Gray matter changes in asymptomatic C9orf72 and GRN mutation carriers

Karteek Popuri, Emma Dowds, Mirza Faisal Beg, Rakesh Balachandar, Mahadev Bhalla, Claudia Jacova, Adrienne Buller, Penny Slack, Pheth Sengdy, Rosa V Rademakers, Dana Wittenberg, Howard H. Feldman, Ian R. Mackenzie, Ging Yuek R. Hsiung

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Frontotemporal dementia (FTD) is a neurodegenerative disease with a strong genetic basis. Understanding the structural brain changes during pre-symptomatic stages may allow for earlier diagnosis of patients suffering from FTD; therefore, we investigated asymptomatic members of FTD families with mutations in C9orf72 and granulin (GRN) genes. Clinically asymptomatic subjects from families with C9orf72 mutation (15 mutation carriers, C9orf72+; and 23 non-carriers, C9orf72−) and GRN mutations (9 mutation carriers, GRN+; and 15 non-carriers, GRN−) underwent structural neuroimaging (MRI). Cortical thickness and subcortical gray matter volumes were calculated using FreeSurfer. Group differences were evaluated, correcting for age, sex and years to mean age of disease onset within the subject's family. Mean age of C9orf72+ and C9orf72− were 42.6 ± 11.3 and 49.7 ± 15.5 years, respectively; while GRN+ and GRN− groups were 50.1 ± 8.7 and 53.2 ± 11.2 years respectively. The C9orf72+ group exhibited cortical thinning in the temporal, parietal and frontal regions, as well as reduced volumes of bilateral thalamus and left caudate compared to the entire group of mutation non-carriers (NC: C9orf72− and GRN− combined). In contrast, the GRN+ group did not show any significant differences compared to NC. C9orf72 mutation carriers demonstrate a pattern of reduced gray matter on MRI prior to symptom onset compared to GRN mutation carriers. These findings suggest that the preclinical course of FTD differs depending on the genetic basis and that the choice of neuroimaging biomarkers for FTD may need to take into account the specific genes involved in causing the disease.

Original languageEnglish (US)
Pages (from-to)591-598
Number of pages8
JournalNeuroImage: Clinical
Volume18
DOIs
StatePublished - Jan 1 2018

Fingerprint

Frontotemporal Dementia
Mutation
Neuroimaging
Gray Matter
granulin precursor protein
Parietal Lobe
Thalamus
Age of Onset
Neurodegenerative Diseases
Genes
Early Diagnosis
Biomarkers
Brain

Keywords

  • C9orf72 mutation
  • Cortical thickness
  • Frontotemporal dementia
  • Granulin mutation
  • Magnetic resonance imaging
  • Subcortical volumes

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging
  • Neurology
  • Clinical Neurology
  • Cognitive Neuroscience

Cite this

Popuri, K., Dowds, E., Beg, M. F., Balachandar, R., Bhalla, M., Jacova, C., ... Hsiung, G. Y. R. (2018). Gray matter changes in asymptomatic C9orf72 and GRN mutation carriers. NeuroImage: Clinical, 18, 591-598. https://doi.org/10.1016/j.nicl.2018.02.017

Gray matter changes in asymptomatic C9orf72 and GRN mutation carriers. / Popuri, Karteek; Dowds, Emma; Beg, Mirza Faisal; Balachandar, Rakesh; Bhalla, Mahadev; Jacova, Claudia; Buller, Adrienne; Slack, Penny; Sengdy, Pheth; Rademakers, Rosa V; Wittenberg, Dana; Feldman, Howard H.; Mackenzie, Ian R.; Hsiung, Ging Yuek R.

In: NeuroImage: Clinical, Vol. 18, 01.01.2018, p. 591-598.

Research output: Contribution to journalArticle

Popuri, K, Dowds, E, Beg, MF, Balachandar, R, Bhalla, M, Jacova, C, Buller, A, Slack, P, Sengdy, P, Rademakers, RV, Wittenberg, D, Feldman, HH, Mackenzie, IR & Hsiung, GYR 2018, 'Gray matter changes in asymptomatic C9orf72 and GRN mutation carriers', NeuroImage: Clinical, vol. 18, pp. 591-598. https://doi.org/10.1016/j.nicl.2018.02.017
Popuri K, Dowds E, Beg MF, Balachandar R, Bhalla M, Jacova C et al. Gray matter changes in asymptomatic C9orf72 and GRN mutation carriers. NeuroImage: Clinical. 2018 Jan 1;18:591-598. https://doi.org/10.1016/j.nicl.2018.02.017
Popuri, Karteek ; Dowds, Emma ; Beg, Mirza Faisal ; Balachandar, Rakesh ; Bhalla, Mahadev ; Jacova, Claudia ; Buller, Adrienne ; Slack, Penny ; Sengdy, Pheth ; Rademakers, Rosa V ; Wittenberg, Dana ; Feldman, Howard H. ; Mackenzie, Ian R. ; Hsiung, Ging Yuek R. / Gray matter changes in asymptomatic C9orf72 and GRN mutation carriers. In: NeuroImage: Clinical. 2018 ; Vol. 18. pp. 591-598.
@article{fea236e2d6634d2293ed0964293abc9a,
title = "Gray matter changes in asymptomatic C9orf72 and GRN mutation carriers",
abstract = "Frontotemporal dementia (FTD) is a neurodegenerative disease with a strong genetic basis. Understanding the structural brain changes during pre-symptomatic stages may allow for earlier diagnosis of patients suffering from FTD; therefore, we investigated asymptomatic members of FTD families with mutations in C9orf72 and granulin (GRN) genes. Clinically asymptomatic subjects from families with C9orf72 mutation (15 mutation carriers, C9orf72+; and 23 non-carriers, C9orf72−) and GRN mutations (9 mutation carriers, GRN+; and 15 non-carriers, GRN−) underwent structural neuroimaging (MRI). Cortical thickness and subcortical gray matter volumes were calculated using FreeSurfer. Group differences were evaluated, correcting for age, sex and years to mean age of disease onset within the subject's family. Mean age of C9orf72+ and C9orf72− were 42.6 ± 11.3 and 49.7 ± 15.5 years, respectively; while GRN+ and GRN− groups were 50.1 ± 8.7 and 53.2 ± 11.2 years respectively. The C9orf72+ group exhibited cortical thinning in the temporal, parietal and frontal regions, as well as reduced volumes of bilateral thalamus and left caudate compared to the entire group of mutation non-carriers (NC: C9orf72− and GRN− combined). In contrast, the GRN+ group did not show any significant differences compared to NC. C9orf72 mutation carriers demonstrate a pattern of reduced gray matter on MRI prior to symptom onset compared to GRN mutation carriers. These findings suggest that the preclinical course of FTD differs depending on the genetic basis and that the choice of neuroimaging biomarkers for FTD may need to take into account the specific genes involved in causing the disease.",
keywords = "C9orf72 mutation, Cortical thickness, Frontotemporal dementia, Granulin mutation, Magnetic resonance imaging, Subcortical volumes",
author = "Karteek Popuri and Emma Dowds and Beg, {Mirza Faisal} and Rakesh Balachandar and Mahadev Bhalla and Claudia Jacova and Adrienne Buller and Penny Slack and Pheth Sengdy and Rademakers, {Rosa V} and Dana Wittenberg and Feldman, {Howard H.} and Mackenzie, {Ian R.} and Hsiung, {Ging Yuek R.}",
year = "2018",
month = "1",
day = "1",
doi = "10.1016/j.nicl.2018.02.017",
language = "English (US)",
volume = "18",
pages = "591--598",
journal = "NeuroImage: Clinical",
issn = "2213-1582",
publisher = "Elsevier BV",

}

TY - JOUR

T1 - Gray matter changes in asymptomatic C9orf72 and GRN mutation carriers

AU - Popuri, Karteek

AU - Dowds, Emma

AU - Beg, Mirza Faisal

AU - Balachandar, Rakesh

AU - Bhalla, Mahadev

AU - Jacova, Claudia

AU - Buller, Adrienne

AU - Slack, Penny

AU - Sengdy, Pheth

AU - Rademakers, Rosa V

AU - Wittenberg, Dana

AU - Feldman, Howard H.

AU - Mackenzie, Ian R.

AU - Hsiung, Ging Yuek R.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Frontotemporal dementia (FTD) is a neurodegenerative disease with a strong genetic basis. Understanding the structural brain changes during pre-symptomatic stages may allow for earlier diagnosis of patients suffering from FTD; therefore, we investigated asymptomatic members of FTD families with mutations in C9orf72 and granulin (GRN) genes. Clinically asymptomatic subjects from families with C9orf72 mutation (15 mutation carriers, C9orf72+; and 23 non-carriers, C9orf72−) and GRN mutations (9 mutation carriers, GRN+; and 15 non-carriers, GRN−) underwent structural neuroimaging (MRI). Cortical thickness and subcortical gray matter volumes were calculated using FreeSurfer. Group differences were evaluated, correcting for age, sex and years to mean age of disease onset within the subject's family. Mean age of C9orf72+ and C9orf72− were 42.6 ± 11.3 and 49.7 ± 15.5 years, respectively; while GRN+ and GRN− groups were 50.1 ± 8.7 and 53.2 ± 11.2 years respectively. The C9orf72+ group exhibited cortical thinning in the temporal, parietal and frontal regions, as well as reduced volumes of bilateral thalamus and left caudate compared to the entire group of mutation non-carriers (NC: C9orf72− and GRN− combined). In contrast, the GRN+ group did not show any significant differences compared to NC. C9orf72 mutation carriers demonstrate a pattern of reduced gray matter on MRI prior to symptom onset compared to GRN mutation carriers. These findings suggest that the preclinical course of FTD differs depending on the genetic basis and that the choice of neuroimaging biomarkers for FTD may need to take into account the specific genes involved in causing the disease.

AB - Frontotemporal dementia (FTD) is a neurodegenerative disease with a strong genetic basis. Understanding the structural brain changes during pre-symptomatic stages may allow for earlier diagnosis of patients suffering from FTD; therefore, we investigated asymptomatic members of FTD families with mutations in C9orf72 and granulin (GRN) genes. Clinically asymptomatic subjects from families with C9orf72 mutation (15 mutation carriers, C9orf72+; and 23 non-carriers, C9orf72−) and GRN mutations (9 mutation carriers, GRN+; and 15 non-carriers, GRN−) underwent structural neuroimaging (MRI). Cortical thickness and subcortical gray matter volumes were calculated using FreeSurfer. Group differences were evaluated, correcting for age, sex and years to mean age of disease onset within the subject's family. Mean age of C9orf72+ and C9orf72− were 42.6 ± 11.3 and 49.7 ± 15.5 years, respectively; while GRN+ and GRN− groups were 50.1 ± 8.7 and 53.2 ± 11.2 years respectively. The C9orf72+ group exhibited cortical thinning in the temporal, parietal and frontal regions, as well as reduced volumes of bilateral thalamus and left caudate compared to the entire group of mutation non-carriers (NC: C9orf72− and GRN− combined). In contrast, the GRN+ group did not show any significant differences compared to NC. C9orf72 mutation carriers demonstrate a pattern of reduced gray matter on MRI prior to symptom onset compared to GRN mutation carriers. These findings suggest that the preclinical course of FTD differs depending on the genetic basis and that the choice of neuroimaging biomarkers for FTD may need to take into account the specific genes involved in causing the disease.

KW - C9orf72 mutation

KW - Cortical thickness

KW - Frontotemporal dementia

KW - Granulin mutation

KW - Magnetic resonance imaging

KW - Subcortical volumes

UR - http://www.scopus.com/inward/record.url?scp=85042855262&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85042855262&partnerID=8YFLogxK

U2 - 10.1016/j.nicl.2018.02.017

DO - 10.1016/j.nicl.2018.02.017

M3 - Article

C2 - 29845007

AN - SCOPUS:85042855262

VL - 18

SP - 591

EP - 598

JO - NeuroImage: Clinical

JF - NeuroImage: Clinical

SN - 2213-1582

ER -