Abstract
PurposeNeuropathological data suggest that ALS with SOD1 mutations (SOD1-ALS) is a distinct form of ALS. We evaluated brain metabolic changes characterizing SOD1-ALS as compared to sporadic ALS (sALS), employing 18fluorodeoxyglucose-positron-emission tomography (18F-FDG-PET).MethodsWe included 18 SOD1-ALS patients, 40 healthy controls (HC), and 46 sALS patients without mutations in SOD1, TARDBP, FUS, and C9ORF72, randomly selected from 665 subjects who underwent brain 18F-FDG-PET at diagnosis between 2008 and 2019 at the ALS Centre of Turin. We excluded patients with frontotemporal dementia. We used the full factorial design in SPM12 to evaluate whether differences among groups exist overall. In case the hypothesis was confirmed, group comparisons were performed through the two-sample t-test model of SPM12. In all the analyses, the height threshold was P < 0.001 (P < 0.05 FWE-corrected at cluster level).ResultsThe full factorial design resulted in a significant main effect of groups. We identified a relative hypometabolism in sALS patients compared to SOD1-ALS cases in the right precentral and medial frontal gyrus, right paracentral lobule, and bilateral postcentral gyrus. SOD1 patients showed a relative hypermetabolism as compared to HC in the right precentral gyrus and paracentral lobule. As compared to HC, sALS patients showed relative hypometabolism in frontal, temporal, and occipital cortices.ConclusionSOD1-ALS was characterized by a relative hypermetabolism in the motor cortex as compared to sALS and HC. Since promising, targeted, therapeutic strategies are upcoming for SOD1-ALS, our data support the use of PET to study disease pathogenesis and to track its course in clinical trials, in both asymptomatic and symptomatic mutation carriers.
Highlights
Amyotrophic lateral sclerosis is characterized by the progressive degeneration of upper and lower motor neurons, leading to voluntary muscle wasting and weakness, and causing death within 2–5 years from onset [1]
Bulbar onset was less frequent in the SOD1 group, in agreement with population-based data from Italy [16]; the pure lower motor neuron (LMN) phenotype was present only in the SOD1-Amyotrophic lateral sclerosis (ALS), in agreement with the published literature reporting that such phenotypic variant is frequent among SOD1 mutations carriers [15, 16]
We identified a relative hypometabolism in the sporadic ALS (sALS) group compared to the SOD1 group in a cluster including the right precentral and medial frontal gyrus, the right paracentral lobule, and bilateral postcentral gyrus (Figure 1; Table 2)
Summary
Amyotrophic lateral sclerosis is characterized by the progressive degeneration of upper and lower motor neurons, leading to voluntary muscle wasting and weakness, and causing death within 2–5 years from onset [1]. SOD1 mutations were identified as a cause of fALS in 1993 [3]. Afterwards, they were detected in ~1% of sALS cases [2]. Recent works have demonstrated that 18F-FDG-PET is able to disclose the metabolic brain correlates of different aspects of ALS phenotype, including the extent of motor deficits [8], and the presence of cognitive [9] and behavioral impairment [10]. 18F-FDG-PET investigations focused on SOD1 mutation carriers are still lacking. The aim of the present study was the identification of brain metabolic changes characterizing SOD1-ALS as compared to sALS, employing 18F-FDG-PET
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