Presymptomatic and early pathological features of MAPT-associated frontotemporal lobar degeneration.
Presymptomatic and early pathological features of MAPT-associated frontotemporal lobar degeneration.
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DOI：
10.1186/s40478-023-01588-9
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发表时间：
2023-08-02
影响因子：
7.1
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中科院分区：
文献类型：
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由于MAPT致病性变异体（FTLD-MAPT）引起的额颞叶变性（FTLD）的早期病理特征尚未得到充分研究，因为早期组织很少可用。在这里，我们报告了三个症状前/早期MAPT变异携带者的独特病理学数据（FTLD临床痴呆评分[FTLD-CDR] = 0-1）。我们在18个灰质（9个皮质，9个皮质下）和13个白色物质（9个皮质，4个皮质下）区域中半定量和数字定量检测了神经元变性的tau蛋白负荷。我们比较了症状前/早期病理与具有相同变体（2个L315 R，10个P301 L，6个G272 V）的中期/终末期队列（FTLD-CDR = 2-3），并开发了P301 L和G272 V变体的临床病理分期模型。68岁的前驱期L315 R携带者（FTLD-CDR = 0）在额叶中、颞叶前下、杏仁核、海马（帕拉）和纹状体中具有与L315 R终末期携带者相似的形态学上有限的tau负荷，沿着与年龄相关的阿尔茨海默病神经病理改变。59岁前驱期P301 L携带者（FTLD-CDR = 0.5）在前扣带回、前颞叶、中/上级额叶、额岛叶皮质和杏仁核中的tau负荷最高。45岁的早期G272 V携带者（FTLD-CDR = 1）在上级额叶和前扣带回皮质、下托和CA 1中具有最高的tau负荷。tau蛋白负荷的严重程度和分布在症状前/早期的变体之间显示出一些区域变异性，而神经元变性，轻度至中度，类似地分布在额颞区。早期tau蛋白负荷和神经元变性都不如中期/终末期病例严重。在用于临床病理分期的一个区域子集（10个GM，8个WM）中，临床严重程度与神经元变性强烈相关（rho = 0.72，p < 0.001），与GM tau负荷不太强烈相关（rho = 0.57，p = 0.006），与WM tau负荷无关（p = 0.9）。临床病理分期显示早期tau病理学的变体特异性模式和跨阶段的进展。这些独特的数据表明，tau病理学和神经元变性已经存在于FTLD-MAPT的症状前/早期阶段，尽管与中期/终末期疾病相比不太严重。此外，早期病理模式，特别是tau蛋白负荷，在特定的MAPT变体之间部分不同。在线版本包含补充材料，可通过10.1186/s40478-023-01588-9获得。
Early pathological features of frontotemporal lobar degeneration (FTLD) due to MAPT pathogenic variants (FTLD-MAPT) are understudied, since early-stage tissue is rarely available. Here, we report unique pathological data from three presymptomatic/early-stage MAPT variant carriers (FTLD Clinical Dementia Rating [FTLD-CDR] = 0–1). We examined neuronal degeneration semi-quantitatively and digitally quantified tau burden in 18 grey matter (9 cortical, 9 subcortical) and 13 white matter (9 cortical, 4 subcortical) regions. We compared presymptomatic/early-stage pathology to an intermediate/end-stage cohort (FTLD-CDR = 2–3) with the same variants (2 L315R, 10 P301L, 6 G272V), and developed a clinicopathological staging model for P301L and G272V variants. The 68-year-old presymptomatic L315R carrier (FTLD-CDR = 0) had limited tau burden morphologically similar to L315R end-stage carriers in middle frontal, antero-inferior temporal, amygdala, (para-)hippocampus and striatum, along with age-related Alzheimer’s disease neuropathological change. The 59-year-old prodromal P301L carrier (FTLD-CDR = 0.5) had highest tau burden in anterior cingulate, anterior temporal, middle/superior frontal, and fronto-insular cortex, and amygdala. The 45-year-old early-stage G272V carrier (FTLD-CDR = 1) had highest tau burden in superior frontal and anterior cingulate cortex, subiculum and CA1. The severity and distribution of tau burden showed some regional variability between variants at presymptomatic/early-stage, while neuronal degeneration, mild-to-moderate, was similarly distributed in frontotemporal regions. Early-stage tau burden and neuronal degeneration were both less severe than in intermediate-/end-stage cases. In a subset of regions (10 GM, 8 WM) used for clinicopathological staging, clinical severity correlated strongly with neuronal degeneration (rho = 0.72, p < 0.001), less strongly with GM tau burden (rho = 0.57, p = 0.006), and did not with WM tau burden (p = 0.9). Clinicopathological staging showed variant-specific patterns of early tau pathology and progression across stages. These unique data demonstrate that tau pathology and neuronal degeneration are present already at the presymptomatic/early-stage of FTLD-MAPT, though less severely compared to intermediate/end-stage disease. Moreover, early pathological patterns, especially of tau burden, differ partly between specific MAPT variants. The online version contains supplementary material available at 10.1186/s40478-023-01588-9.
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影响因子：
12.7
作者：
Arezoumandan S;Xie SX;Cousins KAQ;Mechanic-Hamilton DJ;Peterson CS;Huang CY;Ohm DT;Ittyerah R;McMillan CT;Wolk DA;Yushkevich P;Trojanowski JQ;Lee EB;Grossman M;Phillips JS;Irwin DJ
通讯作者：
Irwin DJ
影响因子：
7.1
作者：
Giannini LAA;Peterson C;Ohm D;Xie SX;McMillan CT;Raskovsky K;Massimo L;Suh E;Van Deerlin VM;Wolk DA;Trojanowski JQ;Lee EB;Grossman M;Irwin DJ
通讯作者：
Irwin DJ
影响因子：
13.6
作者：
Fung CW;Guo J;Fu H;Figueroa HY;Konofagou EE;Duff KE
通讯作者：
Duff KE
影响因子：
4.3
作者：
Giannini, Lucia A. A.;Xie, Sharon X.;Irwin, David J.
通讯作者：
Irwin, David J.
影响因子：
14.5
作者：
Bronner, IF;ter Meulen, BC;van Swieten, JC
通讯作者：
van Swieten, JC