Translational Medicine Friday

Keto diet, Mental Illness, Metabolic Disregulation and Microglia

11/20/2024

The Metabolic Mind folks have gone to great lengths to provide a nuanced view of Keto and in fact recommending "Medical Keto."

That is important because "Keto" can be an extremely unhealthy diet.

Unfortunately, "Medical Keto" is not available to most people with mental illness --- something the Metabolic Mind folks are aware of.

One of the things that really helped me understand what one of the benefits of Keto was involved Microglia.

I would love to have access to Medical Keto.

On the other hand, human beings have been trying to use Highly Prescriptive Diets for EONS to manage their physical and mental health.

For people on the Neuro-Developmental/Psychiatric Continuum ---- we're really talking about "DEVELOPMENTAL HEALTH."

Further, "Metabolic Dysregulation" can be another feature of Maternal Immune Activation.

Theoretically "Medical Keto" could be a safe option for people to access. I'm a big proponent of that.

On the other hand, I'm also greatly interested in the development of treatments that more directly address dysregulated microglia than KETO.

But repair and replacement of Microglia may be down the road and researved for the most serious brain injuries at least initially.

Metabolic Mind
Who should use Keto for Mental Illness?

Dysregulation of immune and metabolism pathways in maternal immune activation induces an increased risk of autism spectrum disorders (2023)

Ketone body β-hydroxybutyrate (BHB) preserves mitochondrial bioenergetics (2023)

The ketone body β-hydroxybutyrate shifts microglial metabolism and suppresses amyloid-β oligomer-induced inflammation in human microglia (2023)

In Born errors in Metabolism

10/20/2024

Val's Take/Conjecture

We tend to have a view that traits are either the result of GENETICS or LIFESTYLE CHOICES.
That is a FALSE DICHOTOMY.
Many Neuro-Divergent People are evidence that PRE-NATAL INFLAMMATION as well as other factors can have dramatic influence over the life course.
Further, our researchers are doing the heavy lifting of understanding multiple systems of the body and the "CROSSTALK" between those systems of the body that are relevant to our most difficult chronic diseases.
- This includes the Neurodevelopmental/Psychiatric Continuum, but it also includes:
- Autoimmune Diseases
- Cancer,
- Neuro-Degenerative Diseases,
- Etc.

Dysregulation of immune and metabolism pathways in maternal immune activation induces an increased risk of autism spectrum disorders (2023)

An overview of inborn errors of metabolism affecting the brain: from neurodevelopment to neurodegenerative disorders (2018)

Microglia and lipids: how metabolism controls brain innate immunity (2021)

In the last years, single-cell analyses have revealed that microglia exhibit diverse phenotypes during development, growth and disease. Emerging evidence suggests that such phenotype transitions are mediated by reprogramming of cell metabolism. Indeed, metabolic …

Pro-Inflammatory Cytokines

10/16/2024

and the Neuro-developmental/Psychiatric continuum and other chronic diseases

Val's Take/Conjecture

The Neuro-Developmental/Psychiatric Continuum is starting to look like other illnesses in which INFLAMMATION is a big key.
The effects of INFLAMMATION IN UTERO may be important for other illnesses, it is certainly important for the Neuro-Developmental/Psychiatric Continuum.
According to the University of Michigan Medical School, people with bipolar disorder have more reactive cells.
- Does that mean, more reactive cells that are producing more pro-inflammatory cytokines?
  - I think it probably does mean that.

Cytokine Imbalance in Schizophrenia. From Research to Clinic: Potential Implications for Treatment (2021)

Gene polymorphisms of several cytokines are associated with the development of the schizophrenia syndrome. In patients with schizophrenia, presence of gene polymorphisms of proinflammatory cytokines, such as IL-1β and IL-6, have been linked to high serum levels of these cytokines.

Inflammation in Bipolar Disorder (2018)

Elevated levels of pro-inflammatory cytokines

Bipolar disorder (BD) is a severe and persistent mental illness associated with increased rates of several inflammatory medical comorbidities. Replicated evidence has demonstrated a strong association between BD and elevated levels of pro-inflammatory cytokines.

Inflammatory Cytokine: An Attractive Target for Cancer Treatment (2022)

"The pro-inflammatory cytokines are associated with advanced cancer stages, resistance to immunotherapy, and poor prognoses, such as in objective response and disease control rates, and progression-free and overall survival.

"In this review, we selected colorectal, pancreatic, breast, gastric, lung, and prostate cancers, which are well-reported for an association between cancer and inflammatory cytokines."

"The related cytokines and their effects on each cancer’s development and prognosis were summarized.

In addition, the treatment strategies targeting inflammatory cytokines in each carcinoma were also described here. By understanding the biological roles of cancer-related inflammatory cytokines, we may modulate the inflammatory tumor microenvironment for potential cancer treatment.

The causal relationship between 41 inflammatory cytokines and hypothyroidism: bidirectional two-sample Mendelian randomization study (2023)

"The high rate of comorbidity between hypothyroidism and psychiatric disorders deserves special attention, indicating the importance of consistent monitoring and timely identification of psychiatric symptoms to prevent disease exacerbation and facilitate therapeutic management."

Role of pro-inflammatory cytokines released from microglia in neurodegenerative diseases (2011)

Microglia are activated in response to a number of different pathological states within the CNS including injury, ischemia, and infection.
Microglial activation results in their production of pro-inflammatory cytokines such as IL-1, IL-6, and TNF-α

Maternal immune activation alters fetal and neonatal microglia phenotype and disrupts neurogenesis in mice

Maternal immune activation (MIA) alters microglial phenotypes in the brain of fetal and neonatal mouse offspring. MIA leads to excessive proliferation and overproduction of neural progenitors in the subventricular zone (SVZ). MIA reduces parvalbumin+ while increases Reelin+ interneurons in the prefrontal cortex.

Maternal immune activation and neuroinflammation in human neurodevelopmental disorders (2021)

Abstract

"Maternal health during pregnancy plays a major role in shaping health and disease risks in the offspring.

"The maternal immune activation hypothesis proposes that inflammatory perturbations in utero can affect fetal neurodevelopment, and evidence from human epidemiological studies supports an association between maternal inflammation during pregnancy and offspring neurodevelopmental disorders (NDDs).

"Diverse maternal inflammatory factors, including obesity, asthma, autoimmune disease, infection and psychosocial stress, are associated with an increased risk of NDDs in the offspring.

"In addition to inflammation, epigenetic factors are increasingly recognized to operate at the gene-environment interface during NDD pathogenesis.

"For example, integrated brain transcriptome and epigenetic analyses of individuals with NDDs demonstrate convergent dysregulated immune pathways.

"In this Review, we focus on the emerging human evidence for an association between maternal immune activation and childhood NDDs, including autism spectrum disorder, attention-deficit/hyperactivity disorder and Tourette syndrome.

"We refer to established pathophysiological concepts in animal models, including immune signalling across the placenta, epigenetic 'priming' of offspring microglia and postnatal immune-brain crosstalk.

"The increasing incidence of NDDs has created an urgent need to mitigate the risk and severity of these conditions through both preventive strategies in pregnancy and novel postnatal therapies targeting disease mechanisms."

Microglia and aging: Maternal Immune Activation & Premature aging

10/13/2024

Val's Take/Conjecture

Ignorance is one of the most anxiety producing states, especially when the stakes are high.
In 2013, the National Institute of Mental Health found that ADHD, Autism, Bipolar Disorder, Depression and Schizopheria were not distinct, and were blurred --- sharing common genes and mechanisms such as calcium channels.

National Institute of Mental Health
Five Mental Disorders Share Some of the Same Genes

Neuro-diversity and "Neuronal Hyper-excitability"

10/8/2024

Val's Take/Conjecture

One of the things that has happened in the last 15 years or so ---- we view these Neuro-Developmental and Psychiatrictric Disorders as much more blurred and having common mechanism.

We are also seeing the common mechanisms among:

Neuro-Developmental and Psychiatric Disorders
Autoimmune Disorders such as Multiple Sclerosis
- "Genome-wide association studies reveal shared genetic haplotypes of autoimmune rheumatic and endocrine diseases with psychiatric disorders."
Endocrine Disorders
- "Most endocrine disorders are associated with psychological disturbances, and, conversely, psychiatric entities induce changes in hormonal activity, as is the case for adrenal and thyroid hormones."
Metabolic Disorders such as Diabetes
- "Dysregulation of immune and metabolism pathways in maternal immune activation induces an increased risk of autism spectrum disorders"
Neuro-Degenerative Disorders such as Parkinson's and Alzheimers
- Pathophysiological Role of Neuroinflammation in Neurodegenerative Diseases and Psychiatric Disorders
Cancer
- Mental Health America and Cancer

Deletion of TRPC6, an Autism Risk Gene, Induces Hyperexcitability in Cortical Neurons Derived from Human Pluripotent Stem Cells. (2023)

"ASD often co-occurs with attention-deficit hyperactivity disorder and epilepsy, which are associated with hyperexcitability of neurons.

"...Our data provide evidence that reduction of SOCE by TRPC6 KO results in neuronal hyperexc …"

Bright, but allergic and neurotic? A critical investigation of the "overexcitable genius" hypothesis. (2022)

"Individuals at the upmost end of the intelligence distribution are reported to be disproportionately afflicted by a set of stress-related physical and mental health conditions: so-called overexcitabilities.

"Few accounts have investigated this issue and no studies are avail …"

Potential of GABA-ergic cell therapy for schizophrenia, neuropathic pain, and Alzheimer's and Parkinson's diseases. (2016)

"Several neurological and psychiatric disorders present hyperexcitability of neurons in specific regions of the brain or spinal cord, partly because of some loss and/or dysfunction of gamma-amino butyric acid positive (GABA-ergic) inhibitory interneurons."

Intergenerational Metabolic Syndrome and Neuronal Network Hyperexcitability in Autism. (2019)

"Maternal insulin resistance, obesity, and diabetes may predispose offspring to ASD by mechanisms involving chronic activation of anabolic cellular pathways and a lack of metabolic switching to ketosis resulting in a deficit in GABAergic signaling and neuronal network hy …"

Disruption of the Na(+)/K(+)-ATPase-purinergic P2X7 receptor complex in microglia promotes stress-induced anxiety. (2024)

"Accordingly, global deletion or conditional deletion of NKAalpha1 in microglia under chronic stress-induced aggravated anxiety-like behavior and neuronal hyperexcitability.

"DR5-12D, a monoclonal antibody that stabilizes membrane NKAalpha1, improved stress-ind …"

Rod-shaped microglia interact with neuronal dendrites to regulate cortical excitability in TDP-43 related neurodegeneration. (Preprint, July 2024)

"Notably, rod-shaped microglia predominantly interact with neuronal dendrites and excitatory synaptic inputs to attenuate motor cortical hyperactivity.

"The elimination of rod-shaped microglia through TREM2 deficiency increased neuronal hyperactivity, ex …"

Researchers are targeting Pro-Inflammatory Microglia ---including wholesale replacement

9/29/2024

Val's Take/Conjecture

One of the many challenging issues with regard to Neuro-Developmental and Psychiatric Disorders:
- Such disorders are often the result of Maternal Immune Activation in utero --- affecting:
  - The Central Nervous System
  - The Immune System
  - The Endocrine System, and
  - The Microbiome
  - in highly individual and idiosyncratic ways
Recognizing the importance of the Immune System and other systems in the body in Neuro-Developmental and Psychiatric Disorders both heightens the seriousness of these disorders, while also playing a role in "DE-PERSONALIZING ILLNESS."

Engineering an inhibitor-resistant human CSF1R variant for microglia replacement. (2023)

"To mitigate the risks of HSCT and expand the potential for microglia replacement, we engineered an inhibitor-resistant CSF1R that enables robust microglia replacement. ...In sum, we engineered a human CSF1R variant that enables nontoxic, cell type, and …"

Efficient Strategies for Microglia Replacement in the Central Nervous System (2020).

Microglia replacement by nonself cells has been proposed to treat microglia-associated disorders. ...In this study, we develop three efficient strategies for microglia replacement: microglia replacement by bone marrow transplantati …

Treatment of a genetic brain disease by CNS-wide microglia replacement. (2022)

"Here, we developed and characterized a near-complete and homogeneous replacement of microglia with bone marrow cells in mice without the need for genetic manipulation of donor or host. ...This proof-of-concept study suggests that efficient microglia replac …"

Microglia: Agents of the CNS [Central Nervous System] Pro-Inflammatory Response. (2020)

"The pro-inflammatory immune response driven by microglia is a key contributor to the pathogenesis of several neurodegenerative diseases. ...Finally, we also discuss current thoughts on the impact of pro-inflammatory microglia in neurodege …"

Targeting microglia-oligodendrocyte crosstalk in neurodegenerative and psychiatric disorders. (2022)

"Therefore, an important challenge to studying complex brain diseases is to interrogate relevant interactions between cell types. The microglia-oligodendroglia interaction is an important example that has fundamental roles in physiological state and brain pathologies. Here, …"

Allogenic microglia replacement: A novel therapeutic strategy for neurological disorders. (2023)

Microglia replacement is a novel approach to correct microglial genetic defects via replacing microglia of genetic defects with allogenic healthy microglia. In this paper, we systematically review the history, rationale and therapeutic perspecti …

Noteworthy perspectives on microglia in neuropsychiatric disorders. (2023)

"Microglia have a profound impact on neuronal survival, brain wiring and synaptic plasticity. ...In this review, we summarized the latest discoveries regarding microglial ontogeny, cell subtypes or state spectrum, biological functions and mechanistic underpinnings of emotional and behavioral disorders."

La, La, La, La, La . . .A Modern Psychiatry that's been "Partially Discredited" andCriminal Justice

9/19/2024

Val's Take

This is not a hashed over Dr. Thomas Szasz of the 1960s and '70s--- saying there's no such thing as "mental illness."

It's more saying there is a biological basis for neuro-developmental and psychiatric disorders and some of our understandings are being abandoned for new understandings based on more recent research and better technology.

On the other hand, current research is calling into question the DSM Categories and finding them inaccurate, albeit on different grounds than Szasz.

How likely is it that MAJOR PARADIGM SHIFTS could happen in our understandings of Neuro-Developmental & Psychiatric Disorders and it not effect Criminal Justice?
Not likely

Immunological perturbations, psychiatric disorders and associated therapeutics: a new era for psychiatry? (2023)

Abstract

The three main theories explaining major mental illness, namely mood disorders, psychoses and dementias, have been partially discredited.

Alongside this, there are emerging links between perturbations of the immune system and the onset and phenotypic features of these disorders.

This article outlines the alternative pathophysiology and suggests potential treatments which could improve disease burden and avoid the need for psychotropic medication, with their associated side effects and relapse following withdrawal.

Dr. Thomas Szasz

Szasz argued throughout his career that mental illness is a metaphor for human problems in living, and that mental illnesses are not "illnesses" in the sense that physical illnesses are, and that except for a few identifiable brain diseases, there are "neither biological or chemical tests nor biopsy or necropsy findings for verifying DSM diagnoses."

-----Wikipedia

University of Michigan found that people with bipolar disorder have more "reactive cells" that ultimately have a life of their own.

This "inflamm--aging" process appears to begin in many cases in utero.

Further, understanding "neuro-developmental" and "psychiatric" disorders could be seen as the study of Humanity over many generations.

Immunophenotypes in psychosis: is it a premature inflamm-aging disorder? (2024)

Maternal Immune Activation -- changing concepts of Neuro-Developmental & Psychiatric Disorders as complex trans-generational immune disorders

9/14/2024

Val's Take/Conjecture

"Maternal Immune Activation" is a common term in the research regarding neuro-developmental and psychiatric disorders----

It's not a common term in public discussions about neuro-developmental & psychiatric disorders
Probably most people are not so interested in personally knowing the specifics ---
- But they want to know that those specifics exist and they are grounded in valid research.

Beyond understanding "Maternal Immune Activation" we also need to understand the consequences of "Transgenerational Effects of Maternal Immune Activation" involving "complex patterns of generation-spanning transmission beyond genetic inheritance."

Further, there are several sources and combinations of sources of "Inflammation" to ignite "Maternal Immune Activation"

The "Exposome" is conceptualized as the measure of all the exposures of an individual in a lifetime and how they relate to health --- CDC
At this point, we can see why there is such diversity in neuro-developmental and psychiatric disorders and why there is such a need for Individualized Precision Medicine.

Additionally, "Maternal Immune Activation" is affecting Microglia (the immune cells of the brain and central nervous system) and cells throughout the body.

At the crux of maternal immune activation: Viruses, microglia, microbes, and IL-17A (2022)

Inflammation during prenatal development can be detrimental to neurodevelopmental processes, increasing the risk of neuropsychiatric disorders.

Prenatal exposure to maternal viral infection during pregnancy is a leading environmental risk factor for manifestation of these disorders.

Question: Are viruses the leading environmental risk factor for subsequent generations?or other sources of "inflammation" --- ?

Sex-Specific Behavioral and Molecular Responses

to Maternal Lipopolysaccharide-Induced Immune Activation in a Murine Model: Implications for Neurodevelopmental Disorders

September 13, 2024

Maternal Immune Activation

***Physical Health Issues, the Immune System & Mental Health

The Trans-Generational Effects of Maternal Immune Activation

9/13/2024

Late prenatal immune activation in mice induces transgenerational effects via the maternal and paternal lineages (2023)

Together, our results suggest that MIA [Maternal Immune Activation] in late pregnancy has the potential to affect cognitive functions and prefrontal gene expression patterns in multiple generations, highlighting its role in shaping disease risk across generations.

Transgenerational consequences of maternal immune activation (2020)

Abstract

Prenatal exposure to infectious or inflammatory insults is increasingly recognized in the etiology of neuropsychiatric diseases, including schizophrenia, autism, depression and bipolar disorder.

New discoveries highlight that maternal immune activation can lead to pathological effects on brain and behavior in multiple generations.

This review describes the transgenerational consequences of maternal immune activation in shaping brain and behavior anomalies and disease risk across generations.

We discuss potential underlying mechanisms of transmission, by which prenatal immune activation can mediate generation-spanning changes in brain development and functions and how external influences could further determine the specificity of the phenotype across generations.

The identification of the underlying mechanisms appears relevant to infection-related neuropsychiatric illnesses independently of existing diagnostic classifications and may help identifying complex patterns of generation-spanning transmission beyond genetic inheritance.

The herein described principles emphasize the importance of considering ancestral infectious histories in clinical research aiming at developing new preventive treatment strategies against infection-related neurodevelopmental disorders and mental illnesses.

Translational ImmunoPsychiatry Unit (TIU) --- U.S. National Institute of Mental Health

9/13/2024

Christopher M Bartley, M.D., Ph.D.
Chief

Translational Immunopsychiatry Unit (TIU)
US National Institute of Mental Health

Research Topics

The Translational Immunopsychiatry Unit (TIU) studies immune processes that contribute to neuropsychiatric illness.he TIU is interested particularly in identifying autoimmune B and T cell reactivities that cause behavioral pathology.

One aim of the lab is to identify rare psychiatric subgroups whose illness is defined by an antigen-specific autoimmune response—thereby helping to parse the staggering heterogeneity of psychiatric illness.

A second aim is to develop technologies that demarcate cells and circuits that are vulnerable to autoimmune responses in the human central nervous system.

A third focus of the TIU is, in collaboration, to study the pathobiological consequences of immune-antigen interactions at different levels of analysis: structure and biochemistry, neurophysiology, and behavior.

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