Pathophysiology in PD
In Parkinson’s disease, the substantia nigra is the chief area that have been affected. It contains a specialized set of neurons that send signals in the form of a neurotransmitter, dopamine which travels through striatum via axons. Researchers from NINDS stated that, “When neurons in the substantia nigra degenerate, the resulting loss of dopamine causes the nerve cells of the striatum to fire excessively. This makes it impossible for people to control their movements, leading to the primary motor symptoms of PD. Many Parkinson's patients eventually lose 80 percent or more of their dopamine-producing cells”(Para 21, 2004).
There are two neuro-pathological findings which proves the cause of the Parkinson's disease:
Also according to another study,“There is strong evidence that it first affects the dorsal motor nucleus of the vagus nerve and the olfactory bulbs and nucleus, then the locus coeruleus, and eventually the substantia nigra. Cortical areas of the brain are affected at a later stage. Damage to these various neuronal systems account for the multi-faceted pathophysiologic changes that cause impairments not just to the motor system but also to the cognitive and neuropsychological systems” (Kwan & Whitehill, 2011).
In Parkinson’s disease, the substantia nigra is the chief area that have been affected. It contains a specialized set of neurons that send signals in the form of a neurotransmitter, dopamine which travels through striatum via axons. Researchers from NINDS stated that, “When neurons in the substantia nigra degenerate, the resulting loss of dopamine causes the nerve cells of the striatum to fire excessively. This makes it impossible for people to control their movements, leading to the primary motor symptoms of PD. Many Parkinson's patients eventually lose 80 percent or more of their dopamine-producing cells”(Para 21, 2004).
There are two neuro-pathological findings which proves the cause of the Parkinson's disease:
- Deficiency or loss of the dopamine neurotransmitter from the “Substantia Nigra Pars Compacta” and the further loss of dopamine increases the overall inclination in excitatory input in basal ganglia.
- “The presence of “Lewy bodies” and “Lewy neurites” in the brain cells.
Also according to another study,“There is strong evidence that it first affects the dorsal motor nucleus of the vagus nerve and the olfactory bulbs and nucleus, then the locus coeruleus, and eventually the substantia nigra. Cortical areas of the brain are affected at a later stage. Damage to these various neuronal systems account for the multi-faceted pathophysiologic changes that cause impairments not just to the motor system but also to the cognitive and neuropsychological systems” (Kwan & Whitehill, 2011).
The motor circuits of a Parkinson’s Disease patient:
The basal ganglia motor circuit modulates the cortical output necessary for normal movement. Hauser states that, "Signals from the cerebral cortex are processed through the basal ganglia-thalamocortical motor circuit and return to the same area via a feedback pathway. Output from the motor circuit is directed through the internal segment of the globus pallidus (GPi) and the substantia nigra pars reticulata (SNr). This inhibitory output is directed to the thalamocortical pathway and suppresses movement. Two pathways exist within the basal ganglia circuit, the direct and indirect pathways, as follows:
• In the direct pathway, outflow from the striatum directly inhibits the GPi and SNr; striatal neurons containing D1 receptors constitute the direct pathway and project to the GPi/SNr
• The indirect pathway contains inhibitory connections between the striatum and the external segment of the globus pallidus (GPe) and between the GPe and the subthalamic nucleus (STN); striatal neurons with D2 receptors are part of the indirect pathway and project to the GPe
The STN exerts an excitatory influence on the GPi and SNr. The GPi/SNr sends inhibitory output to the ventral lateral nucleus (VL) of the thalamus. Dopamine is released from nigrostriatal (substantia nigra pars compacta [SNpc]) neurons to activate the direct pathway and inhibit the indirect pathway. In Parkinson disease, decreased striatal dopamine causes increased inhibitory output from the GPi/SNr via both the direct and indirect pathways.
The increased inhibition of the thalamocortical pathway suppresses movement. Via the direct pathway, decreased striatal dopamine stimulation causes decreased inhibition of the GPi/SNr. Via the indirect pathway, decreased dopamine inhibition causes increased inhibition of the GPe, resulting in disinhibition of the STN. Increased STN output increases GPi/SNr inhibitory output to the Thalamus." (Hauser, 2014).
The basal ganglia motor circuit modulates the cortical output necessary for normal movement. Hauser states that, "Signals from the cerebral cortex are processed through the basal ganglia-thalamocortical motor circuit and return to the same area via a feedback pathway. Output from the motor circuit is directed through the internal segment of the globus pallidus (GPi) and the substantia nigra pars reticulata (SNr). This inhibitory output is directed to the thalamocortical pathway and suppresses movement. Two pathways exist within the basal ganglia circuit, the direct and indirect pathways, as follows:
• In the direct pathway, outflow from the striatum directly inhibits the GPi and SNr; striatal neurons containing D1 receptors constitute the direct pathway and project to the GPi/SNr
• The indirect pathway contains inhibitory connections between the striatum and the external segment of the globus pallidus (GPe) and between the GPe and the subthalamic nucleus (STN); striatal neurons with D2 receptors are part of the indirect pathway and project to the GPe
The STN exerts an excitatory influence on the GPi and SNr. The GPi/SNr sends inhibitory output to the ventral lateral nucleus (VL) of the thalamus. Dopamine is released from nigrostriatal (substantia nigra pars compacta [SNpc]) neurons to activate the direct pathway and inhibit the indirect pathway. In Parkinson disease, decreased striatal dopamine causes increased inhibitory output from the GPi/SNr via both the direct and indirect pathways.
The increased inhibition of the thalamocortical pathway suppresses movement. Via the direct pathway, decreased striatal dopamine stimulation causes decreased inhibition of the GPi/SNr. Via the indirect pathway, decreased dopamine inhibition causes increased inhibition of the GPe, resulting in disinhibition of the STN. Increased STN output increases GPi/SNr inhibitory output to the Thalamus." (Hauser, 2014).
Causes of Parkinsonism
“The term parkinsonism is also associated with disorders such as progressive supranuclear palsy, multiple system atrophy, Lewy body dementia, corticobasal degeneration, vascular parkinsonism, drug-induced parkinsonism, and parkinsonism secondary to infection and other causes (Hohler et al., 2012). A form of reversible parkinsonism can occur from the use of certain neuroleptic drugs, particularly reserpine, antipsychotics (haloperidol), and metoclopramide. Exposure to certain toxins, severe carbon monoxide poisoning, and mercury poisoning can also lead to Parkinsonism.” (Pathophysiology, Module 5).
“The term parkinsonism is also associated with disorders such as progressive supranuclear palsy, multiple system atrophy, Lewy body dementia, corticobasal degeneration, vascular parkinsonism, drug-induced parkinsonism, and parkinsonism secondary to infection and other causes (Hohler et al., 2012). A form of reversible parkinsonism can occur from the use of certain neuroleptic drugs, particularly reserpine, antipsychotics (haloperidol), and metoclopramide. Exposure to certain toxins, severe carbon monoxide poisoning, and mercury poisoning can also lead to Parkinsonism.” (Pathophysiology, Module 5).
"Methamphetamine abuse has also been linked to Parkinsonism. In experimental animals, exposure to methamphetamine damages dopaminergic fibers in the striatum* as well as the cell bodies in the substantia nigra, echoing the degeneration observed in human patients with PD. Selective damage to dopaminergic terminals in the striatum has also been observed in human methamphetamine users, although there is no evidence so far that methamphetamine abuse damages dopaminergic cell bodies in the substantia nigra." (Granado et al., 2013).
Genetic Factors of the Parkinson’s Disease
The latest studies show a deep connection between genes and developing Parkinson’s disease. People with affected first degree relatives (parents,siblings,offspring) are 2 to 14 times at higher risk to develop Parkinson’s disease. The PARK genes table below shows the genes which are likely responsible in causing Parkinson’s disease.
“Mutations in “PARK” genes affect the function and survival of nerve cells critical for normal movement, balance, and coordination." (NIH, 2013a).
"Mutations in three known genes (SNCA, UCHL 1, and LRRK 2) have been reported in families with dominant inheritance. Mutations in three other genes (PARK 2, PARK 7, and PINK 1) have been found in affected individuals who had siblings with the condition but whose parents did not have Parkinson’s disease (recessive inheritance). There is some evidence to suggest that these genes are also involved in early-onset Parkinson’s disease (diagnosed before the age of 30) or in dominantly inherited Parkinson’s disease but it is too early to be certain..Many researchers believe that Parkinsonism can also be caused by infection, trauma and poisoning, drugs such as haloperidol (Haldol) or chlorpromazine (thorazine), which are prescribed for mental illnesses and Chemical toxins such as MPTP (free radicals, 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine).” (Genome.gov, 2011).
Environmental Factors
Parkinson’s Disease is understood to result from both nature and nurture. Scientists are still finding out what lifestyle choices may increase the risk of Parkinson’s.
· Age(older more likely)
· Gender (males more likely)
· Head Injury
· Pesticide Exposure
· Exposure to Metals(recently suggested)
Potential lifestyle choices and factors that may protect against Parkinson’s:
· Coffee and tea
· Increase Uric acid Intake (Men with Parkinson's are found to have low uric acid levels)
· Anti-inflammatory drugs
· Smoking
· Higher Vitamin D
· Exercise
Though these factors are consistently seen, it has not been conclusively proven as effective prevention methods.
Pesticide Exposure
Pesticides are the most consistent chemical exposure linked with Parkinson’s. Even home gardening has been associated in reports. Some pesticides inhibit the enzyme Aldehyde Dehydrogenase genes. Those exposed are at a much higher rate of being diagnosed with the disease, but still have not been established with causing the disease.
"Mutations in three known genes (SNCA, UCHL 1, and LRRK 2) have been reported in families with dominant inheritance. Mutations in three other genes (PARK 2, PARK 7, and PINK 1) have been found in affected individuals who had siblings with the condition but whose parents did not have Parkinson’s disease (recessive inheritance). There is some evidence to suggest that these genes are also involved in early-onset Parkinson’s disease (diagnosed before the age of 30) or in dominantly inherited Parkinson’s disease but it is too early to be certain..Many researchers believe that Parkinsonism can also be caused by infection, trauma and poisoning, drugs such as haloperidol (Haldol) or chlorpromazine (thorazine), which are prescribed for mental illnesses and Chemical toxins such as MPTP (free radicals, 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine).” (Genome.gov, 2011).
Environmental Factors
Parkinson’s Disease is understood to result from both nature and nurture. Scientists are still finding out what lifestyle choices may increase the risk of Parkinson’s.
· Age(older more likely)
· Gender (males more likely)
· Head Injury
· Pesticide Exposure
· Exposure to Metals(recently suggested)
Potential lifestyle choices and factors that may protect against Parkinson’s:
· Coffee and tea
· Increase Uric acid Intake (Men with Parkinson's are found to have low uric acid levels)
· Anti-inflammatory drugs
· Smoking
· Higher Vitamin D
· Exercise
Though these factors are consistently seen, it has not been conclusively proven as effective prevention methods.
Pesticide Exposure
Pesticides are the most consistent chemical exposure linked with Parkinson’s. Even home gardening has been associated in reports. Some pesticides inhibit the enzyme Aldehyde Dehydrogenase genes. Those exposed are at a much higher rate of being diagnosed with the disease, but still have not been established with causing the disease.