Penn Frontotemporal Degeneration Center, Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Department of Clinical Sciences, SciLifeLab, Lund University, 222 42, Lund, Sweden.
Transl Neurodegener. 2023 Dec 7;12(1):57. doi: 10.1186/s40035-023-00389-3.
TDP-43 proteinopathies represent a spectrum of neurological disorders, anchored clinically on either end by amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). The ALS-FTD spectrum exhibits a diverse range of clinical presentations with overlapping phenotypes, highlighting its heterogeneity. This study was aimed to use disease progression modeling to identify novel data-driven spatial and temporal subtypes of brain atrophy and its progression in the ALS-FTD spectrum.
We used a data-driven procedure to identify 13 anatomic clusters of brain volume for 57 behavioral variant FTD (bvFTD; with either autopsy-confirmed TDP-43 or TDP-43 proteinopathy-associated genetic variants), 103 ALS, and 47 ALS-FTD patients with likely TDP-43. A Subtype and Stage Inference (SuStaIn) model was trained to identify subtypes of individuals along the ALS-FTD spectrum with distinct brain atrophy patterns, and we related subtypes and stages to clinical, genetic, and neuropathological features of disease.
SuStaIn identified three novel subtypes: two disease subtypes with predominant brain atrophy in either prefrontal/somatomotor regions or limbic-related regions, and a normal-appearing group without obvious brain atrophy. The limbic-predominant subtype tended to present with more impaired cognition, higher frequencies of pathogenic variants in TBK1 and TARDBP genes, and a higher proportion of TDP-43 types B, E and C. In contrast, the prefrontal/somatomotor-predominant subtype had higher frequencies of pathogenic variants in C9orf72 and GRN genes and higher proportion of TDP-43 type A. The normal-appearing brain group showed higher frequency of ALS relative to ALS-FTD and bvFTD patients, higher cognitive capacity, higher proportion of lower motor neuron onset, milder motor symptoms, and lower frequencies of genetic pathogenic variants. The overall SuStaIn stages also correlated with evidence for clinical progression including longer disease duration, higher King's stage, and cognitive decline. Additionally, SuStaIn stages differed across clinical phenotypes, genotypes and types of TDP-43 pathology.
Our findings suggest distinct neurodegenerative subtypes of disease along the ALS-FTD spectrum that can be identified in vivo, each with distinct brain atrophy, clinical, genetic and pathological patterns.
TDP-43 蛋白病构成了一系列神经退行性疾病，临床以肌萎缩侧索硬化症（ALS）和额颞叶变性（FTD）为两端。ALS-FTD 谱表现出多种多样的临床表现，具有重叠的表型，突出了其异质性。本研究旨在使用疾病进展建模来鉴定 ALS-FTD 谱中脑萎缩的新的基于数据驱动的空间和时间亚型及其进展。
我们使用数据驱动的程序来识别 57 例行为变异型额颞叶痴呆（bvFTD；尸检证实为 TDP-43 或 TDP-43 蛋白病相关基因突变）、103 例 ALS 和 47 例可能为 TDP-43 的 ALS-FTD 患者的 13 个脑容量解剖簇。训练了一个亚型和阶段推断（SuStaIn）模型，以识别 ALS-FTD 谱中具有不同脑萎缩模式的个体亚型，我们将亚型和阶段与疾病的临床、遗传和神经病理学特征相关联。
SuStaIn 确定了三种新的亚型：两种疾病亚型，其主要脑萎缩分别位于前额叶/躯体运动区或边缘相关区，以及没有明显脑萎缩的正常表现组。边缘优势亚型往往表现出更严重的认知障碍、TBK1 和 TARDBP 基因致病性变异的更高频率，以及更高比例的 TDP-43 类型 B、E 和 C。相比之下，前额叶/躯体运动优势亚型 C9orf72 和 GRN 基因的致病性变异频率更高，TDP-43 类型 A 的比例更高。正常表现的脑组与 ALS 患者相比，ALS-FTD 和 bvFTD 患者的频率更高，认知能力更高，较低运动神经元发病的比例更高，运动症状更轻，遗传致病性变异的频率更低。整体 SuStaIn 阶段也与临床进展的证据相关，包括更长的疾病持续时间、更高的 King 分期和认知下降。此外，SuStaIn 阶段在临床表型、基因型和 TDP-43 病理类型之间存在差异。
我们的研究结果表明，ALS-FTD 谱中存在不同的神经退行性疾病亚型，可以在体内识别，每种亚型都具有不同的脑萎缩、临床、遗传和病理模式。
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