Cognitive Disorders

Altered Brain pH Linked to Cognitive Disorders

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Summary: A global study involving 131 researchers from 105 labs across seven countries has found altered brain pH and lactate levels across various animal models of neuropsychiatric and neurodegenerative disorders. This large-scale research reveals a common endophenotype involving energy metabolism dysfunction as a hallmark in disorders such as schizophrenia, autism, and Alzheimer’s.

The study demonstrates that about 30% of the examined animal models showed significant alterations in brain pH and lactate levels, linking these metabolic changes to impaired working memory and suggesting intrinsic disease characteristics rather than effects of medication. These findings open new avenues for understanding the transdiagnostic characteristics of cognitive impairments and developing targeted treatment strategies.

Key Facts:

  1. Widespread Phenomenon: Significant changes in brain pH and lactate levels were observed in 30% of the animal models studied, indicating a common energy metabolism dysfunction across various neuropsychiatric conditions.
  2. Link to Cognitive Impairment: Elevated lactate levels were predominantly associated with impaired working memory, highlighting a direct impact on cognitive function.
  3. Potential for New Treatments: The identification of altered brain energy metabolism as a transdiagnostic endophenotype paves the way for innovative treatment approaches targeting shared metabolic dysfunctions.

Source: Fujita Health University

A global collaborative research group comprising 131 researchers from 105 laboratories across seven countries announces a groundbreaking research paper submitted to Life.

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.

This shows a brain scan.
Additionally, the relationship between alterations in brain pH and lactate levels and specific behavioral abnormalities had not been clearly established.

At the forefront of neuroscience research, the research group sheds light on altered energy metabolism as a key factor in various neuropsychiatric and neurodegenerative disorders. While considered controversial, an elevated lactate level and the resulting decrease in pH is now also proposed as a potential primary component of these diseases.

Unlike previous assumptions associating these changes with external factors like medication, the research group’s previous findings suggest that they may be intrinsic to the disorders.

This conclusion was drawn from five animal models of schizophrenia/developmental disorders, bipolar disorder, and autism, which are exempt from such confounding factors.

However, research on brain pH and lactate levels in animal models of other neuropsychiatric and neurological disorders has been limited. Until now, it was unclear whether such changes in the brain were a common phenomenon.

Additionally, the relationship between alterations in brain pH and lactate levels and specific behavioral abnormalities had not been clearly established.

This study, encompassing 109 strains/conditions of mice, rats, and chicks, including animal models related to neuropsychiatric conditions, reveals that changes in brain pH and lactate levels are a common feature in a diverse range of animal models of disorders, including schizophrenia/developmental disorders, bipolar disorder, autism, as well as models of depression, epilepsy, and Alzheimer’s disease. This study’s significant insights include:

I. 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.

II. 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.

III. 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.

IV. 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.

V. 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.

Abstract

Large-scale animal model study uncovers altered brain pH and lactate levels as a transdiagnostic endophenotype of neuropsychiatric disorders involving cognitive impairment

Increased levels of lactate, an end-product of glycolysis, have been proposed as a potential surrogate marker for metabolic changes during neuronal excitation. These changes in lactate levels can result in decreased brain pH, which has been implicated in patients with various neuropsychiatric disorders.

We previously demonstrated that such alterations are commonly observed in five mouse models of schizophrenia, bipolar disorder, and autism, suggesting a shared endophenotype among these disorders rather than mere artifacts due to medications or agonal state.

However, there is still limited research on this phenomenon in animal models, leaving its generality across other disease animal models uncertain. Moreover, the association between changes in brain lactate levels and specific behavioral abnormalities remains unclear.

To address these gaps, the International Brain pH Project Consortium investigated brain pH and lactate levels in 109 strains/conditions of 2294 animals with genetic and other experimental manipulations relevant to neuropsychiatric disorders.

Systematic analysis revealed that decreased brain pH and increased lactate levels were common features observed in multiple models of depression, epilepsy, Alzheimer’s disease, and some additional schizophrenia models.

While certain autism models also exhibited decreased pH and increased lactate levels, others showed the opposite pattern, potentially reflecting subpopulations within the autism spectrum.

Furthermore, utilizing large-scale behavioral test battery, a multivariate cross-validated prediction analysis demonstrated that poor working memory performance was predominantly associated with increased brain lactate levels. Importantly, this association was confirmed in an independent cohort of animal models.

Collectively, these findings suggest that altered brain pH and lactate levels, which could be attributed to dysregulated excitation/inhibition balance, may serve as transdiagnostic endophenotypes of debilitating neuropsychiatric disorders characterized by cognitive impairment, irrespective of their beneficial or detrimental nature.

Novel Preclinical Drug Could Have Potential to Combat Depression, Brain Injury, and Cognitive Disorders

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Summary: A preclinical drug that inhibits the kinase enzyme Cdk5 may have the potential to treat depression, brain injuries, and disorders associated with cognitive impairment.

Source: University of Alabama Birmingham

James Bibb, Ph.D., and colleagues have described a novel preclinical drug that could have the potential to combat depression, brain injury and diseases that impair cognition. The drug, which notably is brain-permeable, acts to inhibit the kinase enzyme Cdk5.

Cdk5 is a crucial regulator of signaling in brain neurons. Over three decades of study, it has been implicated in neuropsychiatric and neurodegenerative conditions, including Alzheimer’s disease and Parkinson’s disease. Knocking out the enzyme in mice makes them resilient to stress, enhances their cognition, protects neurons from stroke and head trauma, and lessens neurodegeneration.

While inhibitors of Cdk5 could offer potential therapeutic benefits and new ways to study basic brain function, previous first- and second-generation anti-Cdk5 compounds largely get blocked at the blood-brain barrier that restricts movement of solutes from the blood to the central nervous system’s extracellular fluid. To date, no Cdk5 inhibitor has been approved to treat any neuropsychiatric or degenerative diseases.

Bibb and colleagues now report details of their anti-Cdk5, brain-permeable compound, 25-106. They also show that systemic administration of 25-106 alters neurobehavior in mice, reducing anxiety-like behavior.

“As perhaps the first robust systemic inhibitor, 25-106 represents an exciting and expandable and translatable pharmacological tool to study the function of Cdk5 activity in wild-type animals,” said Bibb, a professor in the University of Alabama at Birmingham Department of Surgery.

“Achieving systemic applicability may be considered a step forward toward the testing of Cdk5 inhibitors to treat neuropsychiatric and neurodegenerative diseases. This provides a promising landscape for future studies to assess the effects of brain-permeable Cdk5 inhibitors to combat stress, anxiety, depression, addiction, cancer and neurodegeneration.”

The study, “Systemic administration of a brain permeable Cdk5 inhibitor alters neurobehavior,” is published in the journal Frontiers in Pharmacology.

In the paper, researchers describe synthesis of the aminopyrazole-based inhibitor, and they used molecular modeling to show that 25-106 appears to occupy the same hydrophobic binding pocket as the well-established Cdk5 inhibitor roscovitine.

This shows the outline of a head
Cdk5 is a crucial regulator of signaling in brain neurons.

They showed that 25-106 inhibited Cdk5 activity in a dose-dependent manner in brain striatal slices ex vivo, and that it also penetrated the brain after systemic administration in mice to inhibit Cdk5 in vivo.

They measured the pharmacokinetic and pharmacodynamic parameters of 25-106 in blood plasma and the brains of mice, and the off-target distribution of 25-106 in the liver and kidneys.

Mice given systemic 25-106 showed modulated neurobehavior in the open field maze test and the tail suspension test, anxiolytic changes that have previously been linked to Cdk5 knockout mice.

They found that 25-106 is a non-selective inhibitor of both Cdk5 and another cyclin-dependent kinase, Cdk2, but note that very low levels of Cdk2 are found in the brain. However, any off-target or toxic effects of systemic inhibition of Cdk2 by 25-106 remain unknown.

New Harvard Study Says Fluoridated Water is Causing Cognitive Disorders

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A newly published study in Harvard’s The Lancet weighs in on the toxins causing autism and ADHD (attention-deficit hyperactivity disorder). Researchers from the Harvard School of Public Health (HSPH) and the Icahn School of Medicine at Mount Sinai (ISMMS) say that along with these numerous environmental toxins, fluoridated water is adding to the higher incident of both cognitive and behavioral disorders.

Harvard had already published a study in 2006 that pointed to fluoride as a ‘developmental neurotoxicant’, and this newer study looks to over 27 additional investigations into the matter via meta nalysis. In the previous study, it was already established that fluoride consumption lowered children’s IQ scores. The left-over from industry, passed off as ‘medicine,’ obstructs brain development, and can cause a full spectrum of serious health issues – from autism to dyslexia, ADHD, ADD, and more.

The study calls the effects from this chemical a ‘silent epidemic’ that mainstream media  and many scientific papers have ignored.

Two of the main researchers involved in the study, Philippe Grandjean from HSPH and Philip Landrigan from ISMMS, say that incidences of chemical-related neurodevelopmental disorders have doubled over the past seven years from six to 12.

The study admits that there are numerous chemicals to blame – many of which are untested or ceremoniously approved by the FDA, USDA, and CDC without truly knowing their long term ramifications on human health – but that fluoride is a definite culprit.

“[S]ince 2006, the number of chemicals known to damage the human brain more generally, but that are not regulated to protect children’s health, had increased from 202 to 214,” writes Julia Medew for The Sydney Morning Herald. “The pair said this could be the tip of the iceberg because the vast majority of the more than 80,000 industrial chemicals widely used in the United States have never been tested for their toxic effects on the developing fetus or child.”

 

The fact is that fluoride, pesticides, herbicides, heavy metals, radioactive isotopes, GMO foods, and weather warfare chemicals are creating a neurological-toxic mix that is unprecedented in human history.

Fluoride, like other toxins, accumulates in the blood stream and even makes it past the blood-brain barrier. Eventually, as the body tries to protect itself from these unwanted substances, the substances make it into the bones and the organs, causing cancer, cognitive abnormalities, and even birth defects in unborn children. Fluoride is known to pass into the placenta in pregnant women, yet regulatory agencies ignore its toxic legacy.

The chemicals lurking in our food supply, water supply, and in our air and soil are causing the neurological decline of both young and old.