Alzheimer's, ADHD, Parkinson’s and other Neurodegenerative disorders

Paul L. Reller L.Ac. / Last Updated: August 03, 2017

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The history of the causes of increases in incidence of Parkinson's, Alzheimer's and other neurodegenerative diseases and syndromes

The history of the causes of the neurodegenerative disorders such as Parkinsonism and Alzheimer's disease, which are now known to progress gradually from mild neurodegeneration to the alarming clinical states that most of us associate with the diseases, reveals to us not only the mistakes we made, involving a number of key factors in public health and private choices, but in their solutions.

In the 1950s the food industry stripped vegetable oils of Omega-3 fatty acids to extend the shelf life on products and allow for more success in corporate food production, creating public essential fatty acid imbalances. Transfats were substituted, such as margarine and shortening, for normal healthy and naturally balanced fats in our foods, mainly to increase shelf-life of mass produced foods for supermarkets, and a dramatic increase in incidence of Parkinson's and other neurodegenerative disorders subsequently occurred. Scientists now have linked an imbalance of essential fatty acids to this neurodegenerative pathology. Essential fatty acid balance is a key aspect to immune function and physiological ability to clear excess oxidative free radicals and repair unhealthy tissues. This isn't the complete answer to the cause of neurodegeneration, but it is an important piece of the puzzle, as our research found an array of factors that contributed to this neurohormonal missense generated by such factors as fatty acid imbalance, inflammatory dysfunction, and oxidative stress. As mentioned previously in this article, commercial food production also produced advanced glycation endproducts (AGEs) during this time period, which produced dysfunction in a different way, affecting membrane health and important glycoproteins. At the same time, our country expanded energy production dramatically, mostly with coal fired power plants that spew tons of organic lead and mercury molecules into the air, which enters our lungs, and becomes part of the food and water supply. These heavy metal contaminants accumulate in our brain tissues and eventually cause many problems with neural firing and oxidative clearing (a complete article on lead, mercury and heavy metal pollution is also available on this website). The widely used herbicide paraquat and other pesticides and herbicides have also been implicated in neurotoxicity and Parkinson's disease, and were introduced in this same time period of a dramatic increase in these neurodegenerative diseases. These combinations of unhealthy and poorly regulated environmental toxicities and harmful products of industrial food production are at the root of the explosion of neurodegenerative diseases in the modern population. While we continue to have an unrealistic hope that a single allopathic chemical will just eventually be created to block just one aspect of this complex cycle of causes and repercussions, this will not happen. An integration of treatment protocols to address the whole cycle of dysfunction is needed, and both a number of pharmaceutical allopathic chemicals, and perhaps deep brain stimulation, will need to be combined with intelligent Complementary and Integrative Medicine to achieve the complex holistic treatment protocol needed to reverse and correct this degeneration of the brain, and for many of us, hopefully, to prevent it.

In 2012, a study at Columbia University in New York, headed by Dr. Nikolaos Scarmeas MD, and published in the online medical journal Neurology, confirmed that sufficient levels of omega-3 fatty acids in the diet, such as EPA and DHA, was the most significant nutrient dietary factor associated with lower levels of problematic beta-amyloid proteins AB40 and AB42 in blood plasma, which are linked to plaque accumulation in the brain and Alzheimer's neurodegeneration.

Previous study of diet and neurodegeneration by this research team had indicated that populations that ate a so-called Mediterranean-type diet, with an array and balance of healthy fats, showed a decreased risk of neurodegenerative disease and cognitive impairment (dementia). This further study showed that the decrease in omega-3 fatty acids in the modern diet, a consequence of the modern processing of common vegetable oils to achieve longer shelf-life of processed foods, was directly responsible for increased levels of beta-amyloid, the so-called "sticky protein", which is the key component of neurodegenerative "tangles" associated with Alzheimer's disease. The study group also reviewed levels of saturated fats, monounsaturated fats, omega-6 fatty acids, folate, beta-carotene, and the vitamins C, D, E and B12, to see if these affected the levels of circulating beta-amyloid. None of these nutrients showed a significant relationship to the problematic types of beta-amyloid proteins in blood plasma. This analysis (a study review is available below in additional information) confirms that the change in the content of fatty acids in processed vegetable oils and transfats is responsible for a key factor of neurodegenerative disease, the increase in problematic types of beta-amyloid "sticky proteins" in circulation contributing to the gradual formation of beta-amyloid plaques in the brain, the hallmark of Alzheimer"s disease. This analysis does not rule out the other contributing factors to the disease, but does confirm what many experts have surmised is a key public health factor that has led to the extreme rise in neurodegenerative disease in the United States. Omega-3 essential fatty acids are a group of fatty acids we obtain from our food (essential), and diets that are dominated by consumption of red meat and processed foods create the most deficient states. Over time this creates a metabolic imbalance, and it may take some time to correct this dysfunction. Simply taking an Omega-3 supplement for a few weeks will not magically correct the long-term consequences in the body, and a more holistic and persistent regimen will be needed.

This problem affects a very large percentage of the population, most of whom could be diagnosed with a milder subclinical stage of the diseases if there were available tests. Today, more than 5 percent of people over 75 are diagnosed with some type of serious neurodegenerative disorder, or dementia, and as far back as 1989 studies by Brigham and Women's Hospital in Boston, published in the Journal of the American Medical Society, stated that an estimated 10.3 percent of the population over 65 years of age had probable Alzheimer's disease (JAMA 1989 Nov 10;262(18):2551-6). This means that perhaps 10 percent could be diagnosed with some stage of just one type of these neurodegenerative diseases in 1989, and another 10 percent with other types, and it is clear that the incidence has worsened since 1989. Less serious neurodegenerative disorders, such as attention deficit and hyperactivity disorder, affect an even greater percentage of the population, even our children. These numbers are growing and do not even reflect the undiagnosed population who are just thought to be suffering from the effects of aging, called mild cognitive dysfunction clinically, and cynically called senility in the past. Incidence of neurodegeneration are not just limited to the elderly population, either, as new research uncovers the pathophysiology of Attention Deficit and Hyperactivity Disorder, and this disease too shows that measurable neurodegeneration is occurring, even in children. Early stages of serious neurodegenerative disorder may be without symptoms (asymptomatic) for many years, and treatment at the end-stage may only accomplish a slowing or stopping of the neurodegeneration that causes symptoms at this stage. The aging baby boomer population, and indeed all of us, need to understand that there is a need to act now, both to prevent and reverse one's own neurodegeneration, but also to act now to get our government to address the causes of neurodegenerative diseases in our country. Early diagnostic assessment and introduction of healthy Complementary and Integrative Medicine is the key to a successful treatment protocol.

Of course, changing our commercial food industry, as well as our energy sector, and other industrial concerns that obviously contribute to this alarming rise in neurodegenerative disease will cost a lot of money. To counter the awareness of environmental causes of neurodegenerative disorders and subsequent alarm by the public, many articles and research studies were engendered by industry funding espousing a genetic link to these disorders, rather than an environmental cause. So far, scientific study has found only rare links to potentially inherited Parkinson's and Alzheimer's, though. A mutation of the LRRK2 gene called PARK8 was found in only 5 percent of the Parkinson's population, showing little causative genetic link in reality. Studies of the Major Histocompatibility Compex (MHC), a part of the genetic code that is individualized or subtyped to regulate autoimmune processes, as well as the complement system in our adaptive immune system, have found numerous phenotypes and allelotypes linked to Alzheimer's disease, but follow-up studies often found contradicting data. A simple genetic answer to these diseases will not be forthcoming, especially as we now know from mapping the human genome that it is controlled in a very complex manner, with genes affecting other genes, the epigenetic code affecting these genes, and a separate genetic code in each cell that is varied, located in the mitochondria. The genetic component to these diseases involves a quantum field of factors, and effective medical approaches will thus require a holistic genetic approach. This may not happen anytime soon. The public needs to be diligent to get our government to clean up heavy metal toxicities and to regulate the food industry to prevent these types of neurodegenerative health problems for future generations. The real causes of these neurodegenerative pathologies are not genetic, but a combination of public health issues, industrial food production, environmental toxins, overuse of antibiotics, immunodeficiency, and lifestyle stress. Unless we become educated to this complex problem and act now, the population of the United States is going to face ever increasing problems with these neurodegenerative diseases. Since the cost of care of these patients, and the loss of productivity, is enormous, this health problem affects not only the patients, but all of us, especially when the cost of health care and social spending has already spiraled out of control.

What are the causes or contributors to attention deficit and hyperactivity at an early age? ADHD has also proven to be a neurodegenerative condition, even at an early age. We all know by now of the growing problem of hyperactivity in children and the treatment with the dopamine reuptake inhibitor Ritalin that is also used to treat adult ADHD. Clinical blinded placebo trials have shown that such chemicals as artificial food coloring and sulfite and benzoate preservatives have increased hyperactivity in both children and young adults diagnosed with the disorder (see study links in Additional Information). How do benzoate preservatives and artificial food dyes contribute to neurodegenerative pathology? Once again, the answer is complicated, but a few key points elucidate the basic process. Read on.

Benzoic acid, a common food preservative, has been demonstrated to cause oxidative stress. These preservative acids also have a negative consequence on cellular membranes, that both act to insure effective metabolism at dopamine receptors, and to protect the cell from environmental cytotoxins that enter the bloodstream. Cell membranes protect the mitochondria in our brain cells, the small oxygen factories that supply energy to our cells, and which are the subject of much study of the root of neurodegeneration. While organic food preservative acids, such as benzoic and sorbic acid, are stable, or cytostatic, under conditions used for food preservation, they may cause a disruption of the cellular plasma membrane and cause a cytocidal effect when they reach our brain, especially under acidic conditions in the body. Acidity in the body is increased when there is too much intake of simple carbohydrates like sugar, refined grain, beer, granola, etc. Periods of high body acidity may also occur with poor stomach function, or poor hormonal regulation of key antacids, such as calcium. High body acidity may make benzoic acid food presersetives toxic and damaging to our brain cells.

High intake of benzoic acid preservative, coupled with a lack of healthy fats, or lipids, that make up the phospholipid membranes, and with a deficiency of oxidative potential to clear the damage, results in neurodegenerative cell death and functional cell membrane disruption that may occur at an early age. As mentioned, advanced glycation endproducts (AGEs) are also a dietary and metabolic problem that affects healthy cell membranes. When children eat too much processed food with these ingredients, it is easy to understand how the health of their brain cells are damaged. The problem in children is probably easily reversed by sticking to a healthy diet that avoids preservatives and food dyes, transfats, and simple carbohydrates, and includes sufficient antioxidant foods and omega-3 fatty acids. Even parents that believe that they are keeping their children's diet healthy are sometimes mistaken, as large intake of fructose, in the form of fruit juices and supposedly healthy carbonate beverages, can create an excess of AGEs. Over time, without ingredients for cellular repair, such as antioxidants, essential fatty acids, attention deficit and hyperacitivity disorder may become chronic. All scientific studies of neurodegeneration now demonstrate a measurable decrease in tissue quantity in key areas of the brain that are the result of this type of cellular damage, utilizing newer functional MRI imaging. This objective data is irrefutable.

All of the above causes of neurodegeneration leave our bodies more susceptible to inflammatory degeneration. Most studies of neurodegenerative disorders now focus on excess inflammatory processes and lack of oxidative clearance as the prime problem in neurodegeneration. Studies show that increased exposure to viral illnesses, and the penetration of some strains of these viruses deep into the organ tissues, generates excessive lipopolysaccharides that are released from antigen cell walls, and increase pro-inflammatory cytokines such as interleukin-1 (IL-1) and TNF-alpha. The chronic increases in expression of IL-1 has been shown to have both direct and indirect mechanisms that exacerbate neurodegeneration of dopaminergic neurons as well. IL-1 directly triggers 6-OHDA-triggered dopaminergic toxicity, and increases oxidative stress. Lipopolysaccharides were found to directly accelerate and increase motor signs in study animals, showing a positive link to direct hyperactivity cause. Some of the new pharmaceutical utilized (e.g. Enbrel) inhibit the cytokine TNF-alpha to reduce symptoms. These same effects, inhibition or modulation of inflammatory ctyokines, are proven to be achieved efficiently with herbal medicine. We can't completely eliminate viral illness from our world, but we can work to create a healthier response to viral illnesses in our bodies. Complementary Medicine has many therapeutic tools to enhance the immune system as well as directly help in inhibiting the harmful imbalances of inflammatory mediators. Scientific study allows the TCM physician to better utilize these herbal chemicals and specific acupuncture stimulations to achieve these goals.

In summary, the known history of causes of increased incidence of neurodegenerative disorders in the United States population include unhealthy ingredients in commercial processed foods that go unregulated, increasing amounts of lead, mercury and other heavy metal organic compounds, primarily from dirty coal fired power plants that go unregulated, and the increased oxidative stress and decreased immune health generated by our modern lifestyle, diet, and environment. Hormonal imbalance has also proven to play a significant role in mitochondrial dysfunction and neurodegeneration. As individuals, and as a population, we can change these harmful aspects of our world now, and clean up both our own bodies, and the environment. By utilizing Complementary Medicine, understanding and improving our habits, and urging our politicians to act now, future generations as well as our own will benefit immensely.

The continuing debate over Causes of Neurodegenerative Disorders and the Negative Effect on the Approach to Treatment

To date we still have strong debate about the very nature of Parkinson's, with researchers arguing over the location of the origin of the disease in the central or peripheral nervous system. There is also strong debate continuing over the location of the metabolic and neural oscillations that trigger the tremors and disrupt the cognitive processes, with some arguing that the origins lie within the cells, and others arguing that the neuronal network is responsible. Standard therapeutic approaches with pharmaceutical agents continue to be disappointing, and remain focused on increasing dopamine purely for lack of a better strategy, and despite the fact that we now know that even the dopamine deficiency is related to an imbalance of dopamine stimulation at various receptors, rather than a simple matter of poor dopamine availability. One thing is for certain. This disease is a neurodegenerative disorder that demands a multifaceted and holistic approach in treatment. Research into Parkinsonism has also provided us with a wealth of knowledge and treatment strategy for all of the other neurodegenerative disorders. There is no single pill that will reverse neurodegeneration, which is a complicated multifactored disease mechanism.

We must adopt a more holistic strategy to really prevent, manage and cure Alzheimer's disease, Parkinsonism, and the host of other neurodegenerative diseases that are increasing in incidence in modern industrial societies at an alarming level. While a vast amount of research now shows us that the causes are many and complex, we still resist a more multifaceted approach in treatment, hoping for the single allopathic chemical that will one day miraculously cure these conditions. This is a fairy tale, and the argumentative debates should stop, and a multidisciplinary and holistic approach should start, where all of this research is combined to achieve a workable solution. Obviously, this will require an integration of Complementary Medicine, and not only standard medical doctors, but the patients with early signs of the disease, and the caregivers responsible for the patients with advanced disease must realize this fact.

At the same time as we continue to debate which factor is the real cause of these disorders, much research has supported a variety of key strategies for both relieving symptoms and reversing the neurodegenerative aspects of Parkinson's, as well as Alzheimer's, Attention Deficit Disorder, and other neurodegenerative diseases. We now know that even glaucoma is a neurodegenerative disease. Complementary Medicine must play a key role in these treatment strategies. These include stimulation and bioavailability of dopamine in the central nervous system, coupled with replenishment of endocannabinoids and cholines, which are needed to restore a balance in the regulating cells of the substantia nigra, caudate and putamen striatum of the basal ganglia, to help control the tremors and loss of motor control. Restoration of healthy cellular function is also a key, especially health of the mitochondria, or oxidative energy-producing parts of the cells, which contain the key protein enzymes of the fatty acid oxidation and citric acid cycle. Antioxidant therapy and balance of essential fatty acids, with increase in Omega-3 DHA and EPA are also keys to neuroprotective strategies. Recent research has focused on adrenal stress and chronic overstimulation of neuroreceptors as a key aspect of the overall pathophysiology. Here too, acupuncture and herbal medicine can play a key role in improving the treatment outcome. Acupuncture, or TCM, utilizes a combination of therapeutic protocols based on sound scientific evidence. The licensed Acupuncturist may be skilled and knowledgeable with nutrient therapy, herbal medicine, needle stimulation, and lifestyle advice. This combination is very important when treating or preventing neurodegeneration. Neurodegenerative disease, because of its complex nature, requires a thorough, comprehensive, and persistent treatment approach. Anything less is doomed to failure.

Not only healthy treatment strategies must be added together, but unhealthy causes must be systematically eliminated as a whole. Neurodegeneration usually occurs gradually over time, and the causes are usually multifaceted. Chemical causes are the chief concern, but hormonal imbalance, effects of aging, physiological stress, and a genetic or epigenetic inherited propensity to neurodegeneration are also important concerns. In recent years, theories of a systemic bacterial endotoxicity (see the article on this subject on this website) creating an inflammatory response, has been added to the factors that may cause neurodegeneration and Parkinsonism. Overuse of antibiotics and creation of many antibiotic-resistant strains of bacteria may have contributed to endotoxicity. These disorders present both a public health threat that should be addressed by our government, as well as an individual threat, that should be addressed by the physician most important in the treatment team, you. The individual must take a more proactive approach to prevent or treat neurodegenerative disorders. The complexity of the problem should not deter the individual from taking decisive action, and the Complementary Medicine physician is ideal to integrate into this treatment and prevention strategy at any level. Food additives, preservatives, unhealthy diets, environmental toxins, especially heavy metal toxins, adrenal stress, oxidant stress, fatty acid imbalance, endocrine disorder, especially melatonin dysregulation (e.g. workers on the night shift, or airline attendants), chronic inflammatory states, and advanced glycation endproducts (e.g. patients with obesity, metabolic syndrome, or atherosclerosis) are all significant factors implicated in the pathology of neurodegeneration. This array of causes and contributors is now supported by sound research. Some other important causes are still less well known.

Neurodegeneration and mitochondrial dysfunction may also be a result of iron overload toxicity. Iron is an important metal ion in our body and the levels of iron are usually tightly controlled. Since iron is highly reactive as an oxidative agent, normally up to 70 percent of our iron is bound to the ferritin or transferrin proteins, or other transport and storage proteins, where it cannot participate in oxidative reactions. The fact that it is able to oxidize quickly (as in rusting outside of the body) makes it an ideal carrier of oxygen in our red blood cells. When the neutralizing capacity of these storage and carrier proteins is exceeded, excess iron binds weakly to other proteins in the blood and cells, where it participates in oxidative reactions and peroxidation of cellular components, or organelles, such as mitochondria, lysosomes, and sarcoplastic membranes (integral to nerve conduction). Iron overload toxicity is not uncommon, but is only looked for in diagnosis when it becomes very serious, resulting in heart disease, dysfunctions of the pancreas or liver, or gonadal dysfunction and infertility. Patients with thalassemia, sickle cell anemia, hepatitis, cirrhosis, chronic inflammatory conditions (e.g. autoimmune disorders with rheumatic disease and positive rheumatoid factor), infections, alcoholism, repeated transfusions, or even in patients that take too many iron supplements, or eat an unusual excess of red meat, may have a history of iron overload toxicity. If the iron in our bodies is not handled by the appropriate metabolism of transport and storage, gradual accumulation in tissues may lead to a neurodegenerative condition, and iron chelation may have a positive effect.

An array of food additives called excitotoxins, such as hydrolyzed vegetable protein, aspartame, and MSG, are also the subject of much research into neurodegenerative pathology and central nervous system (CNS) dysfunctions that may lead to neurodegenerative states. A growing body of sound research has linked these food additives to a wide array of neurological problems, including Parkinson's disease, Alzheimer's disease, Huntington's disease, ALS, learning disorders (ADD), developmental disorders, neuropsychiatric disorders, dementia, and even obesity, migraines, seizure disorders, certain endocrine disorders, and CNS problems in chronic aftereffects of Lyme's Disease. These food additives are now present in almost all processed foods. Since scientists discovered health risks associated with MSG additives in the 1970s (MSG is a natural glutamate compound that enhances neurochemical systems related to attraction and enjoyment of food), the food industry did not heed public health warnings, but instead developed a vast array of glutamate compounds, called excitotoxins, that increase our desire to buy their products.

Today, MSG-like excitotoxins are disguised as "natural flavorings", soy protein extract, textured protein, yeast extract, hydrolyzed vegetable protein, and artificial sweeteners such as aspartame (read below to gain a better understanding of aspartame). These altered glutamate molecules accumulate in the brain and cause neural dysfunction over time, as the amino acid glutamate is a key basic building block of many important regulatory chemicals in our brain, as well as itself being a neurotransmitter. Since glutamate is tightly controlled in the brain, and is normally kept at very small concentrations in extracellular fluid, these altered glutamate compounds begin to overload neural firing as they accumulate. The main drug used to treat Parkinson's disorders is L-Dopa, or synthetic dopamine, which itself is a weak excitotoxin that has now been proven to actually accelerate Parkinson's neurodegeneration with chronic use. At first, L-Dopa may relieve symptoms, but in time these symptoms will worsen in an accelerated fashion. The public needs to start expressing outrage that our food industry treats food chemistry with such a cavalier attitude, and demand that the commercial food industry hire public health experts to guide what they put into our food. Surely, we could have processed foods that improve our health rather than destroy it.

Studies investigating the role of bacterial endotoxins in neurodegenerative pathology have turned up some surprising evidence of a multifactorial component to Parkinson's disease. Researchers at Texas Christian University, in 2007 (cited below), found that a combination of inflammatory bacterial endotoxin lipopolysaccharide (LPS) promoted significant dopamine depletion and neurological impairment only when combined with a neurotoxin (MPTP). Such research shows that the various environmental toxicities linked to neurodegeration may only cause significant disease symptoms when combined. To date, research into studying these multifactorial causes has constituted only a small portion of the research. This is because research today is dominated by a need to produce a single allopathic pharmaceutical, and is not centered on purely finding the true array of causes of disease. The neurotoxin studied, MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), has been proven to cause permanent symptoms of Parkinsonism, and so has been utilized as a study model. MPTP may be produced during the manufacture of street narcotics that include MPPP, a synthetic opioid, and the investigation into these drugs led to the discovery of the neurotoxicity of MPTP. MPTP by itself, though, cannot cause neurotoxicity, and the subjects affected by this chemical apparently had other symbiotic factors that caused the neurotoxicity. The search for these symbiotic factors has led to many interesting findings in the etiopathology of Parkinson's. Such research confirms that an array of factors must work together to cause severe disease. Chronic inflammatory pathways, reactive oxygen species, and chemical neurotoxins in the environment are the most likely trio of causes that work synergistically to cause neurodegeneration in most subjects.

Neurohormonal imbalance in Neurodegenerative disease

One intriguing theory as to the origins of the pathophysiological mechanisms that create the Parkinson's syndrome, that has resulted from the more holistic research in recent years, examining the various interrelated problems in the central nervous system, has been the theory that Parkinson's is the result of a neurohormonal imbalance related to melatonin and dopamine interactions. It has been discovered that dopamine supplementation may work to some extent because it has an effect on the circadian production of melatonin, and that deficient circadian melatonin production leads to hyperplasia in key areas of the brain through a variety of mechanisms, including the lack of antioxidant acitivity that melatonin provides. Since the neurotransmitters in the brain are constantly being produced and converted in a balancing manner, restoration of neurohormonal health may be a more productive strategy in the long term therapy than simple supplementation or inhbition of specific neurotransmitters. A 2008 summary of this scientific study from the Brownoski Institute of Behavioral Neuroscience in Victoria, Australia, states: "For the first time, abundant evidence is presented describing Parkinson's Disease (PD) as an endocrine disorder of melatonin hyperplasia. The role of circadian interventive therapies and internal desynchrony in the aetiology and progression of PD provides a new direction for understanding the underlying physiology of a disease which is currently in a state of impasse and provides new hope for those who suffer from its debilitating effects." Melatonin hyperplasia refers to a condition where melatonin producing cells are abnormal in number. This condition would occur when there is a deficiency of melatonin and increased need, or when the hormonal feedback system is stimulating a need for increased melatonin production.

Melatonin is both a hormone and neurotransmitter, and increases in melatonin production and secretion occur naturally in the circadian cycle of wake and sleep at night. In 2010, studies found that more than 10 percent of Americans suffer from insomnia, implying that circadian melatonin imbalance is perhaps a problem for a large number of people (35 million). Secretion of hormones and neurotransmitters in the brain, as well as metabolic conversion and creation of these molecules, is fundamental to healthy brain function. Both the nervous system and the endocrine system must be involved and coordinated in this process, making restoration of health a complicated problems. Research in recent years has explored this link between insomnia and neurodegenerative disease, as there is a very high rate of insomnia and sleep disturbances, such as sleep apnea and anxiety disorder, in the population identified with neurodegeneration. Simply taking melatonin has not been effective, as the much regulated neurohormonal system quickly adapts to supplementation and renders this ineffective after a short period of time. Combinations of herbs and supplements that aid the various balancing mechanisms have been researched because of this, and a combination of cofactor Vitamin B6, 5HTP, St. John's Wort, and melatonin, is one intriguing combination created by the company Vitamin Research. A comprehensive therapeutic protocol is recommended to achieve better sleep and melatonin metabolism, though, and utilization of acupuncture, herbs, nutrient medicine, and hormonal balancing may be needed for an eventual return of healthy neurohormonal function and balance.

Melatonin is produced in abundance by the pineal gland in the cycle of day and night, and this rhythm of secretion is controlled by various suprachiasmatic nuclei in the hypothalamus, the command center of the endocrine, or hormonal system. There is evidence of much occurence of deficient hypothalamic function in the aging population, often related to subclinical hypothyroid disorders and adrenal stress syndromes, and this could cause decreased melatonin bioavailability and stimulate melatonin hyperplasia. Melatonin has a variety of functions in the brain besides stimulating deeper sleep, and has remarkable antioxidant effects. These antioxidant effects are extremely important to maintaining healthy brain cells, as melatonin both stimulates free radical oxidant clearing, and creates melatonyl radicals in this process that combine with superoxide anions (charged mineral molecules) and detoxifies them. Melatonin also stimulates other antioxidant and detoxifying activities, stimulating increases in superoxide dismutase, glutathione enzymes, and glutathione, which is the fundamental detoxifying chemical in our body (read about glutathione metabolism in another article on this website). Researchers at the Hospital Neuro-Cardiologique in Lyon, France, in 2005, explain the complex role of melatonin in our bodies: "The circadian organisation of other physiological functions could depend on the melatonin signal, for instance immune, antioxidative defences, hemostasis, and glucose regulation. Since the regulating system of melatonin secretion is complex, following central and autonomic (nervous system) pathways, there are many pathophysiological situations where the melatonin secretion can be disturbed." (PMID: 15649735). This certainly implies that a thorough holistic treatment protocol is needed in melatonin imbalance, and with careful analysis and a multifactorial treatment tailored to the individual, melatonin production in the circadian cycle can be restored. While increasing melatonin bioavailability may not immediately relieve symptoms of Parkinson's disorder and other neurodegenerative disease, it is a key aspect of the long-term holistic therapy. Research has found that a modest dose of melatonin combined with other cofactors for bioavailability of neurotransmitter precursors, such as P5P and 5HTP, may be the best therapeutic approach, which are combined in the professional nutrient medicine Positrol (Vitamin Research Products). A companion to this supplement formula was advanced through research into the effects of L-Phenylalanine, and Syncholamine may be taken in the morning to improve daytime mood and brain function, or the formula Adrenosen (Health Concerns), with L-phenylalanine and PKA, may be taken with Positrol.

The most important neurohormone involved in circadian rhythms (variations during the 24 hour cycle) is cortisol, a glucocorticoid constantly secreted by the adrenal (tip of the kidney) gland. In hormonal analysis diurnal cortisol levels are very important, and often clearly relate to symptoms. With adrenal insufficiency, or adrenal stress syndrome, cortisol production may be sluggish, resulting in low cortisol during the day and excess production at night, which accounts for daytime sluggishness and insomnia, as well as a cycle of depressed affect during the day and anxiety in the evening and night. Cortisol is also intimately involved in maintaining blood pressure, glucose and fat metablism, muscle weakness due to impaired glucose uptake, protein catabolism, fat redistribution, limited immune responses, and variability in immune suppression and excess immune responses. TNf-alpha, a key immune mediator involved in cellular degeneration and neurodegenerative conditions, may be significantly inhibited by diurnal cortisol imbalance. Recovery of this systemic and chronic condition will not happen overnight. The patient needs to patiently work to restore diurnal melatonin and cortisol homeostasis, address adrenal insufficiency, correct subclinical hypothyroid conditions, and hypothalamic insufficiency. Of course, for those of us that fear neurodegenerative conditions, we need to address these subjects earlier in life, before the neurodegenerative condition becomes symptomatically severe. As we age and are challenged by menopausal and andropausal hormonal deficiencies we should have an analysis of hormonal balance and work to achieve better hormonal homeostasis. The utilization of relatively inexpensive tests to give a hormonal profile with analysis of active hormonal metabolites in saliva and veinous blood stick samples provide the patient and physician a clear objective basis for this rebalancing and restoration.

Recent research has uncovered a number of ways to help restore cortisol balance. A 2010 research study sponsored by the NIH at UCLA proved that deep tissue massage (called TuiNa in Traditional Chinese Medicine) dramatically improved cortisol levels and regulatory modulation (see the article entitled Deep Tissue Massage and it's many benefits on this website. Since cortisol is an adrenal hormone that operates in a feedback mechanism within the neuroendocrine system, therapy to balance hormonal homeostasis, with acupuncture, topical bioidentical hormone creams, and herbal and nutrient medicines, as well as stress reduction therapies, are all important aspects of a comprehensive protocol that may be individually tailored to each patient. Inexpensive tests utilizing saliva samples to measure active hormone metabolites may be utilized to guide this type of therapy. The only way to find out how well this approach works is to try it.

Hypothalamic hypofunction or dysfunction has also been implicated in neurodegenerative disease in other ways than melatonin imbalance. The hypothalamus, coupled with the pituitary, is the chief gland of the brain involved in neurohormonal balance, and the command center of the endocrine system. The glutamate and NMDA metabolism is integral to both hypothalamic function and is implicated in neurodegenerative disease. Excess glutamate metabolism was found to be involved in acute strokes and brain cell destruction in the past, and research showed that the long term effects produced cell death, or apoptosis. This spurred much research into the possibility that excess glutamate could be responsible for neurodegenerative cell damage and death. Today, NMDA glutamate receptor antagonists are used to treat various neurodegenerative diseases. These same drugs were found to affect the hypothalamic functions, and hypothalamic dopamine and corticosteroid metabolism, as well as pathologies related to hypothalamic dysfunction and hormonal imbalances of prolactin. Excess glutamate metabolism was found to hyperstimulate the hypothalamus and result in stress-induced high circulating prolactin and corticosterone. Today, much research has revealed that many patients may suffer form a subclinical hypothalamic deficiency, or hypofunction, that is related to various hormonal imbalances seen clinically. More physicians are treating the hypothalamic dysfunction in a system of hormonal restoration with bioidentical hormones, herbs, nutrient medicine, and acupuncture. Further research may show the potential for benefits in such hormonal restoration as it effects the dysfunction of glutamate metabolism in regards to neurodegenerative disease.

Another aspect of neurodegenerative pathology related to hormonal deficiency and imbalance is the subject of estrogen deficiency and its role in mitochondrial dysfunction. The mitochondria are small parts of the cell that produce much energy from glucose. It has been well established that the mitochondrial dysfunctions are responsible for much of the oxidative stress that leads to neuron degeneration. In 2008, researchers at the University of Southern California Program of Neuroscience found that estrogens signal a number of pathways of cell protection and enhance mitochondrial function (see the link in additional information at the end of this article). Estrogens were found to maintain calcium homeostasis, enhance glycolysis (glucose usage), sustain and enhance mitochondrial functions, protect against free radical oxidative damage, and aid cholesterol metabolism and clear beta-amyloid stick protein accumulation. All of these mechanisms enhanced natural neural defense and maintenance, and explains why many women suffer from neurodegenerative disorders post-menopausally. Some neurodegenerative disorders are seen at a relatively early age postmenopausally, such as primary aphasia, and could be highly related to the estrogen deficiency. The estrogens are a family of hormones that include the abundant estriol, and the more active estrone and estradiol. Synthetic estrogens in hormone replacement are problematic, with much research revealing the array of risks and side effects, but natural bio-identical hormone therapy is becoming very common now. These estrogens must be balanced in the body, and also balanced with the hormone progesterone. Progesterone itself is now proven to aid neural health, with large studies proving, for example, that progesterone administered after traumatic brain injury reduces mortality and achieves a dramatically improved long-term functional improvement in cognitive functions. Achieving physiological normal production of estrogens and an estrogen progesterone balance could both prevent neurodegenerative conditions and treat them effectively. Of course, once neurodegeneration occurs, the treatment protocol should be more thorough, in order to address the many aspects of the cascade of problems seen in study. The research at USC also reveals that there is a danger of metabolic exacerbation with advanced neurodegenerative disease with the use of higher dose synthetic estradiol, since the same mechanisms that would drive improvement in healthy neurons may stimulate exacerbation in unhealthy ones. This is why the use of very low dose bioidentical estriol cream with careful monitoring and hormonal balance is believed to be a potential successful strategy.

Hormonal balancing, especially with restoration of the melatonin and estrogen metabolism, is thus the linchpin of a more thorough holistic protocol when trying to reverse neurodegeneration. No patient wants to hear that their disorder is highly complex and requires a complex treatment protocol, but with neurodegenerative disorders, there is usually limited success unless the patient accepts a complex holistic treatment strategy, and proceeds in a step-by-step manner, hopefully guided by a knowledgeable physician. When utilizing acupuncture combined with herbal and nutrient medicine, an initial course of 12 weeks is seen in most of the scientific studies. Of course, if the results are excellent before this period of 3 months, the treatment may be pared down. Each individual will have a different presentation and need.

So-called sticky protein accumulation and immune disorder

A significant contributor to neurodegeneration in Alzheimer's disease is the misshapen proteins in the brain support tissues, or glial tissues. These are sometimes referred to as 'sticky proteins'. Brain tissue is apparently destroyed by 'sticky proteins', where misshapen beta-amyloid proteins cause adjacent proteins to become misshapen with cross-beta links. Breakdown of APP (amyloid precursor protein), with certain enzymes interfering, coupled with problems with the tau protein found in tangles, a microtubule-assisted protein abundant in neurons in the CNS, are believed to be the results of whatever pathological process lies at the root of the disorder, probably an inflammatory dysfunction and excess accumulation of oxidant free radicals. A similar finding has revealed that altered or defective proteins, and the inability of the body to break down and remove these proteins, may be a core problem in early stages of Parkinsonism. One protein, called alpha-synuclein, reacts with dopamine and is linked to 'sticky proteins' and accumulation of protein fragments that are not efficiently cleared from the CNS, resulting in cell death. 5-10 percent of patients studied revealed mutations of the alpha-synuclein protein, which may cause a more severe problem with cell death. A majority of patients studied in the general population, with normal alpha-synuclein proteins, were able to adapt to this negative effect of alpha-synuclein and dopamine interaction and clear protein fragments, until excess oxidative stress or other health problems decreased the body's ability to handle the problem. Certain antioxidants and proteolytic enzymes have been discovered that are very helpful to clean up this mess. Examples include resveratrol (from the Chinese herb Hu zhang), and serratiopeptidase (from the silkworm), as well as milk thistle, and other herbal chemicals, including curcumin, an anti-inflammatory immunomodulating chemical found in 3 Chinese herbs, E zhu, Yu jin, and Jiang huang (turmeric).

Resveratrol, a chemical constituent of a number of Chinese herbs, especially Hu zhang, or Polygonum cuspidatum (also called Japanese knotweed), is now considered the most promising therapeutic biologic to treat Alzheimer's, due to its proven effect to activate protein enzymes called sirtuins, which are linked to cell protection and neuroprotection in aging. Hu zhang (Polygonum cuspidatum) is the primary source for resveratrol in medicines today, although a miniscule amount of resveratrol is also found in grape skins, and red wine has been touted as a source of resveratrol. Studies have found, though, that almost 2 gallons of red wine per day would be needed to provide a minimal dosage. Small amounts of resveratrol are also found in bilberry, cranberry, blueberry, mulberry, Chinese rhubarb (Da huang), and certain species of pine. The Chinese have been researching resveratrol for many years, and have found that specific extraction methods produce a concentrated dosage of a particular type of resveratrol. Dosage and the correct isomer of the chemical resveratrol are very important therapeutically. The actual chemical name of this herbal and food nutrient is (E)-5-(4-hydroxystyryl)benzene-1,3-diol, or 3,5,4'-trihydroxystilbene. The sirtuin enzymes regulate apoptosis (programmed cell death) and metabolism, and have been found to be the link between metabolism and longetivity in studies.

Currently, the U.S. NIH is sponsoring a second stage human clinical trial with resveratrol, and pharmaceutical companies are experimenting with biologic versions that deliver more of the chemical to the brain. In its natural herbal form, resveratrol has a number of bioactivities that are beneficial, including immunomodulation, modulation of the lipid metabolism, antiproliferation (anticancer), and an antifungal effect, as well as a potent antioxidant mechanism. Resveratrol has been proven to reduce excess triglycerides, and stimulate free fatty acid release in adipose tissues, so that a use of resveratrol in weight reduction as well as normalization of insulin resistance is also being explored. The antifungal aspect of this phyotchemical is also being researched, as the fungal form of candida, and candidiasis is linked to neurodegeneration as well. In addition, resveratrol is also being researched as a novel agent to inhibit the carcinogenic effects of estrogen metabolites, along with N-acetyl-cysteine, R-lipoic acid, and melatonin. As stated above, estrogen metabolites, such as estradiol-3,4-quinone, and 4-hydroxyestradiol, are known to play a significant part in the etiology of breast cancer, but also are implicated in neurodegenerative mechanisms. All of this research points to the use of this Chinese herbal extract as an important part of the holistic therapy in Alzheimer's, Parkinson's, and other neurodegenerative diseases.

In 2004, the Eve Topf and USA National Parkinson Foundation Centers for Neurodegenerative Diseases Research released a report on findings of the complex pathology of Parkinsonism and other neurodegenerative diseases, and the finding of free iron, or iron accumulation, in the central nervous system, was central to the cascade of events that lead to Parkinson's disease (see study link cited below). These researchers found that the abnormal accumulation of iron in the brain, especially the substantia nigra pars compacta and melanin-containing dopamine neurons. Lewy body, a hallmark of Parkinson's disease, is composed of redox-active iron, altered lipids, and aggregated alpha-synuclein, and it was found that this iron accumulation induces the aggregation, or clumping of alpha-synuclein protein into toxic aggregates in Lewy body. Iron accumulation and cytotoxicity also increases oxidative stress and the generation of reactive oxygen radicals, another hallmark of the disease. The accumulation of iron and reactive oxygen species (ROS) in these cells also degrades iron regulatory proteins via ubiquitination, where the protein ubuquitin (not to be confused with ubiquitol, or CoQ10 enzyme), inactivates regulatory proteins within the cells. These researchers noted: "Radical scavengers such as R-apomorphine and green tea catechin polyphinol (-)epigallocatechin-3-gallate, as well as recently developed brain-permeable VK-28 series derivative iron chelators, which are neuroprotective against these neurotoxins in mice and rats, prevent the the accumulation of iron and alpha-synuclein in substantia nigra pars compacta.

This study supports the notion that a combination of iron chelation and antioxidant therapy, as emphasized on several occasions, might be a significant approach to neuroprotection in Parkinson's disease and other neurodegenerative diseases." Chelation formulas with EDTA, and a growing number of Chinese medicinal herbs, are proving effective in reversing iron cytotoxicity. Scutellari baicalensis, or Huang qin, a commonly used Chinese herb, is shown to be a strong chelator of iron accumulation (see study link below). Quercetin, a component of many Chinese herbs, and now available in a standardized form as well, is also shown to effectively modulate iron biochemistry and aid iron chelation, and is found in the herbs Lou bu ma (Apocynum venetum), Sang ji sheng (Loranthus parasiticus), Fan shi liu (Psidium guajava, or Apple guava), Di er cao (Hypericum, or Saint Johns Wort), and Man shan hong (Rhododendron dahuricum). Milk thistle has also been found effective to aid the liver in detoxification of heavy metals. In some formulas, resveratrol, quercetin, pterostilbene and polyphenols from grape skin and other berries are now combined to offer a more complete effect (e.g. Reveratrol Plus from Vitamin Research Products). In 2013, copper accumulation was also linked to accumulation of beta-amyloid plagues in Alzheimer's disease, and is perhaps a fundamental part of the factors that cause this neurodegeneration. Mercury and lead toxicity, and even zinc toxins have long been linked as well to these neurodegenerative diseases, and this should tell us that the natural homeostatic mechanisms of mineral ion regulation and chelation are not working in patients with these neurodegenerative diseases. Restoration of mineral ion regulation has to accompany the protocols of mineral ion chelation to fix this problem.

Inflammatory mediators, or cytokines, are also found to drive the creation of unwanted and misshapen proteins in the neural cell nucleus. TNF-alpha is a cytokine that is much studied in this regard, and is the target of recent therapy to reduce the pathological cellular mechanisms that drive neurodegenerative disesases. The TNF-alpha drug Enbrel (etanerocept) is being used to inhibit TNF-alpha with modest success via injection of the drug around the spinal cord in the neck. Unfortunately, this procedure is still in early phases of clinical trials, and will by costly (estimates of $10-40,000 per year). The effects may give the patient much benefit in the future, though. The current strategies of acetyl-cholinestase and NMDA glutamate receptor inhibitors provide very modest benefits, as do an array of past pharmaceuticals. While TNF-alpha inhibition may be beneficial in the future, the overall damage to the brain in neurodegneration is not addressed by this approach alone. Coupled with this is the research that has shown potent TNF-alpha inhibition with specific herbal chemicals for some time. Complementary Medicine would thus both provide more avenues of TNF-alpha inhibition, as well as modulatory effects, and could provide an array of other studied effects that would be necessary to fully rehabilitate and correct hypometabolic dysfunction, stimulate repair and regeneration, and correct underlying causes that may continue to bring back the disease even if it is improved with pharmacological therapy. TNF-alpha, or tumor necrosis factor, may be just one of the cytokines involved in driving specific neuron and glial cell death. This cytokine is called tumor necrosis factor because it was found to be integral to cancer cell necrosis, or cell death, and while it exerts a beneficial inflammatory response in a balanced system, may exert unwanted necrosis, or cell death (apoptosis), in neurodegenerative disorders. TNF-alpha is not only expressed from immune cells, such as mast cell in acute inflammatory responses, but is also expressed in brain cells. Various mechanisms may drive the unwanted high expressio of this cytokine in neurodegenerative disorders, especially primary progressive aphasia. An integrative medical approach would utilize both the pharmaceutical and an array of holistic therapies to counter this complex disease.

Research now links Advanced Glycation Endproducts (AGEs) with this pathological process related to 'sticky proteins'. These molecules accumulate due to dietary intake as well as metabolic disorder in our bodies, and a complete article on this subject is found on this website under Practitioners and Treatment Protocols. AGEs are unregulated sugar and protein complexes related to modern food production, with use of unnatural sugars such as high-fructose corn syrup, as well as processed and fast foods that cook meat proteins by charring, especially with sweet sauces, or by heating protein foods with carbohydrates in the abscence of water, such as potato chips. Inside our bodies, these unnatural sugar protein complexes may form due to a combination of oxidative stress, dietary regimes, even supposedly healthy dietary habits, liver dysfunction, and metabolic disorder. When diagnosed with neurodegenerative disease, it is very important that you take a serious look into improving your diet and reversing harm that has been caused in the past by a poor diet. We have been tricked into overconsumption of unhealthy processed foods, many of which are advertised as natural and organic, and the time to finally pay attention to the sins of the food industry is now. Utilizing a knowledgeable TCM physician, or Licensed Acupuncturist, to help sort out this information and guide both dietary changes and integrative or complementary treatment is a practical choice. A number of Chinese herbs, as well as the nutrients P5P (active Vitamin B6), thiamin (B1), L-Carnosine, N-acetyl cysteine, and R-Lipoic acid, all have been shown to help clear excess AGEs.

The most intriguing breakthrough in understanding of the problem of 'sticky proteins' has occurred at Harvard Medical College in 2010, where genetic research led by Rudolph E. Tanzi found that expression of the protein beta-amyloid was produced by the same genes that produce protein immune molecules for the innate immune system, the primary immune defense in the brain. An immune modulator, LL-37, was almost identical to the beta-amyloid protein. LL-37 is produced in the body in response to brain infections, and is associated with atherosclerosis. In laboratory studies, A-beta, or amyloid beta, like LL-37, was found to destroy various pathogens, including a variety of bacteria associated with low level deep tissue infections, and Candida albicans, which is also a known cause of brain infections (meningitis). Samples of tissues from Alzheimer's patient brains (obtained from people who had died from Alzheimer's) were 24 percent more active in killing these bacteria and other pathogens. This implies that, for a large percentage of Alzheimer's patients, clearing of chronic infections and overgrowths in the body, and stimulating a better response by the innate immune system, could be a key to resolving the neurodegenerative process. Once again, we see the importance of recognizing the complexity and holistic nature of these diseases, and the need for a comprehensive holistic treatment strategy that is persistent. The patient that keeps looking for the simple 'silver bullet' and does not stick with a sensible comprehensive treatment strategy based on research, will probably not find success. Even if allopathic pharmaceuticals are tried in these disorders, they will not address all of the potential aspects of the disease, and Complementary and Integrative Medicine should play a key role in the overall treatment strategy.

Innate immunity is a type of immune response that utilizes immune modulators that recognize and respond to pathogens in a generic way, as opposed to the adaptive (learned), and autoimmunity (automatically attacking any foreign cell). Innate immunity utilizes the complement cascade of mediators that work together, as well as physical barriers and phagocytic cells (cells that literally eat other cells). Innate immunity may be the oldest form, and the most complicated. It does not rely on antibodies and memory T-cells, which have a difficult time passing the immune barrier into the brain. Most of the chemical mediators in the innate system are called cytokines, and each type of cytokine has a specialty. This cascade of proteins that usually complement the antibody responses is synthesized by the liver. Cytokines identify and tag pathogens, trigger the recruitment of inflammatory mediators, disrupt the membranes of infected cells, causing cellular death, and remove the debris from these immune processes. Foreign substances, such as toxins, may be identified and marked for dissolution by white blood cells, and the adaptive immune response may be activated by presenting the antigen to the B and T cells. This complex cascade of mechanisms is how the innate immune system works. Apparently, when it doesn't work optimally, neurodegeneration may occur. The key cells of the innate immune system are Natural killer (NK) cells, mast cells, eosinophils, basophils, macrophages, neutrophils, and dendritic cells. Some of these cells are highly activated in allergic responses, such as mast cell, macrophages and neutrophils. These processes of killing infected cells and toxins create free radical oxidants, or oxygen molecules that are free from larger molecules. Antioxidants help clean up the mess. Neutrophils attack pathogens by creating reactive oxygen species (ROS). Neutrophils and basophils release histamine as well as free radical oxidants, and also create accumulations of toxic proteins and protein fragments. The excess reaction of the innate immune system creates the oxidant and protein fragment accumulation in the brain tissues that many eventually cause dysfunction and degeneration. As stated, various powerful antioxidants and proteolytic enzymes may help clean up the mess, and various powerful immune stimulating herbs may improve the function of the innate immune system.

Normally, our bodies clean up problems with misshapen and abnormal proteins with the help of a protein complex found in nearly all of our cells. Ubiquitin is a protein that tags misshapen and abnormal proteins for degradation, and the ubiquitin-proteasome system (UPS) ultimately breaks down accumulations of abnormal proteins in our neurons to amino acids. Clumps of abnormal amyloid-beta proteins are found to be resistant to the UPS system of degradation, and the UPS activity may be stressed by excess protein accumulations. Proteolytic enzymes may be beneficial, as well as antioxidants such as CoQ10 (ubiquinone), a potent ubiquitous antioxidant. Deficiency of CoQ10 is found linked to many chronic diseases, and a number of factors may lead to this deficiency, including nutritional deficiencies, excess oxidant stress, and a number of medications that impair biosynthesis, such as statin drugs, tricyclic antidepressants, and beta-blockers. Statin drugs and beta-blockers are now heavily overprescribed as a preventive prescription for cardiovascular disease, reducing cholesterol and lowering blood pressure. The benefits versus risks for these drugs are now heavily debated. Nutritional requirements for biosynthesis of CoQ10 include the vitamins B2, B3, B6, B12, C, folic acid, and pantothenic acid. CoQ10 is heavily researched for its positive benefits in the treatment of Alzheimer's and Parkinson's diseases. Ubiquitin utilization may be enhanced by ATP cofactors, B1 and B2, N-acetyl cysteine, and the Chinese herbs Huang lian (Coptis chinensis) Zi cao (Lithospermum erythrorhizo), and Lei gong teng (Trypterygium wilfordii). The research on enhancing the UPS system is still in preliminary stages, though. Such research is very promising, as a high percentage of regulatory proteins in our cells may be abnormal, needing clearance by the ubiquitin-proteasome system. Aggregation, or clumping, of proteins in the cells also inhibits the UPS, and treatment protocols that achieve prevention of or breaking protein aggregations, are especially important to restoring the UPS.

The brain has a relatively high level of fat, yet a relatively low level of antioxidant activity compared to other organs in the body. Oxidized fatty acids thus accumulate with physiological stress in the brain, and contribute to the various cellular dysunctions described above. Most scientists agree that increased antioxidant activity is needed in these neurodegenerative diseases, especially lipid oxidant clearing from high levels of lipid peroxidation. The chief antioxidant mechanism in the body is the glutathione metabolism. Glutathione is a molecule that practically defines cellular detoxification and antioxidant activity in physiology. It is produced in our cells and kept in balance via a variety of homeostatic mechanisms. As our brain cells are repaired and maintained, oxidant free radicals are produced and the available glutathione accepts the oxidants and then is reduced to transform harmful oxidants into oxygen molecules that can be utilized, such as water, or eliminated, such as carbon dioxide. Glutathione balance and bioavailability is thus extremely important in cellular maintenance in the brain. Since glutathione cannot be simply eaten and utilized well, indirect methods must be employed to aid glutathione metabolism. A separate article on this website helps explain this glutathione metabolism, and suggests the variety of ways one can help improve this most important metabolism in the body. Science continues to search for more direct ways to improve glutathione bioavailability in neurodegenerative disease, and the current hope is that supplementation with liposomal glutathione will have some effect in this protocol. Encapsulating glutathione in liposomes, or fatty encapsulation, will delay the breakdown of glutathione and perhaps allow some of this supplemental glutathione to aid the cellular processes in the brain. Further research will tell whether this approach is effective.

Liver dysfunction has been proven to be a key factor in the systemic cycle of events contributing to amyloid beta (Abeta) accumulation (sticky protein) in the brain in Alzheimer's pathology. Amyloid beta peptide excess coupled with deficiency of low-density lipoprotein receptor protein (LRP) is a hallmark of the disease, and liver clearance of amyloid beta peptide from the blood is a major concern. This amyloid clearance is mediated by low-density lipoprotein receptor-related protein (LRP-1). Research has found that a high incidence of cerebral amyloid beta deposition occurs with insulin resistance and Metabolic Syndrome, typically called Diabetes Type 2. Studies have shown that insulin in the blood circulation facilitates LRP-1 translocation to the liver plasma membrane from the intracellular pool, contributing to LRP deficiency and poor amyloid beta clearance. Correcting metabolic dysfunction and aiding liver health and function are thus key components of a holistic protocol to prevent or reverse Alzheimer's disease. We have also seen that the inability of the liver to remove toxins from the blood may result in hepatic encephalopathy and worsening of brain functions. While standard medicine focuses on this pathology only when it is severe, this points to a need to address liver function before brain function deteriorates. There are a number of known triggers to hepatic encephalopathy, including electrolyte imbalance, potassium deficiency, low grade infections such as hepatitis C, and bacterial endotoxicity, aldehyde toxicity, excess protein consumption with ammonia toxicity, and use of medications that suppress the CNS, such as benzodiazepines. In addition, evidence in recent years has implicated the role of poor copper homeostasis and accumulation of copper in the capillaries and parenchyme (neurons and glial cells) of the brain, associated with accumulation of amyloid-beta in the brain. This dysfunction of copper homeostasis, a highly regulated system, is likely also linked to liver dysfunction, as copper absorbed in the gut is transported to the liver to be conjugated with other specialized protein transporters and enzymes, or excreted via bile. Poor liver function may create this dysfunction of copper homeostasis and transport, as may iron overload toxicity. Holistic medicine offers the patient the professional assessment and treatment of these potential problems.

In August of 2013, researchers at the University of Rochester Medical Center, Rochester, New York, U.S.A., headed by Professor Rashid Deane, showed that copper accumulation in the brain may one of the most important keys to the pathology of Alzheimer's disease. Copper accumulation was shown to impair the systems by which amyloid beta plagues are removed from the brain tissues, and to stimulate increased production of amyloid beta lipoprotein. Copper, iron and zinc have all been shown to contribute to amyloid beta plagues with accumulation in brain tissues, or heavy metal toxicity (PMID: 24159420). Heavy metal chelators could both prevent and treat Alzheimer's disease, as an adjunct, or Complementary medicine (see the article on this website entitled Lead, Mercury et al, neurodegenerative disease to better understand the options for benign heavy metal toxin chelation). High homocysteine levels, a hallmark of cardiovascular disease, has also been associated with increased copper toxicity and neurodegeneration (PMID: 11238735). Homocysteine, a marker but not a cause of disease, is a part of the detox glutathione metabolism, and research showed that homocysteine actually acts to reduce copper accumulation, but that excessive accumulation creates a conjugation of homocysteine and copper ion that both contributes to amyloid beta plagues, and oxidant stress, destructive to neurons.

Once again, a single aspect of this pathological mechanism is not responsible for the disease, but a combination of factors will create both the amyloid beta plague accumulation and neuron destruction. This is why a holistic approach to therapy and prevention is essential, and why allopathic strategies have failed us thus far. Various herbal chemicals have been studied and proven effective to clear copper toxicity and promote glutathione metabolism and detoxification in brain tissues, such as Resveratrol and Curcumin. A 2013 study at Rowan University, Glassboro, New Jersey, U.S.A. found that curcumin, from various Chinese herbs, has been shown to play a role in preventing amyloid beta fibril formation, and this involved chelation of copper ions (PMID: 24121531). The benefits of such herbal chemicals are multiple, unlike pharmacological molecules, and while curcumin may act as a weak chelator of copper toxicity, it also provides various anti-inflammatory, antioxidant, and glutathione promoting effects. A study at Kansai College of Oriental Medicine and the Josai University Department of Pharmaceutical Science, Osaka and Saitama, Japan, in 2000, showed that the herbal and nutrient chemical isoflavones daidzein and daidzin, found in Astragalus root (Huang qi), inhibits protein oxidative modification by copper ions, copper-induced lipoprotein oxidation in serum, and exhibits copper chelating abilities (Shizuo Toda and Yoshiaki Shiritaki). A 2002 study at Peking Union Medical College, Beijing, China, showed that a chemical in the Chinese herb Salvia miltriorrhiza (Dan shen), salvianolic acid-A, could chelate copper ions, and markedly reduced production of malondialdehyde and lipofuscin, and exerted significant antioxidant effects on low-density lipoproteins (Liu YL, Liu GT; PMID: 12579947). These and other studies will demonstrate that herbal formulas in Traditional Chinese Medicine will exert fundamental effects to prevent or reverse the pathology of Alzheimer's disease. The only thing missing is the billions of dollars in advertisements and manipulation of treatment guidelines and prescribing practices that the pharmaceutical industry uses to promote drugs that up to this point haven't worked.

No matter what type of neurodegenerative disease you have been diagnosed with, or whether you are experiencing early signs, or just wanting to have more insurance that you won't end up with these serious health problems in the future, Complementary Medicine provides you with a wealth of evidence-based treatment approaches. While none of these approaches is a 'magic pill', they all improve aspects of neurological and immune health to maintain and improve the health and function of your central nervous system. The benefits to this approach exceed the cure, because we all live a healthier, happier and more productive life when our brain is healthier and well maintained. The key to patients seeking effective treatment protocol in neurodegenerative disease is to combine the key strategies to form a more comprehensive overall treatment. This approach, of course, is not popular, as it entails taking a variety of pills, and getting fairly frequent treatment. The lure of a simple single magic pill still is strong. Yet, more and more patients are educating themselves and deciding that the sensible course involves this approach, and a knowledgable Complementary Medicine physician is needed to guide therapy.

Metabolic dysfunctions and their relationship to Alzheimer's

Researchers have uncovered a variety of metabolic imbalances contributing to the progression of Alzheimer's neurodegeneration. In 2007, researchers at Northwestern University published findings that showed that insulin resistance was a key component of neurological dysfunction. The protein called amyloid beta-derived diffusable ligand (ADDL) appeared responsible for the progression of Alzheimer's dysfunction from synapse to synapse, spreading across the brain, and one effect of this neurotoxicity was the depletion of insulin receptors from neurons. Key research widely accepted by health organizations involved with Alzheimer's disease indicates that levels of brain insulin and insulin receptors on affected cells are lower in Alzheimer's patients, and the level of this insulin and insulin receptor deficiency is a marker of the progression of the disease. Insulin is a hormone in the body with complex effects at a wide array of receptor types. In the brain, insulin does not regulate sugar and energy usage so much, but is integral to development, tissue growth and maintenance, memory and learning (see my article on this website entitled Insulin Use and Support Therapies to gain a better understanding). The binding of ADDLs to brain synapses prevents the accumulation of insulin receptors at these synapses, contributing to poor cellular maintenance and repair. Increased insulin receptors express inside the cell, not on the membrane, decreasing the usage and need for insulin. These researchers at Northwestern University, William L. Klein, professor of neurobiology in the Weinberg College of Arts and Sciences, and Fernanda G. DeFelice, from the Federal University of Rio de Janeiro, found that neurons affected by ADDL showed a virtual abscence of insulin receptors on the dendrites of the neuron, or the branched projections of nerve cells that conduct the electrochemical signals. Dendrites with an abundance of insulin receptors showed no ADDL binding. Clearly, both dysfunction with insulin metabolism and the accumulation of advanced glycation endproducts, such as beta-amyloid, are integral to this aspect of the disease.

The pharmaceutical industry has responded to this research on insulin receptor deficiency by creating aerosol insulin medication to improve the symptoms with alzheimer's disease. Unfortunately, while a dosage of insulin released into the nasal passages may temporarily help alleviate symptoms, this will not correct the problems with insulin receptor deficiencies. The clearing of amyloid-beta diffusable ligands (ADDLs) is clearly an important goal in treatment. A more complex strategy to correct these metabolic problems and restore neural cell functions, clear misshapen protein accumulations, and block the formation of advanced glycation endproducts (AGEs) is needed.

These findings of the ADDL accumulation and effects on neuron maintenance, with decrease in insulin receptors on the membranes of affected cells and the subsequent decrease in insulin effects, explains why there is an unclear association with overall beta-amyloid plaque burden and cognitive defects in all cases. It is probably not just the accumulation of the advanced glycation endproduct plaques that is important, but the accumulation of specific variations on these problematic protein, fat and sugar molecules. These ADDLs, or amyloid beta-derived diffusable ligands, are oligomers of amyloid beta molecules. A number of oligomers, or molecules that consist of just a few atoms or small molecules (monomers) that bind easily to form larger polymers, of beta-amyloid protein complexes, are found to be integral to the Alzheimer's pathology. The most common natural monomer is glucose. A ligand is a small molecule that easily forms a complex with a biomolecule, and serves to increase the signal, or trigger, increased binding to a site on a target protein. Metabolic dysfunction is seen as the origin of these ligands of beta-amyloid protein, fat and sugar complexes.

Metabolic Syndrome, typically still called diabetes type 2, and Alzheimer's disease, both have signs of increased oxidative stress and accumulation of advanced glycation endproducts (AGEs) in common. In fact, many researchers now refer to Alzheimer's disease as Type 3 diabetes for this reason. Patients with Metabolic Syndrome, or diabetes type 2, appear to have an increased risk for Alzheimer's disease, primarily because these AGEs accumulate in neurofibrillary tangles and amyloid plaques. A sequence of studies have demonstrated the importance of this pathological mechanism. The Rotterdam study followed over 6000 elderly patients for a number of years and determined that insulin resistance and Metabolic Syndrome, called type 2 diabetes, doubled the risk of the patient acquiring a neurodegenerative disease, and patients taking synthetic insulin for diabetes type 1 showed 4 times the risk. While many patients are still hoping that these misshapen proteins are purely a problem with their genetic expression, and that a drug will soon be created to fix this, this is definitely not the complete answer. A high incidence of diabetes and Metabolic Syndrome now exists in our aging community, and just the maintenance of blood sugar and total cholesterol with drugs such as synthetic insulin and statins has not decreased the potential for these health dysfunctions to result in neurodegenerative states. In fact, these studies show that the risk is perhaps increased with the use of the synthetic insulin, statin drugs, etc. The term diabetes type 3 was coined in 2005 to define Alzheimer's disease by Dr. Suzanne de la Monte, a neuropathologist at Brown University, when her research on postmortem brain tissue of Alzheimer's patients found that Alzheimer's disease may be defined as a neuroendocrine disease associated with insulin signaling defects. Her research showed that a reduced insulin, insulin-like growth factor, and insulin receptors on the outer parts of neurons, reduced the regulatory tau protein, and ultimately led to cell death. While introduction of synthetic insulin produces immediate improvement in glucose utilization in the brain, memory, and cognitive abilities, long-term use may be problematic, as the Rotterdam study indicated. The restoration of the insulin metabolism, correction of Metabolic Syndrome, inhibition of advanced glycation endproducts (AGEs), and improved neuroendocrine balance, all of which can be accomplished with Complementary Medicine, provides a safe and effective therapeutic protocol to patients.

Another aspect of metabolic dysfunction occurs when regulatory proteins, which are often large molecules, do not fold and unfold properly. The synuclein family of proteins are primarily expressed in neural tissues, and alpha-synuclein has been the focus of much research in Parkinson's since it was found that several families with an inherited autosomal dominant form of the diseases expressed mutated alpha-synuclein. This research has since discovered that alpha-synuclein that fails to fold and unfold properly may lie at the heart of the pathology, contributing to protein aggregation and cell membrane instability. An alpha-synuclein fragment known as the non-Abeta component of amyloid also is found in the amyloid-beta plaques in Alzheimer's. Protein homeostasis involves a complex array of chemicals that control protein folding and unfolding, and when this cycle is dysfunctional, glycosylated proteins may not transported correctly, and advanced glycosylation endproducts (AGEs) may accumulate. Coupled to this are dysfunctions of endoplasmic reticulum-associated degradation (ERAD), leading to alpha-synuclein proteins that do not unfold, and are not transported to the cytosol of cells for degradation. Homeostasis of this protein metabolism is potentially a key to these neurodegenerative pathologies. Research is ongoing to reduce protein aggregation, enhance protein folding, restore protein homeostasis, and stabilize misfolding-prone proteins. Glycosylation is a fundamental part of the endoplastic reticulum's protein quality control, and insuring that this process works is thus very important, as are effort to reduce ER stress. Novel therapeutics to aid in this protocol are nutritional agents to clear excess lectins, plant flavonoids (especially methoxyflavonoids), quercetin, genistein, and formulas to help clear excess AGEs.