Parkinson's Disease


Parkinson’s disease is the second most common neurological disorder, affecting roughly one million individuals in the U.S. It most commonly affects older individuals, and roughly 1 % of the population over the age of 60 is affected.

Symptoms

The disease is diagnosed by observing a set of characteristic symptoms that affect motor control: resting tremor, bradykinesia, and hypertonia.

Other typical features seen as the disease progresses are a stooped posture and slow, shuffling gait. As it becomes more and more difficult to initiate movement, the patient will start to show akinesia, or a lack of movement.  Lack of movement of the facial muscles gives the patient the appearance of having a mask-like, frozen look.

For many patients, the initial presentation is asymmetric, meaning only one limb or one side of the body is affected. This is what is illustrated in the video clip, from a clinical practice article in the New England Journal of Medicine (Nutt JG and Wooten GF. Diagnosis and Initial Management of Parkinson's Disease. N Engl J Med 2005;353(10):1021-7).

The second video clip shows a patient in whom the disease is much more advanced. The patient has a strong resting tremor in the arms, and a stooped posture. Akinesia manifests as freezing of gait, in which the patient has great difficulty in taking a step forward. Amazingly, the second part of the video shows the patient is still able to ride a bicycle. (Snijders, A. H. and Bloem, B. R. Cycling for Freezing of Gait. N Engl J Med 2010;362: e46).


Neurodegeneration in Parkinson's Disease

simple basal ganglia circuitParkinson’s disease is caused by a degeneration of dopaminergic neurons in the substantia nigra of the midbrain. It is considered a disorder of the basal ganglia because the major projection from the substantia nigra is to nuclei of the basal ganglia. The schematic provides a simplified illustration of the connectivity of the basal ganglia.  The basal ganglia receive inputs from multiple cortical areas, and then project to the motor cortex via the thalamus. The substantia nigra is interconnected with nuclei in the basal ganglia.  The basal ganglia integrate these multiple inputs to modulate the output of the motor cortex. Some of the connections are excitatory and some are inhibitory. The loss of dopaminergic input from the substantia nigra alters the balance of the output from the basal ganglia to the motor cortex, and this underlies the symptoms that are seen.

Parkinson’s disease is a progressive neurodegenerative disorder, and over the course of the disease, symptoms will worsen. There are pharmacologic and surgical therapies that do work to decrease the symptoms.

Drug Treatments

Pharmacologic therapy for Parkinson’s disease is aimed at restoring or increasing lost dopamine in the basal ganglia. The most effective therapy along these lines is L-dopa (also known as levodopa), a precursor to dopamine that can be given orally because it crosses the blood-brain barrier. Other treatments are dopamine agonists, and drugs that prolong the action of dopamine by blocking its uptake or inhibiting enzymes involved in its breakdown. A side effect of the various treatments that increase dopamine is dyskinesia, in which there can be uncontrolled involuntary dance-like movements.

Surgical Treatments

There are surgical therapies that can be used to control symptoms in patients whose disease does not respond to pharmacologic therapy. One approach is to create a lesion in particular parts of the thalamus or basal ganglia that become overactive in Parkinson’s disease. A preferred approach, because it is reversible and has fewer adverse effects, is deep brain stimulation (abbreviated DBS). Electrodes are implanted into particular locations, which are then treated with pulses of current. The mode of action of DBS is still not clear: the current may be activating, inhibiting, or affecting synaptic transmission onto neurons in the vicinity of the electrodes. The hypothesis as to why DBS improves symptoms is that similar to surgery, it modulates basal ganglia output that has been disrupted due to the loss of dopaminergic input from the substantia nigra.


Genetics and Parkinson's Disease

The majority of cases of Parkinson's disease are sporadic, meaning that they occur randomly and cannot be attributed to a specific environmental or genetic cause. However, roughly 5% of cases of Parkinson's disease are familial, due to mutations in specific genes. In the past ten years, many specific gene mutations causing familial Parkinson’s disease have been identified. One intriguing example is the locus PARK1, which leads to a mutation in the protein coding for alpha-synuclein. The function of this protein is not entirely clear; it may be important in maintaining the integrity of synaptic terminals. However, its discovery has been exciting because of a link to non-familial Parkinson’s disease. A typical pathological feature of Parkinson’s disease is the presence of Lewy bodies, abnormal intracellular inclusions that can be observed post-mortem in the remaining neurons of the substantia nigra (and sometimes other brain areas). Alpha-synuclein is one of the main proteins found in Lewy bodies, suggesting that alpha-synuclein dysfunction also underlies neurodegeneration in sporadic Parkinson’s disease. The hypothesis is that mutations in alpha-synuclein, or environmental factors (in the case of sporadic Parkinson’s disease) cause alpha-synuclein dysfunction that is somehow toxic to the dopaminergic neurons.


Future Prospects

The identification of genetic causes of Parkinson’s disease has allowed investigators to develop animal models of Parkinson’s disease. These provide a useful tool for understanding the pathogenesis of the disease, as well as a means to develop and test neuroprotective therapies that might slow, stop or reverse the process of neurodegeneration. A particularly powerful approach is the development of disease models in simple, genetically well-characterized organisms such as fruit flies, nematode worms, and even yeast. Genetic screens for enhancers and suppressors of the disease phenotype can be used to identify interacting proteins and potential therapeutic targets.

Another future prospect would be to replace lost neurons through transplantation. The two great difficulties with this approach are obtaining tissue suitable for transplantation, and the need for transplanted cells to establish the complicated connections required to restore function. Recent innovations in stem cell biology have shown that in principle it is possible to “reprogram” adult cells to differentiate as dopaminergic neurons, thus providing a source of tissue for transplantation and an important step toward regenerative therapy for Parkinson’s disease.

Optional further reading for those interested in regenerative therapies for Parkinson's disease:  Hargus et al. (2010) PNAS 107(36): 15921-6  In this paper, induced pluripotent stem cells from Parkinson's disease patients were differentiated and transplanted with some success into a rat model of the disease.



Quick Quiz


Fill in Answer Correct False Correct Answer
1. The oscillating movement that occurs when a patient with Parkinson’s disease is trying to be still is known as ________.
2. Name the term that means “slowness of movement”.
3. What region of the brain degenerates in Parkinson’s disease?
4. Drug therapies for Parkinson’s disease work to increase levels of this neurotransmitter.
5. This term is used to describe a disorder that occurs randomly and cannot be attributed to a specific environmental or genetic cause.
6. Name the protein that is found in large quantities in Lewy bodies.


(Spelling must be correct)




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