White Matter Hyperintensities Precede other Biomarkers in GRN Frontotemporal Dementia
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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 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 -related FTD. When present, they appear early and should be considered in disease progression models.
Highlights
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Elevated WMH volumes in symptomatic GRN carriers, but not in other mutations.
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WMH accumulation is mostly observed in the frontal lobe.
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WMH abnormalities appear early in GRN -FTD, before NfL, atrophy, and ventriculomegaly.
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Longitudinally, WMH volumes can predict subcortical changes, but not vice versa.
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WMHs are key early markers in GRN -FTD and should be included in progression models.
RESEARCH IN CONTEXT
Systematic review
We systematically reviewed the literature on white matter hyperintensities (WMHs) in frontotemporal dementia (FTD) using PubMed. While a few small studies reported increased WMHs in GRN mutation carriers, their sample sizes were limited, and they did not assess the timing of WMHs within disease progression or their temporal relationship to other biomarkers.
Interpretation
We identified a sequence of key biomarkers in GRN -related FTD and demonstrated that WMHs are among the earliest biomarkers, preceding cortical and subcortical atrophy as well as blood biomarkers. This aligns with neuropathological evidence of early white matter involvement in FTLD- GRN . Additionally, using a larger dataset, we validated previous reports of elevated WMHs in GRN carriers, confirming their reliability.
Future directions
Future studies should integrate WMHs into FTD progression models to enhance early diagnosis. Understanding why only a subset of GRN carriers exhibit high WMH volumes remains a key research priority.
