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

基本信息

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
项目类别：
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&apos 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&apos 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

项目摘要

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.

项目概要/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）。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 网络然而，在尸检时的 DLB 和 PD 中，组蛋白乙酰化明显失调。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还不清楚 DLB 中 HDAC 表达变化是否与其他疾病不同。帕金森病痴呆 (PDD)。[11C]Martinostat 的最新开发，第一个标记的放射性示踪剂。活体人类中的 HDAC 能够对人类中的 HDAC 水平和分布进行生前评估 [11C]Martinostat 显示出具有低纳摩尔亲和力的特异性 HDAC 结合，目前正在积极研究中。因此，该提案的总体目标是 1) 评估大脑 HDAC 水平和 [11C]Martinostat 在特征明确的 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) 关联区域 [11C]Martinostat 与路易体病的临床特征和淀粉样蛋白负荷相关，患有 DLB、PDD、认知正常的受试者。 PD、阿尔茨海默病和 NC 将接受标准化的神经学检查、详细的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 的基础上。 [11C]Martinostat PET成像和病理数据，我们将检验以下假设：（1）全局顺序脑部HDAC表达会从AD到NC再到认知正常PD到PDD再到DLB（2）变化；使用 PET 检测到的区域 HDAC 表达将与已知的病理变化拓扑相关联 (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，但会与内部相关：区域 HDAC 表达的群体减少；(4) 壳核中的 HDAC 表达将与运动障碍的严重程度；黑质和纹状体 HDAC 表达的不对称性与运动障碍；(5) 整体皮质和尾状 HDAC 水平与认知测量相关 (6) 后皮质 HDAC 表达与包括视觉在内的精神病有关。 (7) DLB 和 PDD 中的差异 HDAC 表达将解释这些努力将共同揭示痴呆症与运动障碍的关系。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。