Abstract Details

Title Brain Metabolic Changes in the Presymptomatic Stage of Frontotemporal Dementia Associated with GRN Mutations

Topic Behavioral and Cognitive Neurology

Presentation(s) S2 - Behavioral Neurology (2:00 PM-2:12 PM)

Poster/Presentation
Number 006

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.

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.

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.

Authors/Disclosures
Dario Saracino (Paris Brain Institute / Sorbonne Université / Hôpital Pitié-Salpêtrière) PRESENTER	Dario Saracino has nothing to disclose.
Leila Sellami, MD (CSSS de l'Outaouais Hôpital de Hull)	Dr. Sellami has nothing to disclose.
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Florence Pasquier, MD	Dr. Pasquier has nothing to disclose.
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Jeremie Pariente (Universite Paul Sabatier)	No disclosure on file
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Mira Didic, MD (Institut de la maladie)	No disclosure on file
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Isabelle Le Ber, MD, PhD (AP HP)	Dr. Le Ber has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Prevail Therapeutics. Dr. Le Ber has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Alector.