Pathological Influences on Clinical Heterogeneity in Lewy Body Diseases

Abstract

PD, PD with dementia, and dementia with Lewy bodies are clinical syndromes characterized by the neuropathological accumulation of alpha-synuclein in the CNS that represent a clinicopathological spectrum known as Lewy body disorders. These clinical entities have marked heterogeneity of motor and nonmotor symptoms with highly variable disease progression. The biological basis for this clinical heterogeneity remains poorly understood. Previous attempts to subtype patients within the spectrum of Lewy body disorders have centered on clinical features, but converging evidence from studies of neuropathology and ante mortem biomarkers, including CSF, neuroimaging, and genetic studies, suggest that Alzheimer's disease beta-amyloid and tau copathology strongly influence clinical heterogeneity and prognosis in Lewy body disorders. Here, we review previous clinical biomarker and autopsy studies of Lewy body disorders and propose that Alzheimer's disease copathology is one of several likely pathological contributors to clinical heterogeneity of Lewy body disorders, and that such pathology can be assessed in vivo. Future work integrating harmonized assessments and genetics in PD, PD with dementia, and dementia with Lewy bodies patients followed to autopsy will be critical to further refine the classification of Lewy body disorders into biologically distinct endophenotypes. This approach will help facilitate clinical trial design for both symptomatic and disease-modifying therapies to target more homogenous subsets of Lewy body disorders patients with similar prognosis and underlying biology. © 2019 International Parkinson and Movement Disorder Society.

Keywords: Parkinson's disease; alpha synuclein; clinical heterogeneity; dementia with Lewy bodies; neuropathology.

Figure 1

Current criteria separate LBDs into PD and DLB on the basis of the 1-year rule’ (dashed-line). Within LBD, neuropathology ranges from pure synucleinopathy (SYN only: blue) to those with clinically significant AD co-pathology (SYN+AD: red). Emerging biomarker data suggests AD co-pathology may be accurately detected in living patients and we illustrate here a potential strategy to stratify clinical cohorts of LBD by the AD biomarker profiles (dashed lines) to improve clinical trials for SYN and Tau and/or Aβ directed therapies during life for LBD patients (shaded clinical phenotype boxes represent relative frequency of pure SYN or mixed AD co-pathology in large autopsy series in PD, PDD, and DLB).