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

BACKGROUND

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.

RESULTS

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 = 0.013), 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 p = 0.041, isoform 3 p = 0.024) and were reduced in inferior parietal cortex (isoform 1 p < 0.001).

CONCLUSIONS

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.