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What’s the Blood-Brain Barrier? Leaky Brain Causes & Tests

Written by Nattha Wannissorn, PhD (Molecular Genetics) | Last updated:

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Brain Fog

You may have heard of the leaky gut or the leaky 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.

When this protective layer is compromised, the brain is vulnerable to damage from chemicals, inflammatory cytokines, and immune cells.

This post is a must-read if you suffer from any brain disorders, including brain fog (cognitive dysfunction), chronic fatigue, anxiety/depression, neurodegenerative diseases, and multiple sclerosis.

Leaky Brain – Part One of a Three-Part Series

What Is the Blood-Brain Barrier?

The blood-brain barrier 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’s permeability increases. When it is not selective enough, this leads to diseases.

Source: https://www.ncbi.nlm.nih.gov/pubmed/26794270

The blood-brain barrier (BBB) is composed of special parts 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 [1]

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 [2].

Causes of Leaky Brain

  • Inflammation: High levels of inflammation in the brain cause blood-brain barrier (BBB) permeability to increase [3]
  • Stress: Acute stress activates brain mast cells that secrete proinflammatory cytokines that disrupt the BBB [4]
  • Bacterial infections: Bacteria in the brain increase MMP activity, which induces the breakdown of the BBB [5]
  • Toxins: LPS induces inflammation and causes BBB disruption [6]
  • CIRS/Mold illness: Mold toxins and mold components trigger inflammation and increase oxidative damage in the brain, which disrupts the BBB [7]
  • High-fat, high-calorie diet: High-fat diets increase oxidative damage, hypoxia, and inflammation in the brain, which damages the BBB [8]
  • Leaky gut: Change in the gut influences BBB permeability. A leaky gut damages the blood-brain barrier [9, 10]
  • Liver damage: In acute liver failure, the damaged liver releases MMP9 into the bloodstream, which damages tight junctions and increases BBB permeability [11]
  • Diabetes or high blood sugar: Changes in glucose levels cause oxidative stress and inflammation, resulting in a leaky brain [12]
  • Disrupted sleep-wake cycle: Chronic sleep disturbance decreases glucose transport across the BBB, increases inflammation, and impairs BBB permeability [13]
  • Anything that triggers oxidative stress in glial cells and pericytes: Oxidative stress damages the BBB and causes structural and integrity problems [14, 15]
  • Hypoxia: Hypoxia is a condition where there is not enough oxygen available; it damages the cells and tight junctions of the BBB [16]
  • Homocysteine: High levels of homocysteine alter tight junction function and cause BBB dysfunction [17]
  • Excess glutamate: Overstimulation of the glutamate receptors in the brain cause BBB breakdown; glutamate administration in rats increased permeability. Glutamate-treated rats had higher albumin levels in their brain compared to control rats [18, 18]
  • Other agents that 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 [2]

Signs That You have a Leaky Blood-Brain Barrier and Proper Lab Tests

1) GABA Challenge

Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter. It is sold online as a food supplement [19].

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 [19].

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 [19].

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 [19].

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 [20].

2) Higher 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 [23].

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 [23].

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 [23].

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 [23].

3) Elevated MMP9

How MMP-9 cause leaky brain by breaking down tight junction proteins like occludin. Source: https://www.ncbi.nlm.nih.gov/pubmed/17562450

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 [24].

Disruption of the BBB occurs after a stroke and worsens brain injuries. Many animal and postmortem studies of brain tissues 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 rat brains with traumatic brain injuries. After the brain injury, MMP9 levels significantly increased, as did BBB disruption. Additionally, treatment with an MMP inhibitor reduced BBB disruption [26].

4) Other tests:

  • Horseradish peroxidase (HRP)
  • Radiolabeled markers with sucrose or inulin
  • Blood proteins (fibrinogen and immunoglobulin)
  • Sodium fluorescein
  • Dextran [27]

Neurological and Psychiatric Conditions Linked to Leaky Blood-Brain Barriers

A leaky blood-brain barrier is a hallmark of all neurological disorders. In some cases, the leaky brain causes the disease. In others, the disease state such as inflammation or high blood sugar triggers a leaky brain.

1) May Cause 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 ability, problems with concentrating or multitasking, and short and long-term memory loss [28].

Inflammation is 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 [28].

Brain histamine triggers mast cells and induces inflammation. High levels of histamine also cause brain fog and anxiety as well as disrupt the BBB [28].

2) Alzheimer’s Disease Is Linked to Lower Blood-Brain Barrier Function

In Alzheimer’s patients, neurovascular units do not function properly [29].

The destruction of neurovascular units in Alzheimer’s disease is related to the increase in the production of adhesion molecules called VCAM-1 [30].

Alzheimer’s disease is likely caused by a toxic protein called beta-amyloid peptide (Aβ) [31].

The many types of adhesion molecules that destroy the BBB allow Aβ to accumulate in the brain. The proteins enter the nerve cells and form plaques that interfere with their function and eventually kill the brain cells [31].

Aβ receptors at the BBB control the level of Aβ in the brain. There are new therapeutic strategies that aim to manipulate the Aβ receptors at the BBB to decrease the influx of Aβ into the brain [32].

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 [33].

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 [34, 35].

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 [35].

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 [36].

3) Contributes to Huntington’s Disease Symptoms

A leaky blood-brain barrier (BBB) also contributes to Huntington’s disease symptoms. Disruption of the tight junctions that help maintain the BBB function, as well as the altered transport of molecules between the blood and brain, contribute to the progression of the disease [37].

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 an increased BBB leakage in Huntington’s patients [38].

R6/2 mice are an animal model of Huntington’s disease. A study showed that 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 [37].

4) Multiple Sclerosis

Multiple sclerosis (MS) patients have high levels of MMP9, which destroys the nerves [39].

Molecules that initiate inflammation also participate in breaking the blood-brain barrier (BBB) structure in multiple sclerosis [40].

When the patients’ health worsens, the concentration of MMP9 also increases in their spinal fluid [39].

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 [41].

Additionally, if there were immune cells migrating to the brain, the chance of NVUs being destroyed was higher [29].

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 [42].

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 [43].

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 [43].

Scientists found albumin widely dispersed in the brain of multiple sclerosis patients, which indicates BBB dysfunction [44].

Albumin leakage through the BBB in MS patients may lead to epileptic seizures [43].

5) Autism Spectrum Disorders Both Increase and Are Affected By Blood-Brain Barrier Disruption

Changes in blood-brain barrier (BBB) integrity 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 induces BBB disruption [45].

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 [45].

Blood-brain barrier damage influences health in children with autistic disorders, increasing the risk of seizures [46].

There are many mast cells near the BBB. Stress activates the brain mast cells, which leads to BBB disruption [46].

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 [46].

6) Blood-Brain Barrier Dysfunction and Seizures

Blood-brain barrier (BBB) dysfunction is involved in seizures and epilepsy. While seizures cause BBB dysfunction, increased BBB permeability also leads to epilepsy [47].

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 [46, 47].

In many animal models, BBB disruption and albumin levels in the brain were increased after prolonged seizure activity [47].

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 [47].

Blood-brain barrier damage also increases the risk of seizures in autistic children [46].

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 [47].

Blood-Brain Barrier Dysfunction and Psychiatric Disorders

Disruption of the blood-brain barrier may be also connected to psychiatric disorders [48].

7) Found in Schizophrenia

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 [49].

Blood-brain barrier dysfunction is also connected to schizophrenia. The oxidative damage and inflammation that causes schizophrenia also damages the blood-brain barrier (BBB) [49].

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 [49].

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, which indicated that the BBB was disrupted [50].

The mechanisms that cause schizophrenia also disrupt BBB integrity. Conversely, BBB breakdown contributes to toxic inflammatory responses that cause schizophrenia [49].

8) Contributes to Depression

Long-term inflammation may cause neurovascular dysfunction and disrupt normal brain activity. This, in turn, leads to depression or other psychiatric disorders [48].

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 [51].

Oxidative stress associated with major depressive disorder impairs nerve function. Oxidative damage also targets BBB cells [52].

Just like during schizophrenia, brain inflammation impairs nerve function and increases BBB permeability during the major depressive disorder. Astroglial cell loss and proinflammatory cytokines cause BBB dysfunction [52].

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 [53].

Leaky Brain – Part One of a Three-Part Series

To learn how Joe fixed his leaky blood-brain barrier and restored his health, check out SelfHacked Secrets.

About the Author

Nattha Wannissorn

PhD (Molecular Genetics)
Nattha received her Ph.D. in Molecular Genetics from the University of Toronto and her undergraduate degree in Molecular and Computational Biology from the University of Pennsylvania.
Aside from having spent 15 years in biomedical research and health sciences, Nattha is also a registered holistic nutritionist, a certified personal trainer, has a precision nutrition level 1 certification, and is a certified functional diagnostic nutrition practitioner. As a holistic practitioner with a strong science background, Nattha is an advocate of science literacy in health topics and self-experimentation.

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