The biochemical changes that occur in Parkinson’s are far reaching and encompass nearly every system in the body. There is a clear understanding that a lack of dopamine in the brain is the primary cause of the symptoms of Parkinson’s. The synthesis of dopamine in the brain is a complex process which certainly relies on many different biological and chemical actions that take place in the body. It is not fully understood what causes the death of these dopamine producing cells. As the cell death progresses in the disease so do the level of deficiencies and imbalances in other chemicals and nutrients in the body. It is probably a combination of the loss of dopamine and an increase in these imbalances that contribute to the progressive nature of the disease as they likely exacerbate each other.
Not only is it the inhibition of the body’s ability to detoxify in Parkinson’s but it is also the ability of the body to properly absorb and synthesize nutrients. The liver plays a key role in these processes. As liver function continues to decrease the progression of the disease accelerates. It is a slow process in most cases and can be managed with a host of different medications and supplements. Many of these substances can also have a detrimental effect on the liver and other organs in the body leading to further complications. Rates of progression are varied which is quite possibly related to the extent and type of liver damage that has already occurred. It stands to reason that the average age of onset is over the age of 50 as the lifetime toxic load is higher and liver function is decreased with age. It has been noted that people with an early onset of the disease experience a slower progression along with other seemingly distinct differences.
The following characteristics tend to be present in young onset Parkinson’s:
-Young onset Parkinson’s is less likely to lead to dementia and balance problems
-Young onset is more likely to include focal dystonia, which is cramping or abnormal posturing of one part of the body.
-Younger people are more sensitive to the benefits of Parkinson medications, but they tend to experience the dyskinetic side effects of levodopa sooner than older people.
-They also tend to experience dose-related fluctuations at an earlier stage of the disease, including wearing off and the on-off effect.
These differences could easily correlate to the level of liver function. It is quite plausible to believe that dementia and balance problems are lessened due to a lower accumulation of Iron and Lewy bodies in the brain. Dystonia could be increased as a result of immune system response to the illness and that drug side effects and fluctuations could occur as a result of improper dosing. It may be more effective for young onset patients to take medications on an as needed basis rather than a rigid schedule and to include supplements to reduce these side effects as their bodies are more responsive.
The purpose of this chapter is to individually review the different biochemical aspects of this disease. It is critically important to associate these aspects to both the presenting symptoms as well as the function of the liver that supports their proper balance (where applicable). The mechanisms of toxicity are not included in this section
Vitamin E has often been recommended as a supplement to reduce symptoms of Parkinson’s. Vitamin E in supplement form has shown no effect on the disease. Foods containing A-tocopherol may however provide some benefit, but it is unknown as to why. Vitamin E levels have shown to be decreased in certain types of liver disease but supplementation did not always result in a protective effect. Other studies have shown that Vitamin E serum levels in Parkinson’s had no effect on the disease and did not play a role in the pathogenesis of the disease. The fact that levels of A-tocopherol are not clinically relevant in Parkinson’s should be studied as most other vitamin levels are readily affected. Sometimes it is important to study pathways that are seemingly functional to better understand how a properly functioning cell works in comparison to a defective cell.
There is an imbalance between dopamine and Acetylcholine in the brain in Parkinson’s. The level of Acetylcholine remains normal so the imbalance is created by the loss of dopamine and not because of elevated levels of Acetylcholine which interferes with coordination and movement. Anticholinergics have often been used in treatment but only have minor benefits. The imbalances will continue to occur as the levels of dopamine decrease. Acetylcholine is created from choline and acetic acid which is absorbed through the gastrointestinal tract and synthesized in the liver. Even though it is a critical component of the disease, its production and functions appear to be otherwise normal.
Aluminum is known to have toxic effects on the brain. Most often the clinical effects are associated with Alzheimer’s and dementia, not movement disorders. Some evidence of aluminum deposits in the brain of Parkinson’s subjects has been reported but it is not a hallmark feature of Parkinson’s. Aluminum intoxication in Parkinson’s may be more relative to cases that develop dementia but it would not be suspected as the cause of the movement disorders. Aluminum may reduce the antioxidant activities of enzymes in the liver as well as lead to fatty degeneration of the liver. Aluminum should not be ruled out as a cause of certain symptoms. Perhaps it should be studied independently and attempts to treat symptoms associated with it should be undertaken separately.
Arginine is an essential amino acid and a key component of protein. Arginine plays a role in the synthesis of nitric oxide which increases insulin secretion and is converted to urea in the liver. Nitric oxide (listed separately) is thought to be involved in the pathogenesis of the disease so the function, regulation and uptake of Arginine should certainly be of consideration.
Vitamins A, C and E:
A study of elderly patients with Parkinson’s revealed no difference in levels of vitamin A & E but note significantly higher levels of vitamin C in Parkinson’s patients. It has been loosely suggested that a combination of C and E taken throughout the day benefits symptoms by reducing side effects of Levodopa but there appears to be little clinical study to support this. Another study found that C and E combined actually increased the risk of mortality in postmenopausal women with coronary artery disease. These antioxidant vitamins may be beneficial when absorbed through diet but supplementation has shown no real clinical improvements in Parkinson’s.
There does not appear to be much direct association between Vitamin B deficiencies and Parkinson’s. It is however noted that B12 deficiencies may play a role in cognitive impairment. Homocysteine levels have been shown in many different studies to be elevated in Parkinson’s (possibly through administration of Levodopa) which can pose heart risks. B6 supplementation may reduce the risk but not through altering homecysteine levels. Additionally, B-vitamins are not well absorbed independently. A combination of B6 and B12 is thought to enhance the absorption of them.
It has been suggested that calcium may play some role in the pathogenesis of Parkinson’s. Recent studies have investigated this and been mixed. Calcium channel blockers are known to induce types of Parkinsonism. Withdrawal of the drugs reduced rigidity but not tremor. It was also noted that onset was symmetrical which is not characteristic in idiopathic Parkinson’s. Another study refers in part to calcium regulation and Alpha synuclein as a potential treatment. The onset of Parkinson’s being symmetrical in relation to calcium may in itself disqualify it as a cause of Idiopathic Parkinson’s through this mechanism. More study is merited.
CSF Carnitine levels in Parkinson’s do not appear to be an associated risk factor in the disease. Acetyl-l-Carnitine as an antioxidant may play a role in the treatment of Parkinson’s. Carnitine is made in the liver and helps the body turn fat into energy.
Copper is known to cause the inherited disorder Wilson’s disease by accumulating in the liver and brain. It does not appear to be a risk factor for Parkinson’s either through ingestion or genetic factors even though elevated CSF levels have been documented. Copper metabolism in relation to amino acid levels should definitely be studied and considered as possible factors based on the simple knowledge that copper can be toxic to the body.
A study on low levels of LDL cholesterol found that those with cholesterol levels between 91 and 135 were six times more likely to have Parkinson's, and those LDL levels below 91 were four time more likely.
The researchers commented that the link between low cholesterol and Parkinson may be due to the fact that:
-Cholesterol helps rid the body of environmental toxins that might trigger Parkinson's.
-Cholesterol is a precursor for hormones/chemical modulators that are important in central nervous system function. Eighty percent of cholesterol is made in the liver and the brain stores up to 10 times the amount of cholesterol than any other organ in the body. More than 30 different enzymes are responsible for the production of cholesterol.Understanding the precursors and enzymes that produce cholesterol and how it is stored in the brain may very well be a treatment pathway. If in fact low LDL cholesterol levels are a product of the disease, it lends credence to liver dysfunction being a primary feature.
CoQ10 is known to be deficient in Parkinson’s. It can be synthesized by the liver from Tyrosine combine with other vitamins and minerals. Supplementation with CoQ10 shows no clinical effect on the disease. In 2011 the NINDS stopped a clinical trial of CoQ10 for Parkinson’s stating that there was no benefit to Parkinson’s patients. The mechanisms causing this deficiency should be the focus of study. Tyrosine synthesis is a likely path to understanding CoQ10 deficiencies in Parkinson’s. Cytochrome P-450 could also potentially play a role in this chain of events.
DHA deficiency in Parkinson’s is well noted. It has also been noted in Alzheimer’s that dysfunctional protein activity impairs biosynthesis in the liver reducing the amount of DHA available to the brain. Supplementation does not show any plausible effect in treatment of neurological diseases, therefore it must certainly be related to the conversion process that takes place in the liver and its method of delivery to the brain. Improper protein transport could be a feature of this pathology. The mechanisms should be closely studied and the function of the enzymes that support this process should be evaluated.
Ferritin and Transferrin:
Systemic ferritin and transferrin levels are known to be low in Parkinson’s patients. Serum levels are not affected. These results suggest the existence of a defect in the systems that regulate the synthesis of the major proteins of iron metabolism in the liver as well as the brain in Parkinson's disease that may, over time, expedite entry of iron into the brain and decrease iron on the outside of the cell. This is fairly conclusive evidence of liver dysfunction in the disease and should be the primary focus of research. The iron binding capacity and transport of ferritin and transferrin have a direct effect on the etiology of the disease. Iron deposits are noted in both Lewy bodies and Alpha Synuclein clumps in the brain. The role of ferritin and transferrin are quite possibly a critical feature in understanding the pathway of this disease. The key factor to understanding this may be directly related to how enzymes form and code these proteins. At this level of biology it is absolutely essential to determine the exact cause of the defective protein. Although it is possible that Ferritin and Transferrin imbalances or depletion are a product of the disease, it is not likely. Protein depletion is more often a sign of enzymatic dysfunction.
Glutathione depletion is evident in Parkinson’s. The primary cause of this is suspected to be oxidative stress. Glutathione is a powerful antioxidant but there is no conclusive evidence that taking glutathione in any form will reduce or reverse the effects of Parkinson’s disease. The underlying mechanisms of this depletion need to be studied and understood for it to be relative in any way to treatment. There is no clinical evidence that this depletion in and of itself is a direct causative factor in the disease. The liver plays a functional role in the production of glutathione via Cysteine, glycine and glutamate. The highest concentration of glutathione is found in the liver.
Elevated Homocysteine levels are frequently seen in Parkinson’s patients. Elevation is more frequent in patients that take Levodopa. It may also contribute to lower cognitive ability and depression. Supplementation with a combination of B vitamins may help to lower levels. Methionine is the precursor to Homocysteine. The liver plays a central role in the synthesis and metabolism of homocysteine. The majority of dietary methionine is metabolized by the liver.
The formation of hydrogen peroxide can lead to oxidative damage and the binding of reactive oxygen species in the liver. Part of the livers function is to breakdown hydrogen peroxide. Catalase enzymes are responsible for the break down of hydrogen peroxide into water and oxygen. This occurs at the molecular level in the formation of polypeptide chains which in are in turn made up amino acids. It also contains iron which allows Catalase to react with the hydrogen peroxide. Catalase mechanisms are not fully understood but defects in this enzymatic process could play a direct role in the pathogenesis of Parkinson’s and the oxidative stress associated with it. It is probable that changes occurring at the deepest levels in cell structure are inherently responsible for the chain reaction of adverse events that occur in the disease. It is imperative to determine the cause of the inhibition or alteration of enzymes such as Catalase and understand their proper functions.
The role of iron in Parkinson’s disease is probably one of the key factors in the pathogenesis of the disease. Both deficiency’s in nonreactive iron and the abundance of reactive iron are primary features of the illness. It has been repeatedly cited since around 1970 yet research invariably fails to focus on and resolve the issues associated with it. The entry on ferritin and transferrin describes the process. It is frequently absent in research articles that Iron deposits are noted in the accumulation of Alpha Synuclein. Clinical trials related to the removal of Alpha Synuclein or the irons from it have yielded disastrous results. The focus on Iron and the metabolism of it in relation to Parkinson’s needs to remain centered on liver function and the metabolism of Iron in the body.
Cumulative exposure to lead may be an increased risk of Parkinson’s. This is based on a study that investigated the amount of lead contained in bone marrow. Lead can worsen the symptoms of liver disease by increasing certain types of inflammation. Organic lead circulates in the blood and can increase the overall toxic load on the body.
A significant change in lipid metabolism in 73 different types of lipids in Parkinson’s patients has been clearly noted in one study. Lipid peroxidation is a possible pathway to the disease. Understanding the role of ferritin and transferrin in converting and transporting iron along with the mechanism behind hydrogen peroxide generation in the liver may yield important clues. The binding process of oxygen and iron through proteins and enzymes at the molecular level are responsible for lipid peroxidation at some level, it could not occur without them.
Low lysine levels have been noted in many Parkinson’s patients as well as Alzheimer’s patients. Lysine is known to inhibit Arginine as well as suppressing HSV 1. Arginine is known to convert to urea in the liver so its inhibition may help with some symptoms including dementia. Lysine cannot be produced in the body and must be obtained through diet or supplementation. The involvement of HSV in neurological diseases is unproven whereas a reduction in urea may have some clinical effects when the Fenton reaction (a chemical reaction between iron, oxygen and nitrogen that is a key component of oxidative stress) is taken into consideration.
Magnesium has been shown to be low in several sections of the brain in relation to calcium and aluminum. Studies have shown that calcium remained unchanged while aluminum levels are elevated. Liver cirrhosis is often associated with magnesium deficiencies. This correlation certainly merits additional studies in regards to transport and metabolism.
Manganese accumulation in Parkinson’s disease has been well noted both through levels of manganese in the brain and through direct intoxication. Zinc deficiencies have been associated with an increase in manganese. Zinc is an essential mineral and has been shown to play a role in hepatic dysfunction.
MAO-B is distributed at high levels in the liver, brain and platelets. Benzylamine and phenylethylamine are considered selective substrate for MAO-B. MAO-B has a complicated relationship to brain chemistry and enzymatic functions. MAO-A is also of interest as it degrades neurotransmitters in the brain. Both are very relevant in study but imbalances are more likely a result of other biochemical reactions as opposed to being causative effects. This supported by the fact that most MAO inhibitors are only partially effective in the treatment of the disease. There are also significant side effects associated with these drugs further indicating that they are not effective in targeting the cause of the disease but are only targeting particular symptoms. Side effects must certainly be a product of these drugs unintentionally targeting other unassociated biological actions.
Low melatonin levels in Parkinson’s are quite common and may possibly relate to the sleep disturbances associated with the disease. Melatonin is a powerful antioxidant produced in the Pineal gland through the synthesis of serotonin which is also deficient in Parkinson’s. Calcification of the Pineal gland is not uncommon, resulting in abnormal Pineal masses which can cause symptoms including ataxia. Pineal masses in the brain are readily identified on MRI’s and obstructions can often be surgically corrected. It is more likely that the root deficiency of melatonin in Parkinson’s is related to the synthesis of serotonin from tryptophan in the liver.
Methionine is an essential amino acid and its metabolism may play a critical role in the etiology of liver disease. It directly affects Glutathione production in the liver and its role in Parkinson’s disease should be fully investigated. As it may be directly linked to the depletion of Glutathione. There are no significant studies involving Methionine and Parkinson’s disease.
The primary symptom of mercury poisoning in Parkinson’s is tremor although other symptoms present. It inhibits the enzyme pyruvate dehydrogenase which relates to a build up of lactic acid in the body. This enzyme performs some key functions in the liver and deficiencies are well known to cause neurological problems.
Nitric oxide is a known free radical (oxidizer). It can be a contributing factor to oxidation of iron containing proteins which are a known problem in Parkinson’s disease. Levels of certain types of nitric oxide elevation in the brain have been noted. The mechanism by which the liver generates and converts nitric oxide should be fully examined particularly its relationship to the binding and oxidation of iron in specific proteins.
There is an obvious decrease in norepinephrine in the Parkinson’s brain in postmortem studies. Its deficiency is mostly attributed to cognitive loss rather than movement problems. It is a close companion to dopamine because it is a neurotransmitter. Norepinephrine is synthesized in from tyrosine in the liver in the same manner that serotonin is
synthesized from tryptophan which is ultimately a precursor to dopamine. The depletion of norepinephrine is likely a result of other components of the disease. Amino acids should be closely studied as their regulation is much more likely to contribute to an understanding of the etiology of the illness.
There have been numerous suggestions that excess Omega 6 Fatty acids in the brain may play a role in the development of Parkinson’s. There are no clinical studies that confirm this theory to date. It is highly unlikely that there is any relationship to Omega 6 levels and the etiology of Parkinson’s.
Omega 3 fatty acids and DHA are noted deficiencies in the Parkinson’s brain. Clinical trials for the effectiveness of Omega 3 supplementation have shown no conclusive evidence towards improvement. Benefits of eating a diet rich in Omega 3 are a possibility but it must be kept in mind that there is a much more complex relationship to the synthesis of Omega 3 in the body and how it enters the brain. Many foods that contain Omega 3 are high in cholesterol, therefore the contributing factor to improvement may relate much more closely to the type cholesterol content and metabolism rather than the fatty acid content.
Phenylalanine deficiencies are often noted in Parkinson’s but the relationship to Tyrosine balances is often not consistent. Phenylalanine is another essential amino acid that is also tied to tyrosine synthesis and uptake. The role of tyrosine and its metabolites is obviously a critical factor that should be studied in depth.
The aggregation of Alpha Synuclein in the brain in Parkinson’s is regarded as the hallmark of the disease. This is relevant because it is clinically noted in a large number of studies as is Tau in Alzheimer’s. It must be quite clear that these protein aggregations are abnormal in patients already afflicted with these diseases. It is not a causative factor in the etiology of the disease. Research must abandon attempts to treat the resulting factors and focus more on the initial cause. It has already been shown that modifications of these proteins in the brain have little or short lived clinical effects. Removal of these proteins has been shown to actually worsen the condition and stem cell transplants only have shown short term benefits due to the fact that the body continues to manufacture the defective proteins and systematically affect the transplanted cells. Alpha Synuclein deposits are laden with Iron which is metabolized in the liver through various biochemical functions as previously stated. The source of the diseases is directly related to the body’s inability to detoxify on many levels under certain biological circumstances. That is what must be investigated in regards to the etiology of these diseases.
The depletion of Serotonin in Parkinson’s may be pivotal in understanding the etiology of the disease. Serotonin is a precursor to dopamine as well as melatonin. Serotonin is primarily metabolized in the liver through two Amino acids, the primary being tryptophan. This deficiency alone can account for many of the biological changes that occur in Parkinson’s. Supplementation has in some instances shown undesirable effects. Focus on regulating serotonin levels through the synthesis of tryptophan may be a more relevant approach, essentially focusing on the underlying cause.
Taurine levels are also low in Parkinson’s patients. It is an antioxidant that is synthesized in the liver and the brain. Methionine is the major pathway involved in the synthesis of Taurine.
A sudden drop in testosterone in men has been attributed to Parkinson’s. The liver is responsible for the production of testosterone as well as removing excess estrogen. This quite clearly implicates liver function as a core feature if this theory is sound. It may be relevant to study the enzymes involved in testosterone production as well as studying testosterone and estrogen levels in a broader group of subjects including women and different age groups. The depletion of testosterone is not a significant causative factor based on current clinical evidence.
Transferrin receptors are reduced in Parkinson’s. Transferrin is synthesized primarily in the liver and has a known etiology in the disease via the transport of Iron. Its role must be investigated along with the enzymes and amino acids that regulate it.
Tryptophan is an essential amino that cannot be produced by the body and must be obtained through diet. It is found in red meats, dairy, nuts, shellfish legumes and other types of meats. It is directly involved in the production of serotonin which is a precursor to dopamine. Tryptophan is commonly imbalanced in Parkinson’s as well as in other liver diseases and is being closely studied. Tryptophan is also thought to play a role in sleep, mood and regulation of appetite. The impact of Tryptophan on serotonin production at the metabolic level in Parkinson’s may provide insight into the etiology of the disease and provide better treatment pathways. Its interaction with other amino acids must also be studied closely.
Tyramine is an amino acid synthesized in the body from the essential amino acid tyrosine. Tyramine stimulates the release of the catecholamines epinephrine and norepinephrine. The most obvious research conducted on Tyramine and Parkinson’s surrounds the interaction between Tyramine and MAO inhibitors which can lead to a hypertensive crisis. The fact that it is synthesized from Tyrosine should provoke great interest due to the fact that Tyrosine is a direct precursor to the synthesis of dopamine.
Tyrosine is a nonessential amino acid the body makes from another amino acid called phenylalanine. It is a building block for several important brain chemicals called neurotransmitters, including epinephrine, norepinephrine, and dopamine. Neurotransmitters help nerve cells communicate and influence mood. Tyrosine also helps produce melanin, the pigment responsible for hair and skin color. It helps in the function of organs responsible for making and regulating hormones, including the adrenal, thyroid, and pituitary glands. It is involved in the structure of almost every protein in the body.
Having a clear definition of tyrosine is important based on its pivotal role in the synthesis of neurotransmitters and other vital cellular functions. Tyrosine kinases are enzymes that take on the role of activating many different proteins. Dopamine levels tend to fluctuate with tyrosine levels indicating that dopamine is entirely co-dependent on its synthesis. The enzymes responsible for converting phenylalanine into tyrosine are most likely at the core of disrupted tyrosine function. This is one of many complicated biological reactions that appear to essentially be going wrong in Parkinson’s but it is one of the more significant reactions to study. Tyrosine supplementation has been suggested to be somewhat effective over the long term which is promising. Unfortunately it cannot be taken effectively or concurrently with Levodopa which inhibits it.
Zinc is an essential mineral that is involved in the functioning of many different enzymes. It is also a cofactor in the antioxidant enzyme superoxide dismutase as well as being involved in carbohydrate and protein metabolism.
There have been mixed results from studies of zinc in Parkinson’s but most result show a deficiency rather than toxic excess. It is suggested that low zinc and copper levels can lead to free radical formation in the brain. Insufficient zinc levels also contribute to increased levels of manganese in the brain which is more likely a product of the deficiency and is a known form of toxicity. The metabolism of zinc through the enzymatic process and its bioavailability in the body should be of specific interest.
Obviously there are a large number of biochemical imbalances in Parkinson’s. The mechanisms of many of these imbalances are not well understood. It is the intricate web of chemical reactions at a molecular level that appear to be the root cause of deficiencies, imbalances and improper transport mechanisms during the synthesis of proteins. Much of this synthesis occurs in the liver or gastrointestinal tract. This is all part of what research calls a cascading series of events. Often research has focused on the mechanisms of one particular chemical or reaction. It has been in recent years that science has progressed to the understanding that there are multitudes of interactions occurring either simultaneously or as cofactors that makeup the pathway to disease. This is something that simply occurs due to the progressive nature of research and this knowledge grows exponentially with each new discovery. Clearly understanding each amino acid, enzyme and protein individually must be the first priority. Once that level is reached it somewhat simplifies the process of understanding how each one might affect or interact with others. This is a monumental task that has been undertaken by science. The biology of plant life is somewhat better understood probably due to the simplicity, static nature and fewer gene transcription variations in plants. There is still much to learn about plant life and the interactions at the cellular level in the human body and it is likely that plant based compounds may be the source of better treatment and possibly even a cure to Parkinson’s due to their organic solubility.
Treatment of Parkinson’s by supplement alone or in combination with others has not proven to be much more than mildly successful. If an amino acid is made by the body, the depletion of the amino acid or vitamin itself may not be the core feature of its dysfunction so supplementation would be expected to have little to no effect. In the case of essential amino acids (not made by the body) supplementation would be expected to have a mild to moderate effect. The continual problem with supplementation is the absorption and the inability to cross the blood brain barrier. Supplementation may be better achieved through dietary means due to the true organic nature of whole foods and the metabolism of a combination of nutrients by the body.
This overview was intended to provide a glimpse of some of the biological changes that occur in Parkinson’s. It is infinitely more complex than it is described here and it is happening at nearly every level. The liver plays a vital role in this considering that a majority of the synthesis occurs within the liver. The complex functions of this organ are not fully understood and dysfunction has been associated with a number of different conditions. The storing, releasing and metabolism of chemicals and enzymes in the liver appears to be affected in Parkinson’s. The liver has long been implicated in Parkinson’s but lack of technology has probably inhibited understanding it fully. There are already more than 500 different known functions of the liver and that is probably only a portion of the total. A long term study of liver transplant patients with Parkinson’s is ongoing and has indicated that patients that have received transplants have shown continual and marked improvement over time. It certainly isn’t coincidence if all patients are showing these improvements. It should be noted that there are cases where improper liver matches have actually resulted in Parkinson’s symptoms that were not present prior to transplant. Of course, it is not very feasible to give everyone with Parkinson’s a liver transplant so there must be another path. If science can figure out how to get the liver to function properly it may be the most effective and direct method of curing the disease.