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Parkinson's disease, amyotrophic lateral sclerosis(ALS), and Huntington's disease are neurodegenerative motor disorders involving abnormal proteins. While a heterogenous, puzzling set, they all nonetheless share aberrant processing and folding of proteins. This leads typically to the accumulation of aggregates of these proteins. Also, in general, these disorders appear to result from long-term, cumulative insults. (Alzheimer's disease is another, which you will study later.)
Parkinson's disease is a neurodegenerative disease that on average begins at age 60, with a progressively increase in risk with age. It affects roughly 1 % of the population over the age of 60. However, it is not entirely a disorder of the elderly, since five to ten percent of cases begin before age 50.
Most cases of Parkinson's are described as idiopathic. A small percentage are from known genetic causes, toxins and drugs.
The disorder primarily is due to degeneration of a set of neurons in the midbrain called the substantia nigra. These neurons project to the basal ganglia and release the neurotransmitter dopamine.
Neurons in the substantia nigra in Parkinson's typically develop abnormal protein aggregations of the protein alpha-synuclein . These are called Lewy bodies. This typical pathological feature of Parkinson’s disease is observed post-mortem in the remaining neurons of the substantia nigra. Thus, some hypotheses suggest that Parkinson's is due to problems in the system removing abnormal proteins, leading to protein aggregations and apoptosis.
The disease is diagnosed by observing a set of characteristic symptoms that affect motor control: bradykinesia, hypertonia, and resting tremor.
Other typical features seen as the disease progresses are a
stooped posture and slow, shuffling gait.
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(http://content.nejm.org/cgi/content/full/353/10/1021/DC1), from a clinical practice article in the New England Journal of Medicine.
This second video clip(http://www.nejm.org/doi/full/10.1056/NEJMicm0810287) 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. There is no explanation for this. Also amazing is that the researchers were confident enough to send him out into the street without any protective gear.
As mentioned above, Parkinson’s disease is caused by a degeneration of dopaminergic neurons in the substantia nigra of the midbrain. These neurons send axons to the basal ganglia.
The schematic to the right provides a simplified illustration of the interconnections of the basal ganglia. The basal ganglia receive inputs from multiple cortical areas, and then send output to the motor cortex via the thalamus. The basal ganglia integrate these multiple inputs to modulate the output of the motor cortex.
The substantia nigra is interconnected with areas in the basal ganglia. Some of the connections are excitatory and some are inhibitory. The loss of dopaminergic input from the substantia nigra alters the output from the basal ganglia to the motor cortex, and this underlies the symptoms.
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.
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. (Also, dopamine itself also has strong peripheral actions and is sometimes used as an adrenergic type drug.)
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 movements.
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.
The majority of cases of Parkinson's disease are idiopathic, 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.
Amyotrophic lateral sclerosis, which is often just called ALS, results from degeneration of neurons that neurologists call "lower motor neurons" and "upper motor neurons". "Lower motor neurons" refers to the somatic efferent neurons that directly innervate skeletal muscles. "Upper motor neurons" refers to neurons in the cerebral cortex that control the lower motor neurons.
Most, but not all, cases begin in middle age. The mean duration of survival is three to five years. Degeneration of the lower motor neurons produce symptoms such as muscle atrophy, weakness and fasciculations. The latter refers to individual motor units spontaneously contracting as their degenerating efferent neurons spontaneously depolarize. This would show up on an E.M.G., such as we recorded in lab, or it might also be visible. Symptoms of upper motor neuron degeneration include overactive reflexes. For example, an overactive stretch reflex can produce rhythmic oscillations called clonus. Another example is Babinski sign.
Less than 10% of cases of ALS are directly genetic, while the remainder are termed "idiopathic".
Huntington's disease is a genetic disorder in which patients begin to show various spontaneous muscle movements. There may also be intellectual and emotion problems. With time, the involuntary somatic muscle movements can become nearly continual and the term chorea may be used to describe them. The term means "dance" and refers to irregular, involuntary movements of the limbs or facial muscles. To see chorea in Huntington's disease, view this video clip (http://www.nejm.org/doi/full/10.1056/NEJMicm0908798).
The spontaneous somatic movements reflect degeneration of neurons in the basal ganglia.
Huntington's disease is due to a single dominant gene that has extra base sequences appended to one end. The protein encoded by the gene is called huntingtin. The abnormal protein does not fold properly.
The most typical age of onset is middle-age, but it can occur earlier. While degeneration of neurons in certain regions of the basal ganglia lead to the movement abnormalities, the cognitive and psychiatic problems are probably because neurons in the cerebral cortex are often affected too. Patients live on the average 15 to 20 years after symptoms emerge.
There is a specific test for the abnormal gene, which can be given, if it is advisable and desired, before symptoms emerge.
There is no effective treatment or cure yet for this disorder. Therapy for dealing with the movement related problems can be important.
QUESTION: What is meant by bradykinesia and akinesia?
QUESTION: Which of the disorders given above involves degeneration of neurons in the spinal cord (as well as the brain)?
QUESTION: What is meant by the term idiopathic?
QUESTION: Name an abnormal protein, given above, found in Parkinson's disease.
QUESTION: Name the abnormal, rhythmic oscillations that can be caused by a hyperactive stretch reflex.