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Vitamin B12 Deficiency and Parkinson's Disease

Vitamin D deficiency is common in Parkinson's Disease

 

Many studies have shown a high and increasing prevalence of vitamin D deficiency in the general population (Diehl and Chiu, 2010). Vitamin D deficiency is extremely prevalent in Kuwait (54% - Al-Mutairi etal, 2012), India (Babu and Calvo, 2010), Indonesia (45.5% of pregnant women - Ilmiawati etal, 2020), Europe (Brouwer etal, 2012); USA (Wentz etal, 2014; Forrest and Stuhldreher 2011), S. Korea (over 75% of females Park etal, 2020) and deficiency is higher in those with darker skin and during winter (Sawicki etal, 2016). More recently it has been calculated that over 80% of Americans are vitamin D deficient. Vitamin D deficiency is also common now in Australia and New Zealand (Shrapnel and Truswell, 2006; Quaggiotto etal, 2014).

Very few foods have significant levels of vitamin D, which is restricted mainly to fatty fish, beef liver, cheese, margarines, milk and eggs. Potentially this explains why vitamin D levels are significantly lower in vegetarians than non-vegetarians (Brooke etal, 1980). The increased incidence of vitamin D has been associated with the increasing use of sunscreens, long sleeves, following skin cancer campaigns. Using sunscreens with as little as a 15-factor protection factor protection cuts the skin's vitamin D production by 99 percent. There has also been a reduced consumption of foods such as salmon, tuna and mackerel, and vitamin D fortified dairy products such as milk, and a switch to such poor nutritional alternatives such as soy and almond detergent homogenized milk substitutes.

Whilst many are aware of the role of vitamin D in bone health, vitamin D has a unique role in brain development, including homeostasis, embyrogeneisis, neural differentiation, neurodevelopment, gene regulation and immunological modulation (Duan 2013). Vitamin D also has a role in neurotrophism, neuroprotection, and neuroplasticity (Cannell 2013), and vitamin D deficiency has been associated with developmental disorders and abnormal brain development in conditions such as autism (Eyles etal, 2013; 2009; Eissa etal, 2018; Wang etal, 2022). Vitamin D has also been shown to regulate the production of tyrosine hydroxylase. There is a significant association between low levels of vitamin D and the development of Parkinson's disease (Luong and Nguyên 2012). Expression of tyrosine hydroxylase is required for maturation of dopamine-producing neurons (Pertile et al, 2016)

Normal activation of vitamin D, is a well known process in which light from the sun, or more specifically UV light from the sun shines on the skin and causes the conversion of the precursor 7-dehydrocholesterol to be converted to vitamin D3 - cholecalciferol. This molecule then is further processed in the liver and converted to the inactive form 25-hydroxy-vitamin D. Finally the 25-hydroxyvitamin D (Calcidiol) is activated in the kidney to form 1,25di-hydroxyvitamin D (Calcitriol).

The brain is unique amongst the other organs in that it has its own enzyme, 1a-hydroxylase, that activates 25-hydroxyvitamin-D to the active form 1,25-dihydroxy-vitamin D. The active vitamin D so produced, then binds to specific vitamin D receptors in the brain, particularly in the hypothalamus, and dopaminergic neurons of the substantia nigra. High levels of expression of the 1-a-hydroxylase has been in the Purkinje cells in the cerebellum (Eyles etal, 2004). Malfunctioning Purkinje cells are directly associated with the reduced capacity for motor learning in children with autism. These cells are responsible for fine-tuned motor control, balance, proprioception, and the vestibulo-ocular reflex (VOR). The VOR is the reflex that stabilizes the eye movement during head turning, such that the eyes can still focus on a target, even when the head is turned.

Mode of activation of Vitamin D in the brain, following stimulation of the eye by 482 nm light.

Lack of vitamin D has also been associated with a loss in hippocampal volume (an area of the brain that regulates motivation, emotion, learning and memory), and hence low vitamin D would be associated with difficulty learning. Low vitamin D has been associated with cognitive decline in adults (Wentz etal, 2014). Low vitamin D in adults it has been associated with depression, Parkinson's disease and Alzheimer's disease Littlejohns etal, 2014; 2016; Dickens etal, 2011: Fullard and Duda, 2020). In experimental models, gestational vitamin D deficiency has been shown to cause permanent changes in the developing brains of rats (Levenson and Figueiroa, 2009; Feron etal, 2005), and has also been shown to lead to persistent changes in the adult brain (Feron etal, 2005; Eyles etal, 2012). Interestingly vitamin D also promotes tyrosine hydroxylase (TH) and tryptophan hydroxylase 2 (TPH2) expression, AND results in a significant rise in monoamine oxidase A (MAOA) expression (Jianq 2014; Pertile 2016). This later finding is of considerable importance as MAOA is one of the only neurotransmitter related genes that are expressed on the X-chromosome, and hence alterations in MAO expression may provide the first reasonable hypothesis for the increased incidence of the condition in males, who by definition only have one X chromosome.

 

The importance of sun-exposure for the production of vitamin D has been known 1822 (nearly 200 years), and particularly exposure to UVB radiation (290-315 nm) (Holick 2006). However with the advent of sun-protection factors in the early 1870s, and the addition of high SPF value cosmetics and the increase in hours worked indoors, plus various sun-avoidance practices has seen a rise in the incidence of vitamin D deficiency, and an increase in the incidence of rickets with the result that vitamin D deficiency in children has once again reached epidemic proportions (Holick 2006). One of the potential sources of vitamin D is dairy, and so, the reduction in the consumption of dairy products, particularly those from free range cows and the switch to alternative products such as soy, and almond drinks, and adoption of a vegan diet can further reduce vitamin D levels.. Vitamin D deficiency is very common in some countries, and over 42% of Singapore residents (92), 45.5% of Saudi residents, and in 2018 over 82.5% of females in South Korea (an increase from 76% in 2008) were found to be vitamin D deficient. . Vitamin D status decreases with increases in weight. In Australia, the effectiveness of the "Slip, Slop, Slap" campaign promoting sun-protection (starting in the late 1980s), was severely criticized as early as 2002 (Nowson etal, 2002), as at that stage the prevalence of vitamin D deficiency in women had already reached 23%, increasing the risk of osteoporosis, dementia, schizophrenia, Parkinson's disease, respiratory condition, diabetes, coronary disease, breast, and prostate cancer. In New Zealand as long ago as 2015, they were claiming the Slip, Slop, Slap campaign had gone too far. More recently the Australan Cancer council has added a warning to their web-site about vitamin D deficiency, thereby absolving themselves of blame. This is despite the fact that Parkinson's disease is the fastest growing condition in the world. It is almost unbelievable, that with all the references on low vitamin D and Parkinson's disease that any foundation can promote the "slip, slop, slap campaign", and in contrast not be promoting more sun exposure. The rate of growth of PD is over 4% compared with an annual population growth of 1.1%.

Tyrosine Hydroxylase Deficiency in Parkinson's Disease

Parkinson's disease is a progressive condition that is postulated to be caused by lack of production of dopamine in the brain. It is likely that this lack is due to the lack of production of L-DOPA by the enzyme Tyrosine hydroxylase, as treatment of Parkinson's disease involves the administration of L-DOPA ."PD affects specifically TH-containing catecholamine neurons. The most marked neurodegeneration in patients with DA deficiency is observed in the nigro-striatal DA neurons, which contain abundant TH. Accordingly, TH has been speculated to play some important roles in the pathophysiology in PD" (Nagatsu et al, 2019). Production of tyrosine hydroxylase is stimulated by active vitamin D, and it has been shown that 1,25(OH)2D3 promotes the survival of dopaminergic neurons (Cui et al, 2015), and the activation of tyrosine hydroxylase, which is essential for survival of dopamine-producing neurons (Pertile et al, 2016). Vitamin D receptor is present in the substantia nigra, on the cells responsible for production of tyrosine hydroxylase (Cui et al, 2013), and vitamin D increases the expression of the tyrosine hydroxylase gene (Puchasz et al, 1996)

Iron Precipitation, alpha synuclein and Tyrosine Hydroxylase in Parkinson's Disease

Iron that has been taken up by neuronal cells is carried as Fe(III). This has to be reduced to the soluble form, Fe(II) inside the cell. Fe(II) can then be used in the synthesis of tyrosine hydroxylase, which subsequently produces L-DOPA. The enzyme responsible for reduction of Fe(III) to Fe(II) is alpha synuclein. Alpha synuclein mutations and differences in activity have been associated with severity of Parkinson's disease or with Fe(II) levels.  Alpha synuclein functions as a ferrireductase, using copper and NADH as cofactors (Davies etal, 2011). copper appears to be important for both aggregation and cellular localisation of alpha-synuclein. Reduction in cellular copper resulted in a great decrease in aggregate formation both in terms of large aggregates visible in cells and oligomers observed in western blot analysis of cell extracts {Wang etal, 2010). Reduction in copper also resulted in a change in localisation of the protein which became more intensely localised to the plasma membrane in medium with low copperr. Alterred copper metabolism within the cell can lead to copper-induced cell death. This process is characterized by the abnormal accumulation of intracellular copper ions, leading to cellular dysfunction and eventual cell death (Pan et al, 2024). ron that precipitates within the cell is not available for use in the synthesis of iron-sulphur proteins, or ferroproteins such as tyrosine hydroxylase. The availability of Fe(II) is also controlled by levels of reduced glutathione (GSH). In functional vitamin B12 deficiency, levels of GSH are lower, and pyroglutamate is higher.

Iron Precipitation and Parkinson's Disease

Iron precipitation in the brain is a feature of neurodegenerative diseases such as Parkinson's Disease (Mezzaroba et al, 2019; Alverez Jerez et al, 2023; Behl et al, 2022; Hare and Double, 2016)  There is evidence of iron deficiency as lower decreased Complex I activity.

Vitamin B12 and Parkinson's Disease

There is considerable evidence that vitamin B12 deficiency is implicated in PD.

  • Elevated homocysteine

  • Poor Sleep, which is associated with lower production of melatonin. Melatonin has been successfully tested in both in vitro and in vivo models of PD

  • Activation of the melatonin receptor MT1 prevents alph-syn-induced ferroptosis in PD

  • Low muscle strength - including low muscle strength. Lower production of creatine results in reduced muscle strength

  • OAT markers of deficiency - low GSH, elevated pyroglutamate, low CoQ10, elevated HVA, VMA, QA, KA, 5HIAA, low Tetrahydrobiopterin, elevated MMA, elevated branched chain amino acids, leucine, isoleucine, valine, alanine

  • Production of Acetylcholine involves the methylation of phosphatidylethanolamine to produce choline. Lack of methyl B12 activity results in the degeneration of the large cholinergic neurons of the PPN and  Pars compacta,

  • Tau and Beta Amyloid pathologies. Folding of both Tau and Beta Amyloid requires disulfide exchange, which involves a correct balance of GSH:GSSG inside the cell. In functional B2/B12 deficiency, this range is changed, and this potentially will affect the structure of both proteins. In addition, any surface exposed free-thiol groups are then available for aggregation with other molecules of Tau or Beta-amyloid, thereby resulting in the Aggregated Tau and Beta-Amyloid pathologies (Kim etal, 2015:Saito, et al, 2021). In functional B2/B12 deficiency, the enzyme glutathione reductase cannot reduce GSSG, and so levels of free GSH are lower..

Proton Pump inhibitors and Parkinson's Disease

In functional B2 deficiency, there is lack of production of histamine in the stomach, which then stops the cephalic phase of digestion, and so may lead to gastric reflux. Identification of the deficiency is generally missed by the clinician who then prescribes proton pump inhibitors. These then give rise to iron and B12 deficiency. The results of a retrospective, nationwide, population-based cohort study in Tawian indicated that PPI use was associated with a higher risk of PD development. Functional B2 deficiency is common in hypothyroidism, and Hypothyroidism-associated parkinsonism may resemble idiopathic Parkinson's disease

Vitamin D Deficiency and Iron Deficiency

Several studies have shown an association between low iron and low vitamin D levels, presumably because iron is used in processing of vitamin D (Akermanns etal, 2017; in utero and in the new-born has been associated with delayed speech development (Hawes etal, 2015; Kamau etal, 2018; Malczewska-Lenczowska etal, 2018; Russell-Jones 2024).

Altered Phosphate Metabolism in Parkinson's Disease

Active vitamin D is correlated with increased calcium by HMTA, as well as increased secretion of phosphoric acid . Low vitamin D is associated with decreased serum phosphate as is seen in early Parkinson's Disease (Håglin et al, 2016; 2020)

Recent studies have shown a dependency of functional B2, B12, and iron on activation of vitamin D. These findings have formed the basis for the Nexus TheoryTM

Russell-Jones, 2024 a, b

Changing the paradigm

Unfortunately too many cosmetic companies are earning billions of dollars from the sale of the high SPF cosmetics, so it is highly unlikely that they will change the formulations. It is also unlikely that while so many health professionals are making money out of treating vitamin D associated conditions such as autism, dementia, and Parkinson's disease, that they will change their strategy. Hence "“It is difficult to get a man to understand something when his salary depends on his not understanding it.” (John Sinclair, 1932). Hence we have been unable to make progress with the cancer council in getting them to stop recommending the use of sun-protection products, nor several cosmetic companies.  Hence it is not in the best interests of foundations getting millions of dollars in donations, for them to find a mode of prevention or cure for a condition that they are getting donations for. For instance the Australian Cancer Council (https://www.concer.org.au) has a major arm of its fund raising in selling SPF cosmetics, and clothing. This is despite countless publications on the protective effect of vitamin D and also how elevated vitamin D is protective against UVB mediated damage in the skin (Jagoca and Dixon, 2020; Song etal, 2012; Gupta etal, 2006).

Parkinson Disease has no known cause and so no known cure - the paradigm

"Everyday I have fewer reasons to live". This cannot be the inevitability of PD, hence, slowing or stopping the progress of the condition, or being able to reverse the symptoms is the most preferable outcome.. There is reason to be believe that the cause is known, and we have examples of individuals who have reversed the condition by addressing the deficiency in Selenium, vitamin B12 and vitamin D.

References

 

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