A multi-modal biomarker study reveals early brain 18F FDG-PET changes at single subject level in presymptomatic C9orf72 repeat expansion carriers

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 [9] yrs.) and 25 HC (12 [48%] female: mean [SD] age, 47 [10] 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.

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De Vocht J
Blommaert J
Devrome M
Radwan A
Van Weehaeghe D
De Schaepdryver M
Ceccarini J
Rezaei A
Schramm G
Van Aalst J
Chio A
Pagani M
Van Esch H
Lamaire N
Verhaegen M
Mertens N
Poesen K
van den Berg L
Van Es M
Vandenberghe R
Vandenbulcke M
Van den Stock J
Koole M
Dupont P
Van Laere K
Van Damme P
JAMA Neurology (2020).
info:cnr-pdr/source/autori:De Vocht J; Blommaert J; Devrome M; Radwan A; Van Weehaeghe D; De Schaepdryver M; Ceccarini J; Rezaei A; Schramm G; Van Aalst J; Chio A; Pagani M; Van Esch H; Lamaire N; Verhaegen M; Mertens N; Poesen K; van den Berg L; Van Es M
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