Brain Metabolic Changes in the Presymptomatic Stage of Frontotemporal Dementia Associated with GRN Mutations
Dario Saracino1, Leila Sellami1, Hugo Boniface2, Maxime Locatelli2, Mélanie Pelegrini-Issac3, Aurélie Funkiewiez4, Marion Houot1, Daisy Rinaldi1, Karim Dorgham5, Florence Pasquier6, Mathieu Chastan7, Anne Hitzel8, Jérémie Pariente9, Amandine Pallardy10, Eric Guedj11, Mira Didic11, Aurelie Kas12, Marie-Odile Habert13, Isabelle Le Ber1
1Paris Brain Institute / Sorbonne Université / Hôpital Pitié-Salpêtrière, 2CATI Neuroimaging / Hôpital Pitié-Salpêtrière, 3LIB / Sorbonne Université / Hôpital Pitié-Salpêtrière, 4Institute of Memory and Alzheimer Disease / Hôpital Pitié-Salpêtrière, 5CIMI-Paris / Hôpital Pitié-Salpêtrière, 6Hopital Roger Salengro / CHU Lille, 7CHU Charles Nicolle, 8CHU Toulouse, 9CHU Purpan, 10CHU Nantes, 11APHM Hôpital Timone, 12Département de Médecine Nucléaire / Hôpital Pitié-Salpêtrière, 13CATI Neuroimaging / LIB / Département de Médecine Nucléaire / Hôpital Pitié-Salpêtrière
Objective:

To investigate the longitudinal changes of multimodal biomarkers during the presymptomatic phase of GRN-associated frontotemporal dementia (FTD), and in particular to assess the usefulness of FDG-PET to identify early regional metabolic alterations.

Background:
The presymptomatic phase of genetic FTD offers an interesting perspective to study pathophysiological changes and test disease-modifying therapies. Previous studies aimed at tracking preclinical changes in biochemical or imaging biomarkers. Glucose metabolism may be a sensitive marker of early brain changes, and its alterations may significantly precede structural changes. However, there is a lack of longitudinal investigations assessing brain metabolic changes in genetic FTD, and in particular in GRN-associated forms.
Design/Methods:

This prospective study analyzed 58 asymptomatic first-degree relatives of GRN patients recruited in the Predict-PGRN study cohort (NCT04014673). Twenty-seven were mutation carriers and 31 non-carriers. They were longitudinally evaluated over a 5-year period with cognitive/behavioral assessments, plasma samples, brain MRI and FDG-PET imaging. PET data were analyzed with three approaches: voxel-wise comparisons, metabolic percent annual changes maps (PET-PAC) and regions of interest (ROIs) method.

Results:

Demographic and cognitive characteristics were comparable between GRN carriers and non-carriers at baseline. The mean age at inclusion for carriers was 42 years, approximately 17 years before expected onset. Carriers displayed a cluster of significant hypometabolism in the left middle temporal gyrus compared to non-carriers, in absence of cortical atrophy. Some ROIs, namely right middle and superior temporal gyri, left inferior parietal, and bilateral precuneus, exhibited greater annualized metabolic decline in carriers (up to ~20%) compared to non-carriers during follow-up. These changes were paralleled by higher plasma neurofilaments increase in some of the carriers.

Conclusions:

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