Foreseeing Before Disease Onset

The vast heterogeneity regarding clinical features and neuropathologic underpinnings of presentations within the frontotemporal dementia (FTD) spectrum is a well-known, major factor limiting the identification of reproducible and consistent biomarkers of disease progression.¹ Considering that an autosomal dominant pattern of inheritance accounts for up to 30% of all FTD presentations—with pathogenic variants in the C9orf72, GRN, and MAPT genes found in the majority of cases¹—the focus of recent research in this field has shifted toward these genetically determined forms, which eliminate, at least, some intrinsic sources of pathogenic heterogeneity.^2-4 In particular, the assessment of the presymptomatic stage of FTD is a fundamental topic because it may help identify the earliest signs of neurodegeneration and, therefore, direct the choice of the best time window for treatment administration in upcoming intervention trials. Owing to the easy availability and noninvasive nature of structural MRI, the use of automated tools measuring brain atrophy on T1-weighted volumetric sequences seems to be an ideal way to delineate trajectories of early neurodegeneration and suggests proximity to clinical conversion in preclinical FTD. Most previous studies in this field, even in a large, multicentric setting,⁵ were limited by a cross-sectional design. Moreover, the arbitrary use of an “estimated” time to symptom onset based on the age of clinical onset in affected family members or the inclusion of relatively small samples of noncarrier family members as a reference healthy population are debatable points in the previous literature.^6,7