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@ARTICLE{Soltaninejad:283025,
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 Mendonça, 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},
collaboration = {Consortium, GENFI},
title = {{W}hite matter hyperintensities precede other biomarkers in
{GRN} frontotemporal dementia.},
journal = {Alzheimer's and dementia},
volume = {21},
number = {10},
issn = {1552-5260},
address = {Hoboken, NJ},
publisher = {Wiley},
reportid = {DZNE-2025-01437},
pages = {e70695},
year = {2025},
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.},
keywords = {Humans / Frontotemporal Dementia: genetics / Frontotemporal
Dementia: pathology / Frontotemporal Dementia: diagnostic
imaging / White Matter: pathology / White Matter: diagnostic
imaging / Male / Female / Biomarkers: blood / Progranulins:
genetics / Middle Aged / Magnetic Resonance Imaging /
C9orf72 Protein: genetics / Neurofilament Proteins: blood /
Aged / Disease Progression / tau Proteins: genetics /
Atrophy / C9orf72 (Other) / FTD (Other) / GRN (Other) / MAPT
(Other) / biomarker sequence (Other) / dementia (Other) /
disease progression (Other) / early marker (Other) /
event‐based modeling (Other) / magnetic resonance imaging
(Other) / neurodegeneration (Other) / neurofilament light
chain (Other) / neuroimaging (Other) / progranulin (Other) /
white matter (Other) / Biomarkers (NLM Chemicals) /
Progranulins (NLM Chemicals) / GRN protein, human (NLM
Chemicals) / C9orf72 Protein (NLM Chemicals) / Neurofilament
Proteins (NLM Chemicals) / neurofilament protein L (NLM
Chemicals) / tau Proteins (NLM Chemicals) / C9orf72 protein,
human (NLM Chemicals) / MAPT protein, human (NLM Chemicals)},
cin = {Clinical Research (Munich) / AG Levin},
ddc = {610},
cid = {I:(DE-2719)1111015 / I:(DE-2719)1111016},
pnm = {353 - Clinical and Health Care Research (POF4-353)},
pid = {G:(DE-HGF)POF4-353},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:41057914},
pmc = {pmc:PMC12504049},
doi = {10.1002/alz.70695},
url = {https://pub.dzne.de/record/283025},
}