White matter hyperintensities precede other biomarkers in GRN frontotemporal dementia.
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Soltaninejad Mahdie, Dadar Mahsa, Collins D Louis, Rajabli Reza, Venkatraghavan Vikram, Bouzigues Arabella, Russell Lucy L, Foster Phoebe H, Ferry-Bolder Eve, van Swieten John C, Jiskoot Lize C, Seelaar Harro, Sanchez-Valle Raquel, Laforce Robert, Graff Caroline, Galimberti Daniela, Vandenberghe Rik, de Mendonça Alexandre, Tiraboschi Pietro, Santana Isabel, Gerhard Alexander, Levin Johannes, Nacmias Benedetta, Otto Markus, Bertoux Maxime, Lebouvier Thibaud, Butler Chris R, Ber Isabelle Le, Finger Elizabeth, Tartaglia Maria Carmela, Masellis Mario, Rowe James B, Synofzik Matthis, Moreno Fermin, Borroni Barbara, Rohrer Jonathan D, Iturria-Medina Yasser, Ducharme Simon, GENFI Consortium
Аннотация
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.