# Protein Aggregation and Neurotransmitter Deficits in Parkinson Disease

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2022 · $742,741

## 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 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.

## Key facts

- **NIH application ID:** 10522079
- **Project number:** 2R01NS097799-06
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** PAUL T KOTZBAUER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $742,741
- **Award type:** 2
- **Project period:** 2016-08-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10522079

## Citation

> US National Institutes of Health, RePORTER application 10522079, Protein Aggregation and Neurotransmitter Deficits in Parkinson Disease (2R01NS097799-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10522079. Licensed CC0.

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