Multidimensional MRI reveals cortical astrogliosis linked to dementia in Alzheimer's disease.

IF 4.5 Q1 CLINICAL NEUROLOGY
Brain communications Pub Date : 2025-06-18 eCollection Date: 2025-01-01 DOI:10.1093/braincomms/fcaf245
Stephanie Barsoum, Caitlin S Latimer, Amber L Nolan, Alexander Barrett, Koping Chang, Juan C Troncoso, C Dirk Keene, Dan Benjamini
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引用次数: 0

Abstract

Despite the presence of significant Alzheimer's disease pathology, characterized by amyloid β (Aβ) plaques and phosphorylated tau (pTau) tangles, some cognitively unimpaired elderly individuals do not inevitably develop dementia. Cortical astroglial inflammation, a ubiquitous feature of symptomatic Alzheimer's disease, shows a strong correlation with cognitive impairment severity, highlighting the influence of factors beyond classical pathology. However, non-invasively imaging neuroinflammation, particularly astrogliosis, using MRI remains a significant challenge. Here we sought to address this challenge and to leverage multidimensional (MD) MRI, a powerful approach that combines relaxation with diffusion MR contrasts, to map cortical astrogliosis in the human brain by accessing sub-voxel information. Our goal was to investigate whether MD-MRI can map astroglial pathology in the cerebral cortex, and if so, whether it can distinguish cognitively normal state from dementia in the presence of hallmark Alzheimer's disease neuropathological changes. We adopted a multimodal approach by integrating histological and MRI analyses using human postmortem brain samples from two independent discovery and replication cohorts. Ex vivo cerebral cortical tissue specimens were derived from two groups-non-demented individuals with varying levels of postmortem Alzheimer's disease pathology and individuals with both Alzheimer's disease pathology and dementia-and scanned using 7 T MRI. We acquired and processed MD-MRI, diffusion tensor, and quantitative T1 and T2 MRI data, followed by histopathology on the same tissue. By co-registering MRI and microscopy data, we performed quantitative multimodal analyses, leveraging targeted immunostaining to assess MD-MRI sensitivity and specificity towards Aβ, pTau, and glial fibrillary acidic protein (GFAP), a marker for astrogliosis. Our discovery analysis reveals a distinct MD-MRI signature of cortical astrogliosis, enabling the creation of predictive maps for cognitive state amid Alzheimer's disease neuropathological changes. Multiple linear regression analysis linked histological values to MRI changes, revealing that the MD-MRI cortical astrogliosis biomarker was significantly associated with GFAP burden (standardized β = 0.658/0.709, p FDR < 0.0001), but not with Aβ (standardized β = 0.009/0.120, p FDR = 0.913/0.274) or pTau (standardized β = -0.196/0.158, p FDR = 0.051/0.251), for the discovery/replication groups, respectively. Conversely, none of the conventional MRI parameters showed significant associations with GFAP burden in the cortex. Finally, we showed that the MD-MRI-derived astrogliosis biomarker is the only MRI measure capable of predicting cognitive state. While the extent to which pathological glial activation contributes to neuronal damage and cognitive impairment in Alzheimer's disease is uncertain, developing a non-invasive imaging method to see its effects holds promise from a mechanistic perspective and as a potential predictor of cognitive outcomes.

多维MRI显示皮层星形胶质细胞增生与阿尔茨海默病痴呆有关。
尽管存在显著的阿尔茨海默病病理,以β淀粉样蛋白(Aβ)斑块和磷酸化tau蛋白(pTau)缠结为特征,但一些认知功能未受损的老年人并不一定会患上痴呆症。皮层星形胶质细胞炎症是症状性阿尔茨海默病的普遍特征,它与认知功能障碍的严重程度有很强的相关性,突出了经典病理之外因素的影响。然而,使用MRI非侵入性成像神经炎症,特别是星形胶质细胞增生,仍然是一个重大挑战。在这里,我们试图解决这一挑战,并利用多维(MD) MRI,一种结合放松和扩散磁共振对比的强大方法,通过访问亚体素信息来绘制人脑皮层星形胶质细胞形成。我们的目的是研究MD-MRI是否可以绘制大脑皮层的星形胶质细胞病理,如果可以,它是否可以在阿尔茨海默病标志性神经病理改变的情况下区分认知正常状态和痴呆。我们采用多模式方法,对来自两个独立发现和复制队列的人类死后脑样本进行组织学和MRI分析。离体大脑皮质组织标本取自两组——具有不同程度死后阿尔茨海默病病理的非痴呆个体和同时患有阿尔茨海默病病理和痴呆的个体——并使用7t MRI进行扫描。我们获取并处理了MD-MRI、扩散张量、定量T1和T2 MRI数据,随后对同一组织进行了组织病理学检查。通过联合登记MRI和显微镜数据,我们进行了定量多模态分析,利用靶向免疫染色来评估MD-MRI对a β、pTau和胶质纤维酸性蛋白(GFAP)的敏感性和特异性,GFAP是星形胶质细胞增生的标志物。我们的发现分析揭示了皮质星形胶质细胞增生的独特MD-MRI特征,从而能够在阿尔茨海默病神经病理变化中创建认知状态的预测图。多元线性回归分析将组织学值与MRI变化联系起来,显示MD-MRI皮质星形胶质细胞增生生物标志物与GFAP负荷(标准化β = 0.658/0.709, p FDR < 0.0001)显著相关,但与Aβ(标准化β = 0.009/0.120, p FDR = 0.913/0.274)或pTau(标准化β = -0.196/0.158, p FDR = 0.051/0.251)无关。相反,常规MRI参数均未显示与皮层GFAP负荷有显著关联。最后,我们发现md -MRI衍生的星形胶质生物标志物是唯一能够预测认知状态的MRI测量。虽然病理性胶质细胞激活在多大程度上导致阿尔茨海默病中的神经元损伤和认知障碍尚不确定,但从机制角度和作为认知结果的潜在预测因素来看,开发一种非侵入性成像方法来观察其影响是有希望的。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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