Novel data-driven subtypes and stages of brain atrophy in the ALS-FTD spectrum  

作　　者：Ting Shen Jacob W.Vogel Jeffrey Duda Jeffrey S.Phillips Philip ACook James Gee Lauren Elman Colin Quinn Defne A.Amado Michael Baer Lauren Massimo Murray Grossman David J.Irwin Corey T.McMillan 

机构地区：[1]Penn Frontotemporal Degeneration Center,Department of Neurology,Perelman School of Medicine,University of Pennsylvania,Philadelphia,PA 19104,USA [2]Department of Clinical Sciences,SciLifeLab,Lund University,22242 Lund,Sweden [3]Penn Image Computing and Science Lab(PICSL),Department of Radiology,Perelman School of Medicine,University of Penn-sylvania,Philadelphia,PA 19104,USA [4]Department of Neurology,Perelman School of Medicine,University of Pennsylvania,Philadelphia,PA 19104,USA [5]Digital Neuropathology Laboratory,Department of Neurology,Perelman School of Medicine,University of Pennsylvania,Philadelphia,PA 19104,USA.

出　　处：《Translational Neurodegeneration》2023年第1期50-69,共20页转化神经变性病（英文）

基　　金：JWV acknowledges funding from the NIH(T32MH019112);the SciLifeLab&Wallenberg Data Driven Life Science Program(Grant:KAW 2020.0239);Jeffrey S.Phillips was supported by NIH Grant(R01-AG054519,K01-AG061277);supported by NIH funding(P30 AG072979,P01AG066597,R01NS109260);Penn Institute on Aging,Robinson Family Fund,Peisach Family Fund for FTD Research,and Arking Family Fund.

摘　　要：Background 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.Methods 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.Results 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 dif

关 键 词：Amyotrophic lateral sclerosis Frontotemporal degeneration Disease heterogeneity SuStaIn model 

分 类 号：R742[医药卫生—神经病学与精神病学]