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.

Keywords: Enteric nervous system (ENS); Incidental Lewy body disease (iLBD); Lewy body α-Synuclein; Prodromal Parkinson’s disease (PD); REM-sleep behaviour disorder (RBD).

Fig. 1

Neuropathological hallmarks of Parkinson’s disease and associated co-pathologies. a The neuropathological hallmarks of PD are shown in the three sub-panels. From left to right: a normal substantia nigra without any PD features; substantia nigra tissue from a PD patient with Lewy bodies (arrows) and pigmented/dopaminergic neuron loss; an immunohistochemical stain against αSyn (clone 42) from the same PD patient demonstrating intraneuronal Lewy bodies and Lewy neurites. Note that melanin pigment and DAB stain are not easy to distinguish. Scale bar = 50 μm. b Immunohistochemically stained sections of the amygdala from a patient suffering from mixed-type dementia that presented clinically as PD. The amygdala is a region commonly affected by co-pathologies. From left to right: An antibody against phosphorylated tau protein (clone AT8) demonstrates neurofibrillary tangles; immunohistochemistry against amyloid beta (clone 4G8) highlights diffuse and cored amyloid beta plaques; the clone 42 against αSyn marks Lewy bodies, Lewy neurites and a few axonal spheroids. Scale bar = 100 μm

Fig. 2

Schematic illustrating disease progression from the pre-clinical phase of PD to the late clinical phase, including the associated clinical symptoms, Substantia nigra pathology and spread of Lewy body pathology according to Braak’s staging model. Note the presence of neuronal dysfunction in the SNc prior to the appearance of Lewy bodies in this area. Created with Biorender.com

Fig. 3

Schematic summarizing clinical signs and symptoms of pPD and the approximate timescale for conversion to Clinical PD. Created with Biorender.com