Use of Multimodal Imaging and Clinical Biomarkers in Presymptomatic Carriers of C9orf72 Repeat Expansion

Abstract

Importance: During a time with the potential for novel treatment strategies, early detection of disease manifestations at an individual level in presymptomatic carriers of a hexanucleotide repeat expansion in the C9orf72 gene (preSxC9) is becoming increasingly relevant.

Objectives: To evaluate changes in glucose metabolism before symptom onset of amyotrophic lateral sclerosis or frontotemporal dementia in preSxC9 using simultaneous fluorine 18-labeled fluorodeoxyglucose ([18F]FDG positron emission tomographic (PET) and magnetic resonance imaging as well as the mutation's association with clinical and fluid biomarkers.

Design, setting, and participants: A prospective, case-control study enrolled 46 participants from November 30, 2015, until December 11, 2018. The study was conducted at the neuromuscular reference center of the University Hospitals Leuven, Leuven, Belgium.

Main outcomes and measures: Neuroimaging data were spatially normalized and analyzed at the voxel level at a height threshold of P < .001, cluster-level familywise error-corrected threshold of P < .05, and statistical significance was set at P < .05 for the volume-of-interest level analysis, using Benjamini-Hochberg correction for multiple correction. W-score maps were computed using the individuals serving as controls as a reference to quantify the degree of [18F]FDG PET abnormality. The threshold for abnormality on the W-score maps was designated as an absolute W-score greater than or equal to 1.96. Neurofilament levels and performance on cognitive and neurologic examinations were determined. All hypothesis tests were 1-sided.

Results: Of the 42 included participants, there were 17 with the preSxC9 mutation (12 women [71%]; mean [SD] age, 51 [9] years) and 25 healthy controls (12 women [48%]; mean [SD] age, 47 [10] years). Compared with control participants, significant clusters of relative hypometabolism were found in frontotemporal regions, basal ganglia, and thalami of preSxC9 participants and relative hypermetabolism in the peri-Rolandic region, superior frontal 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 participants and increased glucose metabolism in the precentral gyrus and precuneus cortex in up to 71% of preSxC9 participants. Other findings in the preSxC9 group were upper motor neuron involvement in 10 participants (59%), cognitive abnormalities in 5 participants (29%), and elevated neurofilament levels in 3 of 16 individuals (19%) who underwent lumbar puncture.

Conclusions and relevance: The results suggest that [18F]FDG PET can identify glucose metabolic changes in preSxC9 at an individual level, preceding significantly elevated neurofilament levels and onset of symptoms.

Figure 1.. Relative Glucose Metabolism and Gray Matter Volume in Presymptomatic Carriers of a Hexanucleotide Repeat Expansion in the C9orf72 Gene (PreSxC9) Corrected for Age on Axial, Coronal, and Sagittal Sections

Reduced glucose metabolism and gray matter volume depicted in red-yellow, and increased glucose metabolism depicted in blue-white. Data were analyzed at a height threshold of P < .001 and were cluster level corrected for familywise error at P < .05. A, Projections of areas with relative hypometabolism in preSxC9 participants vs healthy controls. B, Volume decline in preSxC9 participants vs healthy controls. C, Relative hypometabolism in preSxC9 participants and healthy controls following voxel-based PVC. D, Relative hypermetabolism in preSxC9 and healthy controls following voxel-based PVC. [¹⁸F]FDG indicates fluorine 18–labeled fluorodeoxyglucose; PET, positron emission tomography; PVC, partial volume correction; and t, t value. Section numbers refer to Montreal Neurological Institute coordinates.

Figure 2.. Neurofilament Levels in the Cerebrospinal Fluid (CSF) of Presymptomatic Carriers of a Hexanucleotide Repeat Expansion in the C9orf72 Gene (PreSxC9)

A, Neurofilament light chain in the CSF of healthy controls and preSxC9 participants. B, Phosphorylated neurofilament heavy chain in the CSF of healthy controls and preSxC9 participants. The dotted line indicates diagnostic cutoff level. The upward arrowheads indicate the controls, and the downward arrowheads indicate the preSxC9 participants. Error bars indicate 95% CIs.

Figure 3.. Individual W-Score Maps of Relative Hypometabolism Observed in PreSxC9 Participants

Thresholds for W-score maps were set at a W score less than or equal to −1.96 and sorted by age, displayed on axial (z = 10), coronal (y = −14), and sagittal (x = −6) sections. Section numbers refer to Montreal Neurological Institute coordinates. Images from participants with elevated neurofilament levels are within red boxes. w indicates W score.