White matter hyperintensities precede other biomarkers in GRN frontotemporal dementia. Soltaninejad, M., Dadar, M., Collins, D L., Rajabli, R., Venkatraghavan, V., Bouzigues, A., Russell, L. L, Foster, P. H, Ferry-Bolder, E., van Swieten, J. C, Jiskoot, L. C, Seelaar, H., Sanchez-Valle, R., Laforce, R., Graff, C., Galimberti, D., Vandenberghe, R., de Mendonça, A., Tiraboschi, P., Santana, I., Gerhard, A., Levin, J., Nacmias, B., Otto, M., Bertoux, M., Lebouvier, T., Butler, C. R, Ber, I. L., Finger, E., Tartaglia, M. C., Masellis, M., Rowe, J. B, Synofzik, M., Moreno, F., Borroni, B., Rohrer, J. D, Iturria-Medina, Y., & Ducharme, S. Alzheimer's & dementia : the journal of the Alzheimer's Association, 21(10):e70695, oct, 2025. doi abstract bibtex INTRODUCTION: Increased white matter hyperintensities (WMHs) have been reported in genetic frontotemporal dementia (FTD) in small studies, but the sequence of WMH abnormalities relative to other biomarkers is unclear. METHODS: Using a large dataset (n = 763 GENFI2 participants), we measured WMHs and examined them across genetic FTD variants and stages. Cortical and subcortical volumes were parcellated, and serum neurofilament light chain (NfL) levels were measured. Biomarker progression was assessed with discriminative event-based and regression modeling. RESULTS: Symptomatic GRN carriers showed elevated WMHs, primarily in the frontal lobe, while no significant increase was observed in symptomatic C9orf72 or MAPT carriers. WMH abnormalities preceded NfL elevation, ventricular enlargement, and cortical atrophy. Longitudinally, baseline WMHs predicted subcortical changes, while subcortical volumes did not predict WMH changes, suggesting WMHs may precede neurodegeneration. DISCUSSION: WMHs are elevated in a subset of GRN-associated FTD. When present, they appear early and should be considered in disease progression models. HIGHLIGHTS: Elevated WMH volumes are found predominantly in symptomatic GRN. WMH accumulation is mostly observed in the frontal lobe. WMH abnormalities appear early in GRN-associated FTD, before NfL, atrophy, and ventriculomegaly. Longitudinally, WMH volumes can predict subcortical changes, but not vice versa. WMHs are key early markers in GRN-associated FTD and should be included in progression models.
@article{Soltaninejad2025,
abstract = {INTRODUCTION: Increased white matter hyperintensities (WMHs) have been reported in genetic frontotemporal dementia (FTD) in small studies, but the sequence of WMH abnormalities relative to other biomarkers is unclear. METHODS: Using a large dataset (n = 763 GENFI2 participants), we measured WMHs and examined them across genetic FTD variants and stages. Cortical and subcortical volumes were parcellated, and serum neurofilament light chain (NfL) levels were measured. Biomarker progression was assessed with discriminative event-based and regression modeling. RESULTS: Symptomatic GRN carriers showed elevated WMHs, primarily in the frontal lobe, while no significant increase was observed in symptomatic C9orf72 or MAPT carriers. WMH abnormalities preceded NfL elevation, ventricular enlargement, and cortical atrophy. Longitudinally, baseline WMHs predicted subcortical changes, while subcortical volumes did not predict WMH changes, suggesting WMHs may precede neurodegeneration. DISCUSSION: WMHs are elevated in a subset of GRN-associated FTD. When present, they appear early and should be considered in disease progression models. HIGHLIGHTS: Elevated WMH volumes are found predominantly in symptomatic GRN. WMH accumulation is mostly observed in the frontal lobe. WMH abnormalities appear early in GRN-associated FTD, before NfL, atrophy, and ventriculomegaly. Longitudinally, WMH volumes can predict subcortical changes, but not vice versa. WMHs are key early markers in GRN-associated FTD and should be included in progression models.},
author = {Soltaninejad, Mahdie and Dadar, Mahsa and Collins, D Louis and Rajabli, Reza and Venkatraghavan, Vikram and Bouzigues, Arabella and Russell, Lucy L and Foster, Phoebe H and Ferry-Bolder, Eve and van Swieten, John C and Jiskoot, Lize C and Seelaar, Harro and Sanchez-Valle, Raquel and Laforce, Robert and Graff, Caroline and Galimberti, Daniela and Vandenberghe, Rik and de Mendon{\c{c}}a, Alexandre and Tiraboschi, Pietro and Santana, Isabel and Gerhard, Alexander and Levin, Johannes and Nacmias, Benedetta and Otto, Markus and Bertoux, Maxime and Lebouvier, Thibaud and Butler, Chris R and Ber, Isabelle Le and Finger, Elizabeth and Tartaglia, Maria Carmela and Masellis, Mario and Rowe, James B and Synofzik, Matthis and Moreno, Fermin and Borroni, Barbara and Rohrer, Jonathan D and Iturria-Medina, Yasser and Ducharme, Simon},
doi = {10.1002/alz.70695},
institution = {GENFI Consortium},
issn = {1552-5279 (Electronic)},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
keywords = {Aged,Atrophy,Biomarkers,C9orf72 Protein,Disease Progression,Female,Frontotemporal Dementia,Humans,Magnetic Resonance Imaging,Male,Middle Aged,Neurofilament Proteins,Progranulins,White Matter,blood,diagnostic imaging,genetics,pathology,tau Proteins},
language = {eng},
month = {oct},
number = {10},
pages = {e70695},
pmid = {41057914},
title = {{White matter hyperintensities precede other biomarkers in GRN frontotemporal dementia.}},
volume = {21},
year = {2025}
}
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D","Iturria-Medina, Y.","Ducharme, S."],"bibdata":{"bibtype":"article","type":"article","abstract":"INTRODUCTION: Increased white matter hyperintensities (WMHs) have been reported in genetic frontotemporal dementia (FTD) in small studies, but the sequence of WMH abnormalities relative to other biomarkers is unclear. METHODS: Using a large dataset (n = 763 GENFI2 participants), we measured WMHs and examined them across genetic FTD variants and stages. Cortical and subcortical volumes were parcellated, and serum neurofilament light chain (NfL) levels were measured. Biomarker progression was assessed with discriminative event-based and regression modeling. RESULTS: Symptomatic GRN carriers showed elevated WMHs, primarily in the frontal lobe, while no significant increase was observed in symptomatic C9orf72 or MAPT carriers. WMH abnormalities preceded NfL elevation, ventricular enlargement, and cortical atrophy. Longitudinally, baseline WMHs predicted subcortical changes, while subcortical volumes did not predict WMH changes, suggesting WMHs may precede neurodegeneration. DISCUSSION: WMHs are elevated in a subset of GRN-associated FTD. When present, they appear early and should be considered in disease progression models. HIGHLIGHTS: Elevated WMH volumes are found predominantly in symptomatic GRN. WMH accumulation is mostly observed in the frontal lobe. WMH abnormalities appear early in GRN-associated FTD, before NfL, atrophy, and ventriculomegaly. Longitudinally, WMH volumes can predict subcortical changes, but not vice versa. WMHs are key early markers in GRN-associated FTD and should be included in progression models.","author":[{"propositions":[],"lastnames":["Soltaninejad"],"firstnames":["Mahdie"],"suffixes":[]},{"propositions":[],"lastnames":["Dadar"],"firstnames":["Mahsa"],"suffixes":[]},{"propositions":[],"lastnames":["Collins"],"firstnames":["D","Louis"],"suffixes":[]},{"propositions":[],"lastnames":["Rajabli"],"firstnames":["Reza"],"suffixes":[]},{"propositions":[],"lastnames":["Venkatraghavan"],"firstnames":["Vikram"],"suffixes":[]},{"propositions":[],"lastnames":["Bouzigues"],"firstnames":["Arabella"],"suffixes":[]},{"propositions":[],"lastnames":["Russell"],"firstnames":["Lucy","L"],"suffixes":[]},{"propositions":[],"lastnames":["Foster"],"firstnames":["Phoebe","H"],"suffixes":[]},{"propositions":[],"lastnames":["Ferry-Bolder"],"firstnames":["Eve"],"suffixes":[]},{"propositions":["van"],"lastnames":["Swieten"],"firstnames":["John","C"],"suffixes":[]},{"propositions":[],"lastnames":["Jiskoot"],"firstnames":["Lize","C"],"suffixes":[]},{"propositions":[],"lastnames":["Seelaar"],"firstnames":["Harro"],"suffixes":[]},{"propositions":[],"lastnames":["Sanchez-Valle"],"firstnames":["Raquel"],"suffixes":[]},{"propositions":[],"lastnames":["Laforce"],"firstnames":["Robert"],"suffixes":[]},{"propositions":[],"lastnames":["Graff"],"firstnames":["Caroline"],"suffixes":[]},{"propositions":[],"lastnames":["Galimberti"],"firstnames":["Daniela"],"suffixes":[]},{"propositions":[],"lastnames":["Vandenberghe"],"firstnames":["Rik"],"suffixes":[]},{"propositions":["de"],"lastnames":["Mendonça"],"firstnames":["Alexandre"],"suffixes":[]},{"propositions":[],"lastnames":["Tiraboschi"],"firstnames":["Pietro"],"suffixes":[]},{"propositions":[],"lastnames":["Santana"],"firstnames":["Isabel"],"suffixes":[]},{"propositions":[],"lastnames":["Gerhard"],"firstnames":["Alexander"],"suffixes":[]},{"propositions":[],"lastnames":["Levin"],"firstnames":["Johannes"],"suffixes":[]},{"propositions":[],"lastnames":["Nacmias"],"firstnames":["Benedetta"],"suffixes":[]},{"propositions":[],"lastnames":["Otto"],"firstnames":["Markus"],"suffixes":[]},{"propositions":[],"lastnames":["Bertoux"],"firstnames":["Maxime"],"suffixes":[]},{"propositions":[],"lastnames":["Lebouvier"],"firstnames":["Thibaud"],"suffixes":[]},{"propositions":[],"lastnames":["Butler"],"firstnames":["Chris","R"],"suffixes":[]},{"propositions":[],"lastnames":["Ber"],"firstnames":["Isabelle","Le"],"suffixes":[]},{"propositions":[],"lastnames":["Finger"],"firstnames":["Elizabeth"],"suffixes":[]},{"propositions":[],"lastnames":["Tartaglia"],"firstnames":["Maria","Carmela"],"suffixes":[]},{"propositions":[],"lastnames":["Masellis"],"firstnames":["Mario"],"suffixes":[]},{"propositions":[],"lastnames":["Rowe"],"firstnames":["James","B"],"suffixes":[]},{"propositions":[],"lastnames":["Synofzik"],"firstnames":["Matthis"],"suffixes":[]},{"propositions":[],"lastnames":["Moreno"],"firstnames":["Fermin"],"suffixes":[]},{"propositions":[],"lastnames":["Borroni"],"firstnames":["Barbara"],"suffixes":[]},{"propositions":[],"lastnames":["Rohrer"],"firstnames":["Jonathan","D"],"suffixes":[]},{"propositions":[],"lastnames":["Iturria-Medina"],"firstnames":["Yasser"],"suffixes":[]},{"propositions":[],"lastnames":["Ducharme"],"firstnames":["Simon"],"suffixes":[]}],"doi":"10.1002/alz.70695","institution":"GENFI Consortium","issn":"1552-5279 (Electronic)","journal":"Alzheimer's & dementia : the journal of the Alzheimer's Association","keywords":"Aged,Atrophy,Biomarkers,C9orf72 Protein,Disease Progression,Female,Frontotemporal Dementia,Humans,Magnetic Resonance Imaging,Male,Middle Aged,Neurofilament Proteins,Progranulins,White Matter,blood,diagnostic imaging,genetics,pathology,tau Proteins","language":"eng","month":"oct","number":"10","pages":"e70695","pmid":"41057914","title":"White matter hyperintensities precede other biomarkers in GRN frontotemporal dementia.","volume":"21","year":"2025","bibtex":"@article{Soltaninejad2025,\nabstract = {INTRODUCTION: Increased white matter hyperintensities (WMHs) have been reported in genetic frontotemporal dementia (FTD) in small studies, but the sequence of WMH abnormalities relative to other biomarkers is unclear. 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