Importance: In an exciting era with potential for novel treatment strategies (e.g. antisense oligonucleotides), early detection of disease manifestations at the single subject level in presymptomatic carriers of a mutation in the C9orf72 gene (PreSxC9) is becoming increasingly relevant.
Objective: To evaluate changes in glucose metabolism prior to symptom onset in PreSxC9, using simultaneous 18F-fluoro-2-deoxy-D-glucose positron emission tomography/magnetic resonance imaging and study its relation to clinical and fluid biomarkers.
Design, setting and participants:
This is a prospective, case-control study, in which 46 participants entered the study from November 2015 until December 2018, at the neuromuscular reference centre of the University Hospitals Leuven. A total of 17 preSxC9 were recruited in this study and compared to a volunteer sample of 29 healthy controls (HC).
Main outcomes and Measures: Neuroimaging data were spatially normalized and analysed at the voxel level, thresholded at pheight < 0.001, with cluster-level Family Wise Error (FWE)-corrected threshold pFWE < 0.05, and at the volume-of-interest level pcorr < 0.05. W-score maps were computed for preSxC9, using the HCs as a reference, to quantify the degree of FDG-PET abnormality. W-score maps were thresholded for abnormality at an absolute W-score >= 1.96. Neurofilament levels were determined, as well as performance on cognitive and neurological examination.
Results: Of the 42 included participants, there were 17 preSxC9 (12 [71%] female: mean [SD] age, 51  yrs.) and 25 HC (12 [48%] female: mean [SD] age, 47  yrs.). Significant patterns of relative hypometabolism were found in frontotemporal regions, basal ganglia and thalami of preSxC9 and relative hypermetabolism in the precentral gyrus and precuneus cortex. W-score frequency maps revealed reduced glucose metabolism with local maxima in the insular cortices, central opercular cortex and thalami in up to 82% of PreSxC9, and increased glucose metabolism in the precentral gyrus and precuneus cortex in up to 71% of preSxC9. Neurological examination revealed upper motor neuron involvement in 59% of PreSxC9, while only 19% displayed elevated neurofilament levels. Cognitive screening demonstrated abnormalities in 29% of preSxC9.
Conclusions and Relevance: Our results demonstrate that FDG-PET identifies a glucose metabolic pattern in preSxC9 at single subject level that precedes symptom onset and significant changes in neurofilament levels.