Magnetic resonance imaging biomarkers in genetic FTD

Abstract

AbstractBackgroundMRI provides a suite of tools for safe, non‐invasive, repeatable and scalable assessment of the changes in brain structure and function associated with neurodegenerative disease. MRI has been part of the principal assessment in the international Genetic Frontotemporal Dementia Initiative since 2012 (GENFI). This presentation reviews the goals and achievements of MRI in GENFI, and considers future directions to elucidate disease mechanisms, inform clinical trials design, and provide single subject prognosis.MethodGENFI established protocols for harmonisation and standardisation of MRI, and coordinated infrastructure for curation and quality control. 3T MRI sequences have been optimised and closely approximated across diverse vendors, for whole‐brain qualification of volume (T1w), diffusion (DWI), perfusion (ASL), macro‐molecular environment (T2) and function (BOLD fMRI), with >2500 assessments from>1000 participants: including symptomatic people with mutations in MAPT, C9orf72 and GRN; pre‐symptomatic mutation‐carriers; and asymptomatic non‐carriers from the same families. There are >20 peer‐reviewed open‐access MRI‐based publications to date.ResultsGENFI MRI revealed a long pre‐symptomatic phase in people with FTD‐associated mutations, with atrophy present and progressive in frontotemporal regions >10 years before estimated onset. For some mutations, differences in mutation carriers (vs non‐carriers) are evident in early adulthood. The pre‐symptomatic structural change is associated with subtle cognitive and behavioural change. It is prognostic and non‐linear, accelerating with aging towards symptom onset. Intriguingly, functional integration is maintained in macro‐scale brain networks of pre‐symptomatic carriers, suggesting a mechanism of functional resilience to progression of underlying neuropathology. The consequences of mutations are not confined to frontotemporal regions: GENFI has highlighted behaviourally‐relevant changes in volume and shape, white‐matter hyperintensity and diffusivity in parietal lobe, basal ganglia, thalamus and cerebellum. The MRI tools can be used to identify stages and subtypes of genetic‐FTD.ConclusionOver ten years, GENFI has shown how MRI can be delivered at scale in multi‐centre studies of genetic FTD, revealing the long pre‐symptomatic phase, with gene‐specific mechanisms and consequences. The sensitivity, reliability and progression of gene‐specific changes in diverse MRI modalities are ideal to support clinical trials of novel therapeutic agents.