Coenzyme Q10: New Hope for Parkinson’s Disease

Parkinson's Disease (PD) is a progressive neurodegenerative disorder typified by bradykinesia, tremor, muscle rigidity and postural instability and is physiologically characterized by the presence of Lewy bodies and a decrease of dopaminergic neurons in the substantia nigra pars compacta. According to the Parkinson Society of Canada, approximately 100,000 Canadians currently suffer from this debilitating disorder.

Because loss of dopamine is believed to account for the impaired nerve and muscle control observed in PD, levodopa tends to be the prescribed treatment of choice. While the causes of PD have yet to be fully elucidated, a defective mitochondrial electron-transport chain appears to play a role in the pathogenesis of sporadic PD. Decreased complex I levels may expose neurons to the damaging effects of oxygen-free radicals. The inhibition of complex I via 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been demonstrated to cause human parkinsonism, thus implicating the enzyme as vital to the elucidation of the molecular causes of PD. Previous research has indicated that coenzyme Q10, the electron acceptor for complexes I and II, may be orally administered to reduce dopamine loss, thus paving the way for the potential use of Q10 as an alternative treatment for early PD.

In a multicentre, randomized, doubleblind test, Shults et al. enrolled 80 early PD patients who had not used PD medication or antioxidants for at least 60 days in order to further evaluate the role of Q10 as a mediator of functional decline in PD patients.

Within one month of selection, patients were assessed clinically and blood samples were taken to ascertain Q10 levels in plasma and complex I activity in platelets. Following a baseline evaluation session, patients were randomly assigned to a Q10 dosage of either 300, 600 or 1200mg/day or to an equivalent placebo dosage. Patients were reassessed at one, four, eight, 12 and 16 months or until sufficient disability had occurred so as to necessitate levodopa treatment. The coenzyme was administered orally four times daily in the form of a wafer that contained vitamin E to function as a lipophilic carrier. Vitamin E was also present in the placebo wafer.

Dosage reductions were not required in any of the treatment groups, demonstrating the widespread tolerability of oral coenzyme Q10 therapy. Treatment efficacy was determined using the Unified Parkinson Disease Rating Scale (UPDRS), an assessment of mental, motor and activities of daily living (ADL) skills. The adjusted mean UPDRS changes were +8.81 for the 300mg/d group, +10.82 for the 600mg/d group, +6.69 for the 1200mg/d group and +11.99 in the placebo group. The primary analysis, a test for correlation between dosage and the mean change in UPDRS score, determined a p value of .09, signifying a linear trend according to prespecified criteria. The greatest reduction in UPDRS score was seen in the 1200mg/d group in the ADL realm of the UPDRS.

Mean plasma Q10 levels were significantly increased in all test groups. Mitochondrial assays demonstrated that complex I activity, which proceeds independently of endogenous coenzyme Q10, was unaffected in the various treatment groups. Conversely, the NADH to cytochrome-c reductase, which depends largely on endogenous Q10 levels, showed increased activity with increased Q10 dosage.

The findings of this clinical trial propose a role for orally administered Q10 in mitochondrial function. However, this role remains questionable with regards to PD, given that the results found in plasma have yet to be replicated in the brain. The authors suggest that high dosages of Q10 may be used in the treatment of neurological diseases which are characterized by defective complex I or complex II enzymes, such as PD and Huntington disease. The linear correlation between dose and decreased cognitive decline suggests that the effect of even higher Q10 dosages should be explored. Additionally, due to the complex interaction between genetic defects and environmental insult which likely contributes to PD, further investigation into the precise mechanism of dopamine loss is imperative for future PD alleviation.

Source

1. Shults CW, Oakes D, Kieburtz K, et al. Effects of coenzyme Q10 in early Parkinson Disease. Arch Neurol 2002;59:1541-50.

A Review of Huntington’s Disease

D'Arcy Little, MD, CCFP, Director of Medical Education, York Community Services, Toronto, ON and Academic Fellow, Department of Family and Community Medicine, University of Toronto, Toronto, ON.

Introduction
Movement disorders have a high prevalence in the elderly. In fact, disorders of gait and mobility are second only to cognitive impairment as the most prevalent neurologic disorders of aging.¹ Huntington's disease (HD) is an inherited neurodegenerative disorder characterized by alterations in mood, memory and movement first described by George Huntington in 1872.^2,3 Recent advances in the elucidation of the pathophysiology of this disease may have implications in the development of more specific and effective treatments. The following article will review the epidemiology, pathophysiology, clinical presentation, diagnosis and treatment of HD, including novel treatments currently under development.

Epidemiology
HD is the most important cause of hereditary chorea. Its prevalence in the Caucasian population is thought to be as high as 10 per 100,000.⁴ However, because many gene carriers have yet to develop symptoms, the actual prevalence is more than twice the number of symptomatic cases. HD is uncommon in Finland, Norway, Japan, China, and in persons of African descent, but is greatly increased along the western shore of Lake Maracaibo, Venezuela.⁵ The condition affects both genders equally.

Depression in Idiopathic Parkinson’s Disease

Christopher Hyson MD, FRCPC, Clinical Fellow, Movement Disorders Program, London Health Sciences Centre, London, ON.

Mandar S Jog MD, FRCPC, Director, Movement Disorders Program, London Health Sciences Centre, London, ON.

Epidemiology
Idiopathic Parkinson's Disease (IPD), which results from degeneration of substantia nigra neurons, is characterized by the typical motor symptoms of rest tremor, rigidity, bradykinesia and postural instability. The estimated prevalence, which has been rising with the aging of the population, is 187/100,000 in the United States, with an annual incidence of 20/100,000. In addition to the well recognized motor disability, neuropsychiatric symptoms, such as depression, anxiety disorders and psychosis, are common, yet under-recognized in patients with IPD.¹ It is, therefore, important that primary care physicians, internists and neurologists who care for patients with IPD be familiar with the occurrence and management of this important symptom.

Depression is the most common neuropsychiatric symptom seen in patients with IPD. It is estimated that approximately 40% of patients with IPD will experience depression at some point over the course of their illness. For 4-6% of these patients, the episode will meet the Diagnostic and Statistical Manual of Mental Disorders' (DSM-IV) definition of major depression. The remainder will meet the diagnostic criteria for minor depression.

What is ALS?

ALS, sometimes called Lou Gehrig's disease or Motor Neuron Disease (MND), is characterized by degeneration of a select group of nerve cells and pathways in the brain and spinal cord, leading to progressive paralysis of the muscles.

ALS involves the loss of motor nerve cells. The nerves affected are in the spinal cord and those that travel to the voluntary muscles, with weakness and wasting in the arms, legs and mouth, throat and respiratory system. The loss of nerve cells results in atrophy, or wasting of the muscles served by those cells.

Although symptoms of ALS usually present on one side of the body, both sides are involved and the effects usually become more symmetrical as the disorder progresses.

ALS does not discriminate. Anyone can get ALS--male or female of any race. It usually becomes evident as one approaches middle age. There is a very rare form transmitted from generation to generation and a very rare juvenile form.

ALS progresses relentlessly. There is no recovery or reversal and few plateaus; it is merely a rapid decline in motor capacity. For many, there is little impairment of the intellect and the senses remain intact.

Approximately 2000 Canadians live with ALS at any one time. Ninety percent of people with ALS will die within six years and the progression of the disease will remove them from society for much of that time. Two to three Canadians die of ALS every day.

What can be done?
Nation-wide, ALS clinics employ a team approach to the treatment of disease symptoms and assisting the person with ALS to live as fully as possible. Along with neurologists and other physicians, the team may include a physiatrist, respiratory therapist, occupational therapist, physiotherapist, dietitian, speech-language pathologist, social worker and pastoral care provider.

ALS Societies across the country make a valuable contribution, providing information and referral, access to specialized equipment in a timely manner, support groups for all concerned and advocacy for those affected by the disease.

These teams help those affected with ALS to make decisions that will assist in the management of ALS and to improve quality of life at each stage. Care-giving and caregiver support become vital as the person quickly progresses from independence to dependence.

ALS research in Canada is advancing toward treatment and a cure and research funding is increasing. For example, the ALS Society of Canada's participation in the Neuromuscular Research Partnership, working with the Muscular Dystrophy Association of Canada and the Canadian Institutes of Health Research, has funded nearly $6 million of research in the past two years.

Internationally respected, Canadian researchers are focussing on several areas including proteomics (the study of protein chemistry) to determine the cause of cell death and developing trials of potentially useful drug combinations.

These initiatives in stimulating research and provision of care will eventually result in increased longevity for those with ALS, with improved quality of life, and the hope of a cure for this devastating disease.

More information is available from the ALS Society of Canada site--www.als.ca.

Parkinsonian Dementia: Diagnosis, Differentiation and Principles of Treatment

Ali Rajput, MBBS, FRCPC and Alex Rajput, MD, FRCPC
Division of Neurology, University of Saskatchewan, Saskatoon, SK.

The terms parkinsonism and Parkinson syndrome (PS) are used interchangeably. Two of the three cardinal features--bradykinesia, rigidity and tremor--are necessary to make a diagnosis of PS. Several pathological entities and neuroleptic drugs may produce PS, the most common being Parkinson's disease or idiopathic Parkinson's disease (PD), which is characterized by marked neuronal loss in the substantia nigra and Lewy body (LB) inclusions (Figure 1 is not available online). The prevalence of PS in the Canadian general population is estimated at 300 per 100,000.¹ The mean age of onset is 62 years, with both incidence and prevalence rates increasing with age. In a Canadian survey of a community population over age 65 years, 3% had PS.²

Alzheimer disease (AD) is the most common dementing illness in the industrialized countries. Marked cortical neuronal loss, plaques and intraneuronal neurofibrillary tangles are pathological features of AD (Figures 2A and 2B are not available online). More than 5% of the general population over 65 years of age have AD.

Because both PD and AD occur in old age, some individuals will have both. Pathological studies suggest that this overlap is higher than expected in unselected large autopsy series.

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

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.