Parkinson's Disease

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General Description

Parkinson's disease is a degenerative disease of the brain (central nervous system) that impairs motor skills, speech, and other functions. Parkinson's disease belongs to a group of conditions called movement disorders. It is characterised by muscle rigidity, tremor, a slowing of physical movement (bradykinesia) and, in extreme cases, a loss of physical movement (akinesia). The primary symptoms are the results of decreased stimulation of the motor cortex by the basal ganglia, caused by the insufficient formation and action of dopamine, which is produced in the dopaminergic neurons of the brain. Secondary symptoms may include high level cognitive dysfunction and subtle language problems. Parkinson's disease is both chronic and progressive.

Issues

There is currently no cure for Parkinson's disease (PD). The costs associated with this disease in the US alone exceed $6 billion annually. This number is expected to increase as the ageing population continues to increase. Parkinson's disease is the most common disorder of movement, affecting at least 3% of the population over the age of 65 years and more than 500,000 US residents. The characteristic motor features are development of rest tremor, bradykinesia, rigidity, and impairment of postural balance. The primary biochemical abnormality in Parkinson's disease is deficiency of dopamine due to degeneration of neurons in the substantia nigra pars compacta.

Current therapy of PD is based primarily on augmentation or replacement of dopamine, using the biosynthetic precursor levodopa or other drugs which activate dopamine receptors [1]. These therapies are often successful for some time in alleviating the abnormal movements, but most patients eventually develop motor complications as a result of these treatments [2] [3]. These complications include wearing off, the abrupt loss of efficacy at the end of each dosing interval, and dyskinesias, involuntary and sometimes violent writhing movements. Wearing off and dyskinesias produce substantial disability, and frequently prevent effective therapy of the disease [4] [5]. Although wearing off and dyskinesias often appear related to the timing of medication doses, they are not simply a consequence of the pharmacokinetics of levodopa. Motor complications are virtually never observed early in the treatment of PD; they appear only after prolonged treatment, usually several years. Furthermore, individuals who do not have PD but receive levodopa for other indications do not develop motor complications. Experiments using controlled administration of dopaminergic drugs support these clinical observations [6] [7]. From this work it is clear that motor complications are not simply a passive manifestation of pharmacokinetics, but rather are the result of actively induced changes in brain function.

Justification

Currently available tools for monitoring and managing motor fluctuations are quite limited. In clinical practice, information about motor fluctuations is usually obtained by asking the patient to recall the number of hours of ON and OFF time they have experienced in the recent past. This retrospective approach is formalized in Subscale Four of the UPDRS (“Complications of Treatment”) which asks patients to report the duration of these symptoms in terms of percent of awake time spent in each state. This kind of self-report is subject to both perceptual bias (patients often have difficulty distinguishing dyskinesia from other symptoms) and recall bias. Another approach is the use of patient diaries, which does improve reliability by recording symptoms as they occur, but does not capture many of the features that are useful in clinical decision making. In clinical trials of new therapies, both the diary-based approach [8] as well as extended direct observations of the patients in a clinical care setting [9] have been used, but both capture only a small portion of the patients daily experience and are burdensome for the subjects.


Research

Research is branching out to several areas including the use of neuroprotective agents, gene therapy, neural transplantation, and complementary therapies. Neuroprotective treatments are at the forefront of the research on Parkinson’s disease, but are still under clinical scrutiny [10]. These agents could protect neurons from cell death induced by the disease resulting in a slower progression of it. Agents currently under investigation as neuroprotective agents include anti-apoptotic drugs, lazaroids, bioenergetics, antiglutamatergic agents and dopamine receptors [11]. Gene therapy and neural transplantation are promising areas of research but years of research work appear to be necessary before clinical applicability can be claimed. Nutrients have been used in clinical studies and are used by people with Parkinson’s disease to manage symptoms. None of these interventions is effective in the long run and therefore the field has shown interest for the development of systems and methods to monitor individuals with Parkinson’s disease with potential for facilitating the management of symptoms.

Major investments have been made in Parkinson's disease research by institutions such as the National Institute of Neurological Disorders and Stroke and the Michael J Fox Foundation.


Future Vision

  • Wearable monitoring systems could be used to identify the characteristics and severity of motor fluctuations in patients with Parkinson’s disease on the basis of data recorded in the home and community settings. The accomplishment of this goal could greatly improve the quality of information available to physicians treating patients with Parkinson’s disease. Such data would provide a quantitative, reliable and reproducible measure of the severity of motor fluctuations that could be used as an endpoint measure in clinical trials of novel therapies thus aiding the development of therapies under research.
  • Medication reminders assist patients in taking their medicine at the correct times to ensure an optimal level of dosage.


Related Interventions in CAPSIL:


Related Enabling Technologies in CAPSIL:


References

  1. ↑ Standaert DG, Young AB, in Goodman and Gilman's Pharmacological Basis of Therapeutics, Tenth Edition, Hardman JG and Limbird LE, Editors, McGraw-Hill, 549-620, 2001
  2. ↑ Chase TN, “Levodopa therapy: consequences of the nonphysiologic replacement of dopamine”, Neurology, 50(Suppl5): S17-S25, 1998
  3. ↑ Obeso JA, Olanow CW, Nutt JG, “Levodopa motor complications in Parkinson's disease”, Trends Neurosci, 23: 2-7, 2000
  4. ↑ Lang AE, Lozano AM, “Parkinson's disease. First of two parts”, N Engl J Med, 339(16): 1044-1053, 1998
  5. ↑ Lang AE, Lozano AM, “Parkinson's disease. Second of two parts”, N Engl J Med, 339(16): 1130-1143, 1998
  6. ↑ Blanchet PJ, Papa SM, Metman LV, Mouradian MM, Chase TN, “Modulation of levodopa-induced motor response complications by NMDA antagonists in Parkinson's disease”, Neurosci Biobehav Rev, 21: 447-453, 1997
  7. ↑ Mouradian MM, Heuser IJ, Baronti F, Chase TN, “Modification of central dopaminergic mechanisms by continuous levodopa therapy for advanced Parkinson's disease”, Ann Neurol, 27(1): 18-23, 1990
  8. ↑ Parkinson Study Group, “Evaluation of dyskinesias in a pilot, randomized, placebo-controlled trial of remacemide in advanced Parkinson disease”, Arch Neurol, 58(10): 1660-1668, 2001
  9. ↑ Adler CH, Singer C, O'Brien C, Hauser RA, Lew MF, Marek KL, Dorflinger E, Pedder S, Deptula D, Yoo K, “Randomized, placebo-controlled study of tolcapone in patients with fluctuating Parkinson disease treated with levodopa-carbidopa. Tolcapone Fluctuator Study Group III”, Arch Neurol, 55(8): 1089-1095, 1998
  10. ↑ Bonuccelli U, Del Dotto P. "New pharmacologic horizons in the treatment of Parkinson disease". Neurology 67(2):30–38, 2006
  11. ↑ Djaldetti R, Melamed E. "New drugs in the future treatment of Parkinson's disease". J. Neurol. 249(Suppl 2):II30–5, 2002


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