Imaging Epigenetic Mechanisms in the Lewy Body Dementias with [11C]Martinostat

项目摘要/摘要 越来越多的证据表明，表观遗传变化--对基因组的功能修饰不会 改变DNA序列，并提供了一种强大的机制，通过这种机制，环境暴露可以影响 基因表达--可能导致路易体痴呆(DLB)和帕金森病(PD)。组蛋白 脱乙酰酶(Hdac)是一类表观遗传酶，通过化学方式调节基因表达。 修改染色质，染色体结构中的蛋白质和DNA网络，以响应生活经验 和环境。在尸检的DLB和PD中，组蛋白乙酰化明显失调。然而，它 目前尚不清楚组蛋白乙酰化相关的表观遗传学改变是否随着卵巢癌的进展而积累 疾病，包括痴呆症，例如反映路易体病理的严重性和地形图，也不 HDAC的改变是否与这些患者运动、认知和行为障碍的积累有关 疾病。DLB中HDAC表达的变化是否与DLB中的不同也是未知的 帕金森病痴呆(PDD)。第一种标记放射性示踪剂[11C]的最新进展 活人体内的HDAC，使得对人类体内HDAC水平和分布的生前评估成为可能 大脑。[11C]Martinostat显示出低纳摩尔亲和力的特定HDAC结合，目前正在积极研究中 几个病人群体。因此，这项建议的总体目标是1)评估大脑HDAC水平和 [11C]马替诺他汀在特征良好的PD、PDD和DLB受试者中的区域分布，与 阿尔茨海默病和年龄匹配的正常对照(NC)受试者，以及2)与区域[11C]马丁诺酮相关 与路易体病相关的临床特征和淀粉样蛋白负荷。患有DLB、PDD、认知正常的受试者 帕金森病、阿尔茨海默氏症和NC将接受标准化的神经学检查，详细的神经心理学 测试，结合[11C]Martinostat PET-MRI和淀粉样蛋白成像与[11C]PIB PET。建立在初步的基础上 [11C]马天诺稳态PET成像和病理数据，我们将检验以下假设：(1)全局顺序 从AD到NC，从认知正常到PD，再到PDD，再到DLB，脑HDAC的表达将增加；(2) PET检测到的区域HDAC表达将与已知的病理改变的拓扑结构相关；(3) 皮质和纹状体淀粉样蛋白沉积不会对这些结果产生定性影响，但会与内部- 局部HDAC表达减少；(4)壳核中HDAC表达将与 运动障碍的严重性；黑质和纹状体HDAC表达的不对称将与运动障碍的不对称相关 运动障碍；(5)整体皮质和尾状核HDAC水平将与认知测量相关 损害；(6)后部皮质HDAC的表达将与包括视觉在内的精神病有关 幻觉；(7)HDAC在DLB和PDD中的不同表达将解释时间上的差异 这些疾病中与运动障碍相关的痴呆症的出现。总而言之，这些努力将使人们明白 生命中基因表达的异常表观遗传控制对PD、PDD和DLB的贡献。

Project Summary/Abstract 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). 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 regional [11C]Martinostat binding to Lewy body disease clinical features and amyloid burden. Subjects with DLB, PDD, cognitively normal PD, Alzheimer’s, and NC will undergo standardized neurological examination, detailed neuropsychological testing, combined [11C]Martinostat PET-MRI, and amyloid imaging with [11C]PiB PET. Building on preliminary [11C]Martinostat PET imaging and pathological 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 topology 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 the putamen will correlate with the severity of motor impairment; asymmetry of nigral and striatal HDAC expression will correlate with asymmetry of motor impairment; (5) Global cortical and caudate HDAC levels will correlate with measures of cognitive impairment; (6) Posterior cortical HDAC expression will be associated with psychosis including visual hallucinations; (7) Differential HDAC expression in DLB and PDD will account for timing differences in the appearance of dementia relative to motor impairment in these diseases. Together, these efforts will shed light on the contribution of dysregulated epigenetic control of gene expression during life to PD, PDD, and DLB.