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

使用 [11C]Martinostat 对路易体痴呆的表观遗传失调进行成像

• 批准号: 10661239
• 负责人: Stephen N. Gomperts
• 金额: $ 82.11万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10661239
• 关键词: Affinity; Age; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Amyloid deposition; Anterior; Autopsy; Behavioral; Binding; Biochemistry; Biological Markers; Biometry; Brain; Brain Diseases; Brain region; 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; HDAC4 gene; Hippocampus; 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; Midbrain structure; Mitochondria; Modification; Motor; Neocortex; Neurologic; Neurologic Examination; Neuropsychological Tests; Neurosciences; Occipital lobe; Parkinson Disease; Parkinson' s Dementia; Participant; Pathologic; Pathology; Patients; Positron-Emission Tomography; Proteins; Radiochemistry; Research; Research Personnel; Resources; Severities; Standardization; Testing; Therapeutic; Time; Toxic effect; Visual Hallucination; aged; amyloid imaging; behavioral impairment; cognitive testing; dopaminergic neuron; drug discovery; motor impairment; nanomolar; neocortical; neuropsychiatry; patient population; putamen; radiotracer; research clinical testing; response; success; synuclein; synucleinopathy; β-amyloid burden

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.

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，通过化学方式调节基因表达 根据生活经历修改染色质、染色体结构中的蛋白质和 DNA 网络 和环境。在尸检时的 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变化是否随着疾病的进展而积累 疾病，包括痴呆症，例如反映路易体病理学的严重程度和地形，也不是 HDAC 的变化是否与这些人的运动、认知和行为障碍的积累有关 疾病。目前还不清楚 DLB 中 HDAC 表达的变化是否与其他人不同。 帕金森病痴呆（PDD），其认知和运动障碍的时间不同。最近的 [11C]Martinostat 的开发是第一个标记活人 HDAC 的放射性示踪剂，使 生前评估人脑中 HDAC 水平和分布。 [11C]Martinostat 显示特定 HDAC 结合具有低纳摩尔亲和力，目前正在多个患者群体中积极研究。整体 因此，该提案的目标是 1) 使用 [11C]Martinostat 评估大脑 HDAC 水平和区域分布 特征明确的 PD、PDD 和 DLB 受试者，与阿尔茨海默病和年龄匹配的正常受试者相比 对照 (NC) 受试者，以及 2) 将区域 [11C]Martinostat 随时间的积累与路易体结合联系起来 疾病的临床特征及其进展以及淀粉样蛋白负荷。患有 DLB、PDD、认知障碍的受试者 正常的PD、阿尔茨海默病和NC将接受标准化的神经学检查、神经心理学检查 测试，结合 [11C]Martinostat PET-MRI 和淀粉样蛋白成像与 [11C]PiB PET，并将在 12 个月时返回 用于重复 [11C]Martinostat PET-MRI 和临床评估。以初步 [11C]Martinostat PET 成像为基础 数据，我们将检验以下假设：（1）全脑HDAC表达顺序将从AD开始增加 NC 至认知正常 PD 至 PDD 至 DLB； (2) PET检测区域HDAC表达变化 将与已知的病理变化地形相关； (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，但会与区域 HDAC 的组内减少相关 表达; (4)中脑和壳核中HDAC的表达会与运动障碍的严重程度相关；前部 扣带回和尾状核的表达与认知障碍的严重程度有关；枕叶皮质表达 会伴有幻视； (5) 区域 HDAC 表达随时间的变化将与 运动、认知和神经精神障碍的进展。这些努力共同将揭示 生命期间基因表达的表观遗传控制失调对 PD、PDD 和 DLB 的影响。