# Cognition in Parkinson's Disease

> **NIH VA I01** · VA SAN DIEGO HEALTHCARE SYSTEM · 2021 · —

## Abstract

Cognitive symptoms in Parkinson's disease (PD) are often overlooked despite their frequency and the high risk
they incur for the development of mild cognitive impairment (MCI) or dementia. However, considerable
heterogeneity exists in the cognitive domains that are affected, suggesting that patterns of neurodegeneration
may differ amongst individuals. The reasons for individual differences in cognitively-related neurodegeneration
are not well understood in PD, which is essential because altered functioning in some domains (executive) is a
risk factor for future cognitive decline, whereas changes in other domains (visuospatial, semantic memory)
predict the development of dementia. There is an urgent need to elucidate the neurobiological mechanisms
underlying cognitive heterogeneity in PD, especially before clinical symptoms manifest, since optimal
therapeutic approaches will depend on early detection and individualized treatments that target specific brain
networks. Changes in patterns of brain functioning that predate the development of MCI and dementia are not
well understood in PD, nor is heterogeneity of neurodegeneration, which may be mediated by genetic factors
that carry different prognostic significance. Cognitive heterogeneity in PD is associated with common genetic
variants in an enzyme that degrades prefrontal cortex dopamine (catchol-O-methyl transferase; COMT) and
the microtubule-associated protein tau (MAPT). Both genes exert strong effects on cognition in PD and are risk
factors for future cognitive decline (COMT) and dementia (MAPT). Little is known about how the expression of
these genes mediates patterns of abnormal intrinsic functional connectivity at rest and context-dependent
connectivity during effortful mental processing. The goals of this project are to characterize disturbances in the
functional connectivity of key brain networks in cognitively normal PD patients (PD-CN) and to determine their
association with genes that may presage future cognitive decline or dementia. PD-CN patients and healthy
volunteers will be studied using resting-state fMRI (rsfMRI), three task-activated fMRI (tafMRI), and diffusion
weighted imaging (dMRI). The tafMRI protocols will characterize context-dependent disturbances in executive,
visuospatial and semantic memory networks in PD-CN, which will then be correlated with abnormalities in task-
positive and negative rsfMRI networks. COMT and MAPT mediation of functional changes during tafMRI and
rsfMRI will also be studied, as will genetic mediation of associations between functional connectivity markers
and structural changes in the brain (dMRI). In a pilot secondary aim, cognitive testing will be repeated 2 years
post-baseline in a subsample of PD patients to explore if aberrant brain functioning, together with genetic
factors, predict various indices of cognitive decline. This research will lead to a more cohesive understanding
of individual differences in neuropathological changes that predat...

## Key facts

- **NIH application ID:** 10291803
- **Project number:** 5I01CX000146-12
- **Recipient organization:** VA SAN DIEGO HEALTHCARE SYSTEM
- **Principal Investigator:** DEBORAH Lynn HARRINGTON
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2009-04-01 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10291803

## Citation

> US National Institutes of Health, RePORTER application 10291803, Cognition in Parkinson's Disease (5I01CX000146-12). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10291803. Licensed CC0.

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