Cerebral perfusion changes in presymptomatic genetic frontotemporal dementia: a GENFI study

Area of Science:

• Neuroimaging
• Genetics
• Neurology

Background:

• Genetic frontotemporal dementia (FTD) is primarily caused by mutations in C9orf72, GRN, or MAPT genes.
• Presymptomatic carriers of these mutations are at risk for developing FTD.
• Cerebral blood flow (CBF) changes are known in symptomatic FTD, but their utility in presymptomatic stages is unclear.

Purpose of the Study:

• To identify the specific cerebral blood flow (CBF) signature in presymptomatic carriers of genetic frontotemporal dementia (FTD).
• To investigate differences in CBF between presymptomatic carriers of C9orf72, GRN, or MAPT mutations and non-carriers.
• To determine the potential of arterial spin labelling (ASL) MRI as a biomarker for early detection of genetic FTD.

Main Methods:

• Utilized voxel-based analysis of arterial spin labelling (ASL) MRI data from the multicentre GENetic Frontotemporal dementia Initiative (GENFI) study.
• Compared cross-sectional CBF between presymptomatic mutation carriers (n=107) and non-carriers (n=113).
• Employed general linear mixed-effects models to analyze CBF differences and their association with the expected age of symptom onset.

Main Results:

• A significant inverse association between CBF and expected symptom onset age was found in presymptomatic carriers, but not non-carriers.
• Affected regions included bilateral insulae/orbitofrontal cortices, anterior cingulate/paracingulate gyri, inferior parietal cortices, and left middle temporal gyrus.
• CBF differences were largely driven by the C9orf72 subgroup and appeared approximately 12.5 years before the expected symptom onset.

Conclusions:

• Presymptomatic genetic frontotemporal dementia mutation carriers exhibit reduced CBF in key FTD-associated brain regions.
• These CBF alterations are detectable significantly before the clinical onset of symptoms.
• ASL MRI shows promise as a non-invasive imaging biomarker for identifying individuals at high risk for presymptomatic genetic FTD.