Brain pH Changes Linked to Wide-Ranging Cognitive Issues

The International Brain pH Project Consortium unveils groundbreaking findings in a large-scale animal model study, indicating altered brain pH and lactate levels as a transdiagnostic endophenotype in neuropsychiatric disorders with cognitive impairment. This collaborative effort, involving 131 researchers across six countries, challenges existing notions and may pave the way for novel strategies in understanding and addressing biologically diverse and debilitating disorders impacting cognitive function. The research paper will be published in eLife.

A global collaborative research group comprising 131 researchers from 105 laboratories across seven countries announces a groundbreaking research paper submitted to eLife. Titled "Large-scale Animal Model Study Uncovers Altered Brain pH and Lactate Levels as a Transdiagnostic Endophenotype of Neuropsychiatric Disorders Involving Cognitive Impairment," the study identifies brain energy metabolism dysfunction leading to altered pH and lactate levels as common hallmarks in numerous animal models of neuropsychiatric and neurodegenerative disorders, such as intellectual disability, autism spectrum disorders, schizophrenia, bipolar disorder, depressive disorders, and Alzheimer’s disease.

1. Common Phenomenon Across Disorders: About 30% of the 109 types of animal models exhibited significant changes in brain pH and lactate levels, emphasizing the widespread occurrence of energy metabolism changes in the brain across various neuropsychiatric conditions.
2. Environmental Factors as a Cause: Models simulating depression through psychological stress, and those induced to develop diabetes or colitis, which have a high comorbidity risk for depression, showed decreased brain pH and increased lactate levels. Various acquired environmental factors could contribute to these changes.
3. Cognitive Impairment Link: A comprehensive analysis integrating behavioral test data revealed a predominant association between increased brain lactate levels and impaired working memory, illuminating an aspect of cognitive dysfunction.
4. Confirmation in Independent Cohort: These associations, particularly between higher brain lactate levels and poor working memory performance, were validated in an independent cohort of animal models, reinforcing the initial findings.
5. Autism Spectrum Complexity: Variable responses were noted in autism models, with some showing increased pH and decreased lactate levels, suggesting subpopulations within the autism spectrum with diverse metabolic patterns.

"This is the first and largest systematic study evaluating brain pH and lactate levels across a range of animal models for neuropsychiatric and neurodegenerative disorders. Our findings may lay the groundwork for new approaches to develop the transdiagnostic characterization of different disorders involving cognitive impairment," states Dr. Hideo Hagihara, the study's lead author.

Professor Tsuyoshi Miyakawa, the corresponding author, explains, "This research could be a stepping stone towards identifying shared therapeutic targets in various neuropsychiatric disorders. Future studies will center on uncovering treatment strategies that are effective across diverse animal models with brain pH changes. This could significantly contribute to developing tailored treatments for patient subgroups characterized by specific alterations in brain energy metabolism."

In this paper, the mechanistic insights into the reduction in pH and the increase in lactate levels remain elusive. However, it is known that lactate production increases in response to neural hyperactivity to meet the energy demand, and the authors seem to think this might be the underlying reason.

Reference: Hagihara H, Shoji H, Hattori S, et al. Large-scale animal model study uncovers altered brain pH and lactate levels as a transdiagnostic endophenotype of neuropsychiatric disorders involving cognitive impairment. Antoine M, Nelson SB, eds. eLife. 2024;12:RP89376. doi: 10.7554/eLife.89376

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