People with Parkinson disease (PD) frequently develop dementia, which is associated with neocortical deposition of alpha-synuclein (?-syn) in Lewy bodies and Lewy neurites. In addition, neuronal loss and deposition of aggregated ?-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 ?-syn likely contributes to impaired function of cortical neurons, which may also be affected by widespread A? accumulation that occurs in approximately 60% 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 accumulation of fibrillar ?-syn, A? and tau, as well as the 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 cognitive, behavior, and gait function. We will sample thalamic, 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 ?-syn, A? and tau deposition and the loss of dopaminergic, serotonergic, noradrenergic and cholinergic innervation. 2) Determine whether fibrillar protein deposition and loss of projections from subcortical nuclei relate to gait, global cognition and specific cognitive phenotypes, including: impaired attention, memory, visuospatial and executive function, fluctuations in attention, hallucinations and delusions. Defining the pathologic substrates for cognitive, behavior and gait impairment in PD will provide further guidance for therapeutic targets and outcome measures for therapeutic trials in PD.

Public Health Relevance

This project will improve our understanding of mechanisms underlying the development of cognitive impairment and gait difficulty in Parkinson disease, which is needed to guide the development of treatments for Parkinson disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS097799-03
Application #
9474701
Study Section
Clinical Neuroscience and Neurodegeneration Study Section (CNN)
Program Officer
Sieber, Beth-Anne
Project Start
2016-08-01
Project End
2021-04-30
Budget Start
2018-05-01
Budget End
2019-04-30
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Washington University
Department
Neurology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Dhavale, Dhruva D; Tsai, Christina; Bagchi, Devika P et al. (2017) A sensitive assay reveals structural requirements for ?-synuclein fibril growth. J Biol Chem 292:9034-9050