原发性进行性失语症伴突变：对非淀粉样蛋白性流畅性失语变体的新认识。
Primary Progressive Aphasia Associated With Mutations: New Insights Into the Nonamyloid Logopenic Variant.
机构信息
From Sorbonne Université (D.S., M.H., L.S., S.E., A.C., S.B., D.R., A.M., R.L., B.D., A.B., O.C., M.T., R.M., I.L.B.), Paris Brain Institute-Institut du Cerveau (ICM), Inserm U1127, CNRS UMR 7225, AP-HP-Hôpital Pitié-Salpêtrière; Reference Centre for Rare or Early Dementias (D.S., S.F., M.N.-L., M.H., A.F., L.S., S.E., D.R., A.M., R.L., B.D., M.T., R.M., I.L.B.), IM2A, Département de Neurologie, AP-HP-Hôpital Pitié-Salpêtrière; Aramis Project Team (D.S., S.E., S.B., A.M., O.C.), Inria Research Center of Paris; Centre of Excellence of Neurodegenerative Disease (CoEN) (M.H.), ICM, CIC Neurosciences, Département de Neurologie, AP-HP-Hôpital Pitié-Salpêtrière, Sorbonne Université; FrontLab (A.F., R.L., B.D., M.T., R.M., I.L.B.), Paris Brain Institute-Institut du Cerveau (ICM); Université Lille (V.D., F.P.), Inserm U1171, CHU Lille, DistAlz, LiCEND, CNR-MAJ; CMRR Service de Neurologie (P.C.), CHU de Limoges; Department of Neurology (J.P., A.G.), Toulouse University Hospital; ToNIC (J.P., A.G.), Toulouse NeuroImaging Centre, Inserm, UPS, University of Toulouse; Normandie Université (D.W., D.H.), UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Neurology and CNR-MAJ, Normandy Center for Genomic and Personalized Medicine; Rouen University Hospital (O.M.), Department of Neurology; Normandie Université (O.M.), UNICAEN, PSL Research University, EPHE, INSERM, U1077, CHU de Caen Normandie, Neuropsychologie et Imagerie de la Mémoire Humaine, Caen; UF de Neurogénétique Moléculaire et Cellulaire (F.C.), Département de Génétique, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière-Charles Foix; EPHE (A.C.), PSL Research University, Paris; CMRR Nouvelle Aquitaine/Institut des Maladies Neurodégénératives clinique (IMNc) (S.A.), CHU de Bordeaux Hôpital Pellegrin; Unit of Neurology of Memory and Language (M.S., J.L., C.R.-J.), GHU Paris Psychiatry and Neurosciences, University of Paris, Hôpital Sainte Anne; Université Paris-Saclay (M.S., J.L., C.R.-J.), CEA, CNRS, Inserm, BioMaps, Orsay; Aix Marseille Université (M.D.), INSERM, Institut de Neurosciences des Systèmes, Marseille; APHM (M.D.), Timone, Service de Neurologie et Neuropsychologie, APHM Hôpital Timone Adultes, Marseille; CHU Nantes (C.B.-B.), Inserm CIC04, Department of Neurology, Centre Mémoire de Ressources et Recherche, Nantes; Centre de génétique (C.T.-R.), Hôpital d'Enfants, CHU Dijon Bourgogne; CMRR Département de Neurologie (F.S.), Hôpitaux Civils, Colmar, INSERM U1118, Université de Strasbourg, Faculté de Médecine, 67085 Strasbourg; CMRR (A.G.), Département de Neurologie, CHU de Montpellier, Inserm U1061, Université de Montpellier i-site MUSE; Department of Neurology (F.E.-B.), CMRR Angers University Hospital, Angers, France; Department of Advanced Medical and Surgical Sciences (C.C.), University of Campania Luigi Vanvitelli, Naples, Italy; and Department of Neurology (M.L.G.-T.), Memory and Aging Center, University of California, San Francisco.
出版信息
Neurology. 2021 Jul 6;97(1):e88-e102. doi: 10.1212/WNL.0000000000012174. Epub 2021 May 12.
OBJECTIVE
To determine relative frequencies and linguistic profiles of primary progressive aphasia (PPA) variants associated with (progranulin) mutations and to study their neuroanatomic correlates.
METHODS
Patients with PPA carrying mutations (PPA-) were selected among a national prospective research cohort of 1,696 patients with frontotemporal dementia, including 235 patients with PPA. All patients with amyloid-positive CSF biomarkers were excluded. In this cross-sectional study, speech/language and cognitive profiles were characterized with standardized evaluations, and gray matter (GM) atrophy patterns using voxel-based morphometry. Comparisons were performed with controls and patients with sporadic PPA.
RESULTS
Among the 235 patients with PPA, 45 (19%) carried mutations, and we studied 32 of these. We showed that logopenic PPA (lvPPA) was the most frequent linguistic variant (n = 13, 41%), followed by nonfluent/agrammatic (nfvPPA; n = 9, 28%) and mixed forms (n = 8, 25%). Semantic variant was rather rare (n = 2, 6%). Patients with lvPPA, qualified as nonamyloid lvPPA, presented canonical logopenic deficit. Seven of 13 had a pure form; 6 showed subtle additional linguistic deficits not fitting criteria for mixed PPA and hence were labeled as logopenic-spectrum variant. GM atrophy involved primarily left posterior temporal gyrus, mirroring neuroanatomic changes of amyloid-positive-lvPPA. Patients with nfvPPA presented agrammatism (89%) rather than apraxia of speech (11%).
CONCLUSIONS
This study shows that the most frequent PPA variant associated with mutations is nonamyloid lvPPA, preceding nfvPPA and mixed forms, and illustrates that the language network may be affected at different levels. testing is indicated for patients with PPA, whether familial or sporadic. This finding is important for upcoming gene-specific therapies.
目的
确定与 （颗粒蛋白前体）突变相关的原发性进行性失语症（PPA）变体的相对频率和语言特征，并研究它们的神经解剖学相关性。
方法
从全国性的额颞叶痴呆前瞻性研究队列的 1696 名患者中筛选出携带 突变的 PPA 患者（PPA-），其中包括 235 名 PPA 患者。所有具有淀粉样蛋白阳性脑脊液生物标志物的患者均被排除在外。在这项横断面研究中，使用标准化评估方法对语言/言语和认知特征进行了描述，并使用基于体素的形态计量学对灰质（GM）萎缩模式进行了描述。将这些患者与对照组和散发性 PPA 患者进行了比较。
结果
在 235 名 PPA 患者中，有 45 名（19%）携带 突变，我们对其中的 32 名进行了研究。结果表明，失读型 PPA（lvPPA）是最常见的语言变体（n = 13，41%），其次是非流利/语法障碍型（nfvPPA；n = 9，28%）和混合形式（n = 8，25%）。语义变体则相对少见（n = 2，6%）。失读型 PPA 患者，即非淀粉样蛋白 lvPPA，表现为典型的失读症缺陷。其中 7 名患者为纯失读症；6 名患者表现出轻微的其他语言障碍，但不符合混合 PPA 的标准，因此被标记为失读症谱变体。GM 萎缩主要累及左侧后颞叶，与淀粉样蛋白阳性 lvPPA 的神经解剖变化一致。nfvPPA 患者表现为语法障碍（89%），而非言语失用（11%）。
结论
本研究表明，与 突变相关的最常见 PPA 变体是非淀粉样蛋白 lvPPA，其次是 nfvPPA 和混合形式，这表明语言网络可能在不同层面受到影响。无论家族性还是散发性 PPA，都应进行 检测。这一发现对于即将出现的针对 基因的特异性治疗非常重要。
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