Brainstem-based imaging biomarkers of premanifest synucleinopathy

基于脑干的突触核蛋白病前期成像生物标志物

• 批准号: 10606490
• 负责人: Marta Bianciardi
• 金额: $ 72.11万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10606490
• 关键词: Adult; Affect; Aging; Alzheimer' s Disease; Animal Model; Animals; Area; Arousal; Atlases; Behavioral; Behavioral Symptoms; Biological Markers; Brain; Brain Stem; Brain region; Cell Nucleus; Clinical; Clinical Research; Complex; Corpus striatum structure; Dementia; Dementia with Lewy Bodies; Dependence; Development; Diagnosis; Diagnostic; Disease; Disease Progression; Early Diagnosis; Early treatment; Elderly; Evaluation; Fostering; Goals; Human; Image; Imaging Techniques; Impaired cognition; Impairment; Individual; Lewy Bodies; Lewy Body Dementia; Location; Magnetic Resonance Imaging; Maps; Methods; Modeling; Morphology; Motor; Multiple System Atrophy; Neocortex; Nerve; Nerve Degeneration; Neurobehavioral Manifestations; Neurodegenerative Disorders; Outcome; Parkinson Disease; Parkinson' s Dementia; Pathogenesis; Pathway interactions; Patients; Physicians; Population; Proteins; REM Sleep Behavior Disorder; Research; Resolution; Reticular Formation; Risk; Role; Structure; Substantia nigra structure; Symptoms; Technology; Testing; Therapeutic; Time; Work; alpha synuclein; biomarker identification; biomarker validation; comparison control; connectome; diagnostic biomarker; disability; dorsal motor nucleus; human model; imaging biomarker; imaging modality; improved; in vivo; locus ceruleus structure; neocortical; neuroimaging; novel; novel diagnostics; olfactory bulb; pars compacta; prevent; protein aggregation; raphe nuclei; research study; synucleinopathy; therapeutic development; tool; young adult

Dementia, the loss of cognitive and behavioral abilities, is one of the major causes of disability and dependency among older people worldwide. Neurodegenerative diseases, such as Alzheimer’s disease and Lewy body dementia (including dementia with Lewy bodies and Parkinson’s disease dementia), are the most common causes of dementia. Currently, there are several diagnostic and therapeutic challenges for these diseases. Validated biomarkers of neurodegeneration, especially at premanifest stages, do not exist. Further, there is no available treatment to slow down or arrest the progression of disease. Thus, there is a huge need of biomarkers able to detect neurodegeneration early in the cascade. Brainstem imaging holds great promise in assessing Lewy body dementia in elderly humans, when Lewy bodies (i.e. neuro-degeneration due to the accumulation of alpha-synuclein protein in the brain) are expected to affect the brainstem and the olfactory bulb, before spreading to other brain areas during symptomatic stages. Brainstem-based biomarkers can fill the currently existing holes in diagnosing the early synucleinopathy stages when treatment can be most effective in delaying the development of full- blown neurodegeneration. However, existing imaging methods are incapable of resolving details of tiny deep brainstem nuclei in living elderly humans, limiting the development of brainstem-based biomarkers of premanifest Lewy body dementia. To fill this gap, the central aim of the proposed research is to create a probabilistic atlas of twenty arousal and motor brainstem nuclei in healthy elderly subjects by ultra-high field (7 T) MRI. The atlas will be used to evaluate brainstem-based biomarkers of premanifest Lewy body dementia (LBD) assessing the integrity of brainstem nuclei microstructure and connectivity pathways. To do so, we will map the brainstem nuclei atlas to both advanced (e.g. 7 T) and clinical (e.g. 3 T) neuroimages of controls, premanifest LBD, as well as de novo manifest LBD; crucially, we will test the hypothesis that brainstem microstructure and/ or connectivity pathway are altered in premanifest LBD compared to controls, and that these changes become stronger and affect more brain regions in de novo manifest LBD. Thus, our project will provide two important new tools, a structural atlas of brainstem nuclei and brainstem-based biomarkers of premanifest LBD. The generated brainstem nuclei atlas will be a useful tool in research and clinical studies of elderly populations able to automatically identify the location of brainstem nuclei in both advanced and clinical MRI of elderly subjects. The developed brainstem- based biomarkers of premanifest LBD will improve our understanding and the diagnosis of early stage Lewy body dementia and the development of better treatment for early stage patients before they manifest cognitive and behavioral symptoms.

痴呆症是认知和行为能力的丧失，是全世界老年人残疾和依赖的主要原因之一。神经退行性疾病，如阿尔茨海默病和路易体痴呆（包括路易体痴呆和帕金森病痴呆），是痴呆最常见的原因。目前，这些疾病的诊断和治疗面临一些挑战。经验证的神经退行性变生物标志物，尤其是在发病前阶段，并不存在。此外，没有可用的治疗方法来减缓或阻止疾病的进展。因此，非常需要能够在级联早期检测神经变性的生物标志物。 脑干成像在评估老年人的路易体痴呆方面具有广阔的前景，因为路易体（即由于大脑中α-突触核蛋白积累而引起的神经变性）预计会影响脑干和嗅球，然后在症状阶段扩散到其他大脑区域。基于脑干的生物标志物可以填补目前在诊断早期突触核蛋白病阶段中存在的漏洞，此时治疗可以最有效地延缓全面神经变性的发展。然而，现有的成像方法无法解析老年人体内微小的深部脑干核的细节，限制了基于脑干的路易体痴呆前期生物标志物的开发。 为了填补这一空白，本研究的中心目标是通过超高场 (7 T) MRI 创建健康老年受试者的 20 个唤醒和运动脑干核团的概率图谱。该图谱将用于评估基于脑干的路易体痴呆前期生物标志物（LBD），评估脑干核微结构和连接通路的完整性。为此，我们将脑干核图谱映射到对照、预显 LBD 以及新显 LBD 的高级（例如 7 T）和临床（例如 3 T）神经图像；至关重要的是，我们将测试这样的假设：与对照组相比，先期 LBD 中的脑干微观结构和/或连接通路发生了改变，并且这些变化在新出现的 LBD 中变得更强并影响更多的大脑区域。 因此，我们的项目将提供两个重要的新工具，脑干核结构图谱和基于脑干的预显 LBD 生物标志物。生成的脑干核图谱将成为老年人群研究和临床研究的有用工具，能够在老年受试者的高级和临床 MRI 中自动识别脑干核的位置。开发的基于脑干的前期 LBD 生物标志物将提高我们对早期路易体痴呆的理解和诊断，并在早期患者出现认知和行为症状之前开发更好的治疗方法。