# Imaging epigenetic dysregulation in the Lewy body dementias with [11C]Martinostat

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $827,629

## 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), which differ in the timing of cognitive and motor impairments. 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 accumulation in regional [11C]Martinostat binding over time to Lewy body
disease clinical features and their progression as well as to amyloid burden. Subjects with DLB, PDD, cognitively
normal PD, Alzheimer’s, and NC will undergo standardized neurological examination, neuropsychological
testing, combined [11C]Martinostat PET-MRI, and amyloid imaging with [11C]PiB PET, and will return at 12 months
for repeat [11C]Martinostat PET-MRI and clinical evaluation. Building on preliminary [11C]Martinostat PET imaging
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 topography 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 midbrain and putamen will relate to the severity of motor impairment; anterior
cingulate and caudate expression will relate to the severity of cognitive impairment; occipital cortex expression
will be associated with visual hallucinations; (5) Changes in region...

## Key facts

- **NIH application ID:** 10833652
- **Project number:** 5R01AG082331-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Stephen N. Gomperts
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $827,629
- **Award type:** 5
- **Project period:** 2023-05-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10833652

## Citation

> US National Institutes of Health, RePORTER application 10833652, Imaging epigenetic dysregulation in the Lewy body dementias with [11C]Martinostat (5R01AG082331-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10833652. Licensed CC0.

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