Lewy body disorders

Lewy body disorders (LBD) include Parkinson’s disease (PD), PD with dementia (PDD) and Dementia with Lewy bodies (DLB). These clinical syndromes are associated with underlying alpha-synuclein proteinopathy (i.e. Lewy bodies and Lewy neurites composed of misfolded alpha-synculein protein) at autopsy (Figure 1); however, there is considerable overlap between PD/PDD and DLB and heterogeneity within each LBD clinical diagnosis which is not clearly understood. This raises a significant problem for clinical care as prognostic markers are lacking. Indeed, the majority of PD will develop cognitive impairment and dementia during the course of illness but there is a large variability in the timing of dementia, with some patients developing dementia early in the course of disease compared to those PD patients who have motor symptoms for a decade or more before developing cognitive impairment. Moreover, the classic features of dementia in DLB (i.e. well-formed visual hallucinations, fluctuations in attention) and also non-cognitive symptoms of DLB (i.e. motor Parkinsonism, autonomic dysfunction, rapid-eye-movement sleep behavior disorder- REM SBD and neuroleptic sensitivity) are common in PDD. Indeed, current clinical criteria for PDD and DLB are largely overlapping with the exception of the “one-year rule” that differentiates dementia in the setting of established PD (i.e. PDD with dementia > one year after the onset of PD) from DLB where dementia may precede or occur within one year of the onset of motor Parkinsonism. Thus, there is a clinicopathological spectrum of LBD with varying cognitive, motor and autonomic symptoms that emerge in disease. Previous work by our group and others find that additional Alzheimer’s disease (AD) co-neuropathology (amyloid-beta plaques and tau neurofibrillary tangles) are common in LBD (~50% of all LBD have sufficient AD neuropathologic change sufficient for a secondary neuropathological diagnosis of medium/high AD= SYN+AD), is associated with greater alpha-synuclein pathology in brain (Figure 1) and has a strong influence on clinical features in both PD/PDD and DLB, including earlier dementia and worse survival that is independent of age (Figure 2).

We hypothesize that AD co-pathology is intimately involved in the neurodegenerative process of LBD, and based on animal and cell-model data, we believe there is a synergistic interaction of alpha-synuclein and tau pathology. Our recent work with digital histology finds that tau pathology has a strong influence on clinical features of dementia in LBD and is associated with the regional distribution of alpha-synculein that diverges from the classic patterns of tau pathology in the brain associated with AD without alpha-synuclein co-pathology. Moreover, emerging work in living patients using biomarkers for AD neuropathology (e.g. CSF, PET molecular imaging) in clinical and autopsy-confirmed LBD patients find important prognostic implications and reflect the deposition of these pathologies in vivo. Thus, we propose natural history studies and clinical trials for LBD should consider AD biomarker profiles to stratify LBD into more biologically meaningful groups (i.e. LBD with AD co-pathology vs LBD without AD co-pathology) than classic LBD clinical syndromes alone (i.e. PD, PDD and DLB) (Figure 3). Please see our publication list below for recent work on this topic.