Brain fog in long COVID - A glutamatergic hypothesis with astrocyte dysfunction accounting for brain PET glucose hypometabolism

For a detailed read, please refer to the article on ScienceDirect: Brain fog in long COVID.

Summary

This article presents a hypothesis regarding the occurrence of brain fog in long COVID patients, suggesting it may be due to astrocyte dysfunction and resulting glutamatergic dysregulation. The authors propose that brain 18F-FDG-PET scans show a glucose hypometabolic pattern in these patients, reflecting impaired astrocyte activity.

Astrocytes, critical for energy metabolism and glutamatergic neurotransmission, may undergo changes due to neuroinflammation, impacting glutamate regulation. This could lead to cognitive fatigue and brain fog, similar to other clinical situations.

Therapeutics targeting astrocytic glutamate regulation could potentially mitigate these neurological manifestations in long COVID.

Treatments

The treatments suggested in the article for addressing brain fog in long COVID focus on targeting astrocyte function and glutamatergic neurotransmission. These include:

α2A-adrenoceptor agonist guanfacine and N-acetylcysteine (NAC), which are under investigation for their potential to improve cognitive function.
Memantine, an NMDA channel blocker, which might help mitigate the detrimental effects of impaired astrocytic glutamate uptake.
β-lactam antibiotics like ceftriaxone, known to promote the expression of glutamate transporters and enhance glutamate uptake by astrocytes.
Metformin, which stimulates glycolysis and lactate production in astrocytes.

Treatments Explained

The treatments suggested aim to address the hypothesized astrocyte dysfunction and glutamatergic dysregulation in long COVID:

Guanfacine and N-acetylcysteine (NAC): Guanfacine may reduce deleterious potassium-mediated channel signaling in neurons, enhancing neuronal firing. NAC could reduce oxidative stress associated with excessive NMDA receptor activation.
Memantine: As an NMDA channel blocker, memantine may help reduce glutamate-induced prolonged calcium influx in neurons, addressing excitotoxicity.
β-Lactam antibiotics (e.g., Ceftriaxone): These enhance glutamate uptake by astrocytes, potentially improving glutamatergic neurotransmission.
Metformin: Known to stimulate glycolysis and lactate production in astrocytes, metformin may support energy metabolism in the brain.

By targeting these mechanisms, the treatments could potentially alleviate cognitive fatigue and brain fog in long COVID patients.

If a patient with hypometabolism associated with long COVID takes a combination of guanfacine, N-acetylcysteine (NAC), memantine, β-lactam antibiotics, and metformin simultaneously, the theoretical hypothesis would be that this regimen could address multiple aspects of the underlying pathology. The combination aims to:

Modulate glutamatergic neurotransmission (through NAC and memantine).
Enhance neuroprotection and reduce oxidative stress.
Improve astrocytic function and glutamate uptake (β-lactam antibiotics).
Stabilize metabolic processes in the brain (metformin).

This could potentially result in an improvement in cognitive symptoms and overall brain function. However, it's important to note that this is a hypothetical scenario and actual outcomes would depend on individual patient responses, the severity of their condition, and careful monitoring for drug interactions and side effects. Clinical trials or robust clinical data would be necessary to validate such a treatment approach.

Note: β-lactam antibiotics, such as ceftriaxone, can have an impact on gut health. Like many antibiotics, they can disrupt the normal gut microbiota, potentially leading to issues such as antibiotic-associated diarrhea. This disruption occurs because antibiotics can kill beneficial gut bacteria along with the harmful bacteria they target. The extent of gut disturbance varies depending on the specific antibiotic, dosage, and individual patient factors. It's important to monitor gastrointestinal symptoms when taking these medications and consider probiotic supplementation or dietary adjustments as necessary. Always consult with a healthcare provider for personalized advice and management strategies.

Additional Treatments for Brain Hypometabolism

Overview

This note compiles various treatment approaches for brain hypometabolism in the context of long COVID, epilepsy, and Alzheimer's Disease. It's important to consult healthcare professionals before starting any treatment.

Treatments for Specific Conditions

Alzheimer's Disease

Cholinesterase Inhibitors: Donepezil, Rivastigmine, Galantamine.
NMDA Antagonist: Memantine.

Epilepsy

Antiseizure Medications: Brivaracetam, Cannabidiol, Cenobamate, Everolimus, Fenfluramine.
Read more here

Dietary Approaches

Ketogenic Diet: Beneficial for epilepsy management.
High-Fat, Low-Carbohydrate Diets: Can sometimes improve brain function.

Supplements

Antioxidants

N-Acetylcysteine (NAC): 600 mg to 1,800 mg/day.
Vitamin C: 500 mg to 1,000 mg/day.
Vitamin E: 100 IU to 400 IU/day.

Neuroprotective Supplements

Omega-3 Fatty Acids (Fish Oil): 1,000 mg to 2,000 mg/day.
Coenzyme Q10: 100 mg to 200 mg/day.
Curcumin: 500 mg to 1,000 mg/day.
Creatine: Aids in energy production.
B Vitamins: Essential for brain health and energy metabolism.

Lifestyle Changes

Regular Physical Exercise: Enhances overall brain function.
Cognitive Rehabilitation: Useful for Alzheimer's and post-brain injury.

Experimental Therapies

Ongoing research in gene therapy and novel drug development.

Treatment of Underlying Conditions

Managing conditions like diabetes, hypertension, etc., which can affect brain metabolism.

Specialized Approaches

Astrocyte-Neuron Lactate Shuttle (ANLS) Targeting: Focusing on lactate metabolism in epilepsy.
Read more here