TY  - JOUR
AU  - Soltaninejad, Mahdie
AU  - Dadar, Mahsa
AU  - Collins, D Louis
AU  - Rajabli, Reza
AU  - Venkatraghavan, Vikram
AU  - Bouzigues, Arabella
AU  - Russell, Lucy L
AU  - Foster, Phoebe H
AU  - Ferry-Bolder, Eve
AU  - van Swieten, John C
AU  - Jiskoot, Lize C
AU  - Seelaar, Harro
AU  - Sanchez-Valle, Raquel
AU  - Laforce, Robert
AU  - Graff, Caroline
AU  - Galimberti, Daniela
AU  - Vandenberghe, Rik
AU  - de Mendonça, Alexandre
AU  - Tiraboschi, Pietro
AU  - Santana, Isabel
AU  - Gerhard, Alexander
AU  - Levin, Johannes
AU  - Nacmias, Benedetta
AU  - Otto, Markus
AU  - Bertoux, Maxime
AU  - Lebouvier, Thibaud
AU  - Butler, Chris R
AU  - Ber, Isabelle Le
AU  - Finger, Elizabeth
AU  - Tartaglia, Maria Carmela
AU  - Masellis, Mario
AU  - Rowe, James B
AU  - Synofzik, Matthis
AU  - Moreno, Fermin
AU  - Borroni, Barbara
AU  - Rohrer, Jonathan D
AU  - Iturria-Medina, Yasser
AU  - Ducharme, Simon
TI  - White matter hyperintensities precede other biomarkers in GRN frontotemporal dementia.
JO  - Alzheimer's and dementia
VL  - 21
IS  - 10
SN  - 1552-5260
CY  - Hoboken, NJ
PB  - Wiley
M1  - DZNE-2025-01437
SP  - e70695
PY  - 2025
AB  - 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.
KW  - Humans
KW  - Frontotemporal Dementia: genetics
KW  - Frontotemporal Dementia: pathology
KW  - Frontotemporal Dementia: diagnostic imaging
KW  - White Matter: pathology
KW  - White Matter: diagnostic imaging
KW  - Male
KW  - Female
KW  - Biomarkers: blood
KW  - Progranulins: genetics
KW  - Middle Aged
KW  - Magnetic Resonance Imaging
KW  - C9orf72 Protein: genetics
KW  - Neurofilament Proteins: blood
KW  - Aged
KW  - Disease Progression
KW  - tau Proteins: genetics
KW  - Atrophy
KW  - C9orf72 (Other)
KW  - FTD (Other)
KW  - GRN (Other)
KW  - MAPT (Other)
KW  - biomarker sequence (Other)
KW  - dementia (Other)
KW  - disease progression (Other)
KW  - early marker (Other)
KW  - event‐based modeling (Other)
KW  - magnetic resonance imaging (Other)
KW  - neurodegeneration (Other)
KW  - neurofilament light chain (Other)
KW  - neuroimaging (Other)
KW  - progranulin (Other)
KW  - white matter (Other)
KW  - Biomarkers (NLM Chemicals)
KW  - Progranulins (NLM Chemicals)
KW  - GRN protein, human (NLM Chemicals)
KW  - C9orf72 Protein (NLM Chemicals)
KW  - Neurofilament Proteins (NLM Chemicals)
KW  - neurofilament protein L (NLM Chemicals)
KW  - tau Proteins (NLM Chemicals)
KW  - C9orf72 protein, human (NLM Chemicals)
KW  - MAPT protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41057914
C2  - pmc:PMC12504049
DO  - DOI:10.1002/alz.70695
UR  - https://pub.dzne.de/record/283025
ER  -