You may have heard of “leaky gut” or the weakening of the intestinal barrier. Just like the gut, the brain can also be “leaky.”
Like the stomach barrier, the blood-brain barrier is lined with one layer of cells that separate the blood from the brain. It only allows a few substances like oxygen, hormones, and certain cytokines in, while blocking out others.
Some researchers have argued that when this protective layer is compromised, the brain may become vulnerable to damage from chemicals, inflammatory cytokines, and immune cells.
If you suffer from any brain disorders, including brain fog (cognitive dysfunction), chronic fatigue, anxiety/depression, neurodegenerative diseases, and multiple sclerosis, then this post is for you.
Leaky Brain – Part One of a Three-Part Series
- Part 1: What is the Blood-Brain Barrier? + “Leaky” Brain Conditions
- Part 2: Factors and Disease States That Cause Leaky Brain
- Part 3: How to Repair a Leaky Blood-Brain Barrier
What Is the Blood-Brain Barrier?
The blood-brain barrier (BBB) is a one-cell layer barrier that separates the brain from the blood. Its main role is to act as a selective (semi-permeable) filter that lets only specific molecules through while blocking others at the right time.
The brain becomes “leaky” when the blood-brain barrier becomes more permeable. A loss of selectivity in the BBB is linked to a variety of diseases.
The blood-brain barrier (BBB) is composed of specialized components called neurovascular units or NVUs, which include:
- Endothelial cells, which line the barrier
- Astrocytic endfeet, which are part of nerve cells that envelope the blood vessels
- Basement membrane that lines the epithelial cells
- Pericytes that provide structural support to the blood vessels, but may also control BBB development and permeability 
Tight junctions seal the gap between endothelial cells in the same layer. Like tight junctions in the gut, the tight junctions between the endothelial cells are made up of claudins, occludins, and junction adhesion molecules. These cells also have zonulin .
Factors Linked to “Leaky Brain”
The factors below have been associated with a “leaky” blood-brain barrier in various studies. However, this is not to say that these factors are direct causes of BBB, or that the BBB will necessarily gain permeability if a person is exposed to them. Researchers have simply found connections between them and the condition colloquially known as “leaky brain.”
Future studies will clarify whether these factors are causally linked to increased permeability in the BBB, and what sort of clinical applications such a link could have. We present this early research here for the sake of interest [3, 4].
- Inflammation: High levels of inflammation in the brain are linked to increased blood-brain barrier (BBB) permeability 
- Stress: Acute stress activates brain mast cells that secrete proinflammatory cytokines 
- Bacterial infections: Bacteria in the brain increase MMP activity, which may induce the breakdown of the BBB 
- Toxins: LPS induces inflammation 
- Mold toxins: Mold toxins and mold components trigger inflammation and increase oxidative damage in the brain 
- High-fat, high-calorie diet: High-fat diets may increase oxidative damage, hypoxia, and inflammation in the brain 
- “Leaky gut:” Changes in the gut have been associated with BBB permeability [11, 12]
- Liver damage: In acute liver failure, the damaged liver releases MMP9 into the bloodstream, which may damage tight junctions 
- Diabetes or high blood sugar: Changes in glucose levels cause oxidative stress and inflammation 
- Disrupted sleep-wake cycle: Chronic sleep disturbance decreases glucose transport across the BBB and increases inflammation 
- Anything that triggers oxidative stress in glial cells and pericytes: Oxidative stress damages the BBB and causes structural and integrity problems [16, 17]
- Hypoxia: Hypoxia is a condition where there is not enough oxygen available; it may damage the cells and tight junctions of the BBB 
- Homocysteine: High levels of homocysteine alter tight junction function and cause BBB dysfunction 
- Excess glutamate: Overstimulation of glutamate receptors in the brain may cause BBB breakdown; glutamate administration in rats increased permeability. Glutamate-treated rats had higher albumin levels in their brain compared to control rats 
- Other agents that may increase BBB permeability: Aspartate, taurine, ATP, endothelin-1, NO, MIP-2, TNF-a, MIP2, IL-h, bradykinin, 5HT, histamine, thrombin, UTP, UMP, quinolinic acid, platelet activating factor, and free radicals 
How Do Researchers Detect a “Leaky” BBB?
In order to research the permeability of the blood-brain barrier, researchers have developed a number of techniques. These are not typical laboratory tests available to a doctor.
1) Albumin in the Brain
Under normal conditions, blood albumin does not cross the blood-brain barrier (BBB). Additionally, higher levels of albumin in the BBB lumen are correlated with aging [21, 22].
A common technique used to check the extent of leakage is to dye blood albumin using Evans Blue. This dye binds to albumin immediately after its injection into the blood. Researchers measured levels of blood-brain barrier leakage by looking at the Evans Blue dye accumulated in the brain via spectrophotometry .
However, this method is not sensitive enough to detect minor leaks or to assess the full amount of leakage in the brain. It also requires extensive tissue processing .
In a new study, researchers used optical imaging on rat brains to check leakage in the BBB after induced strokes. This method was able to map leakage in different brain locations .
Optical imaging data of the Evans Blue-dyed albumin was more sensitive and easier to use than spectrophotometry, making it a viable research technique for BBB studies .
2) Elevated MMP9
Matrix metalloproteinases (MMPs) play a role in the disruption of the blood-brain barrier (BBB), especially MMP9. MMPs are endopeptidases (enzymes that break down peptide bonds) that degrade the extracellular matrix .
Disruption of the BBB occurs after a stroke and worsens brain injuries. Many animal and postmortem studies of brain tissue from stroke patients have shown an increase in MMP9 levels following a stroke [24, 25].
In one study, researchers studied the effect of MMP9 on rats with traumatic brain injuries. After brain injury, MMP9 levels significantly increased, as did BBB disruption. Additionally, treatment with an MMP inhibitor reduced BBB disruption .
What About GABA Challenge?
If you’ve spent some time looking up “leaky brain” online, you may have come across the concept of a “GABA challenge,” which proponents claim can identify high BBB permeability. However, the origin of this concept is unknown, and the test’s validity is not directly supported by the scientific literature.
Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter. It is sold online as a food supplement .
While GABA is thought to be unable to cross the blood-brain barrier (BBB), there are several conflicting studies. Initial studies reported that GABA was unable to cross the BBB. However, later studies reported that GABA does cross the BBB in small amounts .
All of these conflicting reports might be the result of using different methods. To date, no human studies directly have assessed GABA and the blood-brain barrier permeability, due to the limitations of measuring GABA in the human brain .
It is possible that while the amount of GABA that reaches the brain is too small to be clinically significant, this amount is enough to cause changes in the brain. Again, however, this conclusion has no significant clinical support .
One study used a GABA-EEG test to check the blood-brain barrier’s permeability. Researchers tested the selectivity of the BBB in cats. The GABA-EEG test revealed that the permeability of the BBB changes during epileptic shocks. This supports the theory that when the blood-brain barrier is leaky, GABA can pass through it .
Conditions Linked to Compromised BBB
A “leaky” blood-brain barrier has been linked to a number of neurological disorders, but the direction of influence (i.e. whether increased permeability is a cause or effect of such disorders) is unknown. The following conditions have been associated with increased BBB permeability.
1) Brain Fog
Cognitive dysfunction, also known as brain fog, is a collection of symptoms that affect a person’s way of thinking. Brain fog includes reduced mental acuity, problems concentrating or multitasking, and short and long-term memory loss .
Inflammation is considered a possible cause of brain fog. Mast cells both initiate and stop inflammation. They also help control the blood-brain barrier (BBB) selectivity. Activated mast cells secrete proinflammatory factors that increase BBB permeability .
Brain histamine triggers mast cells and induces inflammation. High levels of histamine also cause brain fog and anxiety as well as disrupt the BBB .
2) Alzheimer’s Disease
In Alzheimer’s patients, neurovascular units may not function properly .
The destruction of neurovascular units in Alzheimer’s disease is related to the increase in the production of adhesion molecules called VCAM-1 .
Alzheimer’s disease is likely caused by a toxic protein called beta-amyloid peptide (Aβ) .
The many types of adhesion molecules that destroy the BBB may also allow Aβ to accumulate in the brain. The proteins enter the nerve cells and form plaques that interfere with their function and eventually kill brain cells .
Aβ receptors at the BBB control the level of Aβ in the brain. New research is developing therapeutic strategies that aim to manipulate the Aβ receptors at the BBB to decrease the influx of Aβ into the brain .
Chelating agents bind to excess transition metals and help remove them from the body, therefore reducing oxidative damage. Metal chelation therapy might be able to help reduce brain deterioration in Alzheimer’s patients. However, the chelating agents must be able to pass through the BBB .
Nanoparticles and microparticles cross the BBB to help transport metal chelating agents and drugs across the BBB. This helps improve drug effectiveness and reduces drug toxicity [35, 36].
In one study using human brain cells, researchers studied the effects of nanoparticles and chelating agents. This combination effectively inhibited Aβ accumulation, which helps protect against Aβ-related toxicity .
Additionally, there is a deficiency in insulin transport across the BBB in Alzheimer’s, which causes insulin resistance. The NVU and other factors help with insulin delivery across the BBB and improve Alzheimer’s symptoms .
3) Huntington’s Disease
Disruption of the tight junctions that help maintain the BBB function, as well as the altered transport of molecules between the blood and brain, is believed to contribute to the progression of the disease .
Researchers studied MRI brain scans of 22 Huntington’s patients, 9 controls, and images of human tissue from deceased Huntington’s patients. The analysis of the tissues showed a significant decrease in proteins that help form tight junctions in the BBB. There was also increased BBB permeability in Huntington’s patients .
R6/2 mice are an animal model of Huntington’s disease. A study showed that the cellular production of tight junction proteins is changed in these mice before Huntington’s disease symptoms appear. This suggests that BBB permeability is already increased in the early stages of Huntington’s .
4) Multiple Sclerosis
Multiple sclerosis (MS) patients have high levels of MMP9, which is believed to damage the BBB .
Molecules that initiate inflammation also participate in breaking the blood-brain barrier (BBB) structure in multiple sclerosis .
When the patients’ health worsens, the concentration of MMP9 also increases in their spinal fluid .
Steroid hormone treatments for MS patients, especially methylprednisolone, lead to a decrease in the concentration of MMP9 in the spinal fluid. It also strengthens the BBB by preventing leakage of things across the barrier .
Additionally, if there were immune cells migrating to the brain, the chance of NVUs being destroyed was higher .
Steroids also decrease the level of immune cells in the area. This may explain the lower concentrations of MMP9 and beneficial effects in MS patients .
Albumin also potentially worsens multiple sclerosis symptoms. However, it may also have some protective roles in the disease, but there are currently no human studies available to support this .
High albumin levels in the brain induce proinflammatory cytokine production and prevent potassium levels from being balanced. This makes nerve cells vulnerable to glutamate toxicity, which is a mechanism for MS .
Scientists found albumin widely dispersed in the brain of multiple sclerosis patients, which indicates BBB dysfunction .
Albumin leakage through the BBB in MS patients may lead to epileptic seizures .
5) Autism Spectrum Disorder
Some researchers believe that changes in the blood-brain barrier (BBB) integrity could play a role in autism. In a study of 33 brain sections from deceased patients, researchers found increased gene production of MMP9 in the autistic patients. MMP9 secretion increases BBB permeability .
Moreover, in the same study, the tight junction proteins in the BBB of autistic patients’ brains were altered. There was an increase in pore-forming tight junctions and decreased levels of barrier-forming ones. Typically, this leads to higher BBB permeability .
Blood-brain barrier damage is associated with seizures in children with autism .
There are many mast cells near the BBB. Stress activates the brain mast cells, which leads to BBB disruption .
Blood-brain barrier disruption permits brain inflammation. The activation of brain mast cells also contributes to the onset of migraines that increase the likelihood of seizures .
Blood-brain barrier (BBB) dysfunction is involved in seizures and epilepsy. Some researchers argue that seizures can be both a cause and a result of disrupted BBB function .
Immune system dysfunction and inflammation negatively affect BBB integrity. Stress activates brain mast cells located around the BBB, which leads to BBB disruption. The activation of brain mast cells also contributes to the onset of migraine headaches that increase the likelihood of seizures [47, 48].
In many animal models, BBB disruption and albumin levels in the brain were increased after prolonged seizure activity .
The accumulation of albumin in the brain can cause chronic epilepsy. The uptake of albumin by nerve cells causes cell death. Albumin also increases brain inflammation, which contributes to seizures and epilepsy .
Blood-brain barrier damage also increases the risk of seizures in autistic children .
Possible treatments for BBB leakage during epilepsy and seizures include anti-epileptic or anticonvulsant drugs, microRNA treatments, and mTOR inhibitors. However, some people do not respond to these treatments and more studies are needed before any conclusions are reached .
Schizophrenia is a psychotic disorder with symptoms that include hallucinations, delusions, and other behavioral and cognitive dysfunction. Brain inflammation, oxidative stress, and genetic factors all contribute to this disease .
Blood-brain barrier dysfunction is also connected to schizophrenia. The oxidative damage and inflammation that causes schizophrenia also damages the blood-brain barrier (BBB) .
Brain inflammation causes astroglial cell loss. Astroglial cells help control the BBB. Additionally, proinflammatory cytokines (TNF-α, IL-1β, and IFN-γ) cause a dose-dependent increase in BBB permeability .
Researchers studied the spinal fluid of schizophrenic patients and healthy volunteers. The spinal fluid of 27 schizophrenic patients had a significantly higher concentration of albumin and immunoglobulin compared to healthy people, indicating a disruption of the BBB .
The mechanisms that cause schizophrenia may also disrupt BBB integrity. Conversely, BBB breakdown contributes to the toxic inflammatory responses that have been linked to schizophrenia .
Long-term inflammation may cause neurovascular dysfunction and disrupt normal brain activity. This, in turn, leads to depression or other psychiatric disorders .
Chemokines are a type of cytokine that attracts cells to inflammation sites. Normally, chemokines cannot cross the BBB. However, during cases of increased BBB permeability, like major depressive disorder, chemokines pass through .
Oxidative stress associated with major depressive disorder impairs nerve function. Oxidative stress may also damage BBB cells .
Brain inflammation is believed to impair nerve function and increase BBB permeability during major depressive disorder. Astroglial cell loss and proinflammatory cytokines cause BBB dysfunction .
The results of an analysis of the spinal fluid of 84 elderly female patients indicated high BBB permeability in depressive patients. Fourteen women with depression had higher albumin levels compared to those without depression .