Journal Article

DZNE-2025-01437

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png 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.DZNE* ; 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.Extern* ; Moreno, F. ; Borroni, B. ; Rohrer, J. D. ; Iturria-Medina, Y. ; Ducharme, S. ; Consortium, G. (Collaboration Author)

2025
Wiley Hoboken, NJ

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Please use a persistent id in citations: doi:10.1002/alz.70695

Abstract: 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.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.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.WMHs are elevated in a subset of GRN-associated FTD. When present, they appear early and should be considered in disease progression models.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.

Keyword(s): Humans (MeSH) ; Frontotemporal Dementia: genetics (MeSH) ; Frontotemporal Dementia: pathology (MeSH) ; Frontotemporal Dementia: diagnostic imaging (MeSH) ; White Matter: pathology (MeSH) ; White Matter: diagnostic imaging (MeSH) ; Male (MeSH) ; Female (MeSH) ; Biomarkers: blood (MeSH) ; Progranulins: genetics (MeSH) ; Middle Aged (MeSH) ; Magnetic Resonance Imaging (MeSH) ; C9orf72 Protein: genetics (MeSH) ; Neurofilament Proteins: blood (MeSH) ; Aged (MeSH) ; Disease Progression (MeSH) ; tau Proteins: genetics (MeSH) ; Atrophy (MeSH) ; C9orf72 ; FTD ; GRN ; MAPT ; biomarker sequence ; dementia ; disease progression ; early marker ; event‐based modeling ; magnetic resonance imaging ; neurodegeneration ; neurofilament light chain ; neuroimaging ; progranulin ; white matter ; Biomarkers ; Progranulins ; GRN protein, human ; C9orf72 Protein ; Neurofilament Proteins ; neurofilament protein L ; tau Proteins ; C9orf72 protein, human ; MAPT protein, human

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Contributing Institute(s):

1. Clinical Research (Munich) (Clinical Research (Munich))
2. Clinical Neurodegeneration (AG Levin)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

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Database coverage:
; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; DEAL Wiley ; Essential Science Indicators ; IF >= 10 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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