Journal Article

DZNE-2021-01421

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Characterizing the Clinical Features and Atrophy Patterns of MAPT-Related Frontotemporal Dementia With Disease Progression Modeling.

Young, A. L. ; Bocchetta, M. ; Russell, L. L. ; Convery, R. S. ; Peakman, G. ; Todd, E. ; Cash, D. M. ; Greaves, C. V. ; van Swieten, J. ; Jiskoot, L. ; Seelaar, H. ; Moreno, F. ; Sanchez-Valle, R. ; Borroni, B. ; Laforce, R. ; Masellis, M. ; Tartaglia, M. C. ; Graff, C. ; Galimberti, D. ; Rowe, J. B. ; Finger, E. ; Synofzik, M.DZNE* ; Vandenberghe, R. ; de Mendonça, A. ; Tagliavini, F. ; Santana, I. ; Ducharme, S. ; Butler, C. ; Gerhard, A. ; Levin, J.DZNE* ; Danek, A. ; Otto, M. ; Sorbi, S. ; Williams, S. C. R. ; Alexander, D. C. ; Rohrer, J. D. ; Initiative, G. F. (Collaboration Author) ; Rossor, M. N. ; Fox, N. C. ; Warren, J. D. ; Woollacott, I. ; Shafei, R. ; Heller, C. ; Swift, I. J. ; Moore, K. ; Guerreiro, R. ; Bras, J. ; Thomas, D. L. ; Nicholas, J. ; Mead, S. ; Meeter, L. ; Panman, J. ; Papma, J. M. ; Poos, J. ; van Minkelen, R. ; Pijnenburg, Y. ; Barandiaran, M. ; Indakoetxea, B. ; Gabilondo, A. ; Tainta, M. ; de Arriba, M. ; Gorostidi, A. ; Zulaica, M. ; Villanua, J. ; Díaz, Z. ; Borrego-Ecija, S. ; Olives, J. ; Lladó, A. ; Balasa, M. ; Antonell, A. ; Bargalló, N. ; Premi, E. ; Cosseddu, M. ; Gazzina, S. ; Padovani, A. ; Gasparotti, R. ; Archetti, S. ; Black, S. ; Mitchell, S. ; Rogaeva, E. ; Freedman, M. ; Keren, R. ; Tang-Wai, D. ; Öijerstedt, L. ; Andersson, C. ; Jelic, V. ; Thonberg, H. ; Arighi, A. ; Fenoglio, C. ; Scarpini, E. ; Fumagalli, G. ; Cope, T. ; Timberlake, C. ; Rittman, T. ; Shoesmith, C. ; Bartha, R. ; Rademakers, R. ; Wilke, C.Extern*DZNE* ; Karnath, H. O.Extern* ; Bender, B.Extern* ; Bruffaerts, R. ; Van Damme, P. ; Vandenbulcke, M. ; Ferreira, C. B. ; Miltenberger, G. ; Maruta, C. ; Verdelho, A. ; Afonso, S. ; Taipa, R. ; Caroppo, P. ; Di Fede, G. ; Giaccone, G. ; Prioni, S. ; Redaelli, V. ; Rossi, G. ; Tiraboschi, P. ; Duro, D. ; Almeida, M. R. ; Branco, M. C. ; Leitão, M. J. ; Pereira, M. T. ; Santiago, B. ; Gauthier, S. ; Neto, P. R. ; Veldsman, M. ; Thompson, P. ; Prix, C.Extern* ; Hoegen, T. ; Mag Rer Nat, E. W. ; Loosli, S. ; Schönecker, S. ; Dr Hum Bio, E. S. ; Psych, D. ; Anderl-Straub, S. ; Psych, D. ; Nacmias, B. ; Ferrari, C. ; Polito, C. ; Lombardi, G. ; Bessi, V.

2021
Ovid [S.l.]

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Please use a persistent id in citations: doi:10.1212/WNL.0000000000012410

Abstract: Mutations in the MAPT gene cause frontotemporal dementia (FTD). Most previous studies investigating the neuroanatomical signature of MAPT mutations have grouped all different mutations together and shown an association with focal atrophy of the temporal lobe. The variability in atrophy patterns between each particular MAPT mutation is less well-characterized. We aimed to investigate whether there were distinct groups of MAPT mutation carriers based on their neuroanatomical signature.We applied Subtype and Stage Inference (SuStaIn), an unsupervised machine learning technique that identifies groups of individuals with distinct progression patterns, to characterize patterns of regional atrophy in MAPT-associated FTD within the Genetic FTD Initiative (GENFI) cohort study.Eighty-two MAPT mutation carriers were analyzed, the majority of whom had P301L, IVS10+16, or R406W mutations, along with 48 healthy noncarriers. SuStaIn identified 2 groups of MAPT mutation carriers with distinct atrophy patterns: a temporal subtype, in which atrophy was most prominent in the hippocampus, amygdala, temporal cortex, and insula; and a frontotemporal subtype, in which atrophy was more localized to the lateral temporal lobe and anterior insula, as well as the orbitofrontal and ventromedial prefrontal cortex and anterior cingulate. There was one-to-one mapping between IVS10+16 and R406W mutations and the temporal subtype and near one-to-one mapping between P301L mutations and the frontotemporal subtype. There were differences in clinical symptoms and neuropsychological test scores between subtypes: the temporal subtype was associated with amnestic symptoms, whereas the frontotemporal subtype was associated with executive dysfunction.Our results demonstrate that different MAPT mutations give rise to distinct atrophy patterns and clinical phenotype, providing insights into the underlying disease biology and potential utility for patient stratification in therapeutic trials.

Keyword(s): Adult (MeSH) ; Aged (MeSH) ; Atrophy: genetics (MeSH) ; Atrophy: pathology (MeSH) ; Brain: pathology (MeSH) ; Disease Progression (MeSH) ; Female (MeSH) ; Frontotemporal Dementia: genetics (MeSH) ; Frontotemporal Dementia: pathology (MeSH) ; Humans (MeSH) ; Image Interpretation, Computer-Assisted: methods (MeSH) ; Machine Learning (MeSH) ; Magnetic Resonance Imaging (MeSH) ; Male (MeSH) ; Middle Aged (MeSH) ; Mutation (MeSH) ; Neuroimaging: methods (MeSH) ; tau Proteins: genetics (MeSH) ; MAPT protein, human ; tau Proteins

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Contributing Institute(s):

1. Clinical Dementia Research München (Clinical Dementia Research München)
2. Parkinson Genetics (AG Gasser 1)
3. Library and Information Services (Library and Information Services)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2021

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Database coverage:
; Allianz-Lizenz ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Essential Science Indicators ; IF >= 10 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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