Basic physiology of Parkinson's, Alzheimer's and Neurodegenerative Disorders
While a complete explanation of all the theories of the pathophysiology of these disordes is too extensive for this article, a number of key points are helpful for the patient to understand the pathology. Basic physiological study has confirmed that dysfunction of Dopamine and other neurotransmitters in regulation and inhibition of excess neural transmission in the basal ganglia and putamen is responsible for tremors and a number of symptoms in Parkinson's. An imbalance between cholinergic (autonomic nervous) and dopaminergic influences on striatal tissues in these parts of the brain leads to dysfunction. The striatal tissues contain two types of cells that activate and restrain physical motion, and cellular degeneration leads to the inability to produce sufficient levels of the dopamines and acetylcholines to control this mechanism synergistically and prevent intention tremors. Simply increasing dopamine in circulation has limited effect, as a changing balance and pulsatile release of dopamine at various receptors is needed to maintain a normal physiological effect. Endogenous cannabinoids are produced to control the cholinergic overstimulation when insufficient dopamine occurs. Dopamine depletion may be due to excess metabolic needs, insufficient bioavailability, insufficient production, or excess need in relation to dysfunction of the degenerated neural cells that require dopamine inhibition. Neural degeneration may cause hyperactive states in the surviving cells. Metabolic disorders may contribute to altered rates of neurotransmitter production as well as disorder in the complex control of rates of firing a various receptors. Even the simplest of explanations uncovered about these neurodegenerative disorders poses more questions than answers, but does point us in productive directions.
The key areas of the brain that produce the unwanted tremors in Parkinson's are located in the basal ganglia, which are the large masses of gray matter at the base of the cerebral hemisphere. Modern anatomy defines the basal ganglia as the striatal tissues of the caudate and lentiform nuclei, and the cell groups associated with the striatal tissues, the substantia nigrum and subthalamic nuclei. In neurodegenerative disorders, many of the cells that control body movements may be damaged, and the remaining cells, regulated by dopamine and other neurotransmitters, become hyperactive in the corpus striatum. Study has proven that as Parkinson's worsens past the early stages, that degeneration of neurons and dopamine receptor decline, spreads to the anterior cingulate cortex, the dorsolateral prefrontal cortex, and the thalamus. This is why treatment at later stages may only slow the neurodegeneration, and also why simple drug therapies have limited effect.
Besides the problems of deficiency of bioavailability of dopamine and the endogenous cannabinoids, or metabolic problems with dopamine related protein enzyme regulation, there are a number of dopamine receptors that are implicated in the dopamine metabolic dysfunction. Different receptors respond differently to the same neurotransmitter chemical, and various metabolic deficiencies or other neural pathologies may contribute to neuroreceptor dysfunction. D2 receptors are abundant in the motor regions, such as the striatum, and D3 receptors are in relative abundance in areas of the brain that affect cognitive function and emotional stability, such as the limbic system and globus pallidus. The limbic system is linked to emotional well being as well as the hormonal regulation of the body. The globus pallidus is linked to pre-filtering of external stimuli, and dysfunction leads to an overactive mind and anxious states. A part of the globus pallidus, the ventral pallidum is also involved in the control and regulation of the signals from the striatum, which controls inhibition of movements, or tremors. D3 dopamine receptors are postsynaptic receptors that may be inhibitory to motor locomotion, resulting in the slow movements seen in advanced neurodegenerative disease. Dopamine metabolic dysfunction, whether it involves actual dopamine dificiency or problems with dopamine enzymes and protein regulation, may affect a number of key centers in the brain in different ways. A number of problems with dopamine metabolism and neural metabolism may act together to cause the various symptom presentations to these neurodegenerative disorders, and various approaches in therapy must thus be combined to be effective.
Dopamine receptors D2 and D3 are found within the same cells, and the differences have been studied thoroughly. Scientists find that a number of metabolic factors alter the rates of firing and the affinity for dopamine and dopamine metabolites at these two key receptor sites, explaining why the brain dysfunction changes over time and between patients. In animal studies, when there is less stress or demand upon the receptors, the D3 receptors have a much higher affinity for dopamine agonists than D2 receptors. As the stress on the cells is increased, and they are activated by G-proteins, the affinities for the dopamine molecules is equalized. Dopamine activation of the D3 receptors, though, always results in 2-5 fold less outgoing activity than D2 receptors, even within the same cell. Levels of G-proteins affect the activation states of both of these dopamine receptors. G-proteins are important signaling molecules throughout the body, and a number of pathologies, including diabetes, allergies, depression, cardiovascular defects and certain forms of cancer are thought to arise from derangement of G-protein signalling. Both D2 and D3 receptors can activate more than one pathway in the brain, and the differences in function between these types of receptors is affected not so much by the dopamine agonists and dopamine, but by a number of metabolic factors that act together in a quantum field. These findings present less and less hope for an allopathic solution to the disease.
The subject of G-protein derangement may be another important key to understanding the dysfunctions at dopamine receptors. This protein was discovered by scientists as they sought to understand how adrenaline stimulated cells. They found that when a hormone like adrenaline bound to a receptor, that the receptor did not stimulate enzymes directly, but instead, the receptor stimulated an enzyme to produce a second messenger. This discovery won them the Nobel prize in 1994. In the brain, stress levels induce increased adrenaline and other hormonal responses, that in turn stimulate greater levels of G-protein. The G-protein can be stimulated by either hormones or neurotransmitters like dopamine. Adrenal stress syndromes, and other hormonal imbalances may thus have a large impact on neurodegenerative dysfunction processess. When levels of G-proteins are maintained at a high level, this puts extra oxidative stress on the dopamine receptors. Recent research has focused on Adrenal stress syndromes and the link to neurological disorders. Chronically elevated adrenal hormones, or glucocorticoids, have been shown to desensitize serotonergic 5-HT receptors within the hypothalamus, which may explain suppression of the endocrine system following long periods of adrenal stress. Similar mechanisms could play a significant role on desensitization of dopamine receptors.
There is considerable concern over imbalance of dopamine and serotonin in the brain due to a variety of affectors over time, and the potential effects this would have on dopamine receptor function. Drugs that affect serotonin, especially selective serotonin reuptake inhibitors, or SSRIs, are frequently prescribed in recent years as rates of neurodegenerative diseases increased. Serotonin is balanced with dopamine in the body, and many of the side effects of SSRI medications, such as loss of libido and sexual function, are explained by a relative suppression of dopamine that accompanies increased concentrations of serotonin. In addition, early stages of neurodegenerative diseases usually involve some anxiety and depression which is often treated with SSRI medication. Studies have found that Fluoxetine (Prozac) may increase Parkinson symptoms more than other available SSRIs, and guidelines have recommended other SSRI medications due to this effect. Each patient may react to, or metabolize, SSRI medication differently, and guidelines suggest that each patient be started on a small dose and observed for toleration before increasing the dosage to effective levels. Serotonin syndrome is also seen, usually with concurrent prescription of MAO inhbitors for depression or anxiety, or with a host of other medications, but sometimes because an individual does not metabolize the SSRI at the same rate as another, and the accumulation of the SSRI over time produces a syndrome of serotonin excess. Often, the type of SSRI medication is changed due to side effects and guidelines state that a pause in prescription, or clearing phase, be utilized to avoid Serotonin syndrome. These precaution are often not followed, though, as the patient is anxious about returning to periods of higher anxiety or depression. The array of psych drugs commonly prescribed in recent years has also increased, with off label prescription of anti-seizure and anti-psychotic medications becoming more prevalent, which alter an array of neurotransmitters, incuding serotonin and dopamine. Combinations of these drugs may be problematic in the gradual onset of dopamine receptor dysfunctions.
Complementary Medicine utilizes a number of treatment strategies to affect these disease mechanisms in neurodegenerative disorders. Antioxidant herbs and supplements are utilized, 5HTP from the griffonia seed may be prescribed, and acupuncture may reduce stress levels and benefit adrenal function. Hormonal balance can be analyzed inexpensively in labs that test saliva or bloodstick samples, and topical creams that adjust hormonal levels with very safe low dosage herbal extracts can be utilized. Evidence-based herbal medicine allows the acupuncturist/herbalist to utilize dopaminergic herbs in treatment. Nutritional knowledge helps the Licensed Acupuncturist to effectively guide changes in dietary habits that specifically work for the individual. A number of herbal chemicals have been proven effective as a part of the therapy for various neurodegnerative disorders, such as Huperzine, and these may be incorporated into the overall treatment protocol. Since the disease mechanism is complicated, logic dictates that the treatment protocol will also be complicated. The Licensed Acupuncturist, utilizing Complementary Medicine, can integrate effectively with the M.D. specialists and help make the right choices to narrow this complicated treatment strategy and find the most efficient treatment for each individual. Quality of herbal and nutrient products is also important, and FDA regulation is almost nonexistent. The Licensed Acupuncturist has access to professional products that insure quality and reliable effectiveness.
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, 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 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.