GRN Mutation Carriers Show Metabolic Decline in Predementia Brain

Patients who are progranulin (GRN) mutation carriers show more metabolic decline in some parts of the brain before the onset of frontotemporal dementia (FTD), according to study findings presented at the 2022 American Academy of Neurology (AAN) Annual Meeting, held from April 2 to April 7 in Seattle, Washington, and virtually from April 24-26, 2022.

In prior studies, researchers have sought to track preclinical changes in biochemical or imaging biomarkers. Previous findings suggest glucose metabolism could be a sensitive marker of early brain changes and that its alterations may preview structural changes. However, longitudinal analysis of brain metabolic changes in genetic FTD and its GRN-associated forms is lacking.

In the present study, researchers further investigated the longitudinal changes of multimodal biomarkers in the presymptomatic phase of GRN-associated FTD and whether fluorodeoxyglucose positive emission tomography (FDG-PET)can help identify early regional, metabolic changes.

Researchers analyzed 58 asymptomatic first-degree relatives (27 mutation carriers, 31 non-carriers) of patients who are GRN carriersin the Predict-PGRN study cohort (Clinicaltrials.gov Identifier: NCT04014673) over 5 years. Participants completed cognitive/behavioral assessments, underwent brain magnetic resonance imaging (MRI) and FDG-PET imaging, and provided plasma samples. Researchers analyzed PET data with voxel-wise comparisons, metabolic percent annual changes maps (PET-PAC), and regions of interest (ROI) methods.

They found GRN mutation carriers (aged mean 42 at baseline, 17 years before anticipated onset of FTD) and noncarriers had comparable demographic and cognitive characteristics at baseline. Carriers had more significant hypometabolism in the left middle temporal gyrus and absence of cortical atrophy compared with noncarriers.

Right middle and superior temporal gyri, left inferior parietal, and bilateral precuneus ROIs showed up to 20% greater annualized metabolic decline in carriers compared with noncarriers, researchers found in the follow-up. Some carriers had higher plasma neurofilaments increase compared with noncarriers.

“Brain metabolic changes are useful to monitor the earliest phases of GRN disease, long before the occurrence of structural damage,” the researchers stated. “Longitudinal modifications in selected areas may become a valuable biomarker to assess the efficacy of therapeutic trials in presymptomatic carriers.”

Reference

Saracino D, Sellami L, Boniface H, et al. Brain metabolic changes in the presymptomatic stage of frontotemporal dementia associated with GRN mutations. Presented at: the 2022 AAN Annual Meeting; April 2-7, 2022; Seattle, Washington; April 24-26, 2022; Virtual Meeting. Abstract S2.006.