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

使用 [11C]Martinostat 对路易体痴呆的表观遗传机制进行成像

• 批准号: 10461316
• 负责人: Stephen N. Gomperts
• 金额: $ 77.64万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10461316
• 关键词: Affinity; Age; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloid deposition; Anterior; Appearance; Autopsy; Behavioral; Binding; Biochemistry; Biological Markers; Biometry; Brain; Brain Diseases; Cells; Cessation of life; Chemicals; Chromatin; Chromosome Structures; Clinical; Cognitive; Corpus striatum structure; DNA; DNA Sequence; Data; Data Set; Dementia; Dementia with Lewy Bodies; Denervation; Development; Discipline; Disease; Disease Progression; Disease model; Dopamine; Environment; Environmental Exposure; Enzymes; Epigenetic Process; Family; Functional disorder; Gene Expression; Genetic; Genome; Goals; Hippocampus (Brain); Histone Acetylation; Histone Deacetylase; Histone Deacetylase Inhibitor; Human; Image; Impaired cognition; Impairment; Interdisciplinary Study; Label; Lewy Bodies; Lewy Body Dementia; Lewy Body Disease; Lewy body pathology; Life; Life Experience; Light; Magnetic Resonance Imaging; Measures; Midbrain structure; Mitochondria; Modification; Motor; Motor Manifestations; Neocortex; Neurologic; Neurologic Examination; Neuropsychological Tests; Neurosciences; Parkinson Disease; Parkinson' s Dementia; Parkinsonian Disorders; Pathologic; Pathology; Patients; Positron-Emission Tomography; Proteins; Psychoses; Radiochemistry; Research; Research Personnel; Resources; Severities; Standardization; Testing; Therapeutic; Toxic effect; Visual Hallucination; aged; alpha synuclein; amyloid imaging; base; behavioral impairment; cognitive testing; dopaminergic neuron; drug discovery; motor impairment; nanomolar; patient population; putamen; radiotracer; ranpirnase; response; success; synucleinopathy; β-amyloid burden

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.

项目总结/摘要 越来越多的证据表明，表观遗传变化--对基因组的功能性修饰， 改变DNA序列，并提供了一个强大的机制，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）是表观遗传酶家族，其通过化学作用调节基因表达。 改变染色质，染色体结构中的蛋白质和DNA网络，以响应生活经验 和环境保护在DLB和PD尸检中，组蛋白乙酰化明显失调。但 目前尚不清楚组蛋白乙酰化相关的表观遗传学变化是否会随着疾病的进展而积累。 疾病，包括痴呆，例如反映路易体病理学的严重性和地形，也 HDAC的变化是否与运动，认知和行为障碍的积累有关， 疾病还不清楚DLB中HDAC表达的变化是否与DLB中的HDAC表达的变化不同。 帕金森病痴呆症（PDD）。[11 C]Martinostat的最新发展，第一个标记的放射性示踪剂 在活体人类中的HDAC，使得能够在死前评估HDAC水平和在人类中的分布。 个脑袋[11 C]Martinostat显示出具有低纳摩尔亲和力的特异性HDAC结合，并且正在积极研究中。 多个患者群体。因此，该提案的总体目标是：1）评估大脑HDAC水平， 在充分表征的PD、PDD和DLB受试者中，[11 C]Martinostat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）与局部[11 C]Martinostat相关 结合路易体病临床特征和淀粉样蛋白负荷。认知正常的DLB、PDD受试者 PD，阿尔茨海默氏症和NC将接受标准化的神经系统检查，详细的神经心理学检查， 测试、[11 C]Martinostat PET-MRI联合和[11 C]PiB PET淀粉样蛋白成像。在初步 [11 C]Martinostat PET成像和病理学数据，我们将测试以下假设：（1）整体的顺序 脑HDAC表达将从AD到NC到认知正常的PD到PDD到DLB增加;（2） PET检测到的局部HDAC表达将与已知的病理变化拓扑学相关;（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 HDAC在壳核中的表达将与HDAC的表达相关。 运动障碍的严重程度;黑质和纹状体HDAC表达的不对称性将与运动障碍的不对称性相关。 （5）整体皮质和尾状HDAC水平将与认知功能的测量相关。 （6）后皮质HDAC表达与精神病（包括视觉障碍）有关。 （7）DLB和PDD中的差异HDAC表达将解释DLB和PDD中的时间差异。 在这些疾病中，与运动障碍相关的痴呆症的出现。总之，这些努力将揭示 在PD，PDD和DLB的生命过程中基因表达的表观遗传控制失调的贡献。