Background <p>Histone deacetylases (HDACs) are epigenetic molecules responsible for regulation of gene transcription. Dysregulation of HDACs has been linked to neurodegenerative disease. Here, we used the class I HDAC PET radioligand [¹¹C]Martinostat to quantify and map changes in the distribution of these molecules in the brain in dementia with Lewy bodies (DLB) and Parkinson’s disease (PD). In this exploratory cross-sectional study, we acquired brain PET-MR with [¹¹C]Martinostat in 14 DLB (median age 70 years (IQR 14), 21% female), 10 PD (median age 70 (8), 20% female) including four with cognitive impairment and six without, and 17 healthy control (HC) participants (median age 62 (14), 47% female). [¹¹C]Martinostat uptake was compared amongst groups using whole brain voxel-wise analysis and targeted region of interest (ROI)-based approaches, adjusted for age and sex. Regional levels were also quantified in postmortem brain bank samples.</p> Results <p>Compared to HC, [¹¹C]Martinostat uptake in DLB was increased in precentral gyrus (ROI <i>p</i> = 0.044) and putamen (<i>p</i> &lt; 0.001), as well as in cognitive and limbic circuitry including anterior cingulate (<i>p</i> = 0.042) and entorhinal cortex (<i>p</i> = 0.023). [¹¹C]Martinostat uptake in DLB was decreased in inferior parietal cortex <i>p</i> &lt; 0.001) compared to HC, consistent with prior observations in Alzheimer’s disease. In PD, [¹¹C]Martinostat uptake was also increased in precentral gyrus (<i>p</i> = 0.013), correlating with both disease duration and Hoehn and Yahr motor stage. In postmortem DLB tissue, class I HDAC levels were elevated in anterior cingulate cortex (isoform 1 <i>p</i> = 0.041, isoform 3 <i>p</i> = 0.024) and were reduced in inferior parietal cortex (isoform 1 <i>p</i> &lt; 0.001).</p> Conclusions <p>The findings of this exploratory study reveal elevated levels of class I HDACs in motor cortex in PD and bidirectional changes in their regional density in the Lewy body dementias.</p>