Columbia Researchers Provide New Insight into How the Brain Regulates Its Blood Flow

A group of multi-disciplinary researchers at Columbia University have made an exciting discovery.  They have witnessed how the vascular system regulates blood flow to the brain.
http://engineering.columbia.edu/columbia-engineers-provide-new-insight-how-brain-regulates-its-blood-flow 

The vascular endothelium maintains the lining of all 60,000 miles of our blood vessels, even the vessels inside the brain.  It is the largest secreting organ in the human body.  Neurological researchers had postulated that endothelial cells were not as important in maintaining blood flow inside the brain--that the brain itself was responsible for initiating cerebral blood flow according to neuronal health.  But this theory was wrong.

The brain relies on healthy blood vessels to maintain healthy cerebral blood flow.

The brain was thought to use a different mechanism--and this has lead neurological researchers to focus on the cells surrounding blood vessels in the brain.

According to researcher and professor of biomedical engineering, Elizabeth M.C. Hillman, this supposition has lead to incorrect ideas on brain health.

“Once we realized the importance of endothelial signaling in the regulation of blood flow in the brain,” Hillman adds, “we wondered whether overlooking the vascular endothelium might have led researchers to misinterpret their results.”

Dr. Hillman has spent the past 10 years using advanced medical technology, to study how blood flow is controlled in the brain.  Her research team was comprised of a multi-disciplinary members.  Other lab members who assisted with the study included PhD and MD/PhD students from Columbia Engineering, Neurobiology and Behavior, and Columbia University Medical Center. The group combined their engineering skills with their expertise in neuroscience, biology, and medicine to understand this new aspect of brain physiology.

To tease apart the role of endothelial signaling in the living brain, they had to develop new ways to both image the brain at very high speeds, and also to selectively alter the ability of endothelial cells to propagate signals within intact vessels. The team achieved this through a range of techniques that use light and optics, including imaging using a high-speed camera with synchronized, strobed LED illumination to capture changes in the color, and thus the oxygenation level of flowing blood. Focused laser light was used in combination with a fluorescent dye within the bloodstream to cause oxidative damage to the inner endothelial layer of blood brain arterioles, while leaving the rest of the vessel intact and responsive. The team showed that, after damaging a small section of a vessel using their laser, the vessel no longer dilated beyond the damaged point. When the endothelium of a larger number of vessels was targeted in the same way, the overall blood flow response of the brain to stimulation was significantly decreased.

The researchers damaged the endothelial layer of cells, causing oxidative stress.  After this damage, the blood vessel was no longer able to dilate past the damaged point.  This process restricted blood flow to the neurons.

The damaged endothelium is what initiated lowered blood flow, also known as hypoperfusion.   We see hypoperfusion in MS, Alzheimer's, Parkinson's and dementia.

MS experts have maintained that it is the death of neurons in the brain caused by the unknown disease process we currently call "multiple sclerosis", which leads to a lowered need for cerebral blood flow.   Their assumption has been that the hypoperfusion of the MS brain (which is a scientifically documented fact) is due to MS.  
http://ccsviinms.blogspot.com/2010/08/blood-flow-and-white-matter-lesions.html

But what if this chicken and egg supposition has been wrong?  Have 70 years of EAE postulation and drug development placed the focus on the wrong cells?

Dr. Hillman is urging other researchers to join her in the pursuit of understanding how the vascular endothelium and brain health are connected.  

“Our latest finding gives us a new way of thinking about brain disease—that some conditions assumed to be caused by faulty neurons could actually be problems with faulty blood vessels,” Hillman adds. “This gives us a new target to focus on to explore treatments for a wide range of disorders that have, until now, been thought of as impossible to treat. The brain’s vasculature is a critical partner in normal brain function. We hope that we are slowly getting closer to untangling some of the mysteries of the human brain.”

I share her urgency.  It was seven years ago when I first began looking at the correlation of endothelial dysfunction and neurodegenerative disease.  Blood flow to and from the brain matters.  Understanding how we can reverse endothelial dysfunction and oxidative stress--not only through future drug development---but through present day lifestyle, exercise, nutrition, UV rays, smoking cessation and other means-- is critical in helping those who are suffering from cerebral hypoperfusion found in MS, Parkinson's, Alzheimer's and dementia.

Here's the program I created for Jeff.  I hope it can help you, too!

http://ccsvi.org/index.php/helping-myself/endothelial-health

Time equals brain,

Joan

Full paper A Critical Role for the Vascular Endothelium in Functional Neurovascular Coupling in the Brain  http://jaha.ahajournals.org/content/3/3/e000787.full

Medications for MS: addressing blood flow

August 22, 2013 at 12:16pm

With the growth of research into the connection of MS to cerebral blood flow,  we've seen an interest in exploring new ways to address hypoperfusion (slowed blood flow), endothelial dysfunction (damaged blood vessels) and  brain atrophy (loss of brain tissue).

Why is this?  Because MS specialists, neurologists and advocacy groups are much more comfortable designing, testing and recommending a drug for MS, rather than encouraging healthy lifestyles and treating venous malformations.  You cannot monetize or patent a diet, exercise and angioplasty.  It's impossible to have a placebo-controlled clinical trial for lifestyle.  But you can develop a drug and make a lot of money selling it to a population with a chronic and degenerative disease.  

Please note that I am not recommending these specific drugs at all, I'm just pointing out how MS research is slowly shifting.  

We saw this paradigm change happen with the Vitamin D.  Six years ago, Jeff's neuro chuckled when I asked to have his D3 levels tested. But slowly, with independent research funded by patient advocacy groups like Direct MS,  the research paradigm has changed. And now, neurologists are testing their new patients' vitamin D levels, and adding supplementation accordingly. I believe we will see this shift continue with drug approaches to reducing hypoperfusion. 

This is tacet proof that blood flow matters in MS.  But you will not hear that from neurologists-yet.   They will discuss cerebral blood flow with their patients when they have a prescription they can write.  

Here's some info on a few of these new medications which target blood flow, currently in clinical trials.

Ibudilast (MN-166)

Clinical trials in progressive MS patients to be lead by Dr. Robert Fox and the Cleveland Clinic with the NMSS.  Dr. Fox received NMSS money to study CCSVI, and after finding new venous malformations in the jugular veins of people with MS, he has moved on to a clinical trial using a vasodilating and neuroprotective drug.  Is this coincidental?

http://finance.yahoo.com/news/medicinova-announces-initiation-cooperative-phase-230000864.html

MN-166 has been marketed in Japan and Korea since 1989 to treat cerebrovascular disorders, including post-stroke complications, and bronchial asthma. MediciNova licensed MN-166 (ibudilast), from Kyorin Pharmaceutical for potential utility in MS.

Lisinopril 

An inexpensive blood pressure medication and ACE inhibitor which modulates angiotensin.  This drug opens up blood vessels and allows blood to flow more easily. This older drug is being developed to treat MS by Dr. Lawrence Steinman of Stanford University School of Medicine.  (Dr. Steinman is also one of the inventors of Tysabri--which he has since spoken out against as a first line treatment for MS.) 

... angiotensin immediately causes blood vessels to constrict. “That raises your blood pressure so when you stand up to get out of a chair, you don’t fall down and faint,” said Steinman, who is also the George A. Zimmerman Professor in the medical school. But angiotensin overactivity causes chronic hypertension. Lisinopril controls blood pressure by blocking an enzyme that converts angiotensin’s precursor into the active hormone. The drug also appears to have certain anti-inflammatory properties.

http://med.stanford.edu/ism/2009/august/lisinopril.html

Here is info on the current study:

 In these studies, lisinopril reduced molecular measures of inflammation that accompany MS, yet it did not inhibit overall immune function.

link 

Statins

Although these cholesterol-lowering drugs failed in earlier trials for RRMS, they are now being brought back to life to address brain atrophy in progressive MS.  

Treating Neurodegenerative Diseases--a new approach

August 28, 2010 at 5:27pm

Here's a wonderful piece on a new way of treating brain diseases---a preventative/diagnostic approach rather than a search for a specific pharmaceutical cure--although this piece focuses on Alzheimer’s, I believe the logic behind preventative measures for brain health apply to all neurological diseases.  

"While the search for a pharmaceutical cure plays front and center, quietly in the background countless neuroscientists worldwide have concluded that Alzheimer's, as well as memory decline and other age-related dementias are actually slow-developing chronic diseases, like heart disease and cancer, partly dependent on lifestyle and other treatable diseases.

De la Torre, for example, is convinced that Alzheimer's and dementia are particularly tied to cardiovascular factors, notably, constricted blood flow to brain cells, and that midlife screening to detect and correct such heart-related deficits would help prevent much brain degeneration during aging. 

The special journal issue produced by de la Torre, called "Basics of Alzheimer's Disease Prevention," also included new research on the relationship between Alzheimer's and diabetes, high blood pressure, triglycerides, cholesterol and cholesterol- lowering drugs, (statins), a Mediterranean diet, exercise, fish oil, B vitamins and antioxidants.

http://www.huffingtonpost.com/jean-carper/post_752_b_695706.html