Glucose and Methionine Metabolism in Disorders of Consciousness After Brain Injury: An Exploratory Longitudinal PET Study.

Abstract

Brain glucose metabolism measured by [¹⁸F]fluorodeoxyglucose (FDG) PET is a marker of residual activity in disorders of consciousness (DoC). Brain amino acid metabolism remains poorly characterized. We examined cross-sectional and longitudinal glucose and methionine uptake and associations with improvement of consciousness. This is a single-center, prospective, observational study. We consecutively enrolled patients older than 15 years admitted to our Rehabilitation Center between 2017 and 2022 with DoC after severe brain injury, who had adequate glucose control. Within this cohort, we performed 1) an exploratory cross-sectional analysis based on PET data from baseline evaluation (mean 20.9 ± 42.1 months after injury) and 2) a prospective longitudinal study. Participants underwent serial Coma Recovery Scale-Revised (CRS-R) assessments and both FDG and [¹¹C]methionine (MET) PET during routine care. The primary outcome was improvement of consciousness, defined as a ≥2-point increase in CRS-R. Associations between metabolic measures and ΔCRS-R were assessed using Spearman correlation with 95% CIs, with exploratory logistic regression and receiver operating characteristic analyses. We included 60 patients in the cross-sectional study and 43 in the longitudinal analysis. In cross-sectional analyses vs 28 non-DoC controls, patients showed reduced whole-brain glucose metabolism (SUV_max mean difference -5.99 [95% CI -7.63 to -4.35]; <i>p</i> < 0.0001) and higher brainstem MET uptake (SUV_mean mean difference 0.15 [95% CI 0.01-0.29]; <i>p</i> = 0.03). During the study, 21 (49%) patients demonstrated clinical improvement, with a median 4-point CRS-R increase (mean age 49.6 ± 19.4 years; 33% female; median CRS-R 11 [interquartile range 6-19]). In longitudinal analyses, improvement was associated with increased glucose SUV_max and higher brainstem MET uptake. CRS-R changes correlated with glucose SUV_max (ρ = 0.43 [95% CI 0.15-0.65]; <i>p</i> = 0.004) and brainstem MET SUV_mean (ρ = 0.35 [95% CI 0.06-0.59]; <i>p</i> = 0.021). Brainstem MET SUV_mean ≥2.28 discriminated improvement (area under the curve 0.686 [95% CI 0.527-0.846]). Increased brainstem MET uptake was associated with improvement of consciousness and may complement FDG-PET findings in DoC, although interpretation is limited by the single-center design, exploratory analyses, and sample size. Japan Registry of Clinical Trials: jrct.mhlw.go.jp; identifier: jRCTs031180091. Registration, January 21, 2019.