From the Department of Neurology (S. Schönecker, C.P., E.W., S.V.L., A.D., J.L.), Ludwig-Maximilians-Universität München, Germany; Department of Signal Theory Networking and Communications (F.J.M.-M., J.-M.G.S.), Andalusian Research Institute in Data Science and Computational Intelligence (DaSCI), University of Granada, Spain; Institute for Clinical Radiology (B.-S.R.), Institute for Stroke and Dementia Research (N.F.), and Institute of Neuroradiology (K.B.), Ludwig-Maximilians-Universität München, Germany; Département des Sciences Neurologiques (R.L.), Clinique Interdisciplinaire de Mémoire (CIME); McConnell Brain Imaging Centre (S.D.), Montreal Neurological Institute, McGill University; Department of Psychiatry (S.D.), McGill University Health Centre, McGill University, Montreal, Quebec; Tanz Centre for Research in Neurodegenerative Diseases (M.C.T.), University of Toronto; Department of Clinical Neurological Sciences (E.F.), University of Western Ontario, London, Canada; Department of Neurology and Laboratory of Neurosciences (A.M.), Faculty of Medicine, University of Lisbon; Center for Neuroscience and Cell Biology (I.S.), Faculty of Medicine, Centro Hospitalar e Universitário de Coimbra; Center for Neuroscience and Cell Biology (I.S.), Faculty of Medicine, University of Coimbra, Portugal; Alzheimer's Disease and Other Cognitive Disorders Unit (R.S.-V.), Neurology Service, Hospital Clinic, Institut d'Investigacions Biomediques August Pi I Sunyer; Institut d'Investigació Biomèdica August Pi I Sunyer (R.S.-V.), Barcelona; Department of Neurology (F.M.), Donostio University Hospital, San Sebastian; Neuroscience Area (F.M.), Biodonostia Health Research Institute, San Sebastian, Gipuzkoa, Spain; Department of Neuroscience, Psychology, Drug Research and Child Health (S. Sorbi), University of Florence; IRCCS Fondazione Don Carlo Gnocchi (S. Sorbi), Florence; Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Neurologica Carlo Besta (F.T.), Milano; Centre for Neurodegenerative Disorders (B.B.), Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Italy; Department of Neurology (M.O.), University Hospital Ulm; Department of Neurology (M.O.), Martin-Luther-University Halle-Wittenberg, Germany Department of Neurodegenerative Diseases (M.S.), Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen; Center for Neurodegenerative Diseases (M.S.), Tübingen, Germany; Fondazione IRCCS Ospediale Policlinico (D.G.), Milan; Centro Dino Ferrari (D.G.), University of Milan, Italy; Leuven Brain Institute (LBI) (R.V.), KU Leuven; Laboratory for Cognitive Neurology (R.V.), Department of Neurosciences, KU Leuven; Neurology Department (R.V.), UZ Leuven, Belgium; Department of Neurology (J.S.), Erasmus Medical Centre, Rotterdam, the Netherlands; Nuffield Department of Clinical Neurosciences (C.B.), Medical Sciences Division, University of Oxford; Department of Brain Sciences (C.B.), Imperial College London; Wolfson Molecular Imaging Centre (A.G.), Faculty of Medicine, Biology and Health, University of Manchester, United Kingdom; Departments of Geriatric Medicine and Nuclear Medicine (A.G.), Essen University Hospital, Germany; Swedish FTD Initiative (C.G.), Stockholm; Division of Neurogeriatrics (C.G.), Centre for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet Solna; Unit for Hereditary Dementias (C.G.), Theme Aging, Karolinska University Hospital, Stockholm, Sweden; Dementia Research Centre (J.D.R.), University College London, United Kingdom; Hurvitz Brain Sciences Program (M.M.), Sunnybrook Research Institute, University of Toronto; Division of Neurology (M.M.), Department of Medicine, University of Toronto; Cognitive and Movement Disorders Clinic (M.M.), Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada; Cognition and Brain Sciences Unit (J.R.), Medical Research Council; Department of Clinical Neurosciences (J.R.), University of Cambridge; Cambridge University Hospitals NHS Trust (J.R.), United Kingdom; German Center for Neurodegenerative Diseases (DZNE) (J.L.); Munich Cluster for Systems Neurology (SyNergy) (J.L.); and European Reference Network for Rare Neurological Diseases (ERN-RND) (J.L.), Munich, Germany.
Neurology. 2022 Sep 5;99(10):e1032-e1044. doi: 10.1212/WNL.0000000000200828.
Frontotemporal dementia (FTD) is a highly heritable disorder. The majority of genetic cases are caused by autosomal dominant pathogenic variants in the chromosome 9 open reading frame 72 (), progranulin (), and microtubule-associated protein tau () gene. As motor disorders are increasingly recognized as part of the clinical spectrum, the current study aimed to describe motor phenotypes caused by genetic FTD, quantify their temporal association, and investigate their regional association with brain atrophy.
We analyzed baseline visit data of known carriers of a pathogenic variant in the , , or gene from the Genetic Frontotemporal Dementia Initiative cohort study. Principal component analysis with varimax rotation was performed to identify motor sign clusters that were compared with respect to frequency and severity between groups. Associations with cross-sectional atrophy patterns were determined using voxel-wise regression. We applied linear mixed effects models to assess whether groups differed in the association between motor signs and estimated time to symptom onset.
A total of 322 pathogenic variant carriers were included in the analysis: 122 (79 presymptomatic), 143 (112 presymptomatic), and 57 (43 presymptomatic) pathogenic variant carriers. Principal component analysis revealed 5 motor clusters, which we call progressive supranuclear palsy (PSP)-like, bulbar amyotrophic lateral sclerosis (ALS)-like, mixed/ALS-like, Parkinson disease (PD) like, and corticobasal syndrome-like motor phenotypes. There was no significant group difference in the frequency of signs of different motor phenotypes. However, mixed/ALS-like motor signs were most frequent, followed by PD-like motor signs. Although the PSP-like phenotype was associated with mesencephalic atrophy, the mixed/ALS-like phenotype was associated with motor cortex and corticospinal tract atrophy. The PD-like phenotype was associated with widespread cortical and subcortical atrophy. Estimated time to onset, genetic group and their interaction influenced motor signs. In pathogenic variant carriers, motor signs could be detected up to 25 years before expected symptom onset.
These results indicate the presence of multiple natural clusters of motor signs in genetic FTD, each correlated with specific atrophy patterns. Their motor severity depends on time and the affected gene. These clinicogenetic associations can guide diagnostic evaluations and the design of clinical trials for new disease-modifying and preventive treatments.
额颞叶痴呆（FTD）是一种高度遗传性疾病。大多数遗传病例是由染色体 9 开放阅读框 72（MAPT）、颗粒蛋白前体（GRN）和微管相关蛋白 tau（TAU）基因中的常染色体显性致病性变异引起的。由于运动障碍越来越被认为是临床谱系的一部分，本研究旨在描述遗传 FTD 引起的运动表型，量化其时间关联，并研究其与大脑萎缩的区域关联。
我们分析了遗传额颞叶痴呆倡议队列研究中已知携带 MAPT、GRN 或 TAU 基因致病性变异的患者的基线就诊数据。采用方差最大旋转的主成分分析来识别运动征象聚类，并比较组间的频率和严重程度。使用体素水平回归确定与横断面萎缩模式的关联。我们应用线性混合效应模型来评估各组在运动征象与估计的症状出现时间之间的关联是否存在差异。
共有 322 名致病性变异携带者纳入分析：122 名（79 名处于无症状前阶段）、143 名（112 名处于无症状前阶段）和 57 名（43 名处于无症状前阶段）致病性变异携带者。主成分分析显示有 5 种运动聚类，我们将其称为进行性核上性麻痹（PSP）样、延髓肌萎缩侧索硬化症（ALS）样、混合/ALS 样、帕金森病（PD）样和皮质基底节综合征样运动表型。不同运动表型的征象出现频率在各组间无显著差异。然而，混合/ALS 样运动征象最为常见，其次是 PD 样运动征象。虽然 PSP 样表型与中脑萎缩相关，但混合/ALS 样表型与运动皮层和皮质脊髓束萎缩相关。PD 样表型与广泛的皮质和皮质下萎缩相关。预计发病时间、遗传组及其相互作用影响运动征象。在 MAPT 致病性变异携带者中，甚至在预计症状出现前 25 年就可以检测到运动征象。
这些结果表明，遗传 FTD 存在多种自然聚类的运动征象，每种征象都与特定的萎缩模式相关。其运动严重程度取决于时间和受影响的基因。这些临床遗传学关联可以指导新的疾病修饰和预防治疗的诊断评估和临床试验设计。
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