Some science behind the scenes

Parkinson’s disease causes in detail

From what I can gather from research papers, the disease may have multiple causes, some environmental, some genetic, some illness related and so on.  In other words, trying to trace back the cause and effect chain to some ultimate cause is fruitless because there may be numerous ultimate causes.  There is however some very compelling evidence that links environmental causes  - particularly free radicals - with parkinson’s disease….

Gene mutation

At least 5% of people are now known to have forms of the disease that occur because of a mutation of one of several specific genes. Here the evidence is quite strong, but it is not known what definitively causes the mutations.  The following paper, however, suggests that the cause may be ‘free radical mediated’.

Mitochondrial contribution to Parkinson's disease pathogenesis - Schapira AH, Gegg M; Department of Clinical Neurosciences, UCL Institute of Neurology,  London UK.

….Abnormalities of mitochondrial function and increased free radical mediated damage were described in post mortem PD brain before the first gene mutations causing familial PD were published. Several genetic causes are now known to induce loss of dopaminergic cells and parkinsonism, and study of the mechanisms by which these mutations produce this effect has provided important insights into the pathogenesis of PD and confirmed mitochondrial dysfunction and oxidative stress pathways as central to PD pathogenesis. …..

The most common radical in the lower atmosphere is molecular dioxygen.  Molecular oxygen is relatively unreactive at room temperature except in the presence of a catalytic heavy atom such as iron or copper, so these may have a part to play, as we shall see.

Other environmental free radicals occur in smog.  Persistent radicals are generated in great quantity during combustion.  So there is a high concentration in any city or industrial estate where motor vehicles and heating systems as well as any incineration plants or industrial plants operate.  When a hydrocarbon is burned, a large number of different oxygen radicals are involved.

Excessive amounts of these free radicals can lead to [cell injury] and death.  Many forms of cancer, for example, are thought to be the result of reactions between free radicals and DNA, resulting in mutations that can adversely affect the cell cycle and potentially lead to malignancy.  In addition free radicals contribute to alcohol-induced liver damage, perhaps more than alcohol itself.  And as we have seen above, free radicals may also be involved in Parkinson's disease.

Generally our body has some defences against free radicals but vitamin deficiencies can lead to damage.  Three vitamins, vitamin A, vitamin C and vitamin E and polyphenol antioxidants are key antioxidants. Further, there is good evidence uric acid can act as an antioxidant to help neutralize certain free radicals.

Inherited Genetic

There are some people that appear to inherit a defective gene or genes. Around 15% of individuals with PD have a near relative who has the disease.  However, this does not actually prove the link, it only shows they might have been subjected to the same environmental factors that cause a mutation on the gene.

Mutations in specific genes have been conclusively shown to cause PD. These genes code for alpha-synuclein (SNCA), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), parkin (PRKN), leucine-rich repeat kinase 2 (LRRK2 or dardarin), PTEN-induced putative kinase 1 (PINK1), DJ-1 and ATP13A2.   In most cases, people with these mutations will develop PD.

Dietary

We have already seen that vitamin deficiency may be a cause of Parkinson’s if the person is exposed to free radicals, as the person has lost their defences.  We also saw that uric acid can act as an antioxidant to help neutralize certain free radicals.  If uric acid levels are low, again the body’s defences have been reduced against free radical damage.

Uric acid is created when the body breaks down purine nucleotides.

Purines are found in high concentration in meat and meat products, especially internal organs such as liver and kidney. Examples of high-purine meat and fish sources include: sweetbreads, anchovies, sardines, liver, beef kidneys, brains, meat extracts (e.g., Oxo, Bovril), herring, mackerel, scallops, game meats, beer (from the yeast) and gravy. 

Examples of foods which have a moderate amount of purine  are beef, pork, poultry, and other fish and seafood not mentioned above.

A diet poor in these foodstuffs will thus contribute to the damage done by free radicals as the body will not have the defences it needs to counteract the attack.

Plant based diets are generally low in purines.  So already we have an indication that a person on a vegetarian diet is at increased risk.  In terms of vegetables,  asparagus, cauliflower, spinach, mushrooms, green peas, lentils, dried peas, beans, oatmeal, wheat bran, wheat germ, and hawthorn contain moderate to low amounts.

Low dietary zinc intake can cause lower uric acid levels.

Cerebrospinal fluid levels of transition metals in patients with Parkinson's disease.

Jiménez-Jiménez FJ et al  ; Department of Neurology, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, Spain.

We compared CSF and serum levels of iron, copper, manganese, and zinc, measured by atomic absorption spectrophotometry, in 37 patients with Parkinson's disease (PD) and 37 matched controls. The CSF levels of zinc were significantly decreased in PD patients as compared with controls (p < 0.05). ………….. These results suggest that low CSF zinc concentrations might be related with the risk for PD, although they could be related with oxidative stress processes.

Other notable purines are hypoxanthine, xanthine, theobromine and caffeine.  Caffeine is of course found in coffee, but also in guarana, yerbamate, tea and kola.  Theobromine is found in chocolate and yerba mate.  If you don’t eat chocolate and only drink caffeine free drinks, you may be at risk if you live in an environment in which you are subjected to high free radicals.

Epidemiology and etiology of Parkinson's disease: a review of the evidence.

Wirdefeldt K et al ; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

The etiology of Parkinson's disease (PD) is not well understood but likely to involve both genetic and environmental factors. Incidence and prevalence estimates vary to a large extent-at least partly due to methodological differences between studies-but are consistently higher in men than in women.

There is compelling evidence for protective effects of …. coffee, but the biologic mechanisms for these possibly causal relations are poorly understood. Uric acid also seems to be associated with lower PD risk.

Heavy metals

We saw that the most common radical in the lower atmosphere is molecular dioxygen [O2] and that molecular oxygen is relatively unreactive at room temperature except in the presence of a catalytic heavy atom such as iron or copper.  Some research seems to indicate that these heavy metals play a part by reacting with this common radical, and from there the path is that we saw in the last sub-section – cell death.  In effect, high levels of certain heavy metals particularly in the blood react with the oxygen in the blood to create free radicals.

Serum Vitamins and Heavy Metals in Blood and Urine, and the Correlations among Them in Parkinson's Disease Patients in China - Fukushima T,  Tan X  Luo Y, Kanda H; Department of Hygiene and Preventive Medicine, Fukushima Medical University School of Medicine, Fukushima City, Japan.

Some heavy metals are suspected to be pathogenic [in] Parkinson's disease (PD), ……..

Conclusions: Excessive intake of iron and copper, and accumulation of manganese, vitamin E/copper imbalance in intake, …. might be involved in the etiology of PD.

It is worth adding that the presence of heavy metals in the blood can be even more pronounced in women taking oral contraceptive medication or HRT.  Estrogen increases the half life of Cu, so women with very high estrogen levels and intense blood loss during menstruation are likely to have a high Cu/Fe.  There is the possibility that they are at particularly increased risk during the menopause when estrogen levels are fluctuating wildly and blood loss can be extraordinarily high.

Imbalanced estrogen metabolism in the brain: possible relevance to the etiology of Parkinson's disease. - Gaikwad NW, Murman D, Beseler CL, Zahid M, Rogan EG, Cavalieri EL.; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center , Omaha, NE , USA.

The aim of this study was to discover whether higher levels of estrogen-DNA adducts are associated with PD. Forty estrogen metabolites, conjugates, and DNA adducts were analyzed in urine samples from 20 PD cases….. The levels of adducts in cases versus controls suggest that unbalanced estrogen … could play a causal role in the initiation of PD.

But where do these heavy metals come from?

One source is incinerators.  Although theoretically the European community, for example, regulates the emissions of waste incinerators which are found ironically in hospitals as well as towns and cities as municipal waste disposal mechanisms, there is still concern about the regulation and it is known that arsenic, cadmium, cobalt, chromium, copper, mercury, manganese, nickel, lead, tin, and thallium, are all emitted during  incineration. Waste-derived fuels are especially prone to contain heavy metals, so heavy metals are a concern in consideration of waste as fuel.

Heavy metal pollution can also arise from the purification of metals, e.g., the smelting of copper and the preparation of nuclear fuels. Any plant which processes iron to produce steel will probably result in heavy metal pollutants entering the atmosphere.  Electroplating is the primary source of chromium and cadmium.

We do not have to breathe them to necessarily suffer from them.  Through precipitation of their compounds or by ion exchange into soils and muds, heavy metal pollutants can lay dormant. Unlike organic pollutants, heavy metals do not decay.  Any plants grown in the area polluted may take up the pollutants.  If these are plants used in food products, the cycle will eventually lead back to us.

There are plants and microrganisms that are particularly effective at taking up heavy metal.  These are sometimes used to remove some heavy metals such as mercury. Plants which exhibit ‘hyper accumulation’ can be used to remove heavy metals from soils by concentrating them in their bio matter. But outside of this controlled use at a more general level, these same plants may then be eaten by cattle for example or sheep which then come back to us as food.

One of the largest problems associated with the persistence of heavy metals is the potential for bioaccumulation and biomagnification causing heavier exposure for some organisms than is present in the environment alone. Coastal fish and seabirds (such as the Atlantic Puffin) are often monitored for the presence of such contaminants being particularly susceptible. If we eat fish from a polluted area, we may be ingesting heavy metals.

Inflammation and the immune system

The following describes a long chain of cause and effects. 

Dopamine quinone is the oxidised derivative of dopamine.  It is harmful, acting as a free radical. 

Dopamine can be converted into dopamine quinone in the presence of COX-2.

MPP(+)-induced toxicity in the presence of dopamine is mediated by COX-2 through oxidative stress - Hsieh YC, Mounsey RB, Teismann P; School of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Aberdeen, Scotland.

Accumulating evidence suggests that endogenous dopamine may act as a neurotoxin and thereby participate in the pathophysiology of Parkinson's disease (PD). Cyclooxygenase-2 (COX-2) has been implicated in the pathogenesis of PD due to its ability to generate reactive oxygen species (ROS). Inhibition of COX-2 leads to neuroprotection by preventing the formation of dopamine-quinone.

In this study, we examined whether dopamine mediates 1-methyl-4-phenylpyridinium (MPP(+))-induced toxicity in primary ventral mesencephalic (VM) neurons, in an in vitro model of PD.

Inhibition of COX-2 by a selective COX-2 inhibitor (DFU) or ibuprofen significantly attenuated MPP(+)-induced VM cell toxicity and VM dopaminergic cell apoptosis, which was accompanied by a decrease in ROS production in VM dopaminergic neurons.

These results suggest that dopamine itself mediates MPP(+)-induced VM neurotoxicity and VM dopaminergic cell apoptosis in the presence of COX-2.

Cyclooxygenase-2 (COX-2, prostaglandin H synthase-2, PGHS-2) is unexpressed under normal conditions in most cells, but elevated levels are found during inflammation which is why the use of Ibuprofen helps to inhibit it.

Inflammation is usually a by-product  of the immune system and there is considerable evidence that indeed the immune system influences the brain.  Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis and psychiatric disorders all have links to inflammation and particularly neuroinflammation.

Neuroinflamm-Aging and Neurodegenerative Diseases: An Overview. - Pizza V, Agresta A, D'Acunto CW, Festa M, Capasso A; Department of Pharmaceutical Science, University of Salerno, Italy

Neuroinflammation is considered a chronic activation of the immune response in the central nervous system (CNS) in response to different injuries. This brain immune activation results in various events: circulating immune cells infiltrate the CNS; resident cells are activated; and pro-inflammatory mediators produced and released induce neuroinflammatory brain disease. The effect of immune diffusible mediators on synaptic plasticity might result in CNS dysfunction during neuroinflammatory brain diseases. The CNS dysfunction may induce several human pathological conditions associated with both cognitive impairment and a variable degree of neuroinflammation. Furthermore, …. neuroinflammatory processes may play an important role in toxin generation that causes death or dysfunction of neurons in neurodegenerative diseases.

So if there is injury and the cells are causing inflammation or if the person has an auto immune disease, there is a risk of developing Parkinson’s disease.  Bacterially caused inflammation may have the same effect.

Lipopolysaccharides (LPS), also known as lipoglycans, are found in the outer membrane of Gram-negative bacteria, act as endotoxins and elicit strong immune responses in animals.

The following evidence is interesting because it shows the additional links with the heavy metals.

Inflammation and age-related iron accumulation in F344 rats. - Hunter RL, Liu M, Choi DY, Cass WA  Bing G; Department of Anatomy and Neurobiology, University of Kentucky, Lexington USA.

Evidence suggests chronic inflammation and iron accumulation may play a role in the pathogenesis of Parkinson's disease (PD) as inflammation and iron levels increase with age and appear in the disease pathology.

It is hypothesized that an aggravated inflammatory response and iron accumulation, as a function of age, increase oxidative stress and participate in the pathogenesis of PD.

Intracranial injection of the bacterial endotoxin, lipopolysaccharide (LPS), has been shown to induce microglia activation, oxidative stress, mitochondrial impairment, iron accumulation, and dopaminergic neurodegeneration within the substantia nigra. We tested the hypothesis that injection of LPS into the striatum would increase iron accumulation in the substantia nigra of aged rats compared to young ones. Our results showed that four weeks post injection, LPS significantly increased microglia activation, lipid peroxidation, ferritin expression, and total nigral iron content in aged rats. In addition, LPS significantly altered the turnover ratio of homovanillic acid to dopamine.

Thus, an age-related increase in iron as well as susceptibility to inflammation may play an important role in PD-related neurodegeneration, as free radicals produced from the inflammatory response can become more toxic through increased ferrous iron catalyzed Fenton chemistry. This may enhance oxidative stress, exacerbate microglia activation, and drive the progression of PD.

Toxins such as pesticides

There are studies that link toxins such as pesticides with PD, particularly pesticides on food, as people’s exposure to pesticides under normal conditions is actually quite low…..

Epidemiology and etiology of Parkinson's disease: a review of the evidence.

Wirdefeldt K et al ; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

The etiology of Parkinson's disease (PD) is not well understood but likely to involve both genetic and environmental factors. Incidence and prevalence estimates vary to a large extent-at least partly due to methodological differences between studies-but are consistently higher in men than in women.

Evidence that one or several pesticides increase PD risk is suggestive but further research is needed to identify specific compounds that may play a causal role.

Paraquat, for example,  is the trade name for N,N?-dimethyl-4,4?-bipyridinium dichloride, one of the most widely used herbicides in the world. Paraquat, a viologen, is quick-acting and non-selective, killing green plant tissue on contact. It is also toxic to human beings and animals. Research has shown that it is linked to development of Parkinson's disease.

Bilirubin is responsible for the yellow color of bruises, the yellow color of urine (via its reduced breakdown product, urobilin), the brown color of faeces (via its conversion to stercobilin), and the yellow discoloration in jaundice.  It is excreted in bile and urine, and elevated levels may indicate certain diseases or the presence of toxins in the blood.

Bilirubin is the yellow breakdown product of normal heme catabolism. Heme is found in hemoglobin, a principal component of red blood cells.  Heme oxygenase-1 (HO-1) is an enzyme that converts heme to free iron, carbon monoxide (CO) and biliverdin (bilirubin precursor) and  is only produced in response to various stressors.  Thus elevated biliverdin levels indicate elevated HO-1 levels and elevated HO-1 levels indicate a stressor of some sort.

And  HO-1 is up-regulated in PD- and Alzheimer's disease-affected neural tissues indicating a toxic basis for some instances of the disease.

Overall

I think we can see that most of the causes of Parkinson’s disease are environmental and the causes are self-inflicted causes, in that man has caused them to man.

It is us that burn hydrocarbons, use incinerators, have factories that produce plastics and metals, drive cars and lorries, use pesticides and other toxins and eat ‘junk’ foods.

The toxins or bacterial agents or viruses or similar act on certain genes and cause them to mutate, thus meaning certain cells in the brain malfunction or die.  Some of the cells which are killed are dopamine producing cells which is why dopamine is often reduced in parkinson’s disease sufferers, but this is not the cause of PD, it just happens to be one of many effects.  The absence of dopamine will in turn have its effects, so the symptoms [as we shall see] end up being quite complex – a combination of those resulting from brain neuron death and those related to reduction in this neurotransmitter.