International audienceFrontotemporal lobar degeneration (FTLD) has ahigh frequency of genetic forms; the 2 most commonare GRN (progranulin) and C9ORF72 mutations.Recently, our group reported extensive white matter(WM) lesions in 4 patients with FTLD caused byGRN mutation, in the absence of noteworthy cardiovascularrisk factors,1 in line with other studies inGRN mutation carriers.2,3 Here we compared thecharacteristics of frontal WM lesions in patients withbehavioral variant of FTLD (bv-FTLD) caused byGRN and C9ORF72 mutations

Ameur, Fatima

Azuar, Carole

Bertrand, Anne

Brice, Alexis

Caroppo, Paola

Colliot, Olivier

Dormont, Didier

Dubois, Bruno

Le Ber, Isabelle

Stroer, Sebastian

PubMed

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HAL Id: hal-01266596https://hal.inria.fr/hal-01266596Submitted on 3 Feb 2016HAL is a multi-disciplinary open accessarchive for the deposit and dissemination of sci-entific research documents, whether they are pub-lished or not. The documents may come fromteaching and research institutions in France orabroad, or from public or private research centers.L’archive ouverte pluridisciplinaire HAL, estdestinée au dépôt et à la diffusion de documentsscientifiques de niveau recherche, publiés ou non,émanant des établissements d’enseignement et derecherche français ou étrangers, des laboratoirespublics ou privés.Distributed under a Creative Commons Attribution - NonCommercial - NoDerivatives| 4.0International LicenseWhite matter lesions in FTLD: distinct phenotypescharacterize GRN and C9ORF72 mutationsFatima Ameur, Olivier Colliot, Paola Caroppo, Sebastian Stroer, DidierDormont, Alexis Brice, Carole Azuar, Bruno Dubois, Isabelle Le Ber, AnneBertrandTo cite this version:Fatima Ameur, Olivier Colliot, Paola Caroppo, Sebastian Stroer, Didier Dormont, et al.. White matterlesions in FTLD: distinct phenotypes characterize GRN and C9ORF72 mutations. Neurology Genetics,American Academy of Neurology, 2016, 2 (1), ￿10.1212/NXG.0000000000000047￿. ￿hal-01266596￿Clinical/ScientificNotesFatima Ameur, MDOlivier Colliot, PhDPaola Caroppo, MD, PhDSebastian StröerDidier Dormont, MDAlexis Brice, MDCarole Azuar, MDBruno Dubois, MDIsabelle Le Ber, MD, PhDAnne Bertrand, MD, PhDNeurol Genet2016;2:e47; doi: 10.1212/NXG.0000000000000047Supplemental dataat Neurology.org/ngWHITE MATTER LESIONS IN FTLD: DISTINCTPHENOTYPES CHARACTERIZE GRN ANDC9ORF72 MUTATIONSFrontotemporal lobar degeneration (FTLD) has ahigh frequency of genetic forms; the 2 most commonare GRN (progranulin) and C9ORF72 mutations.Recently, our group reported extensive white matter(WM) lesions in 4 patients with FTLD caused byGRN mutation, in the absence of noteworthy cardi-ovascular risk factors,1 in line with other studies inGRN mutation carriers.2,3 Here we compared thecharacteristics of frontal WM lesions in patients withbehavioral variant of FTLD (bv-FTLD) caused byGRN and C9ORF72 mutations.Methods. Patients. We retrospectively collected clin-ical and MRI data from 28 patients with a diagnosisof bv-FTLD based on the Rascovsky criteria,4 includ-ing 11 GRN mutation carriers and 17 C9ORF72mutation carriers. One patient with multiple cardio-vascular risk factors was excluded from this study; allother patients had no cardiovascular risk factors apartfrom sex, age, or treated and well-controlled hyper-tension. Age at onset was determined as the time ofsymptom appearance reported by the closest relativeof the patient. A group of 11 age-matched healthyindividuals were used as controls. Two GRN patientshave been reported in a previous publication.1 Thisretrospective study was approved by our institutionalreview board. Informed consent was obtained accord-ing to the French legislation for clinical geneticstudies.MRI. All patients had a brain MRI including fluid-attenuated inversion recovery (FLAIR) sequence(1.5T/3T, echo time .100 ms, slice thickness#5 mm). One neuroradiologist (F.A.) assessed theseverity of left and right frontal atrophy using theKipps-Davis scale for frontal atrophy.5 Three neuro-radiologists (F.A., S.S., and A. Bertrand) and 1 neu-rologist (P.C.) characterized the severity of WMlesions on FLAIR images in the left and right frontallobes using an ad hoc 3-level visual score (figure). Allreaders were blinded to clinical and genetic data.Statistical analysis was performed using GraphPadPrism 5.0 (San Diego, CA). Interrater agreementswere assessed using the weighted k test. Comparisonsof sex and symptoms between the 3 groups wereassessed using the x2 test; other comparisons wereassessed using the Kruskal-Wallis test and Dunn posthoc test (when comparing 3 groups) or the Mann-Whitney test (when comparing 2 groups).Results. No significant difference was observedbetween groups regarding sex, age at onset, age atMRI, disease duration, and associated amyotrophic lat-eral sclerosis symptoms (table e-1 at Neurology.org/ng).Interrater agreement between the 4 readers for thecharacterization of WM lesions was moderate to verystrong (k 5 0.536–0.805, median 0.74).Frontal WM lesions were different between the 3groups (p 5 0.007 for the right side and p , 0.0001for the left side, Kruskal-Wallis test). The grade ofWM lesions was higher on both sides in the GRNgroup than in the control group and the C9ORF72group (Dunn post hoc test) (figure).In GRNmutation carriers, the presence of grade CWM lesions on the left side was associated with ahigher degree of left frontal atrophy (p 5 0.003,Mann-Whitney test) but not with longer diseaseduration (p 5 0.082, Mann-Whitney test). No sig-nificant result was observed for the right side, whereWM lesions were less frequent.Discussion. Previous reports have shown that someFTLD cases with GRN mutation present withmarked FLAIR hyperintensities in the WM.1–3,6 Herewe extended these findings by showing that theseWM lesions are frequent: 45% (5/11) of GRN muta-tion carriers had extensive frontal WM lesions (gradeC) in the absence of noteworthy cardiovascular riskfactors. These WM lesions were atypical for commoncerebral small vessel disease because they extendedtoward the subcortical WM (figure) and were associ-ated with a higher degree of left frontal atrophy. Theywere not associated with longer disease duration;thus, they may be a consequence of a faster atrophyprocess than in the other patients. Of note, thepatient excluded from the study because of cardiovas-cular risk factors had only grade A WM lesions in thefrontal lobes.It is interesting that both GRN and C9ORF72mutation carriers are likely to have underlying FTLD-TDP43 pathology. This suggests that gene effects canexceed lesion effects in the phenotypical expression ofNeurology.org/ng © 2016 American Academy of Neurology 1ª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.FTLD. The progranulin protein is normally expressednot only in neurons but also in activated microglia,astrocytes, and oligodendroglia and plays a role ininflammation.7 Histopathologic studies of the WM inGRN mutation carriers have reported microglial activa-tion in the areas of abnormal WM on MRI.2 Theseresults favor the hypothesis of a specific vulnerability ofthe WM to granulin haploinsufficiency.From the Service de Neuroradiologie Diagnostique et Fonctionnelle(F.A., O.C., S.S., D.D., A. Bertrand), Département de Génétiqueet Cytogénétique, Unité Fonctionnelle de Génétique Clinique(A. Brice), Centre de Référence des Démences Rares (C.A., B.D.,I.L.B.), and Département de Neurologie (O.C., C.A., B.D.,I.L.B.), AP-HP Hôpital de la Pitié-Salpêtrière, Paris, France;INSERM (O.C., P.C., D.D., A. Brice, B.D., I.L.B., A. Bertrand),ICM, Paris, France; Sorbonne Université (O.C., P.C., D.D.,A. Brice, B.D., I.L.B., A. Bertrand), UPMC Univ Paris, ICM,France; CNRS (O.C., P.C., D.D., A. Brice, B.D., I.L.B.,A. Bertrand), ICM, Paris, France; INRIA (O.C., D.D., A. Ber-trand), Centre Paris-Rocquencourt, France; ICM (O.C., P.C.,D.D., A. Brice, C.A., B.D., I.L.B., A. Bertrand), Paris, France;Carlo Besta Institute (P.C.), Milan, Italy; and FrontLab (C.A.),INSERM, ICM, Paris, France.Author contributions: Study concept and design: F. Ameur, A. Ber-trand, O. Colliot, and I. Le Ber. Acquisition of data: F. Ameur,A. Bertrand, P. Caroppo, and I. Le Ber. Analysis and interpretationof data: F. Ameur, A. Bertrand, P. Caroppo, S. Ströer, O. Colliot,and I. Le Ber. Drafting of the manuscript: F. Ameur and A. Ber-trand. Critical revision of the manuscript for important intellectualcontent: P. Caroppo, D. Dormont, A. Brice, I. Le Ber, O. Colliot,C. Azuar, and B. Dubois.Study funding: This work was supported by the program “Investissementsd’avenir,” grant ANR-10-IAIHU-06; by the PHRC FTLD-exome,grant NCT02363062 (to I.L.B.); by the Association PSP-France (toI.L.B.); by the France Alzheimer Association, grant R12091DD (to A.Brice); by Neuromics FP7, grant E12009DD (to A. Brice); by the Rogerde Spoelberch Foundation, grant R12123DD (to A. Brice); by thePHRC Predict PGRN, grant AOM08045 (to A. Brice); and by theFondation Plan Alzheimer (to A. Brice). Dr. Paola Caroppo received aPhD Fellowship from Carlo Besta Institute, Milan, Italy.Disclosure: Dr. Ameur reports no disclosures. Dr. Colliot has receivedlecture fees from Roche; has served on the editorial board of MedicalImage Analysis (Elsevier); and has received research support fromAgence Nationale de la Recherche and Fondation Plan Alzheimer.Figure Visual score for the characterization of frontal WM lesions on FLAIR images(A) Grade A: minor fluid-attenuated inversion recovery (FLAIR) hyperintensities, ,4 mm thick, limited to the periventriculararea, no extension into the deep and subcortical white matter (WM). Grade B: moderate FLAIR hyperintensities, ,6 mmthick, affecting the periventricular and deep WM, no extension into the subcortical WM. Grade C: marked FLAIR hyper-intensities, .6 mm thick, affecting periventricular, deep, and subcortical WM. (B) Frontal WM lesions were significantlydifferent between groups on the left side (p , 0.0001, Kruskal-Wallis test) and on the right side (p 5 0.007, Kruskal-Wallistest). Dunn post hoc tests showed statistically significant differences between the GRN group and controls and betweenthe GRN group and the C9ORF72 group for the left and right side.2 Neurology: Geneticsª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.Dr. Caroppo reports no disclosures. Mr. Ströer has received researchsupport from the Société Française de Radiologie. Dr. Dormont hasreceived travel funding from Guerbet Group France; has served onthe editorial board of the American Journal of Neuroradiology;holds a patent as Co-inventor of the Neurinfarct software, which isprotected by an international patent (WO 2008/000973) currentlyowned by Intelligence in Medical Technologies, Paris; and has been aconsultant for Medtronic, France. Dr. Brice has received honorariafrom Lundbeck and has received research support from “Investisse-ments d’avenir” and the France Parkinson Association. Dr. Azuarreports no disclosures. Dr. Dubois has been a consultant for Eli Lillyand has received research support from INSERM, ANR, and PHRC.Dr. Le Ber reports no disclosures. Dr. Bertrand has received researchsupport from IHU-a-ICM. Go to Neurology.org/ng for full disclosureforms. The Article Processing Charge was paid by INRIA.This is an open access article distributed under the terms of the Cre-ative Commons Attribution-NonCommercial-NoDerivatives License4.0 (CC BY-NC-ND), which permits downloading and sharing thework provided it is properly cited. The work cannot be changed inany way or used commercially.Received June 17, 2015. Accepted in final form November 19, 2015.Correspondence to Dr. Bertrand: anne.bertrand@aphp.fr1. Caroppo P, Le Ber I, Camuzat A, et al. Extensive whitematter involvement in patients with frontotemporal lobardegeneration: think progranulin. JAMA Neurol 2014;71:1562–1566.2. Kelley BJ, Haidar W, Boeve BF, et al. Prominent pheno-typic variability associated with mutations in progranulin.Neurobiol Aging 2009;30:739–751.3. Van Swieten JC, Heutink P. Mutations in progranulin(GRN) within the spectrum of clinical and pathologicalphenotypes of frontotemporal dementia. Lancet Neurol2008;7:965–974.4. Rascovsky K, Hodges JR, Knopman D, et al. Sensitivity ofrevised diagnostic criteria for the behavioural variant offrontotemporal dementia. Brain J Neurol 2011;134:2456–2477.5. Kipps CM, Davies RR, Mitchell J, Kril JJ, Halliday GM,Hodges JR. Clinical significance of lobar atrophy infrontotemporal dementia: application of an MRI visualrating scale. Dement Geriatr Cogn Disord 2007;23:334–342.6. Pietroboni AM, Fumagalli GG, Ghezzi L, et al. Phenotypicheterogeneity of the GRN Asp22fs mutation in a large Ital-ian kindred. J Alzheimers Dis 2011;24:253–259.7. Cenik B, Sephton CF, Kutluk Cenik B, Herz J, Yu G.Progranulin: a proteolytically processed protein at the cross-roads of inflammation and neurodegeneration. J Biol Chem2012;287:32298–32306.Neurology: Genetics 3ª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.DOI 10.1212/NXG.00000000000000472016;2; Neurol Genet Fatima Ameur, Olivier Colliot, Paola Caroppo, et al. mutationsC9ORF72 and GRNWhite matter lesions in FTLD: distinct phenotypes characterize This information is current as of January 28, 2016ServicesUpdated Information & http://ng.neurology.org/content/2/1/e47.full.htmlincluding high resolution figures, can be found at:Supplementary Material http://ng.neurology.org/content/suppl/2016/01/28/2.1.e47.DC1.htmlSupplementary material can be found at: References http://ng.neurology.org/content/2/1/e47.full.html##ref-list-1This article cites 7 articles, 2 of which you can access for free at: Subspecialty Collections http://ng.neurology.org//cgi/collection/mriMRI http://ng.neurology.org//cgi/collection/frontotemporal_dementiaFrontotemporal dementia http://ng.neurology.org//cgi/collection/amyotrophic_lateral_sclerosis_Amyotrophic lateral sclerosisfollowing collection(s): This article, along with others on similar topics, appears in the  Permissions & Licensing http://ng.neurology.org/misc/about.xhtml#permissionsits entirety can be found online at:Information about reproducing this article in parts (figures,tables) or in  Reprints http://ng.neurology.org/misc/addir.xhtml#reprintsusInformation about ordering reprints can be found online:Neurology. 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White matter lesions in FTLD: distinct phenotypes characterize GRN and C9ORF72 mutations

HAL Descartes

Fatima Ameur

Olivier Colliot

Paola Caroppo

Sebastian Ströer

Didier Dormont

Alexis Brice

Carole Azuar

Bruno Dubois

Isabelle Le Ber

Anne Bertrand

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Neurology Genetics

White matter lesions in FTLD: distinct phenotypes characterize<i>GRN</i>and<i>C9ORF72</i>mutations

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White matter lesions in FTLD: distinct phenotypes characterize GRN and C9ORF72 mutations

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