Synopsis:From stomach to the brain: The evolution of Parkinson’s disease

 

https://youtu.be/jvVbgnCiyo0Introduction

Parkinson’s disease that has affected celebrities such as Muhammad Ali and Michael J Fox even at an early age than usual, was first described in 1817 by the English physician, James Parkinson, who initially called it paralysis agitans. Parkinson described six cases with the disease, having classic symptoms of resting pill rolling tremor, abnormal posture and gait, paralysis and diminished muscle strength, with progression of the disease over time. Later on, other symptoms of rigidity, weakness and bradykinesia were added to the disease. and renamed the disease in the honor of James Parkinson to “Parkinson’s disease” In 1912 Frederic Lewy discovered the “Lewy bodies”, microscopic particles in the brains of these patients and in 1919, it was discovered that the substantia nigra of the brain and the main source of dopamine production is the main cerebral structure affected. So Levodopa that increases the level of dopamine in this are of the brain soon became the mainstay of medication treatment for Parkinson’s disease.

Over time it was established that Parkinson’s disease is not only a movement disorder, presenting with hand tremors and bradykinesia or slow movement, and rigidity, but also it is a progressive brain degenerating disease that ends in the dysfunction of higher cortical functions, leading to depression and dementia as well. Parkinson’s disease that is a primary condition needs to be differentiated secondary conditions with known causes (Parkinsonism) such as infections such as AIDS and different encephalitis; toxins e.g. carbon monoxide, carbon disulfide, manganese and mercury; Paraneoplastic syndrome caused by antibodies associated with cancers; drug-induced e.g. antipsychotics and anti-emetics such as metoclopramide; vascular Parkinsonism associated with cardiovascular diseases; and punch drunk syndrome or Boxing Parkinsonism, etc.    

Parkinson’s disease is considered to be “idiopathic” in contrast with the secondary parkinsonisms that have known causes, which in fact “idiopathic” due to our lack of knowledge about its real etiology. Genetics has a very minute role in Parkinson’s disease, i.e. 5-10%, surprisingly in contrast with other neurological or psychiatric disorders that may carry multi-genetic or epigenetic mode of inheritance, exhibiting a classical Mendelian type of inheritance. Nowadays, six genes with an autosomal dominant or recessive mode of inheritance have been suspected in in familial Parkinson’s. Lewy bodies the cardinal patho-histological feature of idiopathic or primary Parkinson’s disease is in fact an eosinophilic cytoplasmic inclusion aggregation of proteins (primarily alpha-synuclein) that is highly suspicious of an autoimmune or infectious origin(s).

 In the search of a microbial cause:

Parkinson’s disease like many other neurological or psychiatric disorders, such as Alzheimer’s disease, Multiple sclerosis, Autistic spectrum disorders, schizophrenia and bipolar disorder, detailed in this site, has no immediate or acute cause to be discovered easily. In other words, the causes of all such disorders need to be probed in the past, decades or generations ago. Parkinson’s disease like these disorders share inflammation/infection causation long before the production of the disease process or clinical manifestations. In fact Parkinson’s disease is one of the few of such disorders with strong consensus on such etiology, as early as 1963 when for the first time was linked to infections, specially the influenza epidemic of 1918-1921. Many other neurotropic viruses, such as herpes simplex virus; Epstein-Barr virus; cytomegalovirus ;Varicella zoster virus; Borna virus; Measles; Coxsackie virus; echo virus;Polio virus; Human Immunodeficiency Virus (HIV); West Nile virus; Japanese encephalitis B virus; St. Louis virus; Hepatitis B & C viruses; paratubercluosis virus have also been suspected, studied and reported. But many of these viral insults appear to have caused Parkinsonism or secondary Parkinson’s diseases or Parkinson’s symptoms than the so-called idiopathic Parkinson’s disease with its characteristic Lewy bodies histopathology. Therefore the research on proving a viral etiology of Parkinson’s disease have not been as conclusive as it has been in the case of other disorders of the brain either neurological or psychiatric! In fact some studies to the surprise have found a reduction of the risk of Parkinson’s disease associated with most childhood viral infection, particularly measles. Also the overlapping of some of these viruses with other neurodevelopmental disorders make them less candidate specifically for primary Parkinson’s disease with a much later onset.

Inflammatory and immunologic evidences:

Although viral invasions as etiology to the evolution of Parkinson’s disease have been for more than half a century inconclusive, but the evidence to the neuronal, even systemic inflammation and the immunologic impact in the subjects with the disease have been undeniable. There have been reports as early as 1981 of higher serum immunoglobulin (IgA) and lower IgM in Parkinson’s subjects than normal, with IgM decreasing with age in parkinsonism-dementia. There have also been reports of the occurrence of autoantibodies against neuronal structures and abnormal T cell functions in Parkinson’s disease. Lewy bodies in the substantia nigra of Parkinson’s disease subjects have been shown to be positive for MxA, that is the induced protein of alpha-interferon that is a protein secreted by the immune system against infections. Also mitochondrial mutations, oxidative stress, microglial reactions and apoptosis in the region of substantia nigra of Parkinson’s disease, all caused by inflammatory reactions of immunoglobulin synthesis, cytokines, T-cell activations and production of interferons, are strong evidence of an inflammatory trace in the pathophysiology of the disorder that long before perhaps have been initiated by some microbial invasions.

It has also been shown that systemic or peripheral inflammations could trigger exacerbation or transformation of a “primed” microglia into an “active” state, through induction of the synthesis of cytokines in the brain, that explains the progressive nature of neurodegenerative disorders such as Parkinson’s disease by the way of neurodegeneration of neurons in the substantia nigra of the brain. Lowering the systemic or peripheral inflammation by anti-inflammatory treatment in Parkinson disease has also been shown to slow the progress of the disease to certain degree. Immunotherapy similar to the ones existing in the treatment of MS (Multiple Sclerosis) have been attempted in Parkinson’s such as transforming autoreactive adaptive immune responses into regulatory neuroprotective cells. Most recently animal studies have shown that neuroinvasive viruses, while capable to infect neurons and cause severe diseases such as encephalitis, only select and not all neurons are infected, implying that neurons exhibit innate resistance to viral infections. These researchers have discovered that native neuronal expression of alpha-synuclein protein involved in the pathogenesis of Parkinson’s disease inhibit viral infection in the central nervous system, but in the absence of alpha-synuclein protein, mice exhibited significantly decreased survival, markedly increased viral growth in the brain, and evidence of increased neuronal injury. So in a better word, this means that the damaged alpha-synculein inside the Lewy bodies in Parkinson’s disease, is a solid manifestation of the injury of a protector of the brain, in the war against microbial invasions.  

 The enemy from within:

While viral studies failed to find any causation link between viral insults and formation of Lewy bodies so to prove a viral connection in Parkinson’s disease, bacterial studies were able to do so somewhat as early as 1993, first with Nocardia, a genus of aerobic Gram-positive bacteria, then other bacteria such as Bordotella Pertusis, causing whooping cough in the young children; Toxoplasma gondii, Mycobacterium tuberculosis, and more recently, Helicobater Pylori, a gram-negative microaerophilic bacterium, the most common bacteria in humans world-wide. H.Pylori that has been the most evidenced of all these bacteria has been repeatedly reported more frequent not only in Parkinson’s patients, but in their siblings who shared some parkinsonian features as well. H.Pylori in Parkinson’s is also increasing with age, through antibody titers rising from 30 to 90 years. More recent studies have also shown improvement in Parkinson’s symptoms severity by eradication of H.Pylori and also better and prolonged response to L-dopa. In contrast the presence of untreated H.Pylori caused reduction of levodopa absorption in Parkinson’s disease patients and hindering their improvement.

 Since H.Pylori, as the most common pathogen in humans does not lead to the evolution of Parkinson’s disease in everyone, common immunological and inflammatory predisposing factors and environmental toxins such as cycads have been attempted to explain the missing causal link between parkinsonism and H.pylori infection. Cycads are seed plants, looking like ferns and palms, but totally different with a long fossil history, formerly more abundant and more diverse than they are today, with little changes since the Jurassic time. Cycads grow very slowly and live very long, with some up to 1,000 years, in different conditions, even on rocks and in sands and poor oxygen situations. Cycad seeds produce a neurotoxin that if eaten by humans can cause neurological diseases. Moreover cyanobacteria similar to H.Pylori, are also living in the roots of cycads. A recent large Danish study, comprised of 4484 Parkinson’s patients and 22, 416 population controls between 2008-11, revealed that prescriptions for HP-eradication drugs and proton pump inhibitors, 5 or more years prior to the diagnosis of Parkinson’s were associated with a 45% and 23% increase in the disease risk respectively. Furthermore Parkinson’s patients with H.Pylori have more severe symptoms than non-infected ones. Also the presence of pervasive α-synuclein deposition in the gastrointestinal tract strongly implicates the GI system in the pathogenesis of Parkinson’s disease.

 From stomach to the brain: The evolution of Parkinson’s disease

In conclusion, the vast literature on Parkinson’s disease, with a very high consensus, suspects this common neurodegenerative disease, have been caused by some environmental invasions. These invasions, no matter the nature of the microbial agent(s), lively or prion-like seem to pass on to the substantia nigra neurons through our stomach and intestine. This could have been done directly by infecting agents such as H.Pylori that is very common in humans, but causing the disease only in susceptible individuals. Another possibility is the transportation of infecting agents such as prion proteins through foods to the GI system and from there to the brain again in susceptible subjects. Either ways, the research summarized somewhat here, refute that Parkinson’s disease is idiopathic or in majority genetic, hence untreatable or unpreventable. In either ways, Parkinson’s disease is not only treatable, as many studies reported here have shown, by antibiotics or anti-inflammatory agents, but preventable by preventing the GI infections. What we know for certain is that H.Pylori needs to be seriously treated and prevented. We also need to break the transmission of the infecting agents’ cycle to susceptible hosts, by identifying the infecting prion proteins in foods, animals or other environmental sources. Finally we need to screen susceptible individuals and promote their immunity, by vaccinations, immunotherapy or else!    

 

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