Alzheimer Center, Department of Neurology, Erasmus University Medical Center, Doctor Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands.
Digital Neuropathology Laboratory, Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Acta Neuropathol. 2022 Dec;144(6):1065-1084. doi: 10.1007/s00401-022-02487-4. Epub 2022 Sep 6.
Frontotemporal lobar degeneration with MAPT pathogenic variants (FTLD-MAPT) has heterogeneous tau pathological inclusions postmortem, consisting of three-repeat (3R) or four-repeat (4R) tau isoforms, or a combination (3R + 4R). Here, we studied grey matter tau burden, its relation to neuronal degeneration, and regional patterns of pathology in different isoform groups of FTLD-MAPT. We included 38 FTLD-MAPT autopsy cases with 10 different MAPT pathogenic variants, grouped based on predominant tau isoform(s). In up to eleven regions (ten cortical and one striatal), we quantified grey matter tau burden using digital histopathological analysis and assigned semi-quantitative ratings for neuronal degeneration (i.e. 0-4) and separate burden of glial and neuronal tau inclusions (i.e. 0-3). We used mixed modelling to compare pathology measures (1) across the entire cohort and (2) within isoform groups. In the total cohort, tau burden and neuronal degeneration were positively associated and most severe in the anterior temporal, anterior cingulate and transentorhinal cortices. Isoform groups showed distinctive features of tau burden and neuronal degeneration. Across all regions, the 3R isoform group had lower tau burden compared to the 4R group (p = 0.008), while at the same time showing more severe neuronal degeneration than the 4R group (p = 0.002). The 3R + 4R group had an intermediate profile with relatively high tau burden along with relatively severe neuronal degeneration. Neuronal tau inclusions were most frequent in the 4R group (p < 0.001 vs. 3R), while cortical glial tau inclusions were most frequent in the 3R + 4R and 4R groups (p ≤ 0.009 vs. 3R). Regionally, neuronal degeneration was consistently most severe in the anterior temporal cortex within each isoform group. In contrast, the regions with the highest tau burden differed in isoform groups (3R: striatum; 3R + 4R: striatum, inferior parietal lobule, middle frontal cortex, anterior cingulate cortex; 4R: transentorhinal cortex, anterior temporal cortex, fusiform gyrus). We conclude that FTLD-MAPT isoform groups show distinctive features of overall neuronal degeneration and regional tau burden, but all share pronounced anterior temporal neuronal degeneration. These data suggest that distinct isoform-related mechanisms of genetic tauopathies, with slightly divergent tau distribution, may share similar regional vulnerability to neurodegeneration within the frontotemporal paralimbic networks.
额颞叶变性伴 MAPT 致病性变异（FTLD-MAPT）在死后具有异质的 tau 病理包涵体，由三重复（3R）或四重复（4R）tau 异构体组成，或两者的组合（3R+4R）。在这里，我们研究了不同 FTLD-MAPT 异构体组中灰质 tau 负担及其与神经元变性的关系，以及病理学的区域模式。我们纳入了 38 例 FTLD-MAPT 尸检病例，有 10 种不同的 MAPT 致病性变异，基于主要 tau 异构体进行分组。在多达 11 个区域（10 个皮质和 1 个纹状体）中，我们使用数字组织病理学分析来量化灰质 tau 负担，并为神经元变性（即 0-4）和单独的胶质和神经元 tau 包涵体负担（即 0-3）分配半定量评分。我们使用混合模型比较（1）整个队列中的病理学指标和（2）异构体组内的病理学指标。在整个队列中，tau 负担和神经元变性呈正相关，在前颞叶、前扣带回和经颞叶皮质最为严重。异构体组显示 tau 负担和神经元变性的特征不同。在所有区域中，3R 异构体组的 tau 负担低于 4R 组（p=0.008），而同时 3R 组的神经元变性比 4R 组更为严重（p=0.002）。3R+4R 组具有中间特征，tau 负担相对较高，同时神经元变性也相对严重。4R 组中神经元 tau 包涵体最常见（p<0.001 比 3R），而皮质胶质 tau 包涵体在 3R+4R 和 4R 组中最常见（p≤0.009 比 3R）。在每个异构体组中，神经元变性在前颞叶皮质中始终最为严重。相比之下，tau 负担最高的区域在异构体组中有所不同（3R：纹状体；3R+4R：纹状体、下顶叶、中额皮质、前扣带回皮质；4R：经颞叶皮质、前颞叶皮质、梭状回）。我们得出结论，FTLD-MAPT 异构体组显示出总体神经元变性和区域性 tau 负担的特征，但均表现出明显的前颞叶神经元变性。这些数据表明，具有略微不同 tau 分布的不同异构体相关遗传 tau 病机制可能具有相似的额颞叶偏侧边缘网络神经变性的区域易感性。
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