White matter hyperintensities are seen only in GRN mutation carriers in the GENFI cohort

Carole H. Sudre, Martina Bocchetta, David Cash, David L. Thomas, Ione Woollacott, Katrina M. Dick, John C. Van Swieten, Barbara Borroni, Daniela Galimberti, Mario Masellis, Maria Carmela Tartaglia, James B. Rowe, Caroline Graff, Fabrizio Tagliavini, Giovanni Frisoni, Robert Laforce, Elizabeth Finger, Alexandre de Mendonça, Sandro Sorbi, Sébastien Ourselin & 3 others M. Jorge Cardoso, Jonathan D. Rohrer, Genetic FTD Initiative, GENFI

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Genetic frontotemporal dementia is most commonly caused by mutations in the progranulin (GRN), microtubule-associated protein tau (MAPT) and chromosome 9 open reading frame 72 (C9orf72) genes. Previous small studies have reported the presence of cerebral white matter hyperintensities (WMH) in genetic FTD but this has not been systematically studied across the different mutations. In this study WMH were assessed in 180 participants from the Genetic FTD Initiative (GENFI) with 3D T1- and T2-weighed magnetic resonance images: 43 symptomatic (7 GRN, 13 MAPT and 23 C9orf72), 61 presymptomatic mutation carriers (25 GRN, 8 MAPT and 28 C9orf72) and 76 mutation negative non-carrier family members. An automatic detection and quantification algorithm was developed for determining load, location and appearance of WMH. Significant differences were seen only in the symptomatic GRN group compared with the other groups with no differences in the MAPT or C9orf72 groups: increased global load of WMH was seen, with WMH located in the frontal and occipital lobes more so than the parietal lobes, and nearer to the ventricles rather than juxtacortical. Although no differences were seen in the presymptomatic group as a whole, in the GRN cohort only there was an association of increased WMH volume with expected years from symptom onset. The appearance of the WMH was also different in the GRN group compared with the other groups, with the lesions in the GRN group being more similar to each other. The presence of WMH in those with progranulin deficiency may be related to the known role of progranulin in neuroinflammation, although other roles are also proposed including an effect on blood-brain barrier permeability and the cerebral vasculature. Future studies will be useful to investigate the longitudinal evolution of WMH and their potential use as a biomarker as well as post-mortem studies investigating the histopathological nature of the lesions.

Original languageEnglish
Pages (from-to)171-180
Number of pages10
JournalNeuroImage: Clinical
Volume15
DOIs
Publication statusPublished - 2017

Fingerprint

Heterozygote
Mutation
Chromosomes, Human, Pair 9
Microtubule-Associated Proteins
Open Reading Frames
White Matter
Occipital Lobe
Frontotemporal Dementia
Parietal Lobe
Frontal Lobe
Blood-Brain Barrier
Permeability
Magnetic Resonance Spectroscopy
Biomarkers

ASJC Scopus subject areas

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

Cite this

Sudre, C. H., Bocchetta, M., Cash, D., Thomas, D. L., Woollacott, I., Dick, K. M., ... Genetic FTD Initiative, GENFI (2017). White matter hyperintensities are seen only in GRN mutation carriers in the GENFI cohort. NeuroImage: Clinical, 15, 171-180. https://doi.org/10.1016/j.nicl.2017.04.015

White matter hyperintensities are seen only in GRN mutation carriers in the GENFI cohort. / Sudre, Carole H.; Bocchetta, Martina; Cash, David; Thomas, David L.; Woollacott, Ione; Dick, Katrina M.; Van Swieten, John C.; Borroni, Barbara; Galimberti, Daniela; Masellis, Mario; Tartaglia, Maria Carmela; Rowe, James B.; Graff, Caroline; Tagliavini, Fabrizio; Frisoni, Giovanni; Laforce, Robert; Finger, Elizabeth; de Mendonça, Alexandre; Sorbi, Sandro; Ourselin, Sébastien; Cardoso, M. Jorge; Rohrer, Jonathan D.; Genetic FTD Initiative, GENFI.

In: NeuroImage: Clinical, Vol. 15, 2017, p. 171-180.

Research output: Contribution to journalArticle

Sudre, CH, Bocchetta, M, Cash, D, Thomas, DL, Woollacott, I, Dick, KM, Van Swieten, JC, Borroni, B, Galimberti, D, Masellis, M, Tartaglia, MC, Rowe, JB, Graff, C, Tagliavini, F, Frisoni, G, Laforce, R, Finger, E, de Mendonça, A, Sorbi, S, Ourselin, S, Cardoso, MJ, Rohrer, JD & Genetic FTD Initiative, GENFI 2017, 'White matter hyperintensities are seen only in GRN mutation carriers in the GENFI cohort', NeuroImage: Clinical, vol. 15, pp. 171-180. https://doi.org/10.1016/j.nicl.2017.04.015
Sudre, Carole H. ; Bocchetta, Martina ; Cash, David ; Thomas, David L. ; Woollacott, Ione ; Dick, Katrina M. ; Van Swieten, John C. ; Borroni, Barbara ; Galimberti, Daniela ; Masellis, Mario ; Tartaglia, Maria Carmela ; Rowe, James B. ; Graff, Caroline ; Tagliavini, Fabrizio ; Frisoni, Giovanni ; Laforce, Robert ; Finger, Elizabeth ; de Mendonça, Alexandre ; Sorbi, Sandro ; Ourselin, Sébastien ; Cardoso, M. Jorge ; Rohrer, Jonathan D. ; Genetic FTD Initiative, GENFI. / White matter hyperintensities are seen only in GRN mutation carriers in the GENFI cohort. In: NeuroImage: Clinical. 2017 ; Vol. 15. pp. 171-180.
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abstract = "Genetic frontotemporal dementia is most commonly caused by mutations in the progranulin (GRN), microtubule-associated protein tau (MAPT) and chromosome 9 open reading frame 72 (C9orf72) genes. Previous small studies have reported the presence of cerebral white matter hyperintensities (WMH) in genetic FTD but this has not been systematically studied across the different mutations. In this study WMH were assessed in 180 participants from the Genetic FTD Initiative (GENFI) with 3D T1- and T2-weighed magnetic resonance images: 43 symptomatic (7 GRN, 13 MAPT and 23 C9orf72), 61 presymptomatic mutation carriers (25 GRN, 8 MAPT and 28 C9orf72) and 76 mutation negative non-carrier family members. An automatic detection and quantification algorithm was developed for determining load, location and appearance of WMH. Significant differences were seen only in the symptomatic GRN group compared with the other groups with no differences in the MAPT or C9orf72 groups: increased global load of WMH was seen, with WMH located in the frontal and occipital lobes more so than the parietal lobes, and nearer to the ventricles rather than juxtacortical. Although no differences were seen in the presymptomatic group as a whole, in the GRN cohort only there was an association of increased WMH volume with expected years from symptom onset. The appearance of the WMH was also different in the GRN group compared with the other groups, with the lesions in the GRN group being more similar to each other. The presence of WMH in those with progranulin deficiency may be related to the known role of progranulin in neuroinflammation, although other roles are also proposed including an effect on blood-brain barrier permeability and the cerebral vasculature. Future studies will be useful to investigate the longitudinal evolution of WMH and their potential use as a biomarker as well as post-mortem studies investigating the histopathological nature of the lesions.",
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AU - Sudre, Carole H.

AU - Bocchetta, Martina

AU - Cash, David

AU - Thomas, David L.

AU - Woollacott, Ione

AU - Dick, Katrina M.

AU - Van Swieten, John C.

AU - Borroni, Barbara

AU - Galimberti, Daniela

AU - Masellis, Mario

AU - Tartaglia, Maria Carmela

AU - Rowe, James B.

AU - Graff, Caroline

AU - Tagliavini, Fabrizio

AU - Frisoni, Giovanni

AU - Laforce, Robert

AU - Finger, Elizabeth

AU - de Mendonça, Alexandre

AU - Sorbi, Sandro

AU - Ourselin, Sébastien

AU - Cardoso, M. Jorge

AU - Rohrer, Jonathan D.

AU - Genetic FTD Initiative, GENFI

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N2 - Genetic frontotemporal dementia is most commonly caused by mutations in the progranulin (GRN), microtubule-associated protein tau (MAPT) and chromosome 9 open reading frame 72 (C9orf72) genes. Previous small studies have reported the presence of cerebral white matter hyperintensities (WMH) in genetic FTD but this has not been systematically studied across the different mutations. In this study WMH were assessed in 180 participants from the Genetic FTD Initiative (GENFI) with 3D T1- and T2-weighed magnetic resonance images: 43 symptomatic (7 GRN, 13 MAPT and 23 C9orf72), 61 presymptomatic mutation carriers (25 GRN, 8 MAPT and 28 C9orf72) and 76 mutation negative non-carrier family members. An automatic detection and quantification algorithm was developed for determining load, location and appearance of WMH. Significant differences were seen only in the symptomatic GRN group compared with the other groups with no differences in the MAPT or C9orf72 groups: increased global load of WMH was seen, with WMH located in the frontal and occipital lobes more so than the parietal lobes, and nearer to the ventricles rather than juxtacortical. Although no differences were seen in the presymptomatic group as a whole, in the GRN cohort only there was an association of increased WMH volume with expected years from symptom onset. The appearance of the WMH was also different in the GRN group compared with the other groups, with the lesions in the GRN group being more similar to each other. The presence of WMH in those with progranulin deficiency may be related to the known role of progranulin in neuroinflammation, although other roles are also proposed including an effect on blood-brain barrier permeability and the cerebral vasculature. Future studies will be useful to investigate the longitudinal evolution of WMH and their potential use as a biomarker as well as post-mortem studies investigating the histopathological nature of the lesions.

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