# Citalopram as a posterior cortical protective therapy in Parkinson disease

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $709,919

## Abstract

Abstract
The biological basis of PD with dementia (PDD) is heterogeneous, involves multiple cognitive domains, and is
challenging to characterize. Fronto-striatal executive/attentional impairments are core early features and are
influenced by dopaminergic neurotransmission. PDD arises when a distinct visuospatial cognitive syndrome--
thought to be mediated by non-dopaminergic changes—begins to substantially affect the integrity of posterior
cortical regions. The pathological substrates underlying these impairments are diverse and involve the toxic
effects of misfolded neuronal alpha-synuclein along with non-synuclein pathologies such as Amyloid-beta
(Abeta) plaques, tau aggregates, and vascular cognitive impairment. The heterogeneous nature of these
pathologies and their clinical manifestations is summarized by the “dual-hit” hypothesis: a well-accepted but
never-before-tested principle in current models of PDPDD pathogenesis. We propose a proof-of-concept PD
trial aimed at delaying visuospatial cognitive decline, a critical component of PDD. In PD, low-range cortical
Abeta plaque levels—well below the Alzheimer’s disease (AD) diagnostic threshold—associate with serotonin
terminal losses. This specific serotonin-Abeta characteristic is true of PD but not AD. Our published multicenter
PD observational findings show that selective serotonin reuptake inhibitors (SSRIs) associate with lower PDD
conversion risk and altered CSF Abeta-42 levels. Our preliminary data, using Abeta Pittsburgh compound B
(PiB) positron emission tomography (PET) in PD, show less 2-year visuospatial cortex Abeta plaque accrual
and reduced visuospatial cognitive decline in subjects on serotoninergic medications, perhaps modifying a key
arbiter of PDPDD risk. Our long-term vision is a PDPDD prevention trial, in which citalopram would be
initiated prior to Abeta-linked cognitive decline. Our central hypothesis is that citalopram use in PD will reduce
visuospatial cortex Abeta plaque accrual, leading to an amelioration of visuospatial cognitive decline linked to
PDD. Our objective is to test this hypothesis in a proof-of-concept trial of citalopram 20mg daily over 2 years in
PD subjects (age ≥65) without depression (n=58). In Aim 1, we will test differences in 2-year PiB PET accrual
within the visuospatial cortex between citalopram and placebo groups. In Aim 2, we will measure the impact of
this visuospatial cortex Abeta intervention upon visuospatial cognitive function. In Aim 3, we will test whether
citalopram relative to placebo confers a minimal clinically important difference of benefit as assessed by a
common measure of multi-domain cognition, the Montreal Cognitive Assessment, linked to PDD diagnosis. At
the conclusion of this study, we will have well-powered dataset to assess our rigorous Go/No-Go criteria for
this safe and generalizable PDD prevention therapy. We will also conduct analyses (Aims 1, 2, & 3) that will
help to either substantiate or invalidate the dual-h...

## Key facts

- **NIH application ID:** 10047002
- **Project number:** 1R01AG065246-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Vikas Kotagal
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $709,919
- **Award type:** 1
- **Project period:** 2020-08-15 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10047002

## Citation

> US National Institutes of Health, RePORTER application 10047002, Citalopram as a posterior cortical protective therapy in Parkinson disease (1R01AG065246-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10047002. Licensed CC0.

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