Trajectories of brain and hippocampal atrophy in FTD with mutations in MAPT or GRN

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Abstract

Objective: To use multiple serial MRI to assess rates and trajectories of brain and hippocampal atrophy in subjects with frontotemporal dementia (FTD) with progranulin (GRN) or microtubuleassociated protein tau (MAPT) gene mutations. Methods: In this case-control study, we identified 8 subjects with mutations in GRN and 12 subjects with mutations in MAPT who had at least 2 serial MRIs. Serial MRIs were registered to baseline MRI for each subject using 9 df registration and rate of whole brain atrophy was calculated using the boundary-shift integral. Hippocampal volume was measured using Freesurfer. Mixed effects linear regression models were used to model volume change over time in both groups after adjusting for head size, age at baseline, and disease duration at baseline. Results: The annual rate of whole brain atrophy in the MAPT subjects was 2.4% per year (95% confidence interval [CI] 1.9-2.8). The GRN subjects showed a higher rate of whole brain atrophy at 3.5% per year (95% CI 2.8-4.2; p = 0.01). Rates of hippocampal atrophy were not different across the groups (MAPT = 7.8% [95% CI 3.9-12], GRN=6.5% [95% CI 1.7-11], p = 0.66). Rates of whole brain atrophy in GRN, and hippocampal atrophy in MAPT, were associated with age, with older subjects showing slower rates of atrophy (p = 0.01 and p < 0.001). Conclusions: Subjects with FTD with GRN mutations have a faster rate of whole brain atrophy than subjects with FTD with MAPT mutations, with similar rates of hippocampal atrophy. Rates of atrophy in both groups were associated with age. These findings are important for future treatment trials in FTD that use rates of atrophy as an outcome measure.

Original languageEnglish (US)
Pages (from-to)393-398
Number of pages6
JournalNeurology
Volume77
Issue number4
DOIs
StatePublished - Jul 26 2011

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tau Proteins
Frontotemporal Dementia
Atrophy
Mutation
Brain
Confidence Intervals
Linear Models
Case-Control Studies

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

@article{5091e7263d9b42a6966be8f65a46754b,
title = "Trajectories of brain and hippocampal atrophy in FTD with mutations in MAPT or GRN",
abstract = "Objective: To use multiple serial MRI to assess rates and trajectories of brain and hippocampal atrophy in subjects with frontotemporal dementia (FTD) with progranulin (GRN) or microtubuleassociated protein tau (MAPT) gene mutations. Methods: In this case-control study, we identified 8 subjects with mutations in GRN and 12 subjects with mutations in MAPT who had at least 2 serial MRIs. Serial MRIs were registered to baseline MRI for each subject using 9 df registration and rate of whole brain atrophy was calculated using the boundary-shift integral. Hippocampal volume was measured using Freesurfer. Mixed effects linear regression models were used to model volume change over time in both groups after adjusting for head size, age at baseline, and disease duration at baseline. Results: The annual rate of whole brain atrophy in the MAPT subjects was 2.4{\%} per year (95{\%} confidence interval [CI] 1.9-2.8). The GRN subjects showed a higher rate of whole brain atrophy at 3.5{\%} per year (95{\%} CI 2.8-4.2; p = 0.01). Rates of hippocampal atrophy were not different across the groups (MAPT = 7.8{\%} [95{\%} CI 3.9-12], GRN=6.5{\%} [95{\%} CI 1.7-11], p = 0.66). Rates of whole brain atrophy in GRN, and hippocampal atrophy in MAPT, were associated with age, with older subjects showing slower rates of atrophy (p = 0.01 and p < 0.001). Conclusions: Subjects with FTD with GRN mutations have a faster rate of whole brain atrophy than subjects with FTD with MAPT mutations, with similar rates of hippocampal atrophy. Rates of atrophy in both groups were associated with age. These findings are important for future treatment trials in FTD that use rates of atrophy as an outcome measure.",
author = "Whitwell, {Jennifer Lynn} and Weigand, {S. D.} and Gunter, {J. L.} and Boeve, {Bradley F} and Rademakers, {Rosa V} and M. Baker and Knopman, {David S} and Wszolek, {Zbigniew K} and Petersen, {Ronald Carl} and Jack, {Clifford R Jr.} and Josephs, {Keith Anthony}",
year = "2011",
month = "7",
day = "26",
doi = "10.1212/WNL.0b013e318227047f",
language = "English (US)",
volume = "77",
pages = "393--398",
journal = "Neurology",
issn = "0028-3878",
publisher = "Lippincott Williams and Wilkins",
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TY - JOUR

T1 - Trajectories of brain and hippocampal atrophy in FTD with mutations in MAPT or GRN

AU - Whitwell, Jennifer Lynn

AU - Weigand, S. D.

AU - Gunter, J. L.

AU - Boeve, Bradley F

AU - Rademakers, Rosa V

AU - Baker, M.

AU - Knopman, David S

AU - Wszolek, Zbigniew K

AU - Petersen, Ronald Carl

AU - Jack, Clifford R Jr.

AU - Josephs, Keith Anthony

PY - 2011/7/26

Y1 - 2011/7/26

N2 - Objective: To use multiple serial MRI to assess rates and trajectories of brain and hippocampal atrophy in subjects with frontotemporal dementia (FTD) with progranulin (GRN) or microtubuleassociated protein tau (MAPT) gene mutations. Methods: In this case-control study, we identified 8 subjects with mutations in GRN and 12 subjects with mutations in MAPT who had at least 2 serial MRIs. Serial MRIs were registered to baseline MRI for each subject using 9 df registration and rate of whole brain atrophy was calculated using the boundary-shift integral. Hippocampal volume was measured using Freesurfer. Mixed effects linear regression models were used to model volume change over time in both groups after adjusting for head size, age at baseline, and disease duration at baseline. Results: The annual rate of whole brain atrophy in the MAPT subjects was 2.4% per year (95% confidence interval [CI] 1.9-2.8). The GRN subjects showed a higher rate of whole brain atrophy at 3.5% per year (95% CI 2.8-4.2; p = 0.01). Rates of hippocampal atrophy were not different across the groups (MAPT = 7.8% [95% CI 3.9-12], GRN=6.5% [95% CI 1.7-11], p = 0.66). Rates of whole brain atrophy in GRN, and hippocampal atrophy in MAPT, were associated with age, with older subjects showing slower rates of atrophy (p = 0.01 and p < 0.001). Conclusions: Subjects with FTD with GRN mutations have a faster rate of whole brain atrophy than subjects with FTD with MAPT mutations, with similar rates of hippocampal atrophy. Rates of atrophy in both groups were associated with age. These findings are important for future treatment trials in FTD that use rates of atrophy as an outcome measure.

AB - Objective: To use multiple serial MRI to assess rates and trajectories of brain and hippocampal atrophy in subjects with frontotemporal dementia (FTD) with progranulin (GRN) or microtubuleassociated protein tau (MAPT) gene mutations. Methods: In this case-control study, we identified 8 subjects with mutations in GRN and 12 subjects with mutations in MAPT who had at least 2 serial MRIs. Serial MRIs were registered to baseline MRI for each subject using 9 df registration and rate of whole brain atrophy was calculated using the boundary-shift integral. Hippocampal volume was measured using Freesurfer. Mixed effects linear regression models were used to model volume change over time in both groups after adjusting for head size, age at baseline, and disease duration at baseline. Results: The annual rate of whole brain atrophy in the MAPT subjects was 2.4% per year (95% confidence interval [CI] 1.9-2.8). The GRN subjects showed a higher rate of whole brain atrophy at 3.5% per year (95% CI 2.8-4.2; p = 0.01). Rates of hippocampal atrophy were not different across the groups (MAPT = 7.8% [95% CI 3.9-12], GRN=6.5% [95% CI 1.7-11], p = 0.66). Rates of whole brain atrophy in GRN, and hippocampal atrophy in MAPT, were associated with age, with older subjects showing slower rates of atrophy (p = 0.01 and p < 0.001). Conclusions: Subjects with FTD with GRN mutations have a faster rate of whole brain atrophy than subjects with FTD with MAPT mutations, with similar rates of hippocampal atrophy. Rates of atrophy in both groups were associated with age. These findings are important for future treatment trials in FTD that use rates of atrophy as an outcome measure.

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U2 - 10.1212/WNL.0b013e318227047f

DO - 10.1212/WNL.0b013e318227047f

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JF - Neurology

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