# NOVEL PET MARKERS OF COGNITIVE IMPAIRMENT IN MANGANESE NEUROTOXICITY

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2021 · $604,827

## Abstract

Manganese (Mn) is an established neurotoxicant that causes parkinsonism and cognitive impairment with
features overlapping with Parkinson disease (PD), PD dementia (PDD), and mild cognitive impairment (MCI).
The causes of PD and related dementias are mostly unknown although growing evidence suggests that
exposure to environmental toxicants such as Mn may induce alterations in gene expression that can be linked
to disease susceptibility. Our team has conducted key studies using positron emission tomography (PET) that
demonstrate Mn dose-dependent dopaminergic dysfunction in the midbrain and striatum contribute to clinical
parkinsonism. However, the role of the dopaminergic system in the cognitive dysfunction that is associated
with clinical Mn neurotoxicity is unknown. Recent pre-clinical data also implicate dysfunction of the cholinergic
system in Mn neurotoxicity. The extensive degeneration of the cholinergic system is a well-known hallmark of
age-related dementias, and recent molecular imaging innovations have led to a re-emerging interest in the
cholinergic system as an important mechanism of cognitive dysfunction in PDD. Within the striatum, cholinergic
and dopaminergic systems are highly integrated with extensive reciprocal innervations. Current models of
cognitive decline in PD and PDD propose a “two-hit” effect in which the combined dopaminergic and
cholinergic deficits lead to early cognitive impairment and eventual dementia. Similarly, dysfunction in these
two vital striatal systems has been proposed as a core mechanism for Mn neurotoxicity. Given the dose-
response relationship between Mn-exposure, dopaminergic dysfunction, and parkinsonism this occupationally
exposed cohort provides an invaluable opportunity to study the in-vivo pathophysiology of parkinsonism and
cognitive impairment in humans. In this proposal of 60 Mn-exposed workers, we will use a targeted
neuropsychiatric battery of validated cognitive tasks with the dopaminergic ligand [11C](N-methyl)benperidol
(NMB) to measure D2 receptor (D2R) function and the novel cholinergic PET radioligand (-)-(1-(8-(2-
[(18)F]fluoroethoxy)-3-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-piperidin-4-yl)(4-fluorophenyl)methanone
(VAT) to measure in-vivo vesicular acetylcholine transporter (VAChT) concurrently. The specific aims of this
project are 1) to use NMB PET to evaluate the relationships between Mn exposure, dopaminergic dysfunction,
and cognitive impairment; 2) to use VAT PET to evaluate the relationships between Mn exposure, cholinergic
dysfunction, and cognitive impairment; and 3) to use mediation analysis to quantify the amount of cognitive
dysfunction due to Mn exposure that is attributable to dopaminergic and cholinergic dysfunction respectively.
We will use state-of-the-art imaging methods combined with an innovative statistical approach to understand
the dual roles of the cholinergic and dopaminergic systems in Mn-induced cognitive dysfunction. Ultimately, our
goal is to understa...

## Key facts

- **NIH application ID:** 10171849
- **Project number:** 5R01ES029524-03
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Susan Criswell
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $604,827
- **Award type:** 5
- **Project period:** 2019-09-12 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10171849

## Citation

> US National Institutes of Health, RePORTER application 10171849, NOVEL PET MARKERS OF COGNITIVE IMPAIRMENT IN MANGANESE NEUROTOXICITY (5R01ES029524-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10171849. Licensed CC0.

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