Hi Taylor,

Welcome to the newest edition of the Brainstorm! As a nonprofit organization that focuses on more than 30 different complex chronic conditions, we're no strangers to big challenges. One of those challenges is crafting a newsletter with relevant insights for patients, caregivers, and healthcare professionals from all walks of life, living with, treating, or studying these chronic conditions. From Long COVID and Crohn's disease to Ehlers-Danlos syndrome and multiple sclerosis, we venture to keep everyone up-to-date.

In that spirit, we're particularly excited about this action-packed issue, which offers a little something for everyone—from concise breakdowns of breakthrough research advancing our focus areas, to an exclusive interview with a leading MCAS physician-scientist, Dr. Lawrence Afrin.

But first, let's kick things off with our featured article: a fresh clue into what might be driving brain fog in Long COVID patients.

Let's dive in.

New Insights Into the Driver of Long COVID Brain Fog

Researchers from Japan published a new paper identifying a piece of the Long COVID brain fog (cognitive dysfunction) puzzle. This study is important because it is one of the first to identify unusually high levels of a molecule that directly regulates neuron function: the AMPA receptor. 

Before we discuss the findings of this paper and explain what the AMPA receptor is and why too much might be the culprit of Long COVID brain fog, let’s briefly review some of the previously reported hallmarks of Long COVID cognitive dysfunction (Cog-LC) so we can appreciate why this study is different.

Below is a table summarizing how the brain’s physiology changes in Long COVID patients suffering from cognitive dysfunction. Briefly, Cog-LC is characterized by a reduction in brain mass, blood flow, metabolism, and neural connectivity, as well as an increase in neuroinflammation. While these factors indirectly reduce neuronal function, there has yet to be a dysregulated factor that directly reduces neuronal function in those with brain fog (until now).

AMPA Receptor Function

AMPA receptors (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors) are glutamate receptors critical for fast excitatory synaptic transmission in the brain. They mediate rapid signal propagation between neurons, playing essential roles in learning, memory formation, and overall cognitive processing.

When AMPAR density increases excessively, the neurons can become too excited, leading to a destructive process called excitotoxicity. In essence, the brain's "accelerator" gets stuck, flooding neurons with signals they can't handle, which damages them over time. 

As we mentioned, the density of these receptors is significantly increased in 30 Long COVID patients with known cognitive dysfunction (Cog-LC) compared to 80 healthy controls. Let’s take a closer look at their results.

The Methods and Results

An imaging technique called positron emission tomography (PET) was used to visualize the binding of [¹¹C]K-2, a radiolabeled tracer, to AMPA receptors in living human brains. Here's how it works: The [¹¹C]K-2 tracer is injected intravenously and rapidly crosses the blood-brain barrier (BBB) (into the brain). From here, the [¹¹C]K-2 tracer binds to cell-surface AMPA receptors (multimers) on postsynaptic neurons, concentrating the tracer in AMPAR-rich regions. 

The ¹¹C radioisotope (with a half-life of ~20 minutes) produces a positively charged positron, which collides with a nearby electron. This collision produces a gamma ray that is detected by the PET scanner. The signal intensity, or the number of gamma rays, is proportional to the concentration of bound tracer, and thus to AMPA receptor density. This enabled the researchers to measure relative AMPA receptor density across different brain regions in real time (image below).

Not only was the density of AMPA receptors significantly elevated in the brain of those with Cog-LC, but this elevation positively correlated with the levels of a proinflammatory cytokine, tumor necrosis factor alpha superfamily member 12 (TNFSF12), in the blood. This suggests that the elevation of AMPA receptors might be at least partially attributed to inflammation, yet more studies are needed to identify correlation vs causation.

PET Scanning, A Cognitive Dysfunction Diagnostic Tool?

The researchers argue that [¹¹C]K-2 PET imaging represents a major leap toward objective diagnosis of Cog-LC, achieving 100% sensitivity and 91% specificity in differentiating affected patients from healthy controls. However, there are many reasons why this likely won’t be used as a diagnostic tool in a clinic near you anytime soon. 

First, this is a high-cost scan that would not be covered by your health insurance, as it is not an FDA-approved method for diagnosing Long COVID cognitive dysfunction. Secondly, PET scanners are usually confined to research centers, not clinics. Thirdly, diagnosing cognitive dysfunction generally does not require sophisticated imaging modalities, given its clinical presentation.

However, there is a lot we do not know about the variability in clinical presentation of Long COVID cognitive dysfunction in children, adolescents, and adults. That’s why we will soon be launching the Brain Fog Questionnaire inside the unhide®/Solve Together Project. Keep an eye out for an announcement email in your inbox and learn how you can participate in the study. Back to the study.

Brain Fog Drug Candidate

This discovery opens the door to repurposing existing AMPAR antagonists, such as perampanel (brand name Fycompa), as a targeted therapy for cognitive dysfunction (Cog-LC). Perampanel is an orally available, AMPA receptor blocker already approved to treat epilepsy, where it selectively blocks excessive glutamate-mediated excitation without broadly impairing normal synaptic transmission. However, clinical trials are needed to identify if there is a potential clinical benefit.

Concluding Thoughts

These findings suggest Long COVID brain fog could partially be attributed to excessive AMPA receptor signaling on neurons. However, there are clear limitations to this study. For instance, the Cog-LC cohort consisted exclusively of asian participants in Japan. It’s unknown if the results apply to other ethnic groups around the world.

Although high AMPA receptor density is correlated with the symptoms of Cog-LC, it’s unknown if it is causing those symptoms. Therefore, the clinical significance of this finding won't be known until clinical trials can restore AMAP receptor signaling using a drug such as perampanel. However, with Long COVID impacting ~400 million globally, this could accelerate personalized treatments for Long COVID cognitive dysfunction.

Unraveling MCAS: A Deep Dive with Dr. Larry Afrin

We recently had the privilege of interviewing hematologist-oncologist Dr. Larry Afrin, a globally recognized physician-scientist and leading authority on mast cell disorders. In addition to managing a busy clinical practice, Dr. Afrin has authored numerous high-impact research publications on Mast Cell Activation Syndrome (MCAS). This conversation offered a rare opportunity to explore the current landscape of MCAS research while gaining invaluable insights into its future trajectory from his distinctive vantage point.

One of the interview's most eye-opening insights was the profound ubiquity of mast cells in human health and disease—a far cry from the limited view often taught in medical training, which confines their role primarily to allergic responses. 

Even if you do not have an MCAS diagnosis, you may find the discussion enlightening, as subtle mast cell dysregulation could underlie various symptoms or comorbidities in a subset of people. Inside our latest blog post, you will learn:

• The essential functions of mast cells 

• Their strategic locations throughout the body

• The evolutionary basis for their remarkable functional diversity

• The inherent challenges in studying MCAS

• The frequent overlaps with conditions such as postural orthostatic tachycardia syndrome (POTS), hypermobile Ehlers-Danlos syndrome (hEDS), chronic fatigue syndrome, and fibromyalgia 

• The latest scientific understanding of MCAS's underlying causes

Brain Storm Briefs

Here are concise highlights from recently published scientific studies that we believe could reshape medical perspectives on conditions, drive innovations in diagnostics or treatments, or deliver broad tech breakthroughs to deepen our understanding of diseases. We'll kick things off with a promising biomarker for ME/CFS.

1. Scientists develop the first ‘accurate blood test’ to detect chronic fatigue syndrome

Medical Condition: Myalgic Encephalomyelitis (ME/CFS)

Breakthrough Diagnostic Tool: Scientists have claimed the world's first blood test for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), offering a simple and accurate method to confirm diagnoses, potentially revolutionizing early detection and management of the condition.

Mechanism and Performance: The test analyzes epigenetic markers reflecting changes in DNA accessibility over time (not DNA mutations). They identified a unique pattern in severe ME/CFS patients compared to healthy individuals, with impressive accuracy: 92% sensitivity and 98% specificity.

Limitations and Next Steps: Though promising, the test requires further validation through larger, independent studies to rule out overlaps with similar diseases and confirm reliability across early, mild, and long-term cases; if validated, it may become clinically available years down the road with a cost reported to be $1,300.

Read a summary of the research. 

Access the full study.

2. AI Scores Global First in Predicting Antibiotic Mechanism of Action

Medical Condition: Crohn’s Disease and Irritable Bowel Disease

Breakthrough in Drug Discovery: Researchers have achieved a claimed "global first" by using AI to not only identify potential drug candidates but to predict the precise mechanism of action for an investigational antibiotic, advancing it through the development pipeline far beyond traditional AI applications in drug exploration.

The Antibiotic Enterololin: This narrow-spectrum antibiotic targets adherent-invasive Escherichia coli (AIEC) linked to Crohn's disease and IBD; it's a Bub1 kinase inhibitor fused with a polymyxin B analog to disrupt Gram-negative bacterial membranes, showing potent activity against AIEC while sparing most beneficial gut flora to minimize gut dysbiosis (an imbalance in the gut microbiome).

Rapid Validation and Future Promise: AI tool identified the hypothesized inhibition mechanism in just 100 seconds—slashing lab confirmation from 18-24 months and $2 million to 6 months and $60,000—paving the way for clinical trials in three years and inspiring broader AI-driven advances in antibacterial development.

Read a summary of the research.

Access the full study.

3. KLK15 Emerges as Novel Gene in Hypermobile Ehlers-Danlos Syndrome

Medical Condition: hypermobile Ehlers-Danlos Syndrome (hEDS)

Breakthrough Genetic Discovery: Researchers have pinpointed the gene KLK15 as a novel disease gene for hypermobile Ehlers-Danlos Syndrome, a multisystem connective tissue disorder lacking a defined genetic basis. Methods: DNA sequencing of 200 patients uncovered rare variants in 14 kallikrein genes, with a recurrent KLK15 missense variant (p.Gly226Asp) segregating in a subset of families. This gene is expressed in key hEDS-relevant tissues like skin and tendons.

KLK15's Impact on the Structural Tissue Scaffold (aka Extracellular Matrix): As a secreted serine protease (an enzyme that can ‘cut’ macromolecules like proteins), KLK15 interacts with 10 extracellular matrix components, including fibronectin, part of connective tissue, and lysyl oxidase (LOX). The mutated version was found to disrupt collagen crosslinking and matrix stability essential for connective tissue integrity.

Mouse Model Recapitulates hEDS Pathology: Mice were given one copy of the mutant KLK15 gene. These mutant mice mirrored what is observed in hEDS patients, resulting in:

1. Elastic tendon defects (increased strain, 20% smaller collagen fibrils) 

2. Cardiac issues, like mitral valve prolapse, in 83% of genetic mutants 

3. Systemic immune dysregulation (reduced cytokine levels), reframing hEDS pathogenesis to include proteolytic and inflammatory drivers beyond collagen defects.

This genetic mutation was not found in all hEDS patients, underscoring the potential role of triggers beyond your genetics.

Access the full study

4. Novel Compounds Advance Remyelination Therapy for Multiple Sclerosis

Medical Condition: Multiple Sclerosis

MS Pathology and Unmet Need: Multiple sclerosis (MS), affecting over 2.9 million people worldwide, is a chronic autoimmune disease where the immune system attacks the myelin sheath that insulates nerve fibers. This disrupts nerve signals, causing permanent damage. Although anti-inflammatory treatments exist, no drugs have been identified to protect neurons by restoring the myelin sheath.

Breakthrough Discovery of K102 and K110: In a decade-long collaboration between UC Riverside and the University of Illinois Urbana-Champaign, screening over 60 analogs of a remyelination-promoting compound called indazole chloride. Results yielded two lead compounds, K102 and K110, which demonstrated superior safety, efficacy, and drug-like properties by significantly increasing mature oligodendrocytes and axon-wrapping processes (remyelination) in mouse models of disease and human cells.

Lead Potential and Future Pipeline: K102 emerged as the top candidate for its dual action in promoting remyelination and modulating immune function. These promising results restored nerve conduction and curbed disability; licensed to Cadenza Bio for non-clinical studies toward first-in-human trials. The other candidate, K110, shows more promise for CNS injuries like spinal cord trauma, with broader applications to stroke and neurodegeneration.

Read a summary of the research

Access the full study

Why We Do What We Do

Complex chronic conditions, including infection-associated chronic illnesses (e.g., Long COVID, ME/CFS, post-treatment Lyme disease syndrome), autoimmune disorders (e.g., lupus, autoimmune encephalitis), and neurodegenerative diseases (e.g., multiple sclerosis), share common hallmarks such as neuroinflammation, overlapping immunopathologies, overlapping symptoms and comorbidities, and treatment responses. For instance, many with Long COVID also have POTS or MCAS, while children and adolescents with PANDAS/PANS can also present with POTS, OCD, and eating disorders involving restrictive eating. The overlap between these conditions is staggering.  

That is why we are among the first non-profits to take a collaborative approach to research. Our mission is to complement the work of single-condition advocacy groups by fostering a collective research framework that spans 30+ related conditions. 

These conditions affect millions in the United States, yet no cures exist. You can help us change that. We are actively using our clinical health platform, unhide®, to not only help patients (children, adolescents, and adults) like you uncover hidden patterns in your health, but also to build a collaborative network of researchers with different clinical and scientific backgrounds needed to study these medical conditions with the all-encompassing approach it deserves. You can help by:

1. Download the MyDataHelps App and choose the unhide®/Solve Together Project, or directly set up an account. 

     >IPhone App Store Download

     >Google Play Store Download

2. Recruiting a healthy control to participate, preferably someone similar in age

3. Donating just $10 per month to help us build out this research network 

We humbly thank you in advance for your continued support. Together we can make a difference. 

Sincerely,

The Brain Inflammation Collaborative Team

Brain Inflammation Collaborative

925 Genesee St #180440

Delafield, WI 53018