Protein Aggregation and Neurotransmitter Deficits in Parkinson Disease

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Abstract People with Parkinson disease (PD) frequently develop dementia, which is associated with neocortical deposition of alpha-synuclein (α-syn) in Lewy bodies and referred to as Lewy body dementia (LBD), an Alzheimer’s Disease Related Dementia (ADRD). In addition, neuronal loss and deposition of aggregated α-syn also occurs in multiple subcortical nuclei including substantia nigra (dopaminergic), nucleus basalis of Meynert (cholinergic), locus coeruleus (noradrenergic) and dorsal raphe nuclei (serotonergic). Accumulation of α-syn likely contributes to degeneration of cortical neurons, which may also be affected by widespread Aβ accumulation that occurs in approximately 55% of PD with dementia cases and widespread tau accumulation in fewer cases. However, the affected subcortical nuclei project rostrally to thalamic, striatal, limbic and neocortical regions, and the loss of innervation from these nuclei also may contribute to cognitive impairment in PD. We developed postmortem tissue analysis methods to quantify pathologic accumulation of α-syn, Aβ and tau, neuronal degeneration marked by loss of synaptic terminals, and loss of innervating projections from dopaminergic, serotonergic, noradrenergic and cholinergic subcortical neurons. In this project we will collect autopsies from a longitudinal study of PD participants that measures cognition, neurobehavioral function and gait. We will sample cerebellar, basal ganglia, limbic and neocortical regions from frozen brain tissue for each autopsy case and analyze the tissue with the following goals: 1) Determine the relationship between α-syn, Aβ and tau accumulation, neuronal degeneration, and loss of subcortical projections. 2) Determine whether pathologic protein accumulation, neuronal degeneration and loss of projections from subcortical nuclei relate to global cognition and specific cognitive phenotypes, including impaired attention, memory, visuospatial and executive function. Defining the pathologic substrates for cognitive impairment in PD will provide further guidance for therapeutic targets, biomarkers, and outcome measures for therapeutic trials in PD.