Vita-Salute San Raffaele University, Milan, Italy.
In vivo Human Molecular and Structural Neuroimaging Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.
J Alzheimers Dis. 2020;75(3):1003-1016. doi: 10.3233/JAD-190954.
Alzheimer's disease (AD) is characterized by an involvement of brain dopamine (DA) circuitry, the presence of which has been associated with emergence of both neuropsychiatric symptoms and cognitive deficits.
In order to investigate whether and how the DA pathways are involved in the pathophysiology of AD, we assessed by in vivo neuroimaging the structural and metabolic alterations of subcortical and cortical DA pathways and targets.
We included 54 healthy control participants, 53 amyloid-positive subjects with mild cognitive impairment due to AD (MCI-AD), and 60 amyloid-positive patients with probable dementia due to AD (ADD), all with structural 3T MRI and 18F-FDG-PET scans. We assessed MRI-based gray matter reductions in the MCI-AD and ADD groups within an anatomical a priori-defined Nigrostriatal and Mesocorticolimbic DA pathways, followed by 18F-FDG-PET metabolic connectivity analyses to evaluate network-level metabolic connectivity changes.
We found significant tissue loss in the Mesocorticolimbic over the Nigrostriatal pathway. Atrophy was evident in the ventral striatum, orbitofrontal cortex, and medial temporal lobe structures, and already plateaued in the MCI-AD stage. Degree of atrophy in Mesocorticolimbic regions positively correlated with the severity of depression, anxiety, and apathy in MCI-AD and ADD subgroups. Additionally, we observed significant alterations of metabolic connectivity between the ventral striatum and fronto-cingulate regions in ADD, but not in MCI-AD. There were no metabolic connectivity changes within the Nigrostriatal pathway.
Our cross-sectional data support a clinically-meaningful, yet stage-dependent, involvement of the Mesocorticolimbic system in AD. Longitudinal and clinical correlation studies are needed to further establish the relevance of DA system involvement in AD.
阿尔茨海默病（AD）的特征是大脑多巴胺（DA）回路的参与，其存在与神经精神症状和认知缺陷的出现有关。
为了研究 DA 通路是否以及如何参与 AD 的病理生理学，我们通过活体神经影像学评估了皮质下和皮质 DA 通路和靶点的结构和代谢改变。
我们纳入了 54 名健康对照参与者、53 名因 AD 导致的轻度认知障碍（MCI-AD）的淀粉样蛋白阳性受试者和 60 名因 AD 导致的可能痴呆（ADD）的淀粉样蛋白阳性患者，所有患者均进行了 3T MRI 和 18F-FDG-PET 扫描。我们在解剖学上预先定义的 Nigrostriatal 和 Mesocorticolimbic DA 通路内评估了 MCI-AD 和 ADD 组的 MRI 基于的灰质减少，然后进行 18F-FDG-PET 代谢连接分析，以评估网络水平的代谢连接变化。
我们发现 Mesocorticolimbic 通路比 Nigrostriatal 通路的组织损失更明显。在腹侧纹状体、眶额皮质和内侧颞叶结构中可见萎缩，并且在 MCI-AD 阶段已经趋于稳定。Mesocorticolimbic 区域的萎缩程度与 MCI-AD 和 ADD 亚组中抑郁、焦虑和淡漠的严重程度呈正相关。此外，我们还观察到在 ADD 中，腹侧纹状体和额顶叶区域之间的代谢连接发生了显著改变，但在 MCI-AD 中没有。Nigrostriatal 通路内没有代谢连接变化。
我们的横断面数据支持 Mesocorticolimbic 系统在 AD 中具有临床意义但与阶段相关的参与。需要进行纵向和临床相关性研究，以进一步确定 DA 系统参与 AD 的相关性。
