Causes
Researchers have been unable to identify specific causes of Parkinson's disease but there are many theories regarding factors which may individually or in combination play a role in its development. These include:
· Genetics - Researchers have found gene mutations related to juvenile and early-onset PD. Recently, a new mutation was identified on the LRRK2 gene that is believed to be related to idiopathic PD.
· Family history - According to the National Institute of Neurologic Disorders and Stroke (NINDS) approximately 15-20% of patients with Parkinson's disease have a close relative who exhibited a parkinsonian symptom. Estimates are that the risk for developing PD for family members of a patient with PD is 3-4 times that of the general population. There is a theory that if the right factors come together in an individual with a predisposition based on family history, that individual will develop Parkinson's disease.
· Oxidative damage - Free radicals (unstable molecules) circulating in the brain may cause oxidation resulting in damage to neurons. Some researchers refer to free radicals as endogenous toxins (toxins produced by the body).
· Toxins - Exposure to environmental toxins such as pesticides may cause degeneration of the dopamine producing cells. It is known that exposure to the herbicide Paraquat elevates the risk for PD. Although not clearly understood, it appears that smoking lowers the risk of developing PD.
· Occupational exposure - There is a higher prevalence in certain occupations such as welders, farmers, cabinet makers, and cleaners. In addition, drinking well water and industrial exposure to heavy metals (such as iron, zinc, copper, mercury, and magnesium) also elevate the risk of PD.
· Accelerated aging of neural cells - This theory proposes that for unknown reasons, the normal age-related death of brain cells is accelerated in patients with Parkinson's disease, causing the dopamine-producing cells to "age" and die faster than normal.
Pathophysiology of of Parkinson's Disease
Deep in the brain, below the cerebral cortex, there are interconnected areas of grey matter collectively known as the basal ganglia (literally "basement structures"). These structures include the caudate nucleus, putamen, and globus pallidum internus (GPi) which are involved in controlling voluntary movement. The nerve cells in the substantia nigra (a cluster of cells located next to the basal ganglia) produce dopamine, an essential neurotransmitter that is responsible for transmitting electrical signals between nerve cells. The substantia nigra sends out fibers to the corpus striatum (grey and white bands of tissue in the caudate nucleus and putamen) where the dopamine is released. The transmission of dopamine and its release into the corpus striatum is necessary for smooth, coordinated muscle movement.
Parkinson's disease occurs when there is a disruption of dopamine production which leads to impaired neurotransmission (communication between brain cells) in the basal ganglia. The reduced level of dopamine causes the nerve cells to fire out of control and causes a loss of smooth, controlled muscle activity. The death of dopamine-producing cells in the substantia nigra, resulting in a reduced level of dopamine in the corpus striatum, is the primary pathology in Parkinson's disease. By the time symptoms develop, there is at least a 60% loss of dopamine-producing cells in the substantia nigra and an 80-90% loss of dopamine in the corpus striatum.
There are five major pathways in the brain connecting other brain areas with the basal ganglia. These are known as the
● motor
● oculo-motor
● associative
● limbic
● orbitofrontal circuits
The names indicate the main projection area of each circuit. All of them are affected in PD, and their disruption likely explains much of the symptomatology of the disease since these circuits are involved in a wide variety of functions including movement, attention or learning. Scientifically, the motor circuit has been examined the most intensively.
A particular conceptual model of the motor circuit divides the efferent neurons from the striatum into two different projection systems, known as the direct and indirect pathways.
The direct pathway connects the putamen directly with the globus pallidus pars interna (GPi)- substantia nigra pars reticulata (SNr), and facilitates movement by reducing the output of the basal ganglia. The indirect pathway consists of three links, first a projection from the putamen to the globus pallidus pars externa (GPe); second a projection from GPe to the subthalamic nucleus (STN); and third a projection from STN to SNr.
The indirect pathway, as opposed to the direct, inhibits movement by increasing activity in the basal ganglia. According to this model, dopamine reduction in PD produces functional consequences related to motor symptoms of the disease. The most important consequence is increased activity in the indirect pathway, leading to excessive inhibition of movement and thus to hypokinetic symptoms.
IN NORMAL PERSON
+ and - signs at the point of the arrows indicate respectively whether the pathway is excitatory or inhibitory in effect.
Green arrows refer to excitatory glutamatergic pathways
Red arrows refer to inhibitory GABAergic pathways
Turquoise arrows refer to dopaminergic pathways that are excitatory on the direct pathway and inhibitory on the indirect pathway.
Dis-inhibitory pathways are in effect excitatory on the feedback to the cortex, while dis-dis-inhibitory pathways are inhibitory