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

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

doi:10.1016/j.jad.2024.07.029

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

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

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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 CMRO 2 was observed after acutely administrating MB to all participants. Greater regional CMRO 2 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 CMRO 2 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.

Original language	English
Pages (from-to)	790-798
Number of pages	9
Journal	Journal of Affective Disorders
Volume	362
Early online date	22 Jul 2024
DOIs	https://doi.org/10.1016/j.jad.2024.07.029
Publication status	Published - 1 Oct 2024

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10.1016/j.jad.2024.07.029

Altered oxidative neurometabolic response_Russo_publishedonline22July2024_Gold_VOR (CC BY)Final published version, 768 KBLicence: CC BY

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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

@article{8e4d253bf1f946afb114866d01bf503c,

title = "Altered oxidative neurometabolic response to methylene blue in bipolar disorder revealed by quantitative neuroimaging",

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 CMRO 2 was observed after acutely administrating MB to all participants. Greater regional CMRO 2 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 CMRO 2 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.",

author = "Alfonso Russo and Bal{\'a}zs {\"O}rzsik and Nefize Yalin and Ivor Simpson and Prince Nwaubani and Antonello Pinna and {De Marco}, Riccardo and Harriet Sharp and Amy Kartar and Nisha Singh and Nicholas Blockley and Stone, {Alan John Luke} and Turkheimer, {Federico E} and Young, {Allan H} and Mara Cercignani and Fernando Zelaya and Iris Asllani and Alessandro Colasanti",

note = "Publisher Copyright: {\textcopyright} 2024",

year = "2024",

month = oct,

day = "1",

doi = "10.1016/j.jad.2024.07.029",

language = "English",

volume = "362",

pages = "790--798",

journal = "Journal of Affective Disorders",

issn = "0165-0327",

publisher = "Elsevier",

}

Russo, A, Örzsik, B, Yalin, N, Simpson, I, Nwaubani, P, Pinna, A, De Marco, R, Sharp, H, Kartar, A, Singh, N, Blockley, N, Stone, AJL, Turkheimer, FE , Young, AH, 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, vol. 362, pp. 790-798. https://doi.org/10.1016/j.jad.2024.07.029

TY - JOUR

T1 - Altered oxidative neurometabolic response to methylene blue in bipolar disorder revealed by quantitative neuroimaging

AU - Russo, Alfonso

AU - Örzsik, Balázs

AU - Yalin, Nefize

AU - Simpson, Ivor

AU - Nwaubani, Prince

AU - Pinna, Antonello

AU - De Marco, Riccardo

AU - Sharp, Harriet

AU - Kartar, Amy

AU - Singh, Nisha

AU - Blockley, Nicholas

AU - Stone, Alan John Luke

AU - Turkheimer, Federico E

AU - Young, Allan H

AU - Cercignani, Mara

AU - Zelaya, Fernando

AU - Asllani, Iris

AU - Colasanti, Alessandro

PY - 2024/10/1

Y1 - 2024/10/1

N2 - 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 CMRO 2 was observed after acutely administrating MB to all participants. Greater regional CMRO 2 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 CMRO 2 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.

AB - 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 CMRO 2 was observed after acutely administrating MB to all participants. Greater regional CMRO 2 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 CMRO 2 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.

UR - http://www.scopus.com/inward/record.url?scp=85199176450&partnerID=8YFLogxK

U2 - 10.1016/j.jad.2024.07.029

DO - 10.1016/j.jad.2024.07.029

M3 - Article

C2 - 39019231

SN - 0165-0327

VL - 362

SP - 790

EP - 798

JO - Journal of Affective Disorders

JF - Journal of Affective Disorders

ER -

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

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