Sci. Aging Knowl. Environ., 14 November 2001
Vol. 2001, Issue 7, p. dn4
[DOI: 10.1126/sageke.2001.7.dn4]

NEURODEGENERATIVE DISEASE CASE STUDIES

Parkinson's Disease

Anne E. A. Constantino, and Lawrence S. Honig

The authors are at Columbia University College of Physicians and Surgeons, in the Department of Neurology (A.E.A.C. and L.S.H.), the Center for Parkinson's Disease and Other Movement Disorders (A.E.A.C.), and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, the Sergievsky Center, and the Alzheimer Disease Research Center (L.S.H.), New York, NY 10032, USA. E-mail: ac616{at}columbia.edu (A.E.A.C.)

http://sageke.sciencemag.org/cgi/content/full/sageke;2001/7/dn4

Key Words: Parkinson's disease • tremors • dopamine • L-dopa • substantia nigra

Abstract: In this case study, we describe the symptoms, neurological examination, test results, and brain pathology of a man with Parkinson's disease (PD). PD commonly presents with tremor or changes in one's ability to walk or move. Other major difficulties caused by this disease include rigidity of the body, slowness of movement, and postural imbalance. The disease symptoms principally result from the degeneration of a specific population of neuronal cells in the brain stem, in a region called the pars compacta of the substantia nigra. Pathology shows the loss of these cells and the appearance of characteristic neuronal cytoplasmic inclusions called Lewy bodies, which are composed principally of aggregated {alpha}-synuclein protein.

Introduction Back to Top

Mr. Z consulted a neurologist at age 44 when he noticed a resting tremor in his left leg, and stiffness and slow movement in his left arm and leg. Upon examination, the neurologist noted a tremor in the left leg when the patient sat in a chair; the tremor was resolved upon standing or walking. Other findings included relative slowness of fine rapid movements of his left hand, mild cogwheel rigidity in the left arm, and a decreased left arm swing when he walked. On the basis of the patient's history and these findings, the neurologist's diagnosis was Parkinson's disease (PD) (see Andersen). Levodopa-carbidopa and amantadine were prescribed, and all of the patient's symptoms significantly improved.

For several years, the patient's symptoms were well controlled by the medications. However, over time he noticed a tendency for the medications to lose their benefit about 3 to 4 hours after they were ingested. During these "wearing-off" spells, his parkinsonism returned. By this stage of his disease, he had bilateral resting tremors in all four limbs, bilateral bradykinesia and rigidity, a slow shuffling gait, soft speech, and a tendency to hesitate before starting to walk. There were no falling episodes, autonomic symptoms, hallucinations, dystonia, or dementia. He began to take his levodopa-carbidopa every 3 hours, but the medication failed to control the symptoms (dose failures). He also experienced twisting and writhing movements (dyskinesia) while on these medications.

At age 64, after having PD for 20 years, the patient was evaluated at Columbia-Presbyterian Medical Center. His problems included wearing-off spells that left him with a slowness of voluntary motor activity. His levodopa-carbidopa took at least 30 min to work, and there were frequent dose failures (medication failed to be effective), often associated with food intake. During a so-called off-period, he had marked rigidity in his upper extremities, his walking was very slow, and he experienced gait instability, freezing of movement, and occasional falls. He also reported difficulty swallowing, particularly with solid foods. Even when his medications worked well, he was not completely free of parkinsonism, and he required assistance to walk and eat. When he experienced a so-called on-period, it was complicated by the presence of dyskinesias that involved his head, torso, legs, and arms. Because of the force and persistence of his dyskinesias, he would often lose his balance and fall.

Medical History Back to Top

The patient had no history of high blood pressure, diabetes, or coronary artery disease. He did have a pacemaker inserted for a cardiac arrhythmia. There was no family history of any neurological disease.

Neurological Examination Back to Top

At age 64, about 20 years after the onset of his symptoms, a mental status examination was given to Mr. Z and revealed normal language skills. He was able to name objects presented to him, make lists of objects, and recall the items on the list. He also displayed good visuospatial skills and other cognitive functions. Examination of eye movements revealed good visual pursuit and saccades and the absence of square wave jerks. He appeared to have decreased facial expression. His spoke softly and had increased neck tone (relative to normal tone). His strength was normal. Dystonia involving his left big toe, which curled under his foot, led to abnormal posturing. He had dyskinesias involving primarily his trunk and head but also involving the arms and legs. Testing of fine motor control revealed increased dyskinesias with movement. Despite the dyskinesias, he displayed a slowed response when opening and closing his hands. The speed with which he performed foot taps was slower than normal, especially with his left foot. In addition, the height to which he raised his fingers when performing finger taps was lower than normal. He was unsteady when he stood up, and needed to hold on to a chair when rising. His right leg tended to freeze, and he had significant postural instability, with retropulsion on the pull test.

Laboratory and Imaging Tests Back to Top

Routine blood tests were normal. Brain magnetic resonance imaging (MRI) showed normal brain structures, with some age-appropriate atrophy. Functional imaging using positron emission tomography (PET), with 18F-2-fluoro-2-deoxy-D-glucose (FDG) as a tracer, revealed pronounced FDG uptake in the basal ganglia, especially on the left side of the brain, a pattern consistent with idiopathic (that is, a sporadic disease of unknown origin) PD.

Subsequent Course of the Illness Back to Top

At age 67, because of increasing dyskinesias, the patient underwent a neurosurgical procedure called a pallidotomy, which involves lesioning of the right globus pallidus. He benefited from this procedure, so it was followed by a left pallidotomy 1 year later. These surgeries effectively stopped the dyskinesias and also improved his walking and sense of balance (see video clips). They also stopped his freezing episodes. However, his speech became even more impaired, and he spoke with a notably softer voice.

Neuropathology Back to Top

At age 70, about 25 years after his first symptoms manifested, the patient died, and an autopsy examination of the brain was performed. This study provided a definitive diagnosis of PD. Inspection of the removed brain revealed that it was normal in size and shape; the brain weighed 1410 g, which is normal for the age and gender of the individual. Pathological examination of the brain involves tissue fixation, followed by separation of the brain stem from the cerebral hemispheres. When sectioned into 1-cm slices, the cerebral hemispheres appeared normal and showed no areas of brain injury. However, upon slicing of the brainstem, it was evident to the naked eye that there was marked pallor of the ventral midbrain (Fig. 1A). Normally, the brain stem contains a blackish pigmented band, known as the substantia nigra, as can be seen in a control brain (Fig. 1B).



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Fig. 1. (A) A section of human midbrain from a person affected by PD (about an inch in average dimension). (B) A comparable section from a neurologically normal person of about the same age. In the normal ventral midbrain, there is a dark black band called the substantia nigra (arrow). In the PD brain, this band (arrow) is much paler, reflecting the degeneration and loss of pigmented cells, which is frequently evident even at a macroscopic level.

 
Microscopic examination of midbrain sections also revealed marked changes in the substantia nigra. Sections showed significantly decreased numbers of the pigmented dopaminergic neurons, which contain melanin and are located in the pars compacta of the substantia nigra (Fig. 2A) (for comparison, see normal control in Fig. 2B). Of the remaining neurons, some can be seen to have cytoplasmic, pale, sometimes concentric-ringed, eosinophilic inclusions termed Lewy bodies (Fig. 3). It is now known that these inclusions consist of ubiquitinated {alpha}-synuclein protein present in dense aggregates. As such, Lewy bodies immunostain for both {alpha}-synuclein and ubiquitin. Degeneration of the pigmented neurons in the substantia nigra pars compacta, together with the presence of Lewy bodies, is sufficient to diagnose pathological PD. The loss of neurons is characteristically accompanied by the presence of free melanin, presumed to be detritus from dead cells, and the presence of gliosis, a reactive process including increased astrocytic cells and processes.



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Fig. 2. (A) A microscopic section of human midbrain from the patient presented in this case. There are a few scattered pigmented neurons in the substantia nigra (arrow) but many fewer are present than are seen in the normal substantia nigra (arrow), as shown in the section on the right (B).

 


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Fig. 3. A higher magnification view of the substantia nigra of this patient reveals the presence of pale, pinkish inclusion bodies in the cytoplasm of some neurons (arrow). These bodies are termed Lewy bodies. Immunological staining of such sections reveals that these bodies are immunoreactive for both ubiquitin and {alpha}-synuclein (not shown here, but see Posner).

 
Lewy bodies may also be found in other regions of the brain, notably in other pigmented brainstem nuclei [namely the locus coeruleus, a noradrenergic nucleus in the pons (Fig. 4A), and the dorsal motor nucleus of the vagus in the medulla]. Lewy bodies may also be found in the large cholinergic projecting neurons of the nucleus basalis of Meynert, in the substantia innominata (Fig. 4B). In fact, in 1913, Frederic H. Lewy first identified these structures in this "unnamed" region of the basal forebrain. In many cases of PD, particularly those of long duration or in cases with dementia, Lewy bodies are also found to varying degrees in the cerebral neocortex. Thus, there is pathological overlap between the clinicopathological entities of dementia with Lewy bodies (see Posner ) and PD.



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Fig. 4. High-magnification views of other brainstem and deep nuclear structures, such as the locus coeruleus (A) and nucleus basalis of Meynert (B), reveal the somewhat more widespread distribution of Lewy bodies (arrows) in these nuclei, in addition to the substantia nigra. In this case, Lewy bodies were not present appreciably in the neocortex, as they are in dementia with Lewy bodies (see Posner).

 
Both the mechanism of formation and pathological significance of Lewy bodies are unknown. It has been suggested that the abnormal accumulation of {alpha}-synuclein relates to a protein production or processing problem and that the aggregated state of this protein is the result of conformational changes in the aberrant protein. It is possible that the bodies are harmful to the neurons in which they occur. Alternatively, it is possible that the Lewy body is a product of the process by which neurons dispose of excess or inappropriately aggregated {alpha}-synuclein and that the inclusion body is simply a symptom of a more generalized abnormality pertaining to this synaptic protein. Arguing in favor of a role for {alpha}-synuclein in the manifestation of PD is the finding that a rare group of human families with mutations in the {alpha}-synuclein gene has an autosomal-dominant genetic form of PD that is otherwise nearly indistinguishable from the idiopathic disorder.

Discussion Back to Top

Since the description of this disorder in 1817 by James Parkinson, the etiology of PD has remained unknown. It is a slowly progressive neurodegenerative disorder that occurs throughout the world, and studies report a prevalence in the population of 4 to 21 affected individuals per 100,000. About 1 million people in North America alone are affected, and the prevalence of this disease rises with increasing age. Although PD is rare before age 50, about 5 to 10% of patients have symptoms before the age of 40 years (young-onset PD). The occurrence of this disease is slightly more common among males than among females. Although PD is not a direct cause of death, mortality is two to five times higher in people with PD, as compared with age- and gender-matched unaffected controls.

PD is characterized clinically by the triad of resting tremor, cogwheel rigidity, and slowness or lack of movements (bradykinesia or akinesia, respectively). Postural reflex impairment, or difficulty with balance, has also been included as a cardinal sign. Because there is no biological marker for PD, clinical diagnosis is made by the presence of at least two of the cardinal signs. It is also important to exclude other causes of parkinsonism, such as the use of neuroleptic drugs, postinfectious causes (encephalitis lethargica), head trauma, poisoning from recreational drug use (MPTP) (see Andersen), hydrocephalus, and cerebrovascular disease.

The tremor of PD remains the most noticeable sign of this disease and is also the one that correlates best with classic Lewy body pathology. Seventy-five percent of patients describe tremor as the first motor manifestation, and it is usually noted in one arm. The tremor can become more severe during periods of stress, anxiety, or excitement. Later in the course of the disease, the tremor can spread to the contralateral limbs. Our patient presented with a left leg tremor rather than tremors in the upper extremities. PD patients may also have a moderate degree of action tremor, especially in later stages of the disease. The absence of tremor makes it difficult to make a diagnosis of PD and suggests the possibility of atypical parkinson-plus syndromes, such as multiple system atrophy or progressive supranuclear palsy.

Rigidity is also noted on examination of the PD patient. This is caused by an increase in muscle tone that can affect the trunk and limb muscles. Cogwheel rigidity is the type of rigidity felt on a superimposed resting tremor. Rigidity often is the presenting complaint of a patient with PD, as in this case study. Bradykinesia or akinesia tends to become disabling as the disease progresses. The early manifestations of slow movements or a paucity of movement can involve numerous muscles of the body. Initially, patients complain that they are slower in executing tasks. Hence, their writing becomes smaller (micrographia) and hygienic functions that require repetitive movements (such as brushing teeth or combing hair) become difficult. They have decreased dexterity, hence complaints of having difficulties with buttons or tying their shoelaces. Akinesia of the face is often described as a masklike facies. Related complaints include soft speech, drooling, and irritated eyes due to decreased blinking. All of these features are readily apparent on examination. Patients rapidly become fatigued during repetitive tasks, such as the finger- and foot-tapping tests and during tests that involve rapid alternating hand movements. Furthermore, the patient will have difficulty rising from a chair, the gait will be slow with short steps, and there will be episodes of freezing. Our patient clearly described these diminutions in movements and the difficulty associated with rigidity. A loss of so-called postural reflexes usually appears later in the course of the disease. The patient assumes a stooped posture, arm swing is lost, and the patient starts to walk with short shuffling steps. Postural instability may lead to falls, a dreaded complication of the disease.

Secondary manifestations of PD most notably include dementia, which occurs in 20 to 40% of patients. Patients may notice a slowness of thinking (bradyphrenia). Depression is also common, and PD patients may become passive and apathetic. They may lose their motivation or interest in habitual activities.

Several other neurodegenerative disorders mimic PD. Parkinson-plus syndromes closely resemble PD but tend to present with minimal or no tremor. Striking clinical features such as autonomic symptoms or vertical gaze palsy suggest Shy-Drager syndrome or progressive supranuclear palsy. Early dementia is not a usual characteristic of PD and suggests the possible diagnosis of dementia with Lewy bodies or Alzheimer's disease (see Honig). There are no specific laboratory tests to document PD. Magnetic resonance imaging (MRI) commonly may show some atrophy, but such imaging is most useful to exclude strokes or hydrocephalus, which may cause secondary forms of parkinsonism. The PET scan (positron emission tomography) may be helpful, but medical history and neurological examination are still the best diagnostic tools.

Treatment of PD includes dopaminergic agents, including dopaminergic agonists and levodopa, the precursor of dopamine. In the long term, medication treatment may be complicated by wearing-off motor fluctuations or drug-induced dyskinesias, as was the case with the patient described herein. In the beginning, patients usually experience a smooth, steady, beneficial effect from levodopa; however, as in our patient, with time the potency and duration of benefit wane. Motor fluctuations may sometimes be alleviated by use of a controlled-release preparation of levodopa or by adding a dopamine agonist.

Acknowledgment Back to Top

We thank Steven Chin for the histological pictures in Fig. 2, Fig. 3, and Fig. 4.

November 14, 2001

Abbreviations: Action tremor. Tremor that is present when one moves or maintains a posture. • Amantadine. A drug used to treat patients with influenza and patients with Parkinson's disease. The mechanism of action is not entirely known, but it is believed to trigger release of dopamine from nerve endings, making dopamine more available to activate dopaminergic neurons. • Autonomic symptoms. Changes resulting from dysfunctions of the autonomic nervous system. In Parkinson's disease patients, these may include a fast or slow pulse, marked changes in blood pressure when sitting or standing, bowel symptoms such as constipation, and urinary difficulties such as frequency and incontinence. • Bradykinesia. Slowness rather than lack of movement, so that a prolonged time is required to execute an action. • Cerebrovascular disease. Cerebrovascular refers to blood flow in the brain. Cerebrovascular diseases include abnormalities of the blood vessels in the brain and in bringing blood to the brain (such as blockage of the carotid arteries and aneurysms). Such diseases include strokes and hemorrhages. • Cholinergic. Synthesizing and secreting acetylcholine (for example, a set of neurons may be cholinergic). • Cogwheel rigidity. A resting tremor superimposed on "lead-pipe" rigidity. Lead pipe rigidity refers to a form of increased muscle tone in which there is a constant resistance to the passive stretch of a muscle throughout its range of motion. Cogwheel rigidity is typically seen in all forms of parkinsonism. • Dopaminergic neurons. Neurons that synthesize and secrete dopamine. • Dorsal motor nucleus of the vagus. A general visceral motor nucleus present in the medulla of the brain stem. • Dyskinesia. An involuntary nonrepetitive movement that may affect distal, proximal, or axial musculature in varying combinations. Dyskinesias span a continuum, from the flickers of myoclonus to the slow writhing patterns of dystonia. • Dystonia. Alteration in muscle tone causing sustained abnormal postures and disruption of voluntary movement, existing as a separate disease entity or as one of a complex of symptoms in a broader condition (such as Parkinson's disease). Changes in activity in several brain areas--the basal ganglia, thalamus, and cerebral cortex--appear to be present in dystonia. • Encephalitis lethargica. Also known as "postencephalitic parkinsonism," this condition is a form of encephalitis characterized by lethargy and parkinsonism. • FDG. 18F-2-fluoro-2-deoxy-D-glucose. An analog of glucose that contains fluorine-18. Fluorine radioisotope F-18 decays by positron emission, allowing visualization of the glucose analog by positron emission tomography (see below). • Hallucinations. Sensations or perceptions experienced as real in the absence of any corresponding external stimuli. Occurring in any sensory modality, hallucinations may be provoked by drugs, epilepsy, psychiatric illness, neurodegenerative disease, or sensory deprivation. Degenerative brain changes are more often marked by visual hallucinations but may also produce auditory hallucinations of voices, which are a symptom of schizophrenia. • Globus pallidus. One of the basal ganglia, with connections to the striatum, thalamus, and mesencephalon. The globus pallidus acts as an antagonist of the striatum and facilitates motor information. Dysfunction in this area results in hypokinesia, poor timing of movements, and motor clumsiness. • Lewy bodies. Intracytoplasmic inclusions originally identified within select subcortical and brainstem neurons of patients with Parkinson's disease. Lewy bodies were subsequently found to be more widespread in distribution in patients that exhibited a dementing neurodegenerative disorder. That disorder is now referred to as dementia with Lewy bodies. Lewy bodies contain many proteins, but the prinicipal constituents are {alpha}-synuclein and ubiquitin. • Locus coeruleus. A collection of norepinephrine-rich neurons located in the lateral isthmus of the pons, with projections to the hypothalamus, cerebral cortex, amygdala, hippocampus, and thalamus. The locus coeruleus plays a role in alertness, observational skills, regulation of respiration, micturition, control of central nervous system blood vessels, and REM sleep. There is a decline of neurons in this nucleus in both Alzheimer's and Parkinson's disease. • Magnetic resonance imaging. MRI is a diagnostic technique in which the body to be imaged is inserted into a magnetic field, causing the magnetic spin of the hydrogen nuclei to align with the magnet. Radio signals are used to transiently perturb this alignment. As the nuclei snap back to alignment, weak electromagnetic signals are produced. Multiple signals are integrated by computer to construct an image of the tissue. MRI provides excellent resolution for detecting and localizing brain pathologies. MRI is also referred to as nuclear magnetic resonance imaging. • Medulla. The medulla, or medulla oblongata, is the lowermost part of the brain stem, lying between the spinal cord and pons. Ascending and descending nerve tracts pass through this area, and nerve centers controlling vital functions are housed in the medulla. Injury or disease affecting this region (for example, blows to the base of the skull or bulbar poliomyelitis) can be fatal if impulse conduction is interrupted in the centers controlling cardiovascular and respiratory functions. • Midbrain. Region of the brain stem lying between the pons and the cerebral hemispheres. This area is involved in eye movement and skeletal muscle control and contains auditory and visual relay nuclei. Lesions in the midbrain can cause spastic paralysis, involuntary movement, rigidity, and abnormal eye movement patterns. • MPTP. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Injection of MPTP into animals results in acute parkinsonism, due to the rapid loss of the same set of neurons that are destroyed in Parkinson's disease. • Multiple system atrophy. A neurodegenerative disease marked by a combination of symptoms affecting movement, blood pressure, and other body functions • Neocortex. Six-layered portion of the cerebral cortex that formed most recently during evolution. It consists of the cortex excluding the olfactory, hippocampal, and piriform regions. The wrinkled surface of the neocortex has distinct territories concerned with sensory, motor, and association functions. • Neuroleptic. The effects on cognition and behavior of antipsychotic drugs that reduce confusion, delusions, hallucinations, and psychomotor agitation in patients with psychoses. • Noradrenergic. Describes a structure that synthesizes and secretes noradrenaline (norepinephrine) (for example, a set of neurons or a nucleus may be noradrenergic). • Nucleus basalis. A small region of the basal forebrain that has wide projections to the neocortex and is rich in acetylcholine and choline acetyltransferase. In Alzheimer's disease, there is marked cellular degeneration in this region, with concomitant disorientation, motor unrest, and impairment of memory and speech. • Nucleus. A group of neurons anatomically demarcated from its surrounding environment. • Off-period. A term used in Parkinson's disease that refers to a state in which the patient feels slow and rigid; this usually occurs when a patient's Parkinson's disease medication has worn off. • On-period. Refers to a period during which a patient taking a Parkinson's disease medication usually feels more agile in his or her movements and less rigid, and may also have less tremor. • Pallidotomy. A neurosurgical procedure in which small lesions are made in a part of the brain involved in motor control (the globus pallidus). This procedure can reduce many of the symptoms of Parkinson's disease. • Parkinsonism. Symptoms of the type seen in Parkinson's disease, such as rigidity, loss of balance, certain tremors, or bent posture. • Parkinson-plus syndromes. Diseases that have some of the symptoms of Parkinson's disease, such as progressive supranuclear palsy, Shy-Drager syndrome, corticobasal ganglionic degeneration, and multisystem atrophies. • Pons. Brainstem region lying superior to the medulla. The pons serves as a relay station between the cerebral hemispheres and the cerebellum and is involved in regulating blood pressure, respiration, and aspects of eye movement. Alterations in eye movement are symptomatic of lesions in this region, usually due to stroke. • Positron emission tomography. Also called a PET scan, this diagnostic technique permits functional imaging of the brain, which allows quantitative examination of regional cerebral blood flow, glucose, oxygen metabolism, or brain pharmacology, depending on the radiopharmacologic agent used for imaging. • Progressive supranuclear palsy. A neurological disease characterized by bradykinesia, rigidity, balance problems, loss of voluntary eye movement, and throat muscle weakness. This condition is associated with neurodegenerative changes in the basal ganglia and brain stem and is unresponsive to treatment with L-dopa, unlike Parkinson's disease. • Pull test. This is a test used to check for postural instability in a patient. The examiner can elicit this by standing behind the patient and pulling him or her backward by the shoulders. • Resting tremor. Tremor present when the limb is fully supported against gravity, which disappears when the limb performs a motor task. • Retropulsion. During the pull test, the patient will take more than two steps backward before catching themselves. • Saccades. Fast and brief eye movements used to look around a space at various objects. • Shuffling gait. Characteristic gait in which the patient does not lift the feet up from the floor when walking. • Shy-Drager syndrome. Progressive degenerative disease of the central and autonomic nervous systems, with symptoms of orthostatic hypotension, impotence (in men), lack of bowel and bladder control, loss of sweating, parkinsonian-like symptoms of muscle tremor and rigidity, slow movement, and other widespread neurologic deficits. Preganglionic sympathetic neurons in the lateral horn of the spinal cord are affected, and cell loss in the striatonigral and olivopontocerebellar regions is observed. • Square wave jerks. Abnormal eye movements seen in parkinsonism. • Substantia innominata. An "unnamed" region of the basal forebrain in which Frederic H. Lewy first identified Lewy bodies in 1913. • Substantia nigra. Deeply pigmented subcortical nucleus of the basal ganglia where cells synthesize the neurotransmitter dopamine. This region is critical to movement control, and cellular degeneration in the substantia nigra, as seen in Parkinson's disease, can result in symptoms of rigor, tremor, and akinesia.{alpha}-Synuclein. A small protein originally found associated with synaptic vesicles. The function of this protein has yet to be defined. This protein apppears to be a major component of the pathological inclusions called Lewy bodies, which are characteristic of Parkinson's disease and dementia, and of glial cytoplasmic inclusions characteristic of multiple system atrophy. • Tremor. A low-amplitude high-frequency oscillation that most people show when they hold out their hands. Stress, fatigue, or certain drugs can exaggerate the tremor. • Vertical gaze palsy. Paralysis of upward or downward gaze.

Suggested ReadingBack to Top

  • J. Brooks, in Movement Disorders III, C. D. Marsden, S. Fahn, Eds. (Butterworth-Heinemann, Boston, 1994), pp. 65-87.
  • H. L. Paulson, M. B. Stern, in Movement Disorders, R. L. Watt, W. C. Koller, Eds. (McGraw-Hill, New York, 1997), pp.183-199.
  • C. M. Tanner, J. P. Hubble, P. Chan, in Movement Disorders, R. L. Watt, W. C. Koller, Eds. (McGraw-Hill, New York, 1997), pp. 137-152.








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