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Parkinson’s disease

Catechol-O-methyltransferase Inhibition in Treatment of Parkinson’s Disease

Catechol-O-methyltransferase Inhibition in Treatment of Parkinson’s Disease

Teaser: 

Zhigao Huang, MD, PhD, Clinical Fellow,
Ajit Kumar, DM, Clinical Fellow,
Joseph Tsui, MD, FRCPC, Professor, Department of Medicine, University of British Columbia, Vancouver, BC.

Introduction
Long-term treatment with dopaminomimetic drugs is often complicated by the occurrence of motor complications in Parkinson's Disease (PD) patients. This is especially true with levodopa, which remains to date the mainstay of treatment of PD. These motor complications consist of fluctuations and dyskinesias. Fluctuations refer to predictable or unpredictable changes of motor response that occur in relation to levodopa administration. Dyskinesias refer to abnormal excessive movements. Motor fluctuations can affect up to 50% of PD patients after five years of levodopa treatment.1 The main categories of fluctuations are 'wearing-off' and 'on-off.' Clinically, 'wearing-off' is characterized by a shortened duration of motor response and a rapidly waning effect in response to each oral dose of levodopa. 'On-off' refers to random fluctuations in motor response seemingly unrelated to levodopa administration.2

In early PD, the motor response to levodopa administration lasts longer than would be inferred from the plasma half-life of levodopa. Presumably, this phenomenon is related to surviving nigrostriatal neurons being able to store dopamine (DA) synthesized from exogenous levodopa, thus serving a buffer-like function.

Parkinson’s Disease: An Update on Therapeutic Strategies

Parkinson’s Disease: An Update on Therapeutic Strategies

Teaser: 

Daniel S Sa, MD and Robert Chen, MBBChir, MSc, FRCPC
Division of Neurology and Morton and Gloria Shulman Movement Disorders Centre, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, ON.

The treatment of Parkinson's Disease (PD) has undergone major changes over the past decade with the introduction of new drugs and the development of more advanced and reliable surgical procedures. However, the role of each of these different treatment alternatives is not yet clearly defined. Frequently raised questions include the most appropriate treatment in early PD and determining which patients with more advanced PD are suitable for surgery. In this review, we will attempt to address some of these issues.

Initial Treatment
The first decision to make is when to begin treatment. Since there is no therapeutic strategy proven to halt or slow disease progression, treatment initiation should be related to the level of disability. Therefore, drug therapy should be initiated when symptoms are interfering with social or occupational functions. This is usually due to impaired motor function but sometimes is related to embarrassment.

The next question is which treatment to offer. There is a long-standing debate regarding whether to start with levodopa or dopamine agonists. The levodopa proponents argue that it is still the most effective therapy for PD, and early treatment (before postural instability) has been proven to reduce mortality.

Cognitive and Behavioural Disturbances in Parkinson’s disease

Cognitive and Behavioural Disturbances in Parkinson’s disease

Teaser: 

Taresa Stefurak MSc, MD, FRCPC, Neuropsychiatry Fellow, Rotman Research Institute, Baycrest Centre for Geriatric Care, University Health Network, Department of Neurology, University of Toronto, Toronto, ON.

Introduction
Although Parkinson's disease (PD) is by definition a movement disorder, with a clinical diagnosis made by the presence of two out of three cardinal levodopa-responsive motor signs (tremor, rigidity, bradykinesia), both cognitive and neuropsychiatric symptoms are also important components. The clinical impact of these neurobehavioural symptoms is supported by a study in which the strongest predictor of quality of life perceived by PD patients was the presence of depression.1 Cognitive impairment as well as postural instability and disability also contributed to poor quality of life. Behavioural disturbances and dementia are the primary reasons for nursing home placement in PD patients.2

Characterizing the nature of these symptoms in PD provides an important model to understand the underlying mechanisms of disease progression and brain function. Although psychosocial aspects may play a role in some of the behavioural and mood disturbances in PD, evidence suggests that the underlying mechanism for these symptoms arises from the biological dysfunction of anatomical and neurochemical substrates that occur in PD.

Parkinson’s Disease and Parkinsonism in the Elderly

Parkinson’s Disease and Parkinsonism in the Elderly

Teaser: 

Editors: Jolyon Meara and William C. Koller
Cambridge University Press, 2000
ISBN 0 521 62884 9

Reviewed by Barry Goldlist, MD, FRCPC, FACP

This text is a collaboration between chapter authors and editors from the United Kingdom and the United States.

Of late, there has been an explosion of knowledge and literature in the broad field of movement disorders, so to stand out from this field, the text would have to be well written and truly focus on the elderly. Many texts simply state "condition X" is common in the elderly, and then present a discussion that could have been lifted from any general textbook.

This book is certainly well written. The first chapter gives a glossary of terms that is helpful, particularly for a non-neurologist. The second chapter, on the diagnosis of parkinsonism in the elderly by Professor Rodnitzky, is extremely well written. The chapter is organized in a way that follows normal clinical reasoning, and although concise, contains more than enough information for a generalist physician. Reading this chapter made me feel I was in the company of a master clinician. The third chapter is also very good. Although the neuropathological basis of PD is not age-specific, the chapter discusses specific geriatric issues such as comorbidity, clinical heterogeneity, age-related pattern of disease presentation and the nature of a comprehensive geriatric assessment as it relates to patients with PD. Specific problems related to the elderly are also stressed. There are individual chapters on essential tremor, gait apraxia and epidemiology, and there has been a concerted effort to focus on the elderly. The relatively minimal amount of repetition in the chapters is further evidence of high quality editing.

The numerous chapters on the role of rehabilitation professionals in the care of elderly PD patients really distinguishes this book from a more general text, and might make this text suitable for general neurologists who want specific details about handling older PD patients. It is certainly of value for generalists and geriatricians who manage elderly patients with PD. It is also probably of interest and value to rehabilitation professionals who work with PD patients.

Another Small Step in the Battle Against Parkinson’s Disease

Another Small Step in the Battle Against Parkinson’s Disease

Teaser: 

Neuropathological studies of the brain tissue from patients with Parkinson's disease (PD) reveal the presence of Lewy Bodies in dopaminergic neurons, although no one is sure whether these bodies are causal or a result of the disease process. Two individual proteins, a-synuclein and ubiquitin, are found to accumulate in the Lewy Body inclusions and, recently, research on these proteins has led to some interesting speculation about the causes of some rare familial forms of PD.

Missense mutations in the gene encoding the a-synuclein protein were found in families with an inherited autosomal dominant form of PD, and various mutations in the PARKIN gene were discovered in families with a rare autosomal recessive juvenile form of parkinsonism (AR-JP). A recent study by Shimura and colleagues has now provided a possible link between the mechanisms of disease for both types of familial PD. Knowing that parkin is a ubiquitin ligase, and speculating that parkin and a-synuclein might interact, they found that parkin regulates the degradation of an unusual form of a-synuclein through the attachment of ubiquitin. Ubiquitination of a protein by ubiquitin ligase usually targets that protein for destruction in the proteasome.

a-synuclein is a small phosphoprotein thought be to involved in synaptic vesicle transport. Normal a-synuclein has a tendency to form aggregates but neurons can get rid of these aggregates by labeling them with ubiquitin and targeting them for degradation, a system that apparently fails in patients with PD and AR-JP.

In contrast to the situation in patients with sporadic PD, the brains of AR-JP patients do not contain Lewy Bodies. Shimura et al. surmised that parkin might be required to catalyze the ubiquitination of a-synuclein; absence or impairment of parkin might lead to the accumulation of non-ubiquitinated a-synuclein. They found an interaction between a-synuclein and also found that the a-synuclein species interacting with parkin was glycosylated, giving it a larger molecular weight. The failure of mutant parkin to ubiquinate the glycoslyated a-synuclein means that neurons cannot degrade this form, leading to its accumulation in the brain. This suggests that the accumulation of glycosylated a-synuclein may be associated with the loss of neurons in AR-JP patients. To further support these studies it would be necessary to prove that other parkin substrates accumulate in the brains of these patients as well. Results of this kind have, in fact, just been provided by another study showing that another parkin substrate Pael-R (parkin-associated endothelin receptor-like receptor) does indeed accumulate in the brains of these patients. We'll await further research!

Sources

  1. Shimura H, Schlossmacher MG, Hattori N, Frosch MP, Trockenbacher A, Schneider R, et al. Ubiquitination of a new form of a-synuclein by parkin from human brain: Implications for Parkinson's disease. Science 2001;293:263-9.
  2. Imai Y, Soda M, Inoue H, Hattori N, Mizuno Y, Takahashi R. An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of parkin. Cell 2001;105:891-902.

Stem Cell Transplants Fail to Cure Parkinson’s disease

Stem Cell Transplants Fail to Cure Parkinson’s disease

Teaser: 

A controversial study on the treatment of Parkinson's disease (PD) has come to a disappointing end. Previous open clinical trials had suggested that transplantation of human embryonic dopamine neurons into the brains of patients with Parkinson's disease was beneficial. However, a recent study published in the New England Journal of Medicine has found that in a controlled trial, no significant improvement was noted in patients with transplanted neurons. Freed et al. transplanted precursors of dopaminergic cells in fragments of mesencephalon isolated from human fetuses into the brains of patients with PD. Twenty patients received the operation, in which four holes were drilled in their skulls, and twenty others underwent sham surgery, in which the drill did not go all the way through the skull. Encouragingly, some of the implanted cells were found to have survived and differentiated on histologic examination or positron-emission tomography (PET). However, there was no correlation between these findings and motor improvements in the patients. No significant improvement was noted in elderly patients who had undergone the transplantation. However, younger patients, who make up about 40% of Parkinson's patients, showed a slight improvement of symptoms, but this only lasted for one year after the surgery.

The study had generated considerable controversy, as many people felt that it was unethical to perform sham operations in patients because of the pain and the risk of complications associated with the surgery.

Source

  1. Freed et al. New England Journal of Medicine. 2001; 344:710-719.

Steering Through Murky Ethical Waters

Steering Through Murky Ethical Waters

Teaser: 


Is it Ethical to Use Foetal Tissue for the Treatment of PD?

David Kaplan, MSc(HA)
Joint Centre for Bioethics
Faculty of Medicine,
University of Toronto

Surgical transplantation of foetal brain cells has been reported to substantially improve the symptoms associated with Parkinson's Disease. Parkinson's disease, which is characterized by tremors, muscular rigidity, and akinesia, is believed to result from the deterioration of the brain's dopamine producing cells in the substantia nigra (the neural centre for the initiation and control of movement). This disease afflicts 70,000 Canadians, and unfortunately, approximately ten percent of these patients are refractory to conventional medical therapy. Clearly, new methods to control the disease would be of substantial benefit to these patients. In 1995, the Canadian government introduced legislation that would have made it difficult, if not illegal, to conduct research into foetal tissue transplant. Although this Bill died on the parliamentary order desk, there remains the prospect of reintroducing such legislation. The purpose of this article is to examine the murky ethical waters that surround the topic of research and therapy involving foetal tissue. However, I will not attempt to validate the merits of this therapy in this brief analysis.

Procurement
Obviously, a source of foetal tissue is required, in order to perform foetal tissue transplantation surgery. There are three potential sources for this tissue.

Long-term Care of Your Parkinson’s Patient

Long-term Care of Your Parkinson’s Patient

Teaser: 

Sharon Yardley, RN Clinical
Coordinator, Vancouver Hospital
Movement Disorders Clinic

Co-author
Susan Calne, RN
Coordinator Neurodegenerative
Disorders Centre

Introduction
I work at the Neurodegenerative Disorder Centre at the University of British Columbia, where we currently care for more than 1,500 patients with Parkinson's disease (PD). I work with four neurologists, all of whom have subspecialty training in PD, and on a part-time basis I also have the help of one other nurse. My role as the clinic co-ordinator, is to provide counselling and education to new patients, and as their disease progresses, to continue counselling these patients on an outpatient basis. By providing the patients with knowledge and support, we seek to optimize their quality of life and their independence.1

The clinical co-ordinator focuses primarily on the patients, and provides them with information about PD, the emotional and employment issues that may arise during the course of the illness, and changes that will occur in their lifestyle. Another important function is to provide the patients with education about pharmaceutical treatment and monitoring services, and to support them as they begin antiparkinson therapy, documenting changes in their symptoms and any problems that occur between visits.

Antiglutamate Agents Hold Promise for Control of Hallucinations in PD

Antiglutamate Agents Hold Promise for Control of Hallucinations in PD

Teaser: 


Interview with Dr. Michel Panisset

Dr. Michel Panisset is the Director of the Movement Disorder Clinic at the McGill Centre for Studies in Aging, and an Assistant Professor in the Department of Neurology and Neurosurgery at McGill University. He specializes in neurology and movement disorders and is particularly interested in Parkinson's Disease. He is also a member of the Parkinson Study Group. Dr. Panisset kindly agreed to share his knowledge and views on the best methods to control hallucinations in patients suffering from PD.

Q: Do hallucinations constitute a big problem for your patients who suffer from Parkinson's disease? How do these hallucinations affect a patient's wellbeing and daily functioning? Do they affect a patient's compliance with medication?

A: Approximately 20 to 40% of patients with Parkinson's Disease experience hallucinations. When we look at our own data, we find that this number is closer to 40%. So, it is a very significant problem. Hallucinations usually start in patients suffering from a more advanced stage of the disease, who have greater problems with cognition and require more medications. We do not see a strong effect on compliance in this particular subpopulation of patients. Typically, when a patient suffers from cognitive or psychiatric problems, medications are administered with the help of a caregiver.

Manipulation of Dopaminergic Pathways is Mainstay of Pharmacological Treatment of PD

Manipulation of Dopaminergic Pathways is Mainstay of Pharmacological Treatment of PD

Teaser: 

The history of the use of pharmaceuticals to alleviate the symptoms of Parkinson's disease (PD) began 125 years ago, when belladonna alkaloids were first used in an attempt to control severe drooling in patients suffering from PD. These alkaloids possess anticholinergic activity, and unexpectedly, they alleviated other characteristic symptoms of PD, which include tremor, rigidity, akinesia and postural instability. However, it was not until 1958 that researchers discovered the presence of high levels of dopamine in the striatum of the brain and showed that the dopamine precursor (levodopa or L-dopa) reversed the tranquillization and parkinsonian-like motor impairments induced by treatment with reserpine. This set the stage for the development of the first real pharmacotherapy for treatment of PD.

Sanjiv CC, DM,
Tsui JKC, MD, FRCPC
Neurodegenerative Disorders Centre,
University of British Columbia,
Vancouver, BC, Canada

Dopaminergic Agents
At present, there is no pharmacological cure for Parkinson's disease (PD) and only the symptoms of the disease can be treated. There is no firm evidence to support the notion that any drug has a neuroprotective action in PD; therefore, the mainstay of current drug therapy is the manipulation of the dopaminergic pathways.

Levodopa (L-DOPA)
L-dopa is the most commonly prescribed medication for the treatment of PD.