遗传性额颞叶痴呆患者行为和神经精神症状的频率及纵向病程

Frequency and Longitudinal Course of Behavioral and Neuropsychiatric Symptoms in Participants With Genetic Frontotemporal Dementia.

作者信息

Schönecker Sonja, Martinez-Murcia Francisco J, Denecke Jannis, Franzmeier Nicolai, Danek Adrian, Wagemann Olivia, Prix Catharina, Wlasich Elisabeth, Vöglein Jonathan, Loosli Sandra V, Brauer Anna, Górriz Sáez Juan-Manuel, Bouzigues Arabella, Russell Lucy L, Foster Phoebe H, Ferry-Bolder Eve, van Swieten John C, Jiskoot Lize C, Seelaar Harro, Sanchez-Valle Raquel, Laforce Robert, Graff Caroline, Galimberti Daniela, Vandenberghe Rik, de Mendonça Alexandre, Tiraboschi Pietro, Santana Isabel, Gerhard Alexander, Sorbi Sandro, Otto Markus, Pasquier Florence, Ducharme Simon, Butler Christopher, Le Ber Isabelle, Finger Elizabeth, Tartaglia Maria Carmela, Masellis Mario, Rowe James B, Synofzik Matthis, Moreno Fermin, Borroni Barbara, Rohrer Jonathan D, Priller Josef, Höglinger Günter U, Levin Johannes

机构信息

From the Department of Neurology (S. Schönecker, A.D., O.W., C.P., E.W., J.V., S.V.L., A. Brauer, G.U.H., J.L.), LMU University Hospital, LMU Munich, 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 Stroke and Dementia Research (J.D., N.F.), LMU University Hospital, LMU Munich; Munich Cluster for Systems Neurology (SyNergy) (N.F., G.U.H., J.L.), Germany; Institute of Neuroscience and Physiology and Department of Psychiatry and Neurochemistry (N.F.), The Sahlgrenska Academy, University of Gothenburg, Mölndal and Gothenburg, Sweden; German Center for Neurodegenerative Diseases (DZNE) (J.V., G.U.H., J.L.), Munich, Germany; Dementia Research Centre (A. Bouzigues, L.L.R., P.H.F., E.F.-B., J.D.R.), Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, United Kingdom; Department of Neurology (J.C.v.S., L.C.J., H.S.), Erasmus Medical Centre, Rotterdam, the Netherlands; Alzheimer's disease and Other Cognitive Disorders Unit (R.S.-V.), Neurology Service, Hospital Clínic, Institut d'Investigacións Biomèdiques August Pi I Sunyer, University of Barcelona, Spain; Clinique Interdisciplinaire de Mémoire (R.L.), Département des Sciences Neurologiques, CHU de Québec, and Faculté de Médecine, Université Laval, Canada; Department of Neurobiology, Care Sciences and Society (C.G.), Center for Alzheimer Research, Division of Neurogeriatrics, Bioclinium, Karolinska Institutet; Unit for Hereditary Dementias (C.G.), Theme Inflammation and Aging, Karolinska University Hospital, Solna, Sweden; Fondazione Ca' Granda (D.G.), IRCCS Ospedale Policlinico, Milan; Centro Dino Ferrari (D.G.), University of Milan, Italy; Laboratory for Cognitive Neurology (R.V.), Department of Neurosciences, KU Leuven; Neurology Service (R.V.), University Hospitals Leuven; Leuven Brain Institute (R.V.), KU Leuven, Belgium; Faculty of Medicine (A.d.M.), University of Lisbon, Portugal; Fondazione IRCCS Istituto Neurologico Carlo Besta (P.T.), Milano, Italy; University Hospital of Coimbra (HUC) (I.S.), Neurology Service, Faculty of Medicine, and Center for Neuroscience and Cell Biology (I.S.), Faculty of Medicine, University of Coimbra, Portugal; Division of Psychology Communication and Human Neuroscience Wolfson Molecular Imaging Centre (A.G.), University of Manchester, United Kingdom; Department of Nuclear Medicine (A.G.), Center for Translational Neuro- and Behavioral Sciences, University Medicine Essen; Department of Geriatric Medicine (A.G.), Klinikum Hochsauerland, Arnsberg, Germany; Department of Neurofarba (S. Sorbi), University of Florence; IRCCS Fondazione Don Carlo Gnocchi (S. Sorbi), Florence, Italy; Department of Neurology (M.O.), University of Ulm, Germany; Univ Lille (F.P.); Inserm 1172 (F.P.), Lille; CHU (F.P.), CNR-MAJ, Labex Distalz, LiCEND Lille, France; Department of Psychiatry (S.D.), McGill University Health Centre, and McConnell Brain Imaging Centre (S.D.), Montreal Neurological Institute, McGill University, Montreal, Québec, Canada; Nuffield Department of Clinical Neurosciences (C.B.), Medical Sciences Division, University of Oxford; Department of Brain Sciences (C.B.), Imperial College London, United Kingdom; Sorbonne Université (I.L.B.), Paris Brain Institute, Institut du Cerveau, ICM, Inserm U1127, CNRS UMR 7225, Centre de Référence des Démences Rares ou Précoces (I.L.B.), IM2A, and Département de Neurologie (I.L.B.), AP-HP, Hôpital Pitié-Salpêtrière, Paris, France; Department of Clinical Neurological Sciences (E.F.), University of Western Ontario, London; Tanz Centre for Research in Neurodegenerative Diseases (M.C.T.), and Sunnybrook Health Sciences Centre (M.M.), Sunnybrook Research Institute, University of Toronto, Ontario, Canada; Department of Clinical Neurosciences (J.B.R.), MRC Cognition and Brain Sciences Unit, and Cambridge University Hospitals NHS Trust, University of Cambridge, United Kingdom; Department of Neurodegenerative Diseases (M.S.), Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen; Center for Neurodegenerative Diseases (DZNE) (M.S.), Tübingen, Germany; Cognitive Disorders Unit (F.M.), Department of Neurology, Donostia Universitary Hospital; Neuroscience Area (F.M.), Biodonostia Health Research Institute, San Sebastian, Gipuzkoa, Spain; Neurology Unit (B.B.), Department of Clinical and Experimental Sciences, University of Brescia, Italy; and Department of Psychiatry and Psychotherapy (J.P.), Technical University Munich, Germany.

出版信息

Neurology. 2024 Oct 22;103(8):e209569. doi: 10.1212/WNL.0000000000209569. Epub 2024 Sep 16.

DOI:10.1212/WNL.0000000000209569

PMID:39284109

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11399068/

Abstract

BACKGROUND AND OBJECTIVES

Behavioral and neuropsychiatric symptoms are frequent in patients with genetic frontotemporal dementia (FTD). We aimed to describe behavioral and neuropsychiatric phenotypes in genetic FTD, quantify their temporal association, and investigate their regional association with brain atrophy.

METHODS

We analyzed data of pathogenic variant carriers in the chromosome 9 open reading frame 72 (), progranulin (), or microtubule-associated protein tau () gene from the Genetic Frontotemporal dementia Initiative cohort study that enrolls both symptomatic pathogenic variant carriers and first-degree relatives of known carriers. Principal component analysis was performed to identify behavioral and neuropsychiatric clusters that were compared with respect to frequency and severity between groups. Associations between neuropsychiatric clusters and MRI-assessed atrophy were determined using voxel-based morphometry. We applied linear mixed effects and generalized linear mixed effects models to assess the longitudinal course of symptoms.

RESULTS

A total of 522 participants were included: 221 (138 presymptomatic), 213 (157 presymptomatic), and 88 (62 presymptomatic) pathogenic variant carriers. Principal component analysis revealed 5 phenotypic clusters (67.6% of variance), labeled diverse behavioral, affective, psychotic, euphoric/hypersexual, and tactile hallucinations phenotype. In participants presenting behavioral or neuropsychiatric symptoms, affective symptoms were most frequent across groups (83.6%-88.1%), followed by diverse behavioral symptoms (68.4%-77.9%). In and pathogenic variant carriers, psychotic symptoms (32.0% and 19.4%, respectively) were more frequent than euphoric/hypersexual symptoms (28.7% and 14.2%, respectively), which was the other way around in pathogenic variant carriers (28.6% and 23.8%). Although diverse behavioral symptoms were associated with gray and white matter frontotemporal atrophy, only a small atrophy cluster in the right thalamus was associated with psychotic symptoms. Euphoric/hypersexual symptoms were associated with atrophy in mesial temporal lobes, basal forebrain structures, and the striatum ( < 0.05). Estimated time to symptom onset, genetic group, education, and sex influenced behavioral and neuropsychiatric symptoms ( < 0.05). Particularly, in pathogenic variant carriers, psychotic symptoms may be starting decades before recognition of onset of illness.

DISCUSSION

We identified multiple clusters of behavioral and neuropsychiatric symptoms in participants with genetic FTD that relate to distinct cerebral atrophy patterns. Their severity depends on time, affected gene, sex, and education. These clinical-genetic associations can guide diagnostic evaluations and the design of clinical trials for new disease-modifying and preventive treatments.

摘要

背景与目的

行为和神经精神症状在遗传性额颞叶痴呆（FTD）患者中很常见。我们旨在描述遗传性FTD的行为和神经精神表型，量化它们的时间关联，并研究它们与脑萎缩的区域关联。

方法

我们分析了来自遗传性额颞叶痴呆倡议队列研究的9号染色体开放阅读框72（）、原颗粒蛋白（）或微管相关蛋白tau（）基因的致病变异携带者的数据，该研究纳入了有症状的致病变异携带者和已知携带者的一级亲属。进行主成分分析以识别行为和神经精神集群，并在组间比较其频率和严重程度。使用基于体素的形态学方法确定神经精神集群与MRI评估的萎缩之间的关联。我们应用线性混合效应模型和广义线性混合效应模型来评估症状的纵向病程。

结果

共纳入522名参与者：221名（138名症状前）、213名（157名症状前）和88名（62名症状前）致病变异携带者。主成分分析揭示了5种表型集群（占方差的67.6%），分别标记为多样行为型、情感型、精神病型、欣快/性欲亢进型和触觉幻觉型。在出现行为或神经精神症状的参与者中，情感症状在各组中最为常见（83.6%-88.1%），其次是多样行为症状（68.4%-77.9%）。在和致病变异携带者中，精神病症状（分别为32.0%和19.4%）比欣快/性欲亢进症状（分别为28.7%和14.2%）更常见，而在致病变异携带者中情况则相反（28.6%和23.8%）。虽然多样行为症状与额颞叶灰质和白质萎缩相关，但只有右侧丘脑的一个小萎缩集群与精神病症状相关。欣快/性欲亢进症状与内侧颞叶、基底前脑结构和纹状体的萎缩相关（<0.05）。症状出现的估计时间、基因组、教育程度和性别会影响行为和神经精神症状（<0.05）。特别是，在致病变异携带者中，精神病症状可能在疾病发作被识别前几十年就开始出现。