Altered oxidative neurometabolic response to methylene blue in bipolar disorder revealed by quantitative neuroimaging

Russo, Alfonso; Örzsik, Balázs; Yalin, Nefize; Simpson, Ivor; Nwaubani, Prince; Pinna, Antonello; De Marco, Riccardo; Sharp, Harriet; Kartar, Amy; Singh, Nisha; Blockley, Nicholas; Stone, Alan John Luke; Turkheimer, Federico E.; Young, Allan H.; Cercignani, Mara; Zelaya, Fernando; Asllani, Iris; Colasanti, Alessandro

Abstract

Background: Cerebral mitochondrial and hemodynamic abnormalities have been implicated in Bipolar Disorder pathophysiology, likely contributing to neurometabolic vulnerability–leading to worsen clinical outcomes and mood instability. To investigate neurometabolic vulnerability in patients with BD, we combined multi-modal quantitative MRI assessment of cerebral oxygenation with acute administration of Methylene Blue, a neurometabolic/hemodynamic modulator acting on cerebral mitochondria. Methods: Fifteen euthymic patients with chronic BD-type 1, and fifteen age/gender-matched healthy controls underwent two separate MRI sessions in a single-blinded randomized cross-over design, each after intravenous infusion of either MB (0.5 mg/kg) or placebo. MRI-based measures of Cerebral Blood Flow and Oxygen Extraction Fraction were integrated to compute Cerebral Metabolic Rate of Oxygen in Frontal Lobe, Anterior Cingulate, and Hippocampus–implicated in BD neurometabolic pathophysiology. Inter-daily variation in mood rating was used to assess mood instability. Results: A decrease in global CBF and CMRO2 was observed after acutely administrating MB to all participants. Greater regional CMRO2 reductions were observed after MB, in patients compared to controls in FL (mean = −14.2 ± 19.5 % versus 2.3 ± 14.8 %), ACC (mean = −14.8 ± 23.7 % versus 2.4 ± 15.7 %). The effects on CMRO2 in those regions were primarily driven by patients with longer disease duration and higher mood instability. Limitations: Sample size; medications potentially impacting on response to MB. Conclusions: An altered neurometabolic response to MB, a mitochondrial/hemodynamic modulator, was observed in patients, supporting the hypothesis of vulnerability to neurometabolic stress in BD. Integrating quantitative imaging of cerebral oxygen metabolism with a mitochondrial-targeting pharmacological challenge could provide a novel biomarker of neurometabolic and cerebrovascular pathophysiology in BD.

Citation

Russo, A., Örzsik, B., Yalin, N., Simpson, I., Nwaubani, P., Pinna, A., De Marco, R., Sharp, H., Kartar, A., Singh, N., Blockley, N., Stone, A. J. L., Turkheimer, F. E., Young, A. H., Cercignani, M., Zelaya, F., Asllani, I., & Colasanti, A. (2024). Altered oxidative neurometabolic response to methylene blue in bipolar disorder revealed by quantitative neuroimaging. Journal of Affective Disorders, 362, 790-798. https://doi.org/10.1016/j.jad.2024.07.029

• Journal Article Type: Article
• Acceptance Date: Jul 12, 2024
• Online Publication Date: Jul 15, 2024
• Publication Date: Oct 1, 2024
• Deposit Date: Aug 9, 2024
• Publicly Available Date: Aug 14, 2024
• Journal: Journal of Affective Disorders
• Print ISSN: 0165-0327
• Electronic ISSN: 1573-2517
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 362
• Pages: 790-798
• DOI: https://doi.org/10.1016/j.jad.2024.07.029
• Public URL: https://nottingham-repository.worktribe.com/output/37950164
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S0165032724010851?via%3Dihub