Regional cingulate metabolite-ratio differences exceed longitudinal changes across an approximately 34-h protocol: a prospective quality-controlled proton magnetic resonance spectroscopy study

Abstract

BACKGROUND: Regional organization, acquisition sequence, and measurement quality can obscure the interpretation of longitudinal proton magnetic resonance spectroscopy (1H-MRS) changes. We compared anterior vs. posterior cingulate metabolite-ratio differences with changes across an approximately 34-h protocol and tested whether findings depended on sequence, quality-control rules, respiratory burden, comorbidity, or polysomnographic sleep measures. METHODS: In this prospective single-center observational study, 138 university-affiliated and advertisement-recruited participants underwent baseline evening spectroscopy of the anterior cingulate cortex (ACC) and posterior cingulate cortex (PCC) on day 1, full-night polysomnography from day 2 into day 3, and post-PSG morning spectroscopy on day 3 using MEGA-PRESS and SVS-PRESS. Among 116 participants with complete paired timestamps, the median interval between scan starts was 34.01 h (IQR, 33.86-34.10 h). Primary metabolite-to-creatine ratios were analyzed using age-, sex-, and body mass index-adjusted generalized estimating equations. Sensitivity analyses evaluated effect magnitude, sequence dependence, spectral-quality selection, follow-up availability, exclusion of participants with apnea-hypopnea index (AHI) ≥15 events/h, exclusion of hypertension or diabetes, and associations between metabolite change and seven polysomnographic measures. RESULTS: A total of 137 participants contributed to adjusted primary models. PCC showed higher NAA/Cr in both sequences and higher SVS GlxT/Cr, whereas ACC showed higher Cho/Cr in both sequences and higher MEGA Glu/Cr (all q < 0.001); PCC also showed higher MEGA GABA/Cr (q = 0.020). Cr2 denotes the vendor-fitted second creatine/phosphocreatine resonance, and GlxT denotes the sum of six vendor-fitted glutamate/glutamine components. Follow-up reductions that survived false-discovery-rate correction were confined to SVS Cr2/Cr and GlxT/Cr. Across 11 outcomes, the median absolute paired standardized effect size was 0.571 for region and 0.125 for longitudinal change; the former was 4.6 times the latter, a ratio of median standardized effect magnitudes rather than a biological fold difference. Excluding AHI ≥ 15 events/h preserved the direction of all 12 primary FDR-significant effects, with 11 remaining q < 0.05. None of 77 polysomnographic dose-response tests survived global correction. CONCLUSIONS: In this heterogeneous cohort, regional differences in cingulate metabolite ratios were larger and more robust than longitudinal changes. Because the approximately 34-h contrast combined elapsed time, circadian phase, an intervening monitored night, repositioning, and other uncontrolled influences, it should not be interpreted as a sleep-specific effect. The ratio-based findings should not be interpreted as regional concentration differences.

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