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Parkinson's Disease:

Description:

Parkinson's disease is a degenerative disorder affecting the dopaminergic neurons (neurons which produce dopamine) in the mid-region of the brain in the "Substantia Nigra" (where the motor neurons are located) causing a loss of motor skills, tremors, rigidity and slowness of movement (bradykinesia). The 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 death of neurons in this region of the brain are caused by an aggregation of a mis-folded protein called alpha-synuclein which pass through the cell wall (Endocytosis) into the neuron but due to its mis-folding and aggregation into insoluble, densely packed "fibrils", are not reprocessed by the cell's own lysosomes or passed out, but are accumulated as a plaque 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), 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 causing 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 death and causing Parkinson's symptoms.
Reference Role of Different Alpha-Synuclein Strains in Synucleinopathies.

Parkinson's disease becomes noticable when the about 70% of the dompamine producing neurons in the Substantia Nigra have been lost. This loss of 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 neurins connecting the substantia nigra to the striatum die, cutting off a critical dopamine source, the result is that there is too little dopamine and one has difficulty initiating movement. 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 improve one's condition by providing a dopamine precursor used by the brain to develop more dopamine to make up for the lack of dopamine caused by the loss of dopaminergic neurons.

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 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 amd 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.

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 repidly 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).

Diagnosis:

Diagnosis is usually given by a neurologist who observes behavior and movement. 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. Computed Tomography (CT) scans of people with Parkinson's will appear normal.

Five Stages: observed behavior

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 or arm 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.

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.

Parkinsons stages

Causes:

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

Treatment:

There are drug treatments and even some surgical treatments which address symptoms, but currently there is nothing offered by the medical community to stop the progression of Parkinson's or to cure the damage done.

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. There are detoxification supplements and protocols as well as chelation therapies for the various toxins, to cleanse the body and mind. There are improvements one can make to their diet, 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.