This exciting news and research included in JAMA Neurology, September 2020, is based on the manner in which Parkinson’s has prominent manifestations in the autonomic system, which controls visceral functions such as digestion and heart rate, some of which arise before the motor manifestation of the disease. We know that cutaneous alpha-sinuclein quantified in skin biopsy samples provides high specificity and good sensitivity for the detection of synucleinopathies. Investigators theorize that deposits of alpha-synuclein should subsequently be elevated in cutaneous (skin) structures with autonomic nerves. With these findings, we should be able to test the skin to tell if levels of this protein have gone awry and is beginning to accumulate before it might become detectable in the brain.
Researchers mix a skin sample with the normal protein of interest, like alpha-synuclein. It is known that the presence of a misfolded protein can induce the aggregation of normal proteins. These clumps, in turn, trigger a fluorescent probe that emits a light that can be monitored in real time. Scientist Wenquan Zou, MD, PhD, has received a two-year grant to develop a non-invasive skin test for diagnosing Parkinson’s disease, Alzheimer’s disease, and other neurodegenerative disorders. The skin test is highly sensitive and makes it possible to detect even small amounts of misfolded protein in the skin. With this test and science, we will acquire a much-needed biomarker for Parkinson’s and ideally be able to make a diagnosis perhaps years before damage to the brain is well beyond repair Parkinson’s disease and contributing factors. Unless we had direct experience with the disease, many people were not familiar with Parkinson’s disease until actor and now-advocate, Michael J. Fox, announced his diagnosis in 1998, having first been diagnosed in 1991 with the young-onset form of the condition. Since that time his foundation has raised more than $900 million to fund research to find a cure for the disease that has also affected other celebrities including Muhammed Ali, Neil Diamond, Jesse Jackson, Ozzy Osbourne, Linda Rondstadt and others. But Parkinson’s impacts far more people than we may realize. Nearly 10 million patients worldwide are estimated to be living with the disease and approximately 60,000 new cases will be diagnosed in the U.S. this year, according to the Parkinson’s Foundation. The stark reality is that neurodegenerative diseases have continued to increase over the last few decades. Researchers found that Parkinsonism and Parkinson’s disease increased especially among men over the age of 70. Most experts agree that Parkinson’s is caused by a combination of genetic and environmental factors (chemicals, toxins, head trauma). And the interactions between genes and the environment can be quite complex.1 According to the Parkinson’s Foundation, some of the environmental risk factors include • Head Injury: Traumatic brain injury (TBI), which results in alteration in level of consciousness, has been associated with an increased risk of developing PD years after the injury; however, the mechanisms underlying this are unclear. • Area of Residence: There are differences in the geographic distribution of PD. These could be due to differences in environmental factors and genetic risk factors. • Occupation: Certain occupational categories or job titles have been associated with a higher incidence of PD, but results have been inconsistent. • Pesticide and Herbicide Exposure: A strong link has been shown between PD and exposure to pesticides and herbicides. • Exposure to Metals: Occupational exposures to various metals have been suggested to be related to the development of PD. But long-term exposure to metals is not easily measured and the results of studies measuring PD risk and specific metals have been inconsistent. • Solvents and Polychlorinated Biphenyls (PCBs): Trichloroethylene (TCE) is a solvent used in many industries and is the most common organic contaminant in groundwater. Exposure to TCE was found to be associated with PD among workers whose factory jobs resulted in long-term exposure. PCBs have been found in relatively high concentrations in the brains of people who had PD. Occupational exposure to PCBs has been associated with greater risk of Parkinson's in women, but not in men. • Working with electromagnetic frequencies (EMFs) and electrIcity • Exposure to air pollution • Use of psychostimulants such amphetamines, methamphetamine and cocaine • Cyanobacteria found in blue green algae Proteinopathies in neurodegenerative disease. A proteinopathy refers to a class of diseases in which certain proteins become structurally abnormal and thereby disrupt the function of cells, tissues and organs of the body. Parkinson’s disease along with other related non-PD disorders are considered synucleinopathies, which in broader terms is classified as a proteinopathy. In addition to PD, Lewy body dementia (LBD) and multiple system atrophy (MSA) are also characterized by the accumulation of pathological abnormal proteins aggregates called l α-synuclein (αSynP) in the brain. Synucleinopathies are a group of neurodegenerative disorders in which the protein alpha-synuclein accumulates abnormally to form inclusions in the cell bodies or axons of neurons or oligodendrocytes. Alpha-synuclein (aSyn) plays a fundamental role in the pathogenesis of many neurodegenerative diseases.2 Alpha Synuclein Gone “Off the Rails”. Alpha synuclein (aSyn) is a 14 kDa protein ubiquitously expressed in the presynaptic terminals of the brain. But, in neurodegenerative disease this brain protein turns from friend to foe becoming highly neurotoxic and may in itself propagate disease. So, we must ask, why would this happen? Alpha synuclein is found not just in the brain, but in multiple peripheral organs and tissues of patients with PD, such as the colon, salivary glands, and skin. As such, there is data that suggests “seeding” of this protein can work in ways that self-propagate and once the process gets started it is like a light switch that gets turned on - and then it is difficult to turn off. For more about alpha-synuclein, visit our Scientifically Speaking section[FG1] . The Gut Brain Highway. The earliest evidence that the gut might be involved in Parkinson’s emerged more than 200 years ago. In 1817, the English surgeon James Parkinson reported that some patients with a condition he termed “shaking palsy” experienced constipation. A shift came in 2003, when Heiko Braak, a neuroanatomist at the University of Ulm in Germany, and his colleagues proposed that Parkinson’s may actually originate in the gut rather than the brain for he found that the abnormal proteins, e.g. Lewy bodies, clumps of alpha synuclein appeared in both the brain and the gastrointestinal nervous system. So even if Parkinson’s ends up in the brain, it does not necessarily begin there.3 But why does the protein accumulate in the gut in the first place? One possibility is that alpha-synuclein produced in the gastrointestinal nervous system helps fight off pathogens and or is produced when the gut is highly inflamed and we know now the critical importance of a healthy gut microbiome. The gut-first hypothesis of PD says that in some patients the misfolded α-synuclein protein first begins to accumulate in the nerves of the enteric nervous system decades before the appearance of neurological symptoms. One misfolded α-synuclein triggers additional misfolded α-synuclein proteins, a process that then travels up the vagus nerve to the brainstem and to the dopamine-producing neurons. This bidirectional communication between the gut microbiota and the brain includes many pathways, such as immune mechanisms, the vagus nerve, and microbial neurometabolite production. A pro-inflammatory microbiota profile in the PD patient’s intestinal tract might increase gut permeability, allowing leakage of bacterial products and inflammatory mediators from the intestines.4 The dysregulated microbiota-gut-brain axis in PD might underlie gastrointestinal dysfunctions which predominantly emerge many years prior to the PD diagnosis, corroborating the theory that the pathological process spreads from the gut to the brain. Many studies have shown alteration of the microbiome in PKD. One study out of Saarland University in Germany supports this notion. Like the researchers who conducted the first study, they compared the gut microbial composition of 34 Parkinson’s disease patients with 34 healthy controls. Once again, they found that the abundance of bacteria that produce short-chain fatty acids like butyrate was far lower in the gut microbiota of patients with Parkinson’s disease. The Microbiome Diet: An Ounce of Prevention is Worth a Pound of Cure. As we have always recommended, prevention of disease is critical and should encourage us to all look carefully at our diet and whenever possible strive to eat organic, non-GMO whole foods. High levels of inflammation in the gut that arise from poor dietary choices can trigger a plethora of problems with our general health as well as our brain’s wellbeing. Many factors, such as unbalanced nutrition associated with the standard American diet (SAD), antibiotic use, aging, and infection, environmental chemicals and toxins and similar factors can all result in alteration of microbial metabolites, triggering α-syn accumulation in the intestinal mucosa cells. This is why we’ve also continually emphasized that with any health issue, including Parkinson’s, a healthy diet is regarded as the first line of therapy.5 The worst possible diet to follow is the Western diet is characterized by high intake of protein (animal and processed meat products), saturated fat, refined grain, sugar, alcohol, salt, and high fructose corn syrup and low intake of fruits and vegetables. It promotes inflammation that arises from both structural and behavioral changes in the resident microbiome [100]. Some studies also implicate dairy as a potential factor in development of PD.5 Evidence shows that the Western diet can lead to increased levels of endotoxin-producing bacteria in the intestinal tracts of both humans and mice, resulting in metabolic endotoxemia. Although there are many healthy diets, the Mediterranean diet is regarded as one of the healthiest diets that is also not difficult to follow. Certain prebiotics and probiotics may be helpful in gut health too. You’ll find a number of articles in our blog section about dietary factors and the role of nutrition in neurodegenerative and immune-mediated disease. Please use the “Search” function on each page of our website to find more related topics or let us know if we can direct you to something in particular. It is our hope that one day in the imminent future, we can begin to see a decline in neurodegenerative disease. But we must be active participants in that goal by focusing on the principles of maintaining health and wellness today! In health, Dr. Suzanne Gazda References and additional reading: 1 Driver, J. A., Logroscino, G., Gaziano, J. M., & Kurth, T. (2009). Incidence and remaining lifetime risk of Parkinson disease in advanced age. Neurology, 72(5), 432–438. https://doi.org/10.1212/01.wnl.0000341769.50075.bb https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2676726/ 2 Visanji, N.P., Lang, A.E. & Kovacs, G.G. Beyond the synucleinopathies: alpha synuclein as a driving force in neurodegenerative comorbidities. Transl Neurodegener 8, 28 (2019). https://doi.org/10.1186/s40035-019-0172-x 3 New Evidence Suggests Parkinson's Might Not Start in The Brain. The Cure Parkinson’s Trust. https://www.cureparkinsons.org.uk/news/parkinsons-starts-in-gut (retrieved 10/5/2020) 4 Uyar, G. Ö., & Yildiran, H. (2019). A nutritional approach to microbiota in Parkinson's disease. Bioscience of microbiota, food and health, 38(4), 115–127. https://doi.org/10.12938/bmfh.19-002 5 Jackson, A., Forsyth, C. B., Shaikh, M., Voigt, R. M., Engen, P. A., Ramirez, V., & Keshavarzian, A. (2019). Diet in Parkinson's Disease: Critical Role for the Microbiome. Frontiers in neurology, 10, 1245. https://doi.org/10.3389/fneur.2019.01245 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6915094/ Additional reading: MedicalResearch.com – Interview with Dr. Wenquan Zou, MD/PhD, Professor https://medicalresearch.com/author-interviews/parkinsons-disease-skin-biopsy-may-provide-less-invasive-diagnostic-test/55548/ Ball Nicole, Teo Wei-Peng, Chandra Shaneel, Chapman James. Parkinson's Disease and the Environment. Frontiers in Neurology. (2019) Vol. 10. ISSN 1665-2295. https://www.frontiersin.org/article/10.3389/fneur.2019.00218 DOI: 10.3389/fneur.2019.00218 Butyric acid. https://www.foundationalmedicinereview.com/blog/exploring-potential-health-benefits-butyric-acid/ [FG1]
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AuthorDr. Suzanne Gazda, Integrative Neurology Archives
February 2024
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