Imaging regional histone deacetylase expression in dementia with Lewy bodies with [11C]Martinostat (P13-6.008)

Abstract

<h3>Objective:</h3> To image brain histone deacetylase (HDAC) expression using [¹¹C]Martinostat positron emission tomography (PET) in living participants with dementia with Lewy bodies (DLB). <h3>Background:</h3> Epigenetic modifications via HDACs and other mechanisms regulate transcription of specific genes in response to a cell’s environment or exposure, and epigenetic changes have been observed in postmortem brain tissue in Lewy body diseases. However, whether HDAC changes arise early in disease or only as a late phenomenon, and whether regional brain HDAC expression relates to the clinical or pathologic features of the disease remain uncertain. <h3>Design/Methods:</h3> Seven subjects with DLB and 17 age-matched healthy control (HC) subjects provided informed consent to participate. Participants underwent cognitive, motor, and neuropsychiatric evaluation followed by simultaneous MR and PET imaging with [¹¹C]Martinostat, a radioligand developed at the Massachusetts General Hospital (MGH) Martinos Center for Biomedical Imaging that binds class I HDACs with high affinity and selectivity. Data were reconstructed and standardized uptake value ratios computed using a global reference. A whole-brain voxelwise analysis was followed by region of interest-based analysis. <h3>Results:</h3> Compared to HC subjects, [¹¹C]Martinostat uptake in DLB was increased in regions enriched for Lewy body pathology, including the brainstem, medial temporal lobe, and anterior cingulate. Increased uptake was also observed in regions associated with motor function, including the striatum, motor cortex, and cerebellum. [¹¹C]Martinostat uptake was decreased in parietal cortex. <h3>Conclusions:</h3> These preliminary findings in living participants with DLB identify abnormal class I HDAC expression in regions associated with Lewy body pathology, motor circuitry, and cognition. They set the stage for planned comparisons with antemortem Parkinson’s disease (PD) and with postmortem regional HDAC expression in PD and DLB. <b>Disclosure:</b> The institution of Dr. Goodheart has received research support from American Academy of Neurology. Mr. Yoo has nothing to disclose. Ms. Striar has nothing to disclose. Ms. Quan has nothing to disclose. Prof. Wey has nothing to disclose. Dr. Wang has nothing to disclose. Dr. Gomperts has received personal compensation in the range of $0-$499 for serving as a Consultant for EIP. Dr. Gomperts has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Jannsen. The institution of Dr. Gomperts has received research support from NIH. The institution of Dr. Gomperts has received research support from LBDA. The institution of Dr. Gomperts has received research support from DOD/CDMRP. The institution of Dr. Gomperts has received research support from FFFPRI. The institution of Dr. Gomperts has received research support from NIH. The institution of Dr. Gomperts has received research support from MJFF. The institution of Dr. Gomperts has received research support from NIH. The institution of Dr. Gomperts has received research support from NIH. The institution of Dr. Gomperts has received research support from MJFF. The institution of Dr. Gomperts has received research support from NIH. The institution of Dr. Gomperts has received research support from NIH.