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: 10390422
• 负责人: Marta Bianciardi
• 金额: $ 75.41万
• 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/10390422
• 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; Substantia nigra structure; Symptoms; Technology; Testing; Therapeutic; Time; Work; alpha synuclein; base; biomarker identification; connectome; diagnostic biomarker; disability; dorsal motor nucleus; human model; imaging biomarker; imaging modality; improved; in vivo; locus ceruleus structure; neuroimaging; novel; novel diagnostics; olfactory bulb; pars compacta; prevent; protein aggregation; raphe nuclei; research study; synucleinopathy; technique development; 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，是全球老年人造成混乱和依赖性的主要原因之一。神经退行性疾病，例如阿尔茨海默氏病和刘易体内痴呆症（包括伴有路易身体的痴呆症和帕金森氏病痴呆症），是痴呆症的最常见原因。当前，这些疾病存在一些诊断和治疗挑战。不存在经过验证的神经变性生物标志物，尤其是在末期阶段，不存在。此外，没有可用的治疗方法可以减慢或阻止疾病的进展。这是巨大的生物标志物，能够在级联的早期检测神经退行性。 脑干成像在评估人体中的Lewy体内痴呆症（即由于α-甲核蛋白在大脑中积累而导致的神经分离）时，有很大的希望，预计会影响脑干和嗅觉块，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在治疗最有效地延迟成熟神经变性的发展时，可以填补诊断当前现有的孔洞。但是，现有的成像方法无法解决老年人类中深脑干核的细节，从而限制了脑干的基于脑干的生物标志物的发展。 为了填补这一空白，拟议的研究的核心目的是在健康的受试者中通过超高领域（7 t）MRI创建一个概率唤醒和运动脑干核的概率地图集。该地图集将用于评估基于脑干的生物标志物，以评估脑干核微观结构和连通性途径的完整性。为此，我们将将脑干核图集映射到高级（例如7 T）和临床（例如3 T）对照组的神经图像，Premanifest LBD以及从头明显的LBD；克里克利（Crucilly），我们将检验以下假设：与对照组相比，前命中率LBD的脑干微观结构和/或连通性途径发生了变化，并且这些变化变得更强并影响从头明显LBD的更多大脑区域。 这是我们的项目将提供两个重要的新工具，这是一个脑干和基于脑干的脑干和脑干的结构图集。生成的脑干核图集将是能够自动识别脑干核在基本受试者的高级和临床MRI中的位置的基础研究和临床研究中的有用工具。开发的基于脑干的生物标志物的生物标志物在表现出认知和行为症状之前，将改善我们对早期身体痴呆症早期身体痴呆症的理解和诊断。