Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam University Medical Centers, Amsterdam, The Netherlands.
Department of Pathology, Amsterdam University Medical Centers, Amsterdam Neuroscience, Amsterdam, The Netherlands.
Brain. 2023 Jan 5;146(1):307-320. doi: 10.1093/brain/awac043.
Three subtypes of distinct pathological proteins accumulate throughout multiple brain regions and shape the heterogeneous clinical presentation of frontotemporal lobar degeneration (FTLD). Besides the main pathological subtypes, co-occurring pathologies are common in FTLD brain donors. The objective of this study was to investigate how the location and burden of (co-)pathology correlate to early psychiatric and behavioural symptoms of FTLD. Eighty-seven brain donors from The Netherlands Brain Bank cohort (2008-2017) diagnosed with FTLD were included: 46 FTLD-TAR DNA-binding protein 43 (FTLD-TDP), 34 FTLD-tau, and seven FTLD-fused-in-sarcoma (FTLD-FUS). Post-mortem brain tissue was dissected into 20 standard regions and stained for phosphorylated TDP-43, phosphorylated tau, FUS, amyloid-β, and α-synuclein. The burden of each pathological protein in each brain region was assessed with a semi-quantitative score. Clinical records were reviewed for early psychiatric and behavioural symptoms. Whole-brain clinico-pathological partial correlations were calculated (local false discovery rate threshold = 0.01). Elaborating on the results, we validated one finding using a quantitative assessment of TDP-43 pathology in the granular layer of the hippocampus in FTLD-TDP brain donors with (n = 15) and without (n = 15) hallucinations. In subcortical regions, the presence of psychiatric symptoms showed positive correlations with increased hippocampal pathology burden: hallucinations with TDP-43 in the granular layer (R = 0.33), mania with TDP-43 in CA1 (R = 0.35), depression with TDP-43 in CA3 and with parahippocampal tau (R = 0.30 and R = 0.23), and delusions with CA3 tau (R = 0.26) and subicular amyloid-β (R = 0.25). Behavioural disinhibition showed positive correlations with tau burden in the thalamus (R = 0.29) and with both TDP-43 and amyloid-β burden in the subthalamus (R = 0.23 and R = 0.24). In the brainstem, the presence of α-synuclein co-pathology in the substantia nigra correlated with disinhibition (R = 0.24), tau pathology in the substantia nigra correlated with depression (R = 0.25) and in the locus coeruleus with both depression and perseverative/compulsive behaviour (R = 0.26 and R = 0.32). The quantitative assessment of TDP-43 in the granular layer validated the higher burden of TDP-43 pathology in brain donors with hallucinations compared to those without hallucinations (P = 0.007). Our results show that psychiatric symptoms of FTLD are linked to subcortical pathology burden in the hippocampus, and hallucinations are linked to a higher burden of TDP-43 in the granular layer. Co-occurring non-FTLD pathologies in subcortical regions could contribute to configuring the clinical phenotype of FTLD.
三种不同的病理性蛋白亚型在多个大脑区域积累，形成额颞叶变性（FTLD）的异质临床表现。除了主要的病理亚型外，FTLD 脑供体中还常伴有共存的病变。本研究的目的是探讨（共存）病理学的位置和负担与 FTLD 的早期精神和行为症状之间的相关性。纳入了来自荷兰脑库队列（2008-2017 年）的 87 名被诊断为 FTLD 的脑供体：46 名 FTLD-TAR DNA 结合蛋白 43（FTLD-TDP）、34 名 FTLD-tau 和 7 名 FTLD-融合肉瘤（FTLD-FUS）。死后脑组织被解剖成 20 个标准区域，并对磷酸化 TDP-43、磷酸化 tau、FUS、淀粉样β和α-突触核蛋白进行染色。通过半定量评分评估每个脑区每种病理蛋白的负担。对临床记录进行了回顾，以了解早期的精神和行为症状。计算了全脑临床病理部分相关性（局部错误发现率阈值=0.01）。在阐述结果的基础上，我们使用 FTLD-TDP 脑供体颗粒层中 TDP-43 病理学的定量评估验证了一个发现，这些脑供体中有无幻觉（n=15）。在皮质下区域，精神病症状的存在与海马体病理学负担的增加呈正相关：颗粒层 TDP-43 与幻觉（R=0.33），CA1 中的 TDP-43 与躁狂（R=0.35），CA3 和海马旁 tau 与抑郁（R=0.30 和 R=0.23），CA3 中的 tau 与妄想（R=0.26）和 subicular amyloid-β（R=0.25）。行为抑制障碍与丘脑 tau 负担呈正相关（R=0.29），与 subthalamus 中的 TDP-43 和淀粉样β负担呈正相关（R=0.23 和 R=0.24）。在脑干中，黑质中 α-突触核蛋白共存病理学与抑制障碍相关（R=0.24），黑质中的 tau 病理学与抑郁相关（R=0.25），蓝斑核中的 tau 病理学与抑郁和持续/强迫行为相关（R=0.26 和 R=0.32）。颗粒层中 TDP-43 的定量评估验证了有幻觉的 FTLD 脑供体中 TDP-43 病理学负担高于无幻觉的脑供体（P=0.007）。我们的研究结果表明，FTLD 的精神症状与海马体的皮质下病理学负担有关，而幻觉与颗粒层中 TDP-43 病理学负担的增加有关。皮质下区域共存的非 FTLD 病变可能有助于构成 FTLD 的临床表型。
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