of LB pathology, with significant variations from case to case mainly depending on the prodromal LBD score determined by the associated neurological signs. Finally, our recent finding of 8% αSyn SAA positivity in a large cohort of cognitively unimpaired individuals [ 47 ] suggests that even the asymptomatic “incidental” LBD status may be associated with a variable LB pathology load, likely including Braak stages 3 and 4.…”

“…Besides being the pathological hallmark of dementia with Lewy bodies (DLB) and the majority of Parkinson’s disease (PD) cases, LB pathology often manifests as co-pathology in patients with AD, and it also affects a variable proportion of aged individuals lacking clinical signs of motor disturbances or cognitive decline. The latter condition is known as “incidental LBD” (iLBD) and likely represents the pathological preclinical stage of PD or DLB [ 22 , 33 , 35 ]. As it is increasingly recognized for misfolded proteins linked to neurodegeneration, misfolded αSyn can act as a seed to induce the conversion of the normal cellular αSyn, allowing for the transcellular propagation of LB pathology in a prion-like manner [ 24 , 67 ].…”

Angiotensin type 1 receptor activation promotes neuronal and glial alpha-synuclein aggregation and transmission

“…However, the reason for initiating these processes and their order of appearance remain to be clarified. It is now debated the usual view of α-synuclein aggregation and Lewy body pathology (LBP) as the initial event, and it was suggested the possibility that earlier cellular and molecular changes occur in the most vulnerable dopaminergic neurons 82 , 83 . Before LBP, early neurochemical changes such as a decrease in tyrosine hydroxylase 84 , oxidative damage 85 , and neuroinflammation 86 have been reported.…”

GPR37 Processing and Density in Neurodegeneration: A Potential Marker for Parkinson’s Disease Progression Rate

“…These results, which reinforce the idea that GPR37 density and processing are altered within the pathogenesis of LBD, point toward a disease stage-dependent processing of GPR37 in LBD. Early neurodegenerative events involve in ammatory processes and impaired autophagy and dopaminergic neurotransmission [20]. Importantly, GPR37 has been associated with all these processes [2,27,28,31], suggesting the involvement of the receptor in molecular events occurring during early deposition of LB in the PFC and striatum.…”