Parkinson’s Disease, Alzheimer’s Disease and Multiple Sclerosis: Is Angiogenesis a Treatment or Even a Cure?
By Dr. Jack Jacobs
A healthy and intact vascular system in the brain is critical for normal human functioning, both motor and cognitive. Any disruption in the brain’s blood perfusion system can lead to dire consequences, as the brain neurons are deprived of glucose and oxygen and begin to become dysfunctional. An attractive hypothesis that is emerging from a number of medical research groups is initiation of certain neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease and multiple sclerosis, occurs when the blood vessels and the blood supply in the brain becomes compromised. This can occur either globally (Alzheimer’s disease) or in a highly localized region of the brain as seen in Parkinson’s disease where in many cases only a very small number of dopamine-producing cells deep in the midbrain are affected. As will be discussed below, clinical research has conclusively shown that blood perfusion is diminished in these diseases.
Dysfunctional Blood Flow in Alzheimer’s Disease
In probably the largest study of its kind, researchers from McGill University in Montreal recently completed a study that examined the disease progression in over 1000 patients with Alzheimer’s disease. The researchers analyzed close to 8000 brain imaging studies and examined a number of biomarkers for Alzheimer’s disease, including brain hypo- perfusion, brain atrophy, cognitive decline, and the accumulation of beta amyloid protein. They looked at the 30-year trajectory of each of these markers in the disease and as seen in the figure below they showed that the very first changes seen in Alzheimer’s disease was a deterioration of the microvasculature leading to under-perfusion of brain neurons.
Disease progression in Alzheimer’s disease (AD) patients as analyzed by brain imaging and biomarkers for AD. Vascular deterioration (the brown line in the figure) preceded all other abnormalities, including plaque formation and cognitive decline.
These vasculature changes occurred before any of the symptomatic changes in AD occurred, including cognitive decline or accumulation of beta amyloid plaques.
Can Therapeutic Angiogenesis (Stimulating the Growth of New Blood Vessels) Be Used to Treat Neurodegenerative Diseases?
Therapeutic angiogenesis stimulates the growth of new blood vessels where they are required but where they are lacking. In US FDA-cleared clinical trials, therapeutic angiogenesis has been shown to replenish the blood supply to chronic diabetic foot ulcers to speed healing and preventing unnecessary amputations. Other studies have shown that therapeutic angiogenesis can bring healing to oxygen-starved hearts suffering from severe coronary artery disease, allowing “cardiac cripples” to function close to normal again. There is no reason therapeutic angiogenesis could not be applied to Alzheimer’s disease and other neurodegenerative disease to reverse and reestablish the growth of blood vessels in the brain, thereby restoring an adequate amount of blood perfusion to allow the brain’s
neurons to remain healthy.
Fibroblast Growth Factor 1 (FGF-1), a Potent Stimulator of Angiogenesis
FGF-1, stands out due to its potency and its ability to stimulate the production of not only capillaries, but larger arterioles, which are critical in bringing more blood into the injured tissue. FGF-1 is a natural protein contained within our bodies. It is released upon tissue injury and is the body’s natural response to tissue repair. It has also been shown to be a neurotrophic factor, which is the stimulation of new neuron growth, and it is this characteristic, in addition to its angiogenic properties, that is being exploited for its development as a drug to treat neurodegenerative diseases.
Multiple Sclerosis as a Disease of Vascular Dysfunction
Although multiple sclerosis (MS) has traditionally been viewed and researched as an immune-mediated disease of the brain and spinal cord, recent hypotheses suggest that vascular components may be initiating triggers for the neuronal pathology seen in this disease.
In multiple sclerosis, researchers now believe that a perfect storm of genetic and environmental factors can act together on the brain’s microvasculature and the blood brain barrier resulting in a lack of nourishment to the neurons. This dysfunctional barrier leads to the leakage of immune cells into the central nervous system which then attack neurons as shown in the figure below.
MS is a Vascular Disease. On the left, a healthy blood vessel leads to optimal blood flow and healthy neurons. On the right, multiple insults lead to disruption of the blood-brain barrier resulting in leakage of immune cells and toxic proteins (fibrinogen) which damage neurons in the vicinity.
These two processes, reduced blood flow and disruption of the blood brain barrier, appear to interact in a vicious cycle, driving the destruction of neurons and the generation of focal lesions in the central nervous system, the hallmark of MS pathology.
Parkinson’s Disease is Initiated by Vascular Dysfunction
As discussed above with Alzheimer’s disease and multiple sclerosis, here is also a growing body of evidence that Parkinson’s disease is initiated by vascular dysfunction. Newer imaging technology (functional MRI) can accurately and with high sensitivity determine blood flow in different regions of the brain. A recent study looked at blood flow in the region of the brain that is affected in Parkinson’s disease, a relatively small region deep in the midbrain known as the substantia nigra region of the brain.
The figure below examined blood perfusion in that region of the brain in healthy adults and in adults with Parkinson’s disease. As seen in this figure, blood flow in this region of the brain decreases a significant 50% in patients with Parkinson’s disease (orange bar) when compared to healthy 21-year old’s (blue bar).
The hypothesis is that a lack of blood flow initiates the onset of Parkinson’s disease by choking off the dopamine-producing neurons from nourishment and inefficient removal of metabolic wastes that all functioning cells in our bodies produce. Long-term lack of proper blood supply to this region of the brain eventually leads to the death of these neurons and the progression of Parkinson’s disease.
Previous work in animal models of Parkinson’s disease have indicated that growth factors, such as human FGF-1, can restore motor function in both rodent and primate models of this disease. As shown in the figure below, FGF-1 when given over a period of 6 months, substantially improves motor function in monkeys with experimental Parkinson’s disease. The monkeys were given Parkinson’s disease by injecting a toxin into their brains which selectively destroys dopamine-producing cells. Administration of FGF-1 to these animals results in a significant improvement in their motor skills when compared to animals who received a placebo dose as seen in the right hand side of the figure.
Clinical trials are now being initiated in which subjects with Parkinson’s disease will be treated with human FGF-1. Given that FGF-1 can both potently stimulate the production of both new blood vessel growth and new neuron growth in the brain, make it an attractive candidate to test in Parkinson’s disease and other neurodegenerative diseases.
Don’t miss Dr. Jacobs’ presentation on this topic at the FreedomFest being held in Las Vegas on Friday July 19, 2019 at 11:00 am in the Versailles 2 room. His talk entitled “Cures for Parkinson’s, ALS, Alzheimer’s and Heart Disease are Closer than You Think!”
Dr. Jacobs is President and Chief Science Officer of Zhittya Genesis Medicine, a Las Vegas-based biopharmaceutical company that is developing regenerative biotechnology products through FDA-authorized clinical trials.
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