Brainstem-based imaging biomarkers of premanifest synucleinopathy

痴呆症，即认知和行为能力的丧失，是全球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氏病痴呆)是导致痴呆症的最常见原因。目前，这些疾病的诊断和治疗面临几个挑战。已证实的神经退行性变的生物标记物，特别是在显性前期，并不存在。此外，没有可用的治疗方法来减缓或阻止疾病的发展。因此，对能够在级联反应早期发现神经退行性变的生物标记物的需求巨大。 脑干成像在评估老年人路易体痴呆方面具有很大的前景，当路易体(即由于阿尔法-突触核蛋白在大脑中积累而导致的神经变性)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。基于脑干的生物标记物可以填补目前在诊断早期突触核病阶段存在的空白，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分辨活着的老年人脑干深部微小核团的细节，限制了基于脑干的生物标记物的发展，这些生物标志物是先显性路易体痴呆的。 为了填补这一空白，这项拟议研究的中心目标是利用超高场(7T)MRI建立一个由20个健康老年受试者的觉醒和运动脑干核团组成的概率图谱。该图谱将被用来评估基于脑干的生物标记物，以评估脑干核团的完整性、微结构和连接途径。为此，我们将脑干核团图谱映射到对照组的高级(例如7T)和临床(例如3T)神经图像，预显性LBD以及新出现的LBD；关键的是，我们将检验这样的假设，即与对照相比，预显性LBD的脑干微观结构和/或连接路径发生了改变，并且这些变化变得更强烈，并影响到新出现的LBD中更多的脑区。 因此，我们的项目将提供两个重要的新工具，脑干核团结构图谱和基于脑干的LBD预显性生物标记物。所生成的脑干核团图谱将成为老年人群研究和临床研究中的有用工具，能够在老年受试者的高级和临床MRI中自动识别脑干核团的位置。基于脑干的前驱LBD生物标志物的开发将提高我们对早期路易体痴呆的认识和诊断，并为早期患者在出现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.