Axel Montagne, PhD, on Solving Alzheimer’s and Dementia with Blood-Brain Barrier Repair

Name: Axel Montagne, PhD, on Solving Alzheimer’s and Dementia with Blood-Brain Barrier Repair
Uploaded: 2023-02-28T15:30:10.000Z
Duration: 3 h 14 min 6 s

The Importance of Exercise for Brain Health

In this section, Dr. Axel Monten discusses the importance of exercise for brain health and how lack of exercise can lead to the collapse of tiny blood vessels in the brain.

Exercise is crucial for maintaining healthy brain function

Tiny blood vessels in the brain are even smaller than air in terms of diameter.

Lack of exercise can cause these tiny vessels to collapse and disappear, leading to loss of neurons.

Capillaries represent 90% of brain vasculature, so it's important to maintain their health through regular exercise.

Exercise is also important for heart health and vision.

Dementia as a Vascular Disease

In this section, Dr. Axel Monten discusses how dementia has a vascular component and how understanding vascular dysfunction can help prevent dementia.

Dementia has a vascular component

Studies from 20-30 years ago showed that postmortem brain samples from Alzheimer's patients had vascular problems.

It's only been in the last 10 years that researchers have started paying attention to this vascular phenotype.

Vascular dysfunction is accelerated in people who go towards dementia, including Alzheimer's disease.

All forms of dementia have a vascular component early on in the disease.

Understanding vascular dysfunction can help prevent dementia

Researchers are trying to understand how vascular dysfunction contributes to dementia.

A leaky blood-brain barrier could be more important than beta amyloid plaques or Tau tangles.

Breakdown of the smallest vessels in the brain is responsible for about 50% of all dementias.

Understanding Vascular Dysfunction and its Relationship to Dementia

In this section, the speaker discusses how they developed a technique to detect small leaks in the blood-brain barrier using MRI. They found that certain brain regions become leakier with normal aging, particularly the medial temporal lobe where the learning and memory region is located. The speaker also mentions that they have developed new biomarkers to measure vascular problems in plasma or cerebral spinal fluid.

Leaky Brain Regions with Normal Aging

Normal aging causes certain brain regions to become leakier than others.

The medial temporal lobe, where the learning and memory region is located, is one of these leaky brain regions.

This region is called the entorhinal cortex and it becomes leakier as people age.

This region is also one of the first areas affected by dementia.

Blood-Brain Barrier Breakdown

The speaker's team has developed a technique to visually detect vascular problems in the brain using MRI.

They have also developed new biomarkers to measure vascular problems in plasma or cerebral spinal fluid.

People who have more leakiness at baseline are more likely to experience cognitive decline faster than those with low levels of these biomarkers.

Relationship Between Vascular Dysfunction and Alzheimer's Disease

Leaky brain regions are not necessarily related to areas where amyloid plaques build up.

There are two schools of thought regarding whether amyloid plaques disrupt vessels or if vascular dysfunction promotes amyloid plaque formation.

Early vascular problems need to be addressed in order for the brain to function normally and avoid dementia.

Early Diagnostics

The speaker mentions the importance of detecting vascular problems early, before cognitive decline occurs.

More sensitive types of MRI and plasma biomarkers can potentially be used as diagnostic tools for detecting leaky vessels in cognitively normal individuals.

Alzheimer's Disease and Vascular Problems

In this section, the speaker discusses how people carrying the polyproprotein E4 gene have a higher chance of developing Alzheimer's disease. They also discuss how these individuals have more vascular problems in the brain, which can be detected up to 10 years before any cognitive symptoms appear.

Targets for Intervention

There are several promising targets currently being tested in animal and clinical trials to protect blood vessels in the brain.

These targets aim to maintain the integrity of the neurovascular unit by targeting different cell types such as endothelial cells and pericytes.

Researchers are exploring gene therapy and stem cell therapy as potential interventions.

Screening for Treatment

Screening individuals based on their APOE genotype is one way to identify those who may benefit from treatment.

However, since only a quarter of the population has an APOE genotype associated with increased risk, it may not be realistic to screen everyone.

Biomarkers could be used to identify individuals who would benefit from treatment before cognitive symptoms appear.

Potential Impact

If successful, interventions that target blood vessel function could postpone cognitive symptoms by several years.

While a cure for Alzheimer's disease may not be possible through this approach, improving quality of life for even a few additional years would be significant progress.

Parasites and the Blood-Brain Barrier

In this section, the speaker discusses the impact of aging on parasites and the blood-brain barrier. They explore whether these changes are normal or abnormal and how they relate to cognitive decline.

Parasite Detachment and Aging

Parasites are vulnerable cells that detach and die as you age.

There is a 10 to 20 percent loss of these cells with normal aging.

Some regions have fewer parasites than others, such as the Epic campus compared to the cortex of the human brain at baseline.

Causes of Parasite Loss

One hypothesis for parasite loss is that it may be caused by undertale cells turning into a pro-inflammatory phenotype as we age.

When parasites detach, there is leakage of the blood-brain barrier and flow problems.

Properties of Parasites

Parasites wrap around vessels to ensure there's no straight barrier between blood and brain.

Parasites have contractile proteins that allow them to constrict or dilate vessels.

Detachment of Brain Parasites and Inflammation

The speaker discusses the detachment of brain parasites and how inflammation can trigger this process. They also mention the physiological detachment of brain parasites as we age.

Detachment of Brain Parasites

Brain parasites need to detach physically from vessels to allow immune cells to go through and do their job.

As we age, brain parasites lose the capability to reattach physiologically, which can lead to more detachment.

Inflammation in blood vessels can cause physiological detachment of brain parasites, leading to shortening processes that push blood through vessels.

Chronic inflammation in blood vessels can cause chronic detachment and shortening processes, leading to leakage of the barrier over time.

Role of Inflammation

Inflammation in blood vessels is a trigger for parasite detachment and shortening processes.

Targeting inflammation with drugs injected intravenously could improve vascular function.

Omega-3 fatty acids have been shown to regulate blood-brain barrier function through the mfsd2a transporter and resolving inflammation. Studies suggest that omega-3 status could be clinically relevant in regulating dementia-associated blood-brain barrier leakiness.

Reduction in Mfsd2a Transporter

Recent studies show that as we age and with dementia, mfsd2a receptor for omega-3 is reduced at capillaries where most parasites are located.

Reduction on mfsd2a on blood vessels leads to parasite loss, which causes leakiness of the barrier.

Reduction of mfsd2a transporter at the capillary bed has an impact on parasite function and leakiness of the barrier.

The Importance of Exercise for Brain Health

In this section, the speaker emphasizes the importance of exercise for maintaining healthy blood vessels in the brain and preventing neuron loss.

Exercise is Crucial for Brain Health

Regular exercise ensures that tiny blood vessels in the brain remain open and functioning properly.

Failure to exercise can cause these small vessels to constrict, collapse, and disappear, leading to neuron loss.

Exercise is also important for maintaining eye health and preventing vision loss as we age.

Small Vessel Disease vs. Alzheimer's Disease

Small vessel disease is a multi-factorial disease that involves breakdown of blood vessels in the brain.

This disease can lead to microbleeds, small strokes, and white matter hyperintensities.

These symptoms are different from those associated with Alzheimer's disease but may overlap in terms of brain imaging.

Conclusion

Exercise is crucial for maintaining healthy blood vessels in the brain and preventing neuron loss.

Small vessel disease is a complex condition that involves breakdown of blood vessels in the brain.

Small Vessel Disease

In this section, the speaker discusses small vessel disease and its differences from Alzheimer's disease. They also talk about the importance of targeting blood vessels in treating small vessel disease.

Small Vessel Disease

Small vessel disease is a disease that is independent of amyloids.

Microvessels have some problems in Alzheimer's disease, but they do have problems in small vessel disease as well.

The endothelium gets pro-inflamed in small vessel disease, which leads to high levels of soluble form of cell addition molecules that can be detected in biofluids.

There is evidence that pericytes surrounding the microvessels are also dysfunctional in small vessel disease.

Biomarkers and Imaging Features

In small vessel disease, there are high levels of parasite dysfunction and pro-inflammation of the vasculature.

Biomarkers can be used to relate with neural imaging features seen in people with cognitive problems.

Cognition is studied to see if there is any predictive value or correlational association between biomarkers and cognitive problems.

Genetic Forms

There are two forms of small vessel diseases: sporadic and genetic forms.

Cadazio and Carousel are two known genetic forms involving parasites and vascular muscle cells.

Conclusion

Small vessel diseases are very common, more than we think. It is important to target blood vessels for treatment since it affects cognition.

Small Vessel Disease and Dementia

The speaker discusses the complexity of dementia, including comorbidities such as cerebral amyloid angiopathy (CAA), Lewy body disease, and Parkinsonism. They also mention the UK Biobank's brain tissue samples for studying small vessel disease (SVD).

Comorbidities in Dementia

Dementia is complex and often involves comorbidities such as CAA, Lewy body disease, and Parkinsonism.

SVD can coexist with other forms of dementia.

It is common to have two forms of dementia simultaneously.

Blood-Brain Barrier and Glucose Metabolism

Breakdown of the blood-brain barrier can affect glucose metabolism in the brain.

Reduced brain glucose metabolism can be measured up to decades before any Alzheimer's or dementia symptoms occur.

Glucose transport at the blood-brain barrier is important for brain function.

FDG PET signal has to be carefully analyzed because it could be neuronal activity or indirectly a marker of vascular problems.

Glucose Transporters in Alzheimer's Disease

People with Alzheimer's disease have much less glucose transporter 1 at the blood-brain barrier than healthy individuals.

Omega-3 deficiency may cause a reduction in glucose transporter 1 transporters in the brain.

Omega-3 and Blood-Brain Barrier

The speaker discusses the relationship between omega-3 deficiency and blood-brain barrier breakdown, as well as the need for more longitudinal studies to fully understand this relationship.

Omega-3 Deficiency and Blood Flow

Studies are needed to better understand the relationship between omega-3 deficiency and blood flow in humans.

There is a vicious circle where under-table parasite crosstalk may be involved in blood-brain barrier problems.

Omega-3 deficiency can lead to a reduction of vascular cell adhesion molecule 1 (VCAM), which plays a major role upstream of parasite detachment.

Role of MFSD2A and Omega-3 in APOE4 Carriers

The speaker wrote an interactive review article on the important role of MFSD2A and omega-3 in APOE4 carriers.

Giving omega-3 to aged animals can reduce hyper activation of the brain on the tillium, including reducing levels of VCAM.

Proteins Involved in Maintaining Blood Brain Barrier

Tony Weiss Corey has identified proteins that help maintain blood-brain barrier function as we age.

Identifying these proteins could help slow down aging processes.

Fibrinogen and the Blood-Brain Barrier

In this section, the speaker discusses fibrinogen, a protein involved in blood coagulation and inflammation that is not supposed to be present in the brain. The speaker explains how fibrinogen can cross the blood-brain barrier when it becomes leaky, leading to neurotoxicity and white matter disease. The speaker also describes how reducing fibrinogen levels can help restore vascular function and prevent damage to the brain.

Fibrinogen's Role in Brain Damage

Fibrinogen is a protein that is not supposed to be present in the brain but can cross the blood-brain barrier when it becomes leaky.

Extravascular deposition of fibrinogen has been found in Alzheimer's disease and small vessel disease brains.

Fibrinogen is neurotoxic and toxic to oligodendrocytes, which make up myelin and ensure proper white matter function.

Oligodendrocytes are sensitive to fibrinogen uptake, which leads to autophagy (cell death), white matter disease, and brain damage.

Reducing Fibrinogen Levels

Reducing fibrinogen levels systemically in mice with blood-brain barrier issues was shown to reduce damage caused by extravascular deposition of fibrinogen.

Reducing fibrinogen levels partially restored vascular function and integrity of the barrier.

Blocking interaction between fibrinogen and microglia using an antibody developed by Katarina Kasudo can avoid overexpression of inflammation or overactivation of cells surrounding the brain.

Significance of Fibrinogen

Fibrinogen can activate brain resident immune cells through CD11b, leading to overreaction and inflammation of the brain.

Katarina Kasudo developed an antibody that blocks interaction between fibrinogen and microglia to avoid overexpression of inflammation or overactivation of cells surrounding the brain.

Omega-3 and Fibrinogen

In this section, the speakers discuss the role of fibrinogen in blood coagulation and its ability to cross into the brain. They also talk about how inflammation activates microglia cells and causes white matter dysfunction. The speakers suggest that omega-3 could be used to prevent this dysfunction.

Omega-3 and Fibrinogen

Fibrinogen is involved in blood coagulation and can cross into the brain, causing inflammation and activating microglia cells.

High levels of air particulate matter cause fibrinogen to increase, which is an inflammatory marker. However, taking high amounts of omega-3 can blunt this increase in fibrinogen in plasma.

It would be interesting to see if omega-3 could blunt white matter dysfunction caused by fibrinogen getting into the brain in animal models. This could be a prevention method for people at risk for Alzheimer's disease.

Pollution is linked to dementia, as studies have shown that living in a big city increases the chances of developing some sort of dementia due to environmental factors like pollution.

Airborne Particles and Vascular Function

In this section, the speakers discuss how airborne particles from pollution affect vascular function and contribute to dementia.

Airborne Particles and Vascular Function

Studies have shown that living in a big city increases the chances of developing some sort of dementia due to environmental factors like pollution.

Mice exposed to airborne particles from Los Angeles highways showed rapid blood-brain barrier breakdown and parasite degeneration within days after exposure. There is debate on whether these particles penetrate the brain through the olfactory area or directly through the bloodstream.

Pollution is a big factor to consider when it comes to dementia and vascular function because people breathe it every day.

Filtering out the air with HEPA filters and taking omega-3 supplements can help reduce the impact of airborne particles on vascular function.

Comparing the Effects of Pollution and Masks on Vascular Functions

In this section, the speakers discuss the possibility of comparing highly polluted cities with people wearing filtering masks to see whether they can preserve vascular functions better.

Pollution and Mask Study

The speakers suggest that a study could be conducted to compare highly polluted cities with people wearing filtering masks.

Ongoing studies are mentioned regarding apoe4, which is a big genetic risk factor for late-onset Alzheimer's disease. About a quarter of the population has one allele.

Blood-brain barrier breakdown is discussed in earlier non-cognitively normal individuals. A protein called cyclophyll and matrix metalloproteinase are identified as proteins involved in inflammation that affect blood-brain barrier integrity.

People carrying at least one allele of apoe4 tend to have more leakage in the middle temporal lobe that can be seen with MRI and biomarkers.

The major source of apoe are astrocytes. When astrocytes make Sabri, there is a different affinity to one of the apoe receptors called nrp1 on parasites. Astrocytes and parasites maintain vascular tree function and neurovascular coupling.

People carrying the apoe4 allele have less chance to bind to nrp1, which triggers a cascade within parasites involving NS Kappa B, cyclophyllin A expression, and release of MMP9 from parasites.

MMP9 disrupts tight junctions between endothelial cells causing gaps leading to breakdown of blood-brain barrier integrity. It also eats up displacement Opera wrapping around vessels and pericytes.

MMP9 as a Marker for Blood-Brain Barrier Leakage

MMP9 is a marker that goes well with blood-brain barrier permeability. After stroke, there is a breakdown of the blood-brain barrier within the next few hours, and this breakdown is correlated with high levels of MMP9.

In ischemic stroke, there is a second breakdown a few days later, which is called bifazic phasic animal. Both mmp9 and cyclophyllin A levels were elevated in several spinal fluid of people carrying the apoe4 gene.

The transcript was in English.

Different Cell Types and Baseline Parasite Production

In this section, the speaker discusses their research on different cell types and baseline parasite production.

Parasites without P3 Produce More On-Site Refiner and MFP9

Donors from MAPUI4 and donors from MP3 were used to study different cell types.

At baseline, parasites without P3 produce more on-site refiner and MFP9 than parasites with P3.

Targeting Cyclophene to Restore Vascular Function

In this section, the speaker discusses their research on targeting cyclophene to restore vascular function.

Using Humanized Apple for Mice

The speaker used humanized Apple for mice in their research.

As the mice aged, MRI was done to look at blood flow and brain function.

Restoring Vascular Function by Blocking Cyclopheneic

A non-type innovative of cytrophin day called debut 025 was given every day for one month to the airport for mice.

By blocking cyclopheneic, Thai junctions were restored, parasite coverage of vasculature was restored, neuronal damage was reduced, and cognitive problems were lessened.

Safety of Debut 025 Drug

In this section, the speaker discusses the safety of debut 025 drug.

Clinical Trials Stopped Due to Safety Concerns

There have been a few clinical trials using debut 025 drug that have been stopped due to safety concerns.

The drug has been used for Hepatitis C and COVID-19, but the trials have not been successful.

Need to Design Trials Carefully

The speaker suggests that trials need to be designed carefully and given to the right people.

Targeting cyclophene may not be the best approach, and other targets such as MMP9 are being studied.

Restoring Vascular Function and Cognitive Abilities

In this section, the speaker discusses their research on restoring vascular function and cognitive abilities.

Studying Targets to Restore Brain Function

The goal of the research is to restore brain function by studying targets that can restore vascular function and prevent leakiness in the blood-brain barrier.

There are a list of other targets being studied that may help achieve this goal.

Receptors and Blood-Brain Barrier

In this section, the speaker discusses how receptors such as RAGE and others are important for clearing waste from the brain while sleeping. Dysfunction of these receptors can lead to an accumulation of toxins in the brain. The speaker also talks about the importance of blood vessels and blood-brain barrier integrity in clearing out toxins.

Importance of Receptors

Receptors such as RAGE are important for clearing waste from the brain while sleeping.

Dysfunction of these receptors can lead to an accumulation of toxins in the brain.

Blood Vessels and Blood-Brain Barrier Integrity

Fixing blood vessels is a promising target for improving blood-brain barrier integrity.

Disruption of these vessels can impair the glymphatic system, which clears out amyloid plaques during sleep.

If there is vascular disruption, toxins will not be cleared out properly, leading to an accumulation of toxins in the brain.

Glymphatic System and Toxin Clearance

In this section, the speaker discusses how disruption to blood vessels can impact toxin clearance through both lymphatic and intramural perioral drainage systems. The speaker emphasizes that targeting only amyloid may not be sufficient for treating cognitive decline.

Impact on Toxin Clearance

Disruption to blood vessels can impair toxin clearance through both lymphatic and intramural perioral drainage systems.

Targeting only amyloid may not be sufficient for treating cognitive decline.

Research needs to focus on targeting dysfunction early on before plaque buildup becomes too severe.

Targeting Amyloid Beta Plaque

In this section, the speaker discusses recent drug developments that target amyloid beta plaque, such as lacanumab. While there is evidence of plaque removal, the impact on cognition is still controversial. The speaker suggests a cocktail approach to treatment that includes improving blood vessel function and clearance.

Recent Drug Developments

Lacanumab targets protofibril fibril, a soluble form of amyloid.

Evidence shows some improvement in plaque removal but the impact on cognition is still controversial.

Cocktail Approach to Treatment

A combination of treatments that improve blood vessel function and clearance may be more effective than targeting only amyloid.

Research needs to focus on early intervention before plaque buildup becomes too severe.

Hypertension and its Impact on the Brain

In this section, the speaker discusses how hypertension affects the brain and dementia risk.

Early Hypertension is More Harmful

Early hypertension in young adults is more harmful than if you have it later in life.

Sustained hypertension over many years can impact the stiffness of your blood vessels and affect parasite function.

Basal ganglia and deep structures suffer quite a lot from hypertension. People with hypertension tend to have more micro bleedings in this area.

Hypertension triggers prevalent barrier leakage and parasite loss.

Duration of Hypertension is Critical

The chronic part of hypertension is very critical. If you have that for many years, your table stiffness will be disturbed and damaged over time, degrading your preparing barrier value much faster than a normal tensive person.

Cumulative exposure seems to be the more important thing here.

Studies show that giving anti-hypertensive drugs has a positive impact on cognition.

Controversies around Hypertension

Early onset hypertension increases the likelihood of developing cognitive decline quickly as compared to a normotensive person of the same age.

During one's 70's, early onset hypertension does not impact their likelihood to develop dementia.

Chronic slow low-grade inflammation disrupts vessels slowly probably similar to what happens with too much hypertension.

Challenges in Studying Hypertension

It's hard to disentangle what pure hypertension is doing to the blood vessels because there are always comorbidities like obesity and other things.

Statistical correction with covariates is quite hard to study.

Importance of Exercise and Sauna for Vascular Function

The speaker discusses the importance of exercise and sauna in improving vascular function, which is critical for preventing dementia and Alzheimer's disease.

Exercise Improves Vascular Function

Exercise is important for opening up small vessels and ensuring they are functional.

Even starting to exercise in your 70s can improve cardiovascular health, although earlier is better.

Exercise improves blood pressure, arterial function, heart rate variability, and can help prevent dementia and Alzheimer's disease.

Sauna Use Improves Vascular Function

Sauna use dose-dependently reduces the risk of dementia and Alzheimer's disease by up to 60% if used four to seven times a week.

Using the sauna two to three times a week reduces the risk by 20% after adjusting for other factors.

Heat stress from sauna use has similar effects on blood pressure and heart rate variability as moderate aerobic exercise.

Effects of Alcohol on Vascular Function

The speaker discusses how alcohol consumption affects vascular function, with chronic consumption leading to leaky blood-brain barriers that increase inflammation. Moderate drinking has conflicting results.

Chronic Drinking Leads to Leaky Blood-Brain Barriers

Chronic alcohol consumption leads to leakier blood-brain barriers that impair parasite functions and possibly lead to leakage.

Males who chronically drink alcohol have more vascular issues than females due to estrogen having anti-inflammatory properties.

Conflicting Results on Moderate Drinking

Moderate drinking has conflicting results on brain function and vascular properties of the brain.

Studies show that moderate drinking can be protective against dementia, but only in people who are not apoe4 carriers.

Alcohol, Obesity, and Blood-Brain Barrier

In this section, the speakers discuss the impact of alcohol consumption and obesity on the blood-brain barrier.

Alcohol Consumption

Red wine contains slovenues that are important for brain and vascular functions.

Moderate drinking of red wine may be helpful for brain function.

Daily drinking should be avoided.

Obesity

Studies show that obesity can lead to higher levels of pro-inflammatory markers in the blood, which can impact barrier function.

William Banks suggests that barrier leakage triggers obesity rather than the other way around.

Dysfunction in areas controlling starvation due to leaky vasculature can cause people to eat too much.

Homocysteine and Blood Pressure

The speakers discuss homocysteine's association with high blood pressure and cognitive dysfunction.

Homocysteine

High homocysteine is associated with brain dysfunction and dementia.

Treatment with B6 B12 folate can improve cognition and blood-brain barrier in people with high homocysteine levels.

Blood Biomarkers for Alzheimer's Disease

In this section, the speakers discuss the possibility of using blood biomarkers to diagnose Alzheimer's disease.

Possibility of Diagnosing Alzheimer's with a Drop of Blood

Researchers are working on developing a method to diagnose Alzheimer's disease by analyzing a drop of blood.

The idea is similar to getting blood glucose levels from a finger prick.

The test would measure amyloid status and amirate 42 levels to determine if someone has Alzheimer's disease or not.

Clinical Trials for Soluble Platelet-Derived Growth Factor Receptor

The soluble platelet-derived growth factor receptor is currently being tested in clinical trials in the US.

The trials have been done on hundreds of patients, but researchers need to validate the results with a larger group before it can be used clinically.

If successful, this biomarker could be available within months or years.

Thanking Researchers for Their Work

In this section, the speakers express gratitude towards researchers who are working on identifying new biomarkers and treatments for dementia and Alzheimer's disease.

Thanking Axel Montagne and Other Researchers

The host thanks Axel Montagne and other researchers for their work in identifying new biomarkers and treatments for dementia and Alzheimer's disease.

They mention Dr. Slovovic and others who are trying to understand these diseases in different ways.

Axel Montagne tweets interesting studies related to these topics on his Twitter handle @Axl_montagne.

Importance of Vascular Function in Cognitive Function

Vascular function plays an important role in cognitive function and preventing neurodegenerative diseases.

Understanding vascular function can lead to more preventative measures against these diseases.