# Imaging Epigenetic Mechanisms in the Lewy Body Dementias with [11C]Martinostat

> **NIH NIH R56** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $776,355

## Abstract

Project Summary/Abstract
Accumulating evidence suggests that epigenetic changes - functional modifications to the genome that do not
change the DNA sequence and that provide a powerful mechanism by which environmental exposure can impact
gene expression – may contribute to dementia with Lewy bodies (DLB) and Parkinson disease (PD). Histone
deacetylases (HDACs) are a family of epigenetic enzymes that regulate gene expression by chemically
modifying chromatin, the network of proteins and DNA in chromosomal structure, in response to life experience
and the environment. In DLB and PD at autopsy, histone acetylation is markedly dysregulated. However, it
remains unclear whether histone acetylation-associated epigenetic changes accumulate with progression of
disease including to dementia, for example reflecting the severity and topography of Lewy body pathology, nor
whether HDAC changes relate to the accumulation of motor, cognitive, and behavioral impairments in these
diseases. It is also unknown whether HDAC expression changes in life in DLB are distinct from those of
Parkinson disease dementia (PDD). The recent development of [11C]Martinostat, the first radiotracer that labels
HDACs in living humans, has enabled the antemortem assessment of HDAC levels and distribution in the human
brain. [11C]Martinostat shows specific HDAC binding with low nanomolar affinity and is actively under study in
several patient populations. The overall goals of this proposal are thus 1) to evaluate brain HDAC levels and
regional distribution with [11C]Martinostat in well-characterized PD, PDD, and DLB subjects, contrasted with
Alzheimer’s disease and age-matched normal control (NC) subjects, and 2) to relate regional [11C]Martinostat
binding to Lewy body disease clinical features and amyloid burden. Subjects with DLB, PDD, cognitively normal
PD, Alzheimer’s, and NC will undergo standardized neurological examination, detailed neuropsychological
testing, combined [11C]Martinostat PET-MRI, and amyloid imaging with [11C]PiB PET. Building on preliminary
[11C]Martinostat PET imaging and pathological data, we will test the following hypotheses: (1) The order of global
brain HDAC expression will increase from AD to NC to cognitively normal PD to PDD to DLB; (2) Changes in
regional HDAC expression detected with PET will correlate with the known topology of pathologic changes; (3)
Cortical and striatal amyloid deposition will not qualitatively impact these results but will be associated with within-
group reductions in regional HDAC expression; (4) HDAC expression in the putamen will correlate with the
severity of motor impairment; asymmetry of nigral and striatal HDAC expression will correlate with asymmetry of
motor impairment; (5) Global cortical and caudate HDAC levels will correlate with measures of cognitive
impairment; (6) Posterior cortical HDAC expression will be associated with psychosis including visual
hallucinations; (7) Differential HDAC expression in DLB and PDD will...

## Key facts

- **NIH application ID:** 10461316
- **Project number:** 1R56AG070827-01A1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Stephen N. Gomperts
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $776,355
- **Award type:** 1
- **Project period:** 2021-09-30 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10461316

## Citation

> US National Institutes of Health, RePORTER application 10461316, Imaging Epigenetic Mechanisms in the Lewy Body Dementias with [11C]Martinostat (1R56AG070827-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10461316. Licensed CC0.

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