Imaging brain class I histone deacetylase changes in the Lewy body dementias and Parkinson's disease

Histone deacetylases (HDACs) are epigenetic molecules responsible for regulation of gene transcription. Altered expression 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 these molecules in the brain in dementia with Lewy bodies (DLB) and Parkinson's disease (PD). In this 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 expression was also quantified in postmortem brain bank samples.

Compared to HC, [¹¹C]Martinostat uptake in DLB was increased in precentral gyrus (ROI p = 0.044) and putamen (p < 0.001), as well as in cognitive and limbic circuitry including anterior cingulate (p = 0.042) and entorhinal cortex (p = 0.023). [¹¹C]Martinostat uptake in DLB was decreased in inferior parietal cortex p < 0.001) compared to HC, consistent with prior observations in Alzheimer's disease. In PD, [¹¹C]Martinostat uptake was also increased in precentral gyrus (p = 0.019 in those with normal cognition, p = 0.047 in those with impaired cognition), correlating with both disease duration and stage. In cognitively impaired PD, [¹¹C]Martinostat uptake was additionally reduced in inferior parietal cortex (p = 0.011), similar to DLB. In postmortem DLB tissue, class I HDAC expression was elevated in anterior cingulate cortex (isoform 1 p = 0.041, isoform 3 p = 0.024) and reduced in inferior parietal cortex (isoform 1 p < 0.001).

These findings reveal evidence of elevated class I HDACs in motor cortex in PD and bidirectional changes in their regional expression in the Lewy body dementias.