Parkinson's Disease:

What is Parkinson's disease? What are the symptoms? What can you do? Test, detox, repair!

Description:

Parkinson's disease is a degenerative disorder affecting the dopaminergic neurons (neurons which produce dopamine for nervous system communications) in the mid-region of the brain in the "Substantia Nigra" and "Globus Pallidus" (where the motor neurons which activate muscles are located) causing a loss of motor skills, tremors, rigidity and slowness of movement (bradykinesia). The dysfunction and death of neurons diminishes the amount of dopamine available for communication with the nervous system to the muscle to perform movement of limbs and motor function. The dysfunction of neurons in this region of the brain are caused by an aggregation of a mis-folded protein called alpha-synuclein which either pass through the cell wall (Endocytosis) into the neuron or are natively resident in the neuron but due to its mis-folding and aggregation into insoluble, densely packed "fibrils", are not reprocessed by the cell's own lysosomes, but are accumulated as a waste product known as Lewy bodies until the neuron cell becomes dysfunctional or bursts (Lysis). Properly folded, soluble alpha-synuclein proteins are an integral part of the neuron cell's repair apparatus and synaptic communication but the formation of Lewy bodies are found to be detrimental and eventually lethal to the neuron cell.

The synuclein family of proteins:

• α-synuclein: found in brain tissue
• β-synuclein: found in brain tissue
• ɣ-synuclein: found primarily in the peripheral nervous system and retina

Alpha-synuclein (α-synuclein) is a dynamic protein, taking on various folded shapes and aggregating in chains (polymers: one dimensional chain also known as a dimer), depending on its intended purpose. Neuron cell chaperones, lysosmes and proteasomes (biological elements within a neuron cell) actively recycle alpha-synuclein proteins to keep the alpha-synuclein quantities and chain lengths in balance. When the alpha-synuclein protein polymer chains become too long to process, they form oligomers (three dimensional structure) and ultimately fibrils which aggregate into Lewy bodies. The presense of a mis-folded alpha-synuclein will cause other alpha-synuclein proteins to change and mis-fold and can cause a cascading effect which spreads from neuron to neuron in a mechanism called permissive templating or prion like propagation (the mechanism of mad cow disease), resulting in massive neuron dysfunction or death and causing Parkinson's symptoms.
Reference Role of Different Alpha-Synuclein Strains in Synucleinopathies.

The dopamine producing neurons in the Substantia Nigra have long axons which extend to the putamen and caudate nucleus regions of the brain to release dopamine there to control muscle movement. Dopamine is the signalling molecule responsible for providing communications from the brain. As dopamine producing neurons become dysfunctional or are lost, communications and movement becomes inhibited.

Not Dead Yet:

Parkinson's disease becomes noticeable when the about 60% to 70% of the dompamine producing neurons in the Substantia Nigra have become non-operational, either by cellular death or by becoming dormant and dysfunctional. Korean researchers at IBS, KIST and AMC institutes have found that for those with mild Parkinson's progression, that 55% of the dopamine neurons could be dormant while for those with severe and advanced stages of Parkinson's, about 27% of dopamine neurons could be dormant, leaving open the possibility that these dormant neurons could be recoverable.

References:

• Waking up dormant dopaminergic neurons to reverse Parkinson's disease (Jan 2020 article Medical-X-Press) - overview
• Disease duration and the integrity of the nigrostriatal system in Parkinson’s disease (2013)
  Study compares loss of dark melanized nigral neurons vs dopamine markers (tyrosine hydroxylase: l-dopa and dopamine precursor) and concludes that it lags. There were neurons that were alive and present but not actively generating dopamine thus leaving open the possibility of neuroprotective/restorative therapies.
  DOI: 10.1093/brain/awt192

Loss of Motor Control and Dysfunction:

This loss of neuron function and motor control is responsible for slowness of movement (Bradykinesia), rigidity, postural instability, reduced movement amplitude (Hypokinesia) and difficulty in swallowing (Dysphagia). The mechanism for the brain to control muscles begins to fail. When the neurons connecting the substantia nigra to the striatum fail or die, cutting off a critical dopamine source, the result is that there is too little dopamine and one has difficulty initiating movement. The loss of nerves which activate muscles causes many muscles to undergo denervation atrophy and become dysfunctional. Another brain pathway affected by Parkinson's occurs with interneurons which enable local communication within the striatum.

Description of Parkinson's and the participation of Alpha-synuclein and Lewy bodies

The most common symptom of Parkinson's disease are the tremors which most typically occur in a leg, arm or jaw. The tremors are caused by a feedback loop which puts the neurons in control of motion in the Substantia Nigra, controlled by the cerebellum and cerebral cortex which controls coordination and voluntary movements respectively, to be challenged by the part of the brain responsible for self awareness (thalamus and subthalamic nucleus) as to where the limbs are located. The failure to flow proper quantities of dopamine also causes a failure to control and locate the limb properly and a failure to properly sense its location.

Drugs targeting Parkinson's disease typically improve one's condition by providing a dopamine precursor (levodopa) used by the brain to develop more dopamine to make up for the lack of dopamine caused by the loss of dopaminergic neurons. Note that these treatments are not a cure, don't slow down the progression of Parkinson's and often have permanent long term side effects.

Genetics:

Parkinson's has known genetic mutations associated with the disease but 75% of the cases have no known cause and this is known as idiopathic or sporatic Parkinson's disease. It is thought that idiopathic Parkinson's disease is caused by environmental pathogens and is thus a unique disease to that individual in cause, rate of progression and motor disruption symptoms. Parkinson's disease is not a single illness with a single set of symptoms. When Parkinson's afflicts those under the age of 50, it is known as Young Onset Parkinson's Disease or YOPD.

The Environment:

Parkinson's strikes men 40% more often than women but men are more exposed to toxins through the workplace as men make up 75% of the farmers (pesticide and herbicide exposure), 90% of chemical workers, 96% of welders (manganese exposure), 97% of pest control workers (pesticide exposure) and 80% of metals and plastic laborers. The usage of chemicals, pesticide and herbicide worldwide have grown rapidly and so has the prevelence of Parkinson's disease with the age adjusted rate for Parkinson's worldwide up 22%, India up 30% and China up by 116% over the last 25 years (ref). On the other hand, The Netherlands has banned paraquat and other pesticides linked to Parkinson's and saw that the number of incidences of Parkinson's decreased dramatically (1990-2011 ref).

Due to the growth in the use and generation of neurotoxic chemicals, the global burden of Parkinson's disease has doubled since 1990 (1990-2016: ref) and is expected to double again by 2040.

Diagnosis:

Observation: Diagnosis is usually given by a neurologist who observes behavior and movement.

DaTscan: Definitive diagnosis can be done with a DaTscan which can visualize the brain’s dopamine. The DaTscan requires the injection of a radioactive agent into the blood stream many hours before the scan is performed. The higher the number of healthy cells having dopamine, the brighter the images. The DaTscan can distinguish the cause of tremors as being the result of Parkinson's disease or of another movement disorder such as essential tremor or drug-induced parkinsonism.

SPECT scan: Computed Tomography (CT) scans of people with Parkinson's will appear normal but the more advanced single photon emission computed tomography (SPECT) scan can show how blood flows to tissues and organs. A SPECT scan requires a radioactive isotope injection which emits gamma rays that can be detected by the scanner. Radioisotopes used in SPECT scans are typically iodine-123, technetium-99m, xenon-133, thallium-201, and fluorine-18. SPECT scans differ from positron emission tomography (PET) scans in that the radioactive tracer remains in the blood stream thus imaging areas of blood flow rather than being absorbed by surrounding tissues.

Syn-One: The Syn-One test from CND Life Sciences is a lab test for abnormal alpha-synuclein in cutaneous (skin) nerve fibers to provide objective pathological evidence of synucleinopathy (staining and analysis for phosphorylated synuclein). This test can help distinguish essential tremor from a Parkinson's tremor, Alzheimers dementia from Lewy bodies dementia, etc.

aSyn-SAA: Alpha-synuclein Seeding Amplification Array

Five Stages: observed behavior - Hoehn and Yahr (H & Y)

There are 5 stages of Parkinson's disease based on observed behavior:

1. Stage one: onset of tremors, typically at rest. Tremors typically affect one side of the body first. A shaky leg, arm or finger is often the first indication of the disease. The arm on the affected side of the body usually swings less than the other while walking. Coordinated control starts to become more difficult which includes actions such as double clicking a computer mouse or writing in script (Micrographia). Script may start with large letters, gradually diminishing in size. Constipation, anxiety (eg. claustrophobia, heat and thermodysregulation, etc), restless sleep (kicking, flailing arms), loss of sense of smell and a weakness in one's voice are other early signs. Parkinson's may cause a disorder called dysautonomia that affects their autonomic nervous system which regulates automatic functions of the body, including the body’s response to heat and GI bowel flow.
2. Stage two: similar to stage one but with more noticeable symptoms. Tremors become more pronounced, posture may start to change with a leading chin, hunched shoulders and stooped posture. Tasks become more difficult and take longer to perform. Typing becomes less coordinated. Facial expressions often resemble a blank stare with a serious look on their face despite their actual mood.
3. Stage three: progression of the disease starts to affect balance and reflexes. Falls become more common. Walking turns into shuffling of one's feet. Loss of one's drivers license is common. Daily tasks become more difficult.
4. Stage four: Loss of mobility. Loss of independence. Use of a walker or other assistance device is required. Living alone may make many tasks impossible or even dangerous.
5. Stage five: stiffness in legs can cause freezing. A wheel chair is often required. Assistance is required. Prescription dosage is often much higher at stage five causing Levodopa side effects such as hallucinations, and delusions. Vivid and convincing visions and sounds can cause a great deal of confusion. Levodopa side effects include a lowering of vitamin B12 and a rise in dementia, affecting 75 percent of people with Parkinson’s. It is best to plan palliative care early before cognition is affected.

Fourty percent of Parkinson's patients develop severe disease within the first four years of illness (stage 3, disabled). It is common for about 1/3 of Parkinson's patients to remain in stage 1 or 2 for up to 10 years. On average, Parkinson's patients will go up one stage every 2 years except for stage two which is aproximately 5 years. Among patients first diagnosed with Parkinson's disease within the last five years, over one-quarter are either severely disabled or desceased. This proportion rises to 60% of those first observed five to nine years ago, to over 80% of those first observed ten to fourteen years ago, and to almost 90% of those first observed fifteen years ago.

Reference:

• Parkinsonism onset, progression, and mortality Neurology (Hoehn and Yahr, 1967)
• YouTube Video: Parkinson's Progression

Six Stages: neurological degradation - Braak staging:

Braak staging refers to measure Parkinson's pathology based on cell death as Lewy bodies propagate from the vagus nerve through to the central nervous system.
Phases:

1. First affected are the structures of the lower brainstem and the olfactory system. Alpha-synuclein aggregates, are more prevalent than Lewy bodies in this stage.
2. The disease then moves up the brainstem, traveling from the medullary structures to the locus ceruleus in the pontine tegmentum.
3. The disease enters the substantia nigra and Lewy body lesions begin to form.
4. Characterized by severe dopaminergic cell destruction in the pars compacta. The neocortex remains unaffected.
5. The disease has started to invade the neocortex and spreads into the structures of the temporal, parietal, and frontal lobes.
6. The disease has fully invaded the neocortex, affecting the motor and sensory areas in the brain.

Causes:

Causes of Parkinson's can include genetics, environmental toxins including mercury and mold toxins as well as inflammation, viruses and head trauma.

Treatment:

There are drug treatments and even some surgical treatments which address symptoms, but currently there is nothing approved by the medical community to stop the progression of Parkinson's or to reverse the damage done. There are however drugs in clinical trials and drugs in off label use which hold promise.

One can remove neurotoxic sources by eating organic meals to avoid neurotoxic pesticides and herbicides, eliminating mold toxins (or moving to a mold free environment), replace mercury amalgam fillings, etc. Living toxic free goes a long way to improving one's health and even avoiding Parkinson's disease in the first place. There are detoxification supplements and protocols as well as chelation therapies (beware, some are dangerous) for the various toxins, to cleanse the body and mind. There are improvements one can make to supplement their diet, scheduling and duration of food consumption, probiotics and exercise and physical therapy which can help to resist the decline as much as possible. Some have been successful reversing their ailments substantially by restoring damaged but not dead motor neurons. This outcome is more likely with those who have been newly diagnosed and have some motor neurons that can be saved. Growing new replacement neurons is a tougher path and is that taken by stem cell researchers in the hope for a future treatment.

There are drugs under development as well as stem cell therapies under development but it seems that advancements have been elusive.

Take Action:

Upon receiving a diagnosis of Parkinson's disease one can take the following steps (test, detox, repair):

• Genetics:
  Determine if their version of Parkinson's is genetic or idiopathic.
  • If genetic, one can enter drug trials for drug therapies specific to their genetic mutation. For example if one possesses the LRRK2 mutation, follow Denali therapeutics and their specialized drug treatment specific to this mutation.
    See Parkinson's drugs in trials for a list of drugs in clinical trials to address those with genetic predispositions (LRRK2, GBA).
  • If ideopathic, find the environmental root causes through tests and mitigate if possible.
  See our coverage of genetic mutations and snippets for direct genetic links to Parkinson's as well as influential predispositions: genetics testing
• Test:
  Test for environmental root causes of Parkinson's. Tests should include:
  • environmental and industrial toxins (if positive, remove source and detox)
  • mold toxins (if positive clean up mold or move)
  • toxic metals including mercury (remove source)
  Root causes such as head trauma are much more difficult to address as the damage of the trauma can not be reversible.
  Inflammation may be harder to test for and diagnose but if it is suspect, the root cause of the inflammation should be addressed. See our coverage of inflammation and Parkinson's.
• Therapies:
  • Detox: Remove and detoxify one's self of pathogens linked to Parkinson's that showed up in tests.
  • Autophagy: Change your eating schedule to induce neuron lysosomes to clean up alpha-synuclein proteins which are the root cause of neuron dysfunction and neuron death. See our coverage of autophagy and Parkinson's.
  • Exercise and PT: Vigorous exercise has been shown to help the body produce neurotrophic factors which help restore neuron health to slow down and hopefully even reverse some of the effects of Parkinson's. See our coverage of exercise and physical therapy.
  • Diet: Diet mostly addresses supplements and vitamins and associated foods which help the liver detoxify, help counter inflammation, support neuronal health and help with Parkinson's afflictions such as constipation. See our coverage of vitamins, supplements and diet for Parkinson's.
  • Probiotics: While the therapeutic properties of probiotics has only been tested in transgenic worms (worms with human DNA sequences edited into the worm DNA). One can take this low risk step which may help (no evidence of efficacy in humans, yet). See our coverage of probiotics and Parkinson's
• Medical Treatments:
  • FDA approved drugs: these typically help with symptoms and are not a cure. Note that some drugs contribute to an improved short term condition but also contribute to a long term decline with permanent side effects. One will have to weigh the pros and cons. See our coverage of FDA approved drugs.
  • Drugs in trail and development: Many phase 1, 2 and 3 drug trials allow enrollment to try the experimental drug. Many of these are intended to halt or reverse progression. Some address genetic mutations, alpha-synuclein aggregation and inflammation pathways. See our coverage of Parkinson's drugs in trials and off label use. If a drug trial is not available to you, note that there are repurposed drugs, already FDA approved for other ailments, that show hope for Parkinson's and can be prescribed "off-label".
  • Surgical Treatments: These are reserved for those who have found that drug therapies are no longer effective. These treatments address Parkinson's symptoms. See our coverage of surgical treatments.
  • Stem Cells: Advances are being made in stem cell therapies. They are mostly experimental but such therapies offer the hope of replenishing motor neurons to reverse the damage done by Parkinson's. See our coverage of stem cell therapies under development.

This website outlines steps one can take to help their condition. Note that we mention but do not endorse therapies or products.