TY - JOUR
T1 - Cortical atrophy and language network reorganization associated with a novel progranulin mutation
AU - Cruchaga, Carlos
AU - Fernández-Seara, Maria A.
AU - Seijo-Martínez, Manuel
AU - Samaranch, Lluis
AU - Lorenzo, Elena
AU - Hinrichs, Anthony
AU - Irigoyen, Jaione
AU - Maestro, Cristina
AU - Prieto, Elena
AU - Martí-Climent, Josep M.
AU - Arbizu, Javier
AU - Pastor, Maria A.
AU - Pastor, Pau
PY - 2009/8
Y1 - 2009/8
N2 - Progressive nonfluent aphasia (PNFA) is an early stage of frontotemporal degeneration. We identified a novel Cys521Tyr progranulin gene variant in a PNFA family that potentially disrupts disulphide bridging causing protein misfolding. To identify early neurodegeneration changes, we performed neuropsychological and neuroimaging studies in 6 family members (MRI [magnetic resonance imaging], fMRI [functional MRI], and 18f-fluorodeoxygenlucose positron emission tomography, including 4 mutation carriers, and in 9 unrelated controls. Voxel-based morphometry (VBM) of the carriers compared with controls showed significant cortical atrophy in language areas. Grey matter loss was distributed mainly in frontal lobes, being more prominent on the left. Clusters were located in the superior frontal gyri, left inferior frontal gyrus, left middle frontal gyrus, left middle temporal gyri and left posterior parietal areas, concordant with 18FDG-PET hypometabolic areas. fMRI during semantic and phonemic covert word generation (CWGTs) and word listening tasks (WLTs) showed recruitment of attentional and working memory networks in the carriers indicative of functional reorganization. During CWGTs, activation in left prefrontal cortex and bilateral anterior insulae was present whereas WLT recruited mesial prefrontal and anterior temporal cortex. These findings suggest that Cys521Tyr could be associated with early brain impairment not limited to language areas and compensated by recruitment of bilateral auxiliary cortical areas.
AB - Progressive nonfluent aphasia (PNFA) is an early stage of frontotemporal degeneration. We identified a novel Cys521Tyr progranulin gene variant in a PNFA family that potentially disrupts disulphide bridging causing protein misfolding. To identify early neurodegeneration changes, we performed neuropsychological and neuroimaging studies in 6 family members (MRI [magnetic resonance imaging], fMRI [functional MRI], and 18f-fluorodeoxygenlucose positron emission tomography, including 4 mutation carriers, and in 9 unrelated controls. Voxel-based morphometry (VBM) of the carriers compared with controls showed significant cortical atrophy in language areas. Grey matter loss was distributed mainly in frontal lobes, being more prominent on the left. Clusters were located in the superior frontal gyri, left inferior frontal gyrus, left middle frontal gyrus, left middle temporal gyri and left posterior parietal areas, concordant with 18FDG-PET hypometabolic areas. fMRI during semantic and phonemic covert word generation (CWGTs) and word listening tasks (WLTs) showed recruitment of attentional and working memory networks in the carriers indicative of functional reorganization. During CWGTs, activation in left prefrontal cortex and bilateral anterior insulae was present whereas WLT recruited mesial prefrontal and anterior temporal cortex. These findings suggest that Cys521Tyr could be associated with early brain impairment not limited to language areas and compensated by recruitment of bilateral auxiliary cortical areas.
KW - 18FDG-PET
KW - FMRI
KW - Frontotemporal dementia
KW - Language
KW - Primary progressive aphasia
KW - Progranulin gene
UR - http://www.scopus.com/inward/record.url?scp=67651091752&partnerID=8YFLogxK
U2 - 10.1093/cercor/bhn202
DO - 10.1093/cercor/bhn202
M3 - Article
C2 - 19020205
AN - SCOPUS:67651091752
VL - 19
SP - 1751
EP - 1760
JO - Cerebral Cortex
JF - Cerebral Cortex
SN - 1047-3211
IS - 8
ER -