# Protein Aggregation and Neurotransmitter Deficits in Parkinson Disease

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $506,507

## Abstract

Abstract
People with Parkinson disease (PD) frequently develop dementia, which is associated with neocortical
deposition of alpha-synuclein (α-syn) in Lewy bodies and Lewy neurites. 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 impaired function of cortical neurons, which
may also be affected by widespread Aβ 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 α-syn, Aβ 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 α-syn, Aβ 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.

## Key facts

- **NIH application ID:** 9928127
- **Project number:** 5R01NS097799-05
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** PAUL T KOTZBAUER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $506,507
- **Award type:** 5
- **Project period:** 2016-08-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9928127

## Citation

> US National Institutes of Health, RePORTER application 9928127, Protein Aggregation and Neurotransmitter Deficits in Parkinson Disease (5R01NS097799-05). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9928127. Licensed CC0.

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