Characterizing the Clinical Features and Atrophy Patterns of MAPT-Related Frontotemporal Dementia With Disease Progression Modeling

Alexandra L Young; Martina Bocchetta; Lucy L Russell; Rhian S Convery; Georgia Peakman; Emily Todd; David M Cash; Caroline V Greaves; John van Swieten; Lize Jiskoot; Harro Seelaar; Fermin Moreno; Raquel Sanchez-Valle; Barbara Borroni; Robert Laforce; Mario Masellis; Maria Carmela Tartaglia; Caroline Graff; Daniela Galimberti; James B Rowe; Elizabeth Finger; Matthis Synofzik; Rik Vandenberghe; Alexandre de Mendonça; Fabrizio Tagliavini; Isabel Santana; Simon Ducharme; Chris Butler; Alex Gerhard; Johannes Levin; Adrian Danek; Markus Otto; Sandro Sorbi; Steven Cr Williams; Daniel C Alexander; Jonathan D Rohrer; Genetic FTD Initiative (GENFI)

doi:10.1212/WNL.0000000000012410

Characterizing the Clinical Features and Atrophy Patterns of MAPT-Related Frontotemporal Dementia With Disease Progression Modeling

Alexandra L Young, Martina Bocchetta, Lucy L Russell, Rhian S Convery, Georgia Peakman, Emily Todd, David M Cash, Caroline V Greaves, John van Swieten, Lize Jiskoot, Harro Seelaar, Fermin Moreno, Raquel Sanchez-Valle, Barbara Borroni, Robert Laforce, Mario Masellis, Maria Carmela Tartaglia, Caroline Graff, Daniela Galimberti, James B RoweElizabeth Finger, Matthis Synofzik, Rik Vandenberghe, Alexandre de Mendonça, Fabrizio Tagliavini, Isabel Santana, Simon Ducharme, Chris Butler, Alex Gerhard, Johannes Levin, Adrian Danek, Markus Otto, Sandro Sorbi, Steven Cr Williams, Daniel C Alexander, Jonathan D Rohrer, Genetic FTD Initiative (GENFI)

Research output: Contribution to journal › Article › peer-review

15 Citations (Scopus)

Abstract

BACKGROUND AND OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Original language	English
Pages (from-to)	e941-e952
Journal	Neurology
Volume	97
Issue number	9
Early online date	22 Jun 2021
DOIs	https://doi.org/10.1212/WNL.0000000000012410
Publication status	Published - 31 Aug 2021

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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., ... Genetic FTD Initiative (GENFI) (2021). Characterizing the Clinical Features and Atrophy Patterns of MAPT-Related Frontotemporal Dementia With Disease Progression Modeling. Neurology, 97(9), e941-e952. https://doi.org/10.1212/WNL.0000000000012410

@article{327a800bab9c45398a8498c203bf1b98,

title = "Characterizing the Clinical Features and Atrophy Patterns of MAPT-Related Frontotemporal Dementia With Disease Progression Modeling",

abstract = "BACKGROUND AND OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.",

author = "Young, {Alexandra L} and Martina Bocchetta and Russell, {Lucy L} and Convery, {Rhian S} and Georgia Peakman and Emily Todd and Cash, {David M} and Greaves, {Caroline V} and {van Swieten}, John and Lize Jiskoot and Harro Seelaar and Fermin Moreno and Raquel Sanchez-Valle and Barbara Borroni and Robert Laforce and Mario Masellis and Tartaglia, {Maria Carmela} and Caroline Graff and Daniela Galimberti and Rowe, {James B} and Elizabeth Finger and Matthis Synofzik and Rik Vandenberghe and {de Mendon{\c c}a}, Alexandre and Fabrizio Tagliavini and Isabel Santana and Simon Ducharme and Chris Butler and Alex Gerhard and Johannes Levin and Adrian Danek and Markus Otto and Sandro Sorbi and Williams, {Steven Cr} and Alexander, {Daniel C} and Rohrer, {Jonathan D} and {Genetic FTD Initiative (GENFI)}",

note = "Publisher Copyright: Copyright {\textcopyright} 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.",

year = "2021",

month = aug,

day = "31",

doi = "10.1212/WNL.0000000000012410",

language = "English",

volume = "97",

pages = "e941--e952",

journal = "Neurology",

issn = "0028-3878",

publisher = "LIPPINCOTT WILLIAMS & WILKINS",

number = "9",

}

Young, AL, Bocchetta, M, Russell, LL, Convery, RS, Peakman, G, Todd, E, Cash, DM, Greaves, CV, van Swieten, J, Jiskoot, L, Seelaar, H, Moreno, F, Sanchez-Valle, R, Borroni, B, Laforce, R, Masellis, M, Tartaglia, MC, Graff, C, Galimberti, D, Rowe, JB, Finger, E, Synofzik, M, Vandenberghe, R, de Mendonça, A, Tagliavini, F, Santana, I, Ducharme, S, Butler, C, Gerhard, A, Levin, J, Danek, A, Otto, M, Sorbi, S, Williams, SC, Alexander, DC, Rohrer, JD & Genetic FTD Initiative (GENFI) 2021, 'Characterizing the Clinical Features and Atrophy Patterns of MAPT-Related Frontotemporal Dementia With Disease Progression Modeling', Neurology, vol. 97, no. 9, pp. e941-e952. https://doi.org/10.1212/WNL.0000000000012410

TY - JOUR

T1 - Characterizing the Clinical Features and Atrophy Patterns of MAPT-Related Frontotemporal Dementia With Disease Progression Modeling

AU - Young, Alexandra L

AU - Bocchetta, Martina

AU - Russell, Lucy L

AU - Convery, Rhian S

AU - Peakman, Georgia

AU - Todd, Emily

AU - Cash, David M

AU - Greaves, Caroline V

AU - van Swieten, John

AU - Jiskoot, Lize

AU - Seelaar, Harro

AU - Moreno, Fermin

AU - Sanchez-Valle, Raquel

AU - Borroni, Barbara

AU - Laforce, Robert

AU - Masellis, Mario

AU - Tartaglia, Maria Carmela

AU - Graff, Caroline

AU - Galimberti, Daniela

AU - Rowe, James B

AU - Finger, Elizabeth

AU - Synofzik, Matthis

AU - Vandenberghe, Rik

AU - de Mendonça, Alexandre

AU - Tagliavini, Fabrizio

AU - Santana, Isabel

AU - Ducharme, Simon

AU - Butler, Chris

AU - Gerhard, Alex

AU - Levin, Johannes

AU - Danek, Adrian

AU - Otto, Markus

AU - Sorbi, Sandro

AU - Williams, Steven Cr

AU - Alexander, Daniel C

AU - Rohrer, Jonathan D

AU - Genetic FTD Initiative (GENFI)

PY - 2021/8/31

Y1 - 2021/8/31

N2 - BACKGROUND AND OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

AB - BACKGROUND AND OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

UR - http://www.scopus.com/inward/record.url?scp=85116958916&partnerID=8YFLogxK

U2 - 10.1212/WNL.0000000000012410

DO - 10.1212/WNL.0000000000012410

M3 - Article

C2 - 34158384

SN - 0028-3878

VL - 97

SP - e941-e952

JO - Neurology

JF - Neurology

IS - 9

ER -

Characterizing the Clinical Features and Atrophy Patterns of MAPT-Related Frontotemporal Dementia With Disease Progression Modeling

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