Organic Acids, Cognitive Function, and Brain Health

by Christina O'Brien, DC

Organic acids are pivotal in the vast landscape of metabolic processes, serving as intermediates in the degradation of proteins, fats, and carbohydrates. These compounds, often measured through urine organic acid tests, provide a snapshot of an individual's metabolic state, offering insights into various physiological and pathological conditions. This biochemical data is not only important for understanding general health but also plays a significant role in assessing cognitive function and brain health.

The brain, a highly metabolically active organ, requires a constant and efficient supply of nutrients and the rapid removal of waste products to maintain its function. Organic acids are at the heart of this metabolic flux, influencing everything from energy production to the synthesis and breakdown of neurotransmitters. Neurotransmitters such as serotonin, dopamine, and norepinephrine, regulated by organic acid pathways, are essential for mood regulation, alertness, and cognitive capabilities.

Moreover, the balance of these neurotransmitters is tightly regulated by methylation processes, which involve the transfer of methyl groups to and from molecules, a critical epigenetic signaling tool that governs the expression of genes and the function of proteins. Imbalances in methylation, such as undermethylation or overmethylation, can lead to altered levels of neurotransmitters like serotonin, manifesting in varied cognitive and emotional disturbances.

Understanding the interplay between organic acids and brain function not only enhances our grasp of cognitive health but also directs us toward potential interventions that could mitigate the risks or progression of cognitive impairments. As we delve into the roles of specific organic acids, their pathways, and their impact on neurotransmitter levels, we unveil potential strategies to harness this knowledge for better mental health outcomes and disease prevention.

Key Organic Acids and Their Neurological Roles

Glutathione: The Master Antioxidant's Role in Brain Health and Cognitive Preservation

Glutathione stands out as the master antioxidant in the body, playing a pivotal role in neutralizing free radicals and maintaining the oxidative balance needed for brain health. This tripeptide, composed of glycine, cysteine, and glutamic acid, is important not only for detoxifying harmful substances but also for supporting immune function and thus, indirectly, protecting the brain.

In the brain, glutathione helps to prevent the oxidative stress that can lead to neuronal damage, a key factor in cognitive decline and neurodegenerative diseases like Alzheimer’s. Furthermore, the synthesis and regulation of glutathione are influenced by genetic factors. Variations in genes responsible for synthesizing and recycling glutathione can affect an individual's capacity to handle oxidative stress and can influence susceptibility to neurological disorders. Epigenetic mechanisms, which include DNA methylation and histone modification, also play a role in regulating these genes, highlighting the adaptive responses of cells to their changing environment and the potential for nutritional and lifestyle interventions to impact brain health through these pathways.

Indican: Its Links to Gut Dysbiosis and Subsequent Effects on Brain Function

Indican, an organic acid produced as a result of tryptophan metabolism by intestinal bacteria, serves as a marker of gut dysbiosis—an imbalance in the gut microbiota. This connection is crucial, as emerging research underscores the gut-brain axis as a significant pathway through which the gastrointestinal tract influences mental and neurological health.

Increased levels of indican in the urine suggest an overgrowth of harmful bacteria in the gut that can interfere with the proper digestion and absorption of nutrients, including those necessary for neurotransmitter synthesis. Gut dysbiosis has been linked to a variety of cognitive and behavioral issues, from decreased cognitive function to increased anxiety and depression symptoms, illustrating the gut’s role in mental health.

From an epigenetic standpoint, gut dysbiosis can influence the expression of genes involved in inflammation and immune responses, which in turn can affect brain function. The metabolites produced by gut bacteria, including indican, can act as signaling molecules that modify the epigenetic landscape, influencing gene expression in the brain. These interactions highlight the importance of maintaining gut health not only for overall wellness but also as a proactive approach to safeguard cognitive functions and mitigate neurological disorders.

The Serotonin Connection: Methylation and Mood Regulation

Explanation of Methylation and Its Importance in Neurotransmitter Synthesis

Methylation is a biochemical process involving the transfer of a methyl group (one carbon atom attached to three hydrogen atoms) onto amino acids, proteins, enzymes, and DNA in every part of the body. In the brain, methylation plays a vital role in synthesizing and breaking down neurotransmitters, which are chemical messengers that govern mood, concentration, sleep, and other cognitive functions.

This process is especially important in the production and function of serotonin, a key neurotransmitter that influences mood, emotion, sleep, and appetite. Serotonin synthesis begins with the amino acid tryptophan, which is converted into 5-hydroxytryptophan (5-HTP) and then into serotonin. Methylation influences this pathway by regulating the enzymes involved in converting these substances. The proper function of these enzymes ensures adequate serotonin levels and, by extension, balanced mood and cognitive function.

Discussing Undermethylation and Overmethylation, Focusing on Serotonin Production

Undermethylation and overmethylation describe conditions where the body's ability to add methyl groups to its biological molecules is compromised or excessive, respectively. Both conditions can significantly impact brain health and mood by altering neurotransmitter levels, particularly serotonin.

• Undermethylation: This condition often leads to a shortage of methyl groups necessary for the efficient production of serotonin. Individuals who are undermethylated typically have several distinct symptoms and traits, such as seasonal allergies, dry eyes, low pain tolerance, and a history of high achievement. In terms of mood, they may suffer from obsessive-compulsive disorder (OCD), oppositional defiance, and depression, all linked to insufficient serotonin activity.
• Overmethylation: Conversely, overmethylation results in an excess of methyl groups, which can lead to an overly efficient production of certain neurotransmitters, including serotonin. People who are overmethylated may exhibit symptoms such as anxiety, panic disorders, and hyperactivity. They often report food and chemical sensitivities, along with a tendency towards high anxiety, which can be related to excessive serotonin and dopamine levels.

How Low Serotonin Levels Correlate with Cognitive Challenges and Mood Disorders

Low serotonin levels are closely tied to a variety of cognitive and mood disorders. Clinically, insufficient serotonin can manifest as depression, anxiety, sleep disturbances, and other mood disorders. This neurotransmitter is not only pivotal in regulating mood but also plays a role in cognition, influencing everything from memory to decision-making processes.

The relationship between low serotonin and cognitive disorders is also evident in conditions such as Alzheimer's disease and Parkinson’s disease, where altered serotonin pathways are commonly observed. Studies have shown that managing serotonin levels can help mitigate symptoms and, in some cases, slow the progression of cognitive decline.

From a broader perspective, addressing methylation imbalances can be a strategic approach to enhancing serotonin production and achieving better cognitive and emotional health. This can include dietary adjustments to increase or decrease methionine intake (a key methyl donor), supplementation with B vitamins (co-factors in methylation pathways), and lifestyle changes to reduce stress, which can negatively impact methylation balance.

Other Essential Neurotransmitters: Beyond Serotonin

Dopamine and Norepinephrine: Their Pathways and Impact on Cognition and Emotional Regulation

Dopamine and norepinephrine are two neurotransmitters that play pivotal roles in both the central and peripheral nervous systems. Their influence extends across a wide range of psychological functions, from emotional response to cognitive abilities like attention and decision-making.

• Dopamine: Often dubbed the 'feel-good' neurotransmitter, dopamine is integral in the brain's reward system. It is produced in several areas of the brain, including the substantia nigra and the ventral tegmental area. Dopamine is not only used for experiencing pleasure and satisfaction but also plays a significant role in motor control and cognitive function. It influences focus, motivation, and memory. Disruptions in dopamine levels are linked to conditions such as Parkinson’s disease, characterized by motor control issues, and schizophrenia, noted for cognitive and emotional disturbances. Low levels of HVA, the breakdown product of dopamine, have been associated with Autism.
• Norepinephrine: This neurotransmitter is predominantly produced in the locus coeruleus, an area of the brainstem, and acts as a stress hormone and neurotransmitter. It is pivotal in the body's fight-or-flight response, increasing arousal and alertness, accelerating reaction time, and stimulating the release of glucose for energy. In the brain, norepinephrine enhances memory retrieval, attention to detail, and the formation of emotional memories. It is imperative for cognitive alertness and also plays a role in emotional regulation. Imbalances in norepinephrine levels, reflected by low levels of VMA, are associated with mood disorders such as depression, while high levels of VMA are associated with anxiety, as well as attention-deficit hyperactivity disorder (ADHD).

Cortisol and Adrenal Hormones: Their Role in Stress Response and Mental Clarity

Cortisol, often referred to as the stress hormone, is produced in the adrenal cortex under the regulation of the hypothalamic-pituitary-adrenal (HPA) axis. It has numerous functions including regulating metabolism, reducing inflammation, and controlling the sleep-wake cycle. Its most noted role, however, is in managing how the body responds to stress.

• Cortisol: In the short term, cortisol can provide a necessary boost to energy, heightened memory functions, increased immunity, and a higher pain threshold – all experienced during acute stress situations. However, prolonged elevation of cortisol levels can lead to detrimental effects such as weight gain, high blood pressure, disrupted sleep, and a compromised immune response. Chronic high cortisol can also lead to mental cloudiness and decreased cognitive performance, often referred to as 'brain fog.'
• Adrenal Hormones: Besides cortisol, the adrenal glands produce other hormones such as adrenaline (epinephrine) and smaller amounts of sex hormones. Adrenaline, like norepinephrine, plays a significant role in the fight-or-flight response, preparing the body for quick action. In terms of cognitive function, adrenaline boosts alertness and can enhance memory consolidation; however, excessive levels can lead to anxiety and decreased concentration over time.

The balance of these neurotransmitters and hormones is necessary for optimal cognitive and emotional health. Dysregulation can lead to a variety of cognitive deficits and emotional disorders, emphasizing the need for a balanced neurochemical environment for maintaining mental clarity and emotional stability.

Nutritional Influences on Neurotransmitter Production

Vitamin B6 and Biotin Deficiencies: Impact on Neurotransmitter Synthesis

• Vitamin B6: Also known as pyridoxine, Vitamin B6 is used for the normal function of enzymes that produce neurotransmitters, including serotonin, dopamine, and gamma-aminobutyric acid (GABA). This vitamin plays a pivotal role in the decarboxylation and transamination reactions that convert amino acids into these neurotransmitters. A deficiency in Vitamin B6 can lead to decreased synthesis of these brain chemicals, which may manifest as mood disturbances, impaired cognitive function, and increased susceptibility to stress and anxiety. Moreover, Vitamin B6 is involved in the modulation of homocysteine levels, an amino acid that, at high levels, is associated with neurodegenerative diseases such as Alzheimer's.
• Biotin: Biotin, or Vitamin B7, is another B-vitamin that impacts health, including cognitive functions, through its role in the metabolism of fats, carbohydrates, and proteins. It supports the activities of several enzymes essential for the production of energy and neurotransmitters. Biotin deficiency, though rare, can lead to neurological symptoms such as lethargy, depression, and hallucinations due to its role in synthesizing neurotransmitters that regulate mood and cognitive functions.

Dietary Sources and Supplements to Support Neurotransmitter Health

To prevent deficiencies and support neurotransmitter health, incorporating rich sources of Vitamin B6 and Biotin in the diet is recommended, along with considering supplementation if necessary:

• Dietary Sources of Vitamin B6: Rich sources of Vitamin B6 include poultry like chicken and turkey, fish such as salmon and tuna, and leafy green vegetables, bananas, and chickpeas. These foods can help maintain adequate levels of Vitamin B6, supporting the production of neurotransmitters and overall brain health.
• Dietary Sources of Biotin: Biotin can be found in a wide range of foods, such as organ meats (especially liver), egg yolks, nuts like almonds and peanuts, soybeans, whole grains, and mushrooms. Regular consumption of these foods can help maintain healthy biotin levels.
• Supplementation: In cases where dietary intake might not be sufficient, or for individuals with increased nutritional needs, supplements can help maintain optimal levels of these vitamins. It's important to consult with a healthcare provider before starting any supplementation, especially since B vitamins are water-soluble and excess amounts are typically excreted in urine, although they can sometimes cause side effects at very high doses.

Additionally, lifestyle factors such as managing stress, ensuring adequate sleep, and regular physical activity can enhance the body’s ability to utilize these nutrients effectively, thereby supporting neurotransmitter synthesis and overall mental health.

Cognitive Disorders and Organic Acid Dysregulation

The Connection Between Organic Acid Imbalances and Cognitive Disorders Like Alzheimer’s

Organic acids play a role in cellular metabolism, including the brain's energy production and detoxification processes. Imbalances in these acids can indicate or contribute to metabolic disruptions that affect brain health. One clear example is the role of mitochondrial dysfunction in neurodegenerative diseases like Alzheimer's disease. Mitochondria, responsible for energy production, rely heavily on the proper functioning of the Krebs cycle, where several organic acids like citric acid, alpha-ketoglutarate, and malic acid are key components.

Disruptions in these cycles can lead to decreased energy production and increased oxidative stress—conditions often observed in Alzheimer's patients. Moreover, certain organic acids are directly neurotoxic if allowed to accumulate due to metabolic impairments, potentially contributing to the neuronal damage seen in cognitive disorders.

Furthermore, markers such as homocysteine, an amino acid processed in the methylation cycle, can accumulate when there are deficiencies in B vitamins (B6, B12, folate), leading to increased risk factors for Alzheimer’s disease. Elevated homocysteine levels are associated with greater neurotoxicity and higher incidences of vascular issues, which compromise blood flow to the brain and exacerbate cognitive decline.

The Role of Hormone Metabolites and Neurotransmitter Imbalances in Degenerative Brain Diseases

Hormone metabolites also play significant roles in brain health and function. For instance, cortisol, a steroid hormone produced in the adrenal glands, helps regulate metabolism, inflammation, and response to stress. However, prolonged elevated cortisol levels can lead to neuronal damage and are associated with memory loss and decreased cognitive function seen in Alzheimer’s and other forms of dementia.

Additionally, neurotransmitter imbalances are central to the pathology of degenerative brain diseases. For example, Alzheimer's disease is characterized not only by the hallmark amyloid plaques and tau protein tangles but also by a significant decrease in acetylcholine, a neurotransmitter important for learning and memory. This decrease is partly attributed to disrupted metabolic pathways influenced by organic acid imbalances.

Neurotransmitters like serotonin and dopamine are also affected in neurodegenerative diseases, contributing to the mood and behavioral symptoms often seen in these conditions. For example, Parkinson's disease involves the significant depletion of dopamine due to the degeneration of dopaminergic neurons in the brain, impacting both motor and cognitive functions.

Strategies for Addressing Organic Acid Dysregulation

To address these challenges, it’s necessary to ensure metabolic balance and support mitochondrial function through targeted nutrition, supplementation, and lifestyle changes. Diets rich in antioxidants, essential fats, and adequate proteins can support mitochondrial health and reduce oxidative stress. Supplements like Coenzyme Q10, alpha-lipoic acid, and N-acetyl cysteine may help improve mitochondrial function and overall metabolic health. Regular physical activity and strategies to manage stress levels can also significantly impact hormone balance and neurotransmitter production, supporting overall brain health and reducing the risk of cognitive decline.

Addressing Fatigue and Cognitive Decline

The Interplay Between Fatigue, Hormone Levels, and Cognitive Function

Fatigue, a common complaint in both clinical and everyday settings, is often more than just a symptom of poor sleep; it can be deeply intertwined with hormonal imbalances and cognitive decline. Hormones such as cortisol, thyroid hormones, and sex hormones (estrogen, progesterone, and testosterone) play significant roles in regulating energy levels, mood, and cognitive functions.

• Cortisol: Known as the "stress hormone," cortisol has a natural rhythm — high in the morning to promote wakefulness and declining throughout the day. Disruptions in this rhythm, whether due to stress, poor sleep, or adrenal dysfunction, can lead to persistent fatigue and reduced cognitive capabilities, such as decreased concentration and memory.
• Thyroid Hormones: These are imperative for metabolism regulation. Hypothyroidism, or low thyroid hormone levels, can manifest as fatigue, sluggishness, and cognitive slowing, severely impacting daily functioning.
• Sex Hormones: Estrogen and testosterone influence energy levels and brain function. Estrogen enhances serotonin and norepinephrine, impacting mood and cognitive functions, while testosterone levels are associated with energy and motivation. Imbalances in these hormones can lead to fatigue and cognitive fog.

Moreover, neurotransmitter imbalances also play a role in the perception of fatigue. For example, low levels of dopamine can reduce motivation and drive, whereas imbalances in serotonin can affect sleep patterns and mood, contributing to fatigue.

Practical Tips for Managing Fatigue Through Hormonal and Neurotransmitter Balance

Addressing fatigue and preventing cognitive decline require a multifaceted approach. Here are some practical strategies:

1. Regular Sleep Patterns: Ensuring consistent and quality sleep helps regulate cortisol and supports overall hormonal balance, which is crucial for reducing fatigue and maintaining cognitive functions.
2. Balanced Diet: A diet rich in antioxidants, proteins, and essential fatty acids supports neurotransmitter and hormone production. Foods high in B vitamins (like leafy greens and whole grains) and omega-3 fatty acids (such as fish and flaxseeds) can enhance energy levels and cognitive health.
3. Physical Activity: Regular exercise boosts endorphin levels, which can help combat fatigue. It also stimulates the production of more neurotransmitters, such as dopamine and serotonin, which improve mood and energy levels.
4. Stress Management: Techniques such as mindfulness, yoga, or even simple breathing exercises can reduce cortisol levels and improve both mental and physical health.
5. Supplementation: Supplements such as Vitamin D, magnesium, and adaptogenic herbs like ashwagandha can support hormonal balance and neurotransmitter functions. It's important to consult with a healthcare provider before starting any new supplement regimen.
6. Hydration: Adequate hydration is vital for maintaining the efficiency of metabolic processes and the transport of hormones and nutrients within the body.
7. Medical Evaluation: For persistent fatigue, a thorough evaluation by a healthcare provider can determine if underlying issues such as adrenal dysfunction or hypothyroidism are contributing factors. Approaches like DUTCH testing can be particularly insightful for understanding hormones and their metabolites.

Take Charge of Brain Health Through Testing

As we navigate the complexities of brain health and the intricate biochemical interactions that support it, the importance of personalized health assessments becomes undeniable. Understanding your unique metabolic, hormonal, and neurotransmitter profiles is not just about identifying problems—it's about forging pathways to optimal health and wellness.

Tools like the DUTCH test, which provides detailed insights into sex and adrenal hormones, their metabolites, and organic acids, offer more than just data; they offer a blueprint for health interventions that are as unique as you are. These tests can reveal imbalances that may not yet manifest as symptoms but could be silently impacting your cognitive function and overall well-being.

By testing, you empower yourself not only to understand the current state of your health but also to take effective, personalized actions that enhance your brain function and overall vitality. Don't wait for symptoms to dictate your health strategy. Be proactive and take control of your health journey today!

If you want to learn more about this topic, watch Christina O'Brien's webinar on The Science of Cognition!

Become a DUTCH Provider to learn more about how comprehensive adrenal and sex hormone testing can help you create informed patient treatment plans.

References

Garvey MJ, Noyes R Jr, Woodman C, Laukes C. Relationship of generalized anxiety symptoms to urinary 5-hydroxyindoleacetic acid and vanillylmandelic acid. Psychiatry Res. 1995 Jun 29;57(1):1-5. doi: 10.1016/0165-1781(94)02510-p. PMID: 7568554.

Arias-Carrión O, Stamelou M, Murillo-Rodríguez E, Menéndez-González M, Pöppel E. Dopaminergic reward system: a short integrative review. Int Arch Med. 2010 Oct 6;3:24. doi: 10.1186/1755-7682-3-24. PMID: 20925949; PMCID: PMC2958859.

Ko JH, Strafella AP. Dopaminergic neurotransmission in the human brain: new lessons from perturbation and imaging. Neuroscientist. 2012 Apr;18(2):149-68. doi: 10.1177/1073858411401413. Epub 2011 May 2. PMID: 21536838; PMCID: PMC3479149.

Marsden CA. Dopamine: the rewarding years. Br J Pharmacol. 2006 Jan;147 Suppl 1(Suppl 1):S136-44. doi: 10.1038/sj.bjp.0706473. Erratum in: Br J Pharmacol. 2021 Dec;178(23):4772. PMID: 16402097; PMCID: PMC1760752.

Kałuzna-Czaplińska J, Socha E, Rynkowski J. Determination of homovanillic acid and vanillylmandelic acid in urine of autistic children by gas chromatography/mass spectrometry. Med Sci Monit. 2010 Sep;16(9):CR445-50. PMID: 20802418.

Gutierrez L, Folch A, Rojas M, Cantero JL, Atienza M, Folch J, Camins A, Ruiz A, Papandreou C, Bulló M. Effects of Nutrition on Cognitive Function in Adults with or without Cognitive Impairment: A Systematic Review of Randomized Controlled Clinical Trials. Nutrients. 2021 Oct 22;13(11):3728. doi: 10.3390/nu13113728. PMID: 34835984; PMCID: PMC8621754.