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

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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 regional HDAC expression over time will relate to progression of motor, cognitive, and neuropsychiatric impairments. Together, these efforts will shed light on the contribution of dysregulated epigenetic control of gene expression during life to PD, PDD, and DLB.