Neuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum
Neuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum
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DOI：
10.1093/brain/awaa033
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发表时间：
2020-03-01
期刊：
影响因子：
14.5
通讯作者：
Rowe, James B.
中科院分区：
文献类型：
--
作者：
Bevan-Jones, W. Richard;Cope, Thomas E.;Rowe, James B.
额颞叶痴呆的临床综合征在临床和神经病理学上是异质性的，但神经炎症等过程在疾病谱中可能是常见的。我们研究了神经炎症如何与tau蛋白和TDP-43病理学的定位以及临床疾病的异质性相关。我们在体内使用PET，其中（i）C-11-PK-11195，一种活化的小胶质细胞的标志物和神经炎症的替代指标;和（ii）F-18-AV-1451，一种放射性配体，其与tau蛋白病和TDP-43相关疾病中的病理影响区域的结合增加，并且其用作非淀粉样蛋白-α蛋白聚集的替代标志物。我们评估了31例额颞叶痴呆患者（10例行为变异，11例语义变异和10例非流利变异），其中28例接受了F-18-AV-1451和C-11-PK-11195 PET，并匹配对照受试者（14例接受（18）FAV-1451，15例接受C-11-PK-11195）。我们使用了一个单变量的区域感兴趣的分析，成对的相关性分析的两个配体的结合分布之间的区域关系，结合的空间分布的主成分分析，和多变量分析的结合的分布，明确控制TDP-43和不同的tau亚型的配体亲和力的个体差异。在感兴趣区域分析和结合的主要空间成分比较中，我们发现每个患者组和对照组之间额颞区的C-11-PK-11195结合存在显著的组间差异。（18）与颞区对照相比，语义变异型原发性进行性失语症中的FAV-1451结合增加，并且语义变异型原发性进行性失语症和行为变异型额颞痴呆分别在跨颞和额颞皮质的结合的主要空间成分的表达方面与对照不同。在所有疾病组中，C-11-E 'K-11195和F-18-AV-1451摄取在广泛的皮质区域之间存在强正相关。我们通过对12个大脑进行尸检量化证实了这种关联，证明了FTLD-TDP（A）、FTLD-TDP（C）和FTLD-Pick中小胶质细胞的区域密度与神经病理学之间存在强相关性。这是由变形虫（激活）小胶质细胞驱动的，分枝（无柄）小胶质细胞的密度没有变化。与F-18-AV-1451相比，C-11-PK-11195结合的多变量分布与临床异质性的相关性更好：神经炎症的不同空间模式与不同的额颞叶痴呆综合征相关，并支持参与者的准确分类。这些在体内的研究结果表明，在额颞叶痴呆症的神经炎症和蛋白质聚集之间的密切联系。炎症成分可能是重要的，在形成临床和神经病理模式的不同临床综合征的额颞叶痴呆。
The clinical syndromes of frontotemporal dementia are clinically and neuropathologically heterogeneous, but processes such as neuroinflammation may be common across the disease spectrum. We investigated how neuroinflammation relates to the localization of tau and TDP-43 pathology, and to the heterogeneity of clinical disease. We used PET in vivo with (i) C-11-PK-11195, a marker of activated microglia and a proxy index of neuroinflammation; and (ii) F-18-AV-1451, a radioligand with increased binding to pathologically affected regions in tauopathies and TDP-43-related disease, and which is used as a surrogate marker of non-amyloid-a protein aggregation. We assessed 31 patients with frontotemporal dementia (10 with behavioural variant, 11 with the semantic variant and 10 with the non-fluent variant), 28 of whom underwent both F-18-AV-1451 and C-11-PK-11195 PET, and matched control subjects (14 for (18)FAV-1451 and 15 for C-11-PK-11195). We used a univariate region of interest analysis, a paired correlation analysis of the regional relationship between binding distributions of the two ligands, a principal component analysis of the spatial distributions of binding, and a multivariate analysis of the distribution of binding that explicitly controls for individual differences in ligand affinity for TDP-43 and different tau isoforms. We found significant group-wise differences in C-11-PK-11195 binding between each patient group and controls in frontotemporal regions, in both a regions-of-interest analysis and in the comparison of principal spatial components of binding. (18)FAV-1451 binding was increased in semantic variant primary progressive aphasia compared to controls in the temporal regions, and both semantic variant primary progressive aphasia and behavioural variant frontotemporal dementia differed from controls in the expression of principal spatial components of binding, across temporal and frontotemporal cortex, respectively. There was a strong positive correlation between C-11-E'K-11195 and F-18-AV-1451 uptake in all disease groups, across widespread cortical regions. We confirmed this association with post-mortem quantification in 12 brains, demonstrating strong associations between the regional densities of microglia and neuropathology in FTLD-TDP (A), FTLD-TDP (C), and FTLD-Pick's. This was driven by amoeboid (activated) microglia, with no change in the density of ramified (sessile) microglia. The multivariate distribution of C-11-PK-11195 binding related better to dinical heterogeneity than did F-18-AV-1451: distinct spatial modes of neuroinflammation were associated with different frontotemporal dementia syndromes and supported accurate dassification of participants. These in vivo findings indicate a close association between neuroinflammation and protein aggregation in frontotemporal dementia. The inflammatory component may be important in shaping the clinical and neuropathological patterns of the diverse clinical syndromes of frontotemporal dementia.