Brainstem-based imaging biomarkers of premanifest synucleinopathy

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），是痴呆的最常见原因。目前，这些疾病的诊断和治疗存在一些挑战。神经退行性变的有效生物标志物，特别是在预显阶段，并不存在。此外，没有可用的治疗来减缓或阻止疾病的进展。因此，非常需要能够在级联反应的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症方面具有很大的前景，当路易体（即由于大脑中α-突触核蛋白的积累而引起的神经变性）在症状阶段扩散到其他大脑区域之前，预计会影响脑干和嗅球。基于脑干的生物标志物可以填补目前存在的诊断早期突触核蛋白病阶段的漏洞，此时治疗可以最有效地延迟全面神经变性的发展。然而，现有的成像方法无法解析活体老年人中微小的深层脑干核的细节，限制了基于脑干的预显路易体痴呆生物标志物的发展。 为了填补这一空白，所提出的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个觉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预显路易体痴呆（LBD）生物标志物，评估脑干核团微结构和连接通路的完整性。为了做到这一点，我们将脑干核图谱映射到两个先进的（例如7 T）和临床（例如，3 T）对照、预显现LBD以及新生显现LBD的神经图像;重要的是，我们将检验这一假设，即与对照组相比，在表现前LBD中脑干微结构和/或连接通路发生了改变，并且这些变化变得更强，并且在从头表现的LBD中影响更多的脑区域。 因此，我们的项目将提供两个重要的新工具，脑干核团的结构图谱和基于脑干的预表现LBD生物标志物。所产生的脑干核图谱将是一个有用的工具，在研究和临床研究的老年人群能够自动识别脑干核的位置在先进的和临床MRI的老年受试者。开发的基于脑干的预显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，并在早期患者表现出认知和行为症状之前开发更好的治疗方法。

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.