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

As the international quest to map and sequence the entire human genome continues, myriad medi-cal conditions of a genetic origin will be recognized, and tests to identify individuals at risk for these conditions will become available. An enormous amount of medical information can be gleaned from testing a person's genetic material. Health care providers could use this information to predict, and possibly prevent, future disability and disease. For over a decade, physicians have referred patients for genetic testing. In the early part of the last decade, this testing was often done without proper counselling. Numerous questions should be considered before referring an individual for genetic counselling and testing. Which patients should be sent for genetic testing and for which diseases should testing be available? Do traditional ethical and legal concepts of patient confidentiality, consent and disclosure apply to genetic information in the same manner as they apply to a patient's medical history? Are physicians liable for negligent counselling on the part of a non-physician genetic counsellor? This paper will highlight the ethical issues and legal implications of referring adult patients for genetic testing and counselling.

 

Anna Liachenko, BSc, MSc
Managing Editor,
Geriatrics & Aging

A number of groundbreaking studies seem to suggest that only a few genes are responsible for the multiple changes in our bodies, which lead to the gradual physiological decline, we call aging. The small number of genes involved in aging supports a thesis that was first proposed by Dr. George Martin of the University of Washington.

Using a new technology called oligonucleotide microarrays (or gene chips), to detect the rates of gene transcription, Dr. Richard A. Lerner together with Dr. Peter G. Schultz and other colleagues, recently examined 6000 genes expressed in human fibroblasts from both young and aging humans. They found that only 61 genes consistently showed changes in levels of expression with aging. More than half of these genes were involved in either cell cycle progression or remodeling of extracellular matrix. These cellular markers of aging may be fibro-blast-specific or at least mitotically-active-tissue specific as they are different from those found in post-mitotic tissues. Indeed, Dr. Tomas A. Prolla, who examined transcription rates in post-mitotic mouse gastrocnemius muscle, found a different (but, interestingly, just as narrow) subset of genes, for which the transcription rates were significantly altered with age.

In light of the small number of genes that presumably are able to cause the decline of multiple physiological systems, it is interesting to look at a group of genetic disorders called progerias. Progeria means early aging, in Greek.

Anna Liachenko, BSc, MSc
Managing Editor, Geriatrics & Aging

Despite the fact that colon cancer is preventable, over 16,000 elderly Canadians were diagnosed with the disease in 1999. One out of every three patients diagnosed with the disease, died. Prevention of colon cancer requires discovery and removal of the precursor polyp at an early stage. However, elderly patients, who are at risk of developing colon cancer are largely underscreened. The reasons range from high invasiveness of current techniques and, thus, poor patient acceptance, to inability of the current methods to efficiently detect small polyps. Fortunately, a new non-invasive and highly efficient technique--virtual colonoscopy--has recently been introduced. This article will describe the technique and compare this technique with the traditional methods of colonoscopy and barium enema.

David J. Vining and associates, at the Bowman Gray School of Medicine first described virtual colonoscopy in 1994. It is based on analysis of two sets of axial images obtained from thin-section helical computed tomography (CT) scans of the abdomen and pelvis. The procedure starts with cleansing the patient's bowel (using a standard barium enema or colonoscopy bowel preparation) followed by colonic insufflation with room air or carbon dioxide. Then, the abdomen and pelvis are scanned with the patient holding their breath for the first 15 to 20 seconds (to cover the upper abdomen) and gently respiring for the remainder of the scan.

Kimby N. Barton, MSc
Assistant Editor,
Geriatrics & Aging

Dramatic results presented in Cell have demonstrated that turning off the expression of a mutated protein in mice with Huntington's disease, results in either a cessation or a reversion of the symptoms associated with the disease.

Huntington's disease (HD) is an autosomal dominant inherited disorder characterized by motor disturbances such as chorea and dystonia, personality changes, and cognitive decline. These symptoms seem to result from neural degeneration, which occurs primarily in the striatum and cortex of the brain. HD typically manifests in mid-life and death follows 10 to 20 years after disease onset. Currently, no specific cure or treatment is available.

HD is caused by an expansion of glutamine (CAG) repeats near the 5' end of the gene that codes for a protein called huntingtin. The translated protein then contains an expanded glutamine (polyQ) sequence in the N-terminal portion. Normal individuals possess a polyQ length of approximately 6 to 34 repeats whereas individuals with more than 40 repeats develop HD. The longer the polyQ expansion, the earlier the onset of symptoms.

The pathogenesis of HD is poorly understood. It is believed that somehow the expansion of the polyQ sequence in the N-terminal portion of the protein results in a deleterious gain of function mechanism. Neuronal nuclear aggregates are found in the brains of patients with the disease as well as in transgenic animal models studied to date. These aggregates contain the mutant huntingtin protein and are also often found to be ubiquitinated suggesting that they have been targeted for proteasomal degradation. However, it remains to be determined whether these nuclear aggregates are themselves responsible for the neural degeneration or whether they are merely a byproduct of some other toxic response.

Amazingly, suppression of the mutant protein in mice between the ages of 18 and 34 weeks either halted or reversed the different aspects of the HD-like phenotype.

In this study, researchers created a conditional model of HD by expressing a mutated huntingtin protein under the control of a tet-regulated system. Essentially, they expressed a mutant protein in mice and looked at the effect it had on neuropathology of the brain and on the behaviour of the mice. Mice with the mutated huntingtin protein 'turned on' developed neuronal nuclear aggregates and showed behaviour consistent with that of having HD. Mice, as young as 4 weeks of age, were beginning to exhibit unusual behaviour. By 20 weeks, some, but not all, of the mice began to show a mild tremor that developed into a jerking motion. By 36 weeks the HD mice were clearly hypoactive and remained so until their death.

The most interesting part of the study, was when the researchers were able to turn the mutant protein 'off'. Adding an antibiotic to water consumed by the mice, turned off gene expression of the mutated protein. Amazingly, suppression of the mutant protein in mice between the ages of 18 and 34 weeks either halted or reversed the different aspects of the HD-like phenotype. Specifically, the neuronal and nuclear aggregates in the brain disappeared, the number of reactive astrocytes decreased, and the progressive striatal atrophy along with the decrease in D1 receptor levels was halted. In addition, stopping the expression of the HD gene prevented the further exacerbation of the HD behavioural characteristics and ameliorated their condition to a degree approaching those in control mice.

This is the first study that has ever demonstrated that the symptoms and characteristics of HD are reversible, implying that irreversible changes which commit the cell to neuronal dysfunction or death have not necessarily taken place. The findings also suggest that therapeutic approaches to target and specifically destroy the mutant huntingtin protein may be effective in returning patients with HD to a normal phenotype. Understanding the mechanisms responsible for this disease may provide new targets for therapeutic interventions in patients suffering from HD and other progressive neurodegenerative disorders.

Source

1. Yamamoto A., Lucas JJ. and Hen R. 2000. Cell. 101:57-66.

Philip Dopp, BSc

The disturbing statistics with regard to the prevalence of osteoporosis among older women are well known. By 65 years of age, one in four women have experienced an osteoporotic fracture, and the rate of incidence rises to one in two by the age of 75. The incidence of hip fractures among women in the United States is 2 per 1000 patient years by the age of 65 and 30 per 1000 patient years by the age of 85.1 More importantly, hip fractures in the elderly are associated with a high mortality rate. Both men and women are between two and five times more likely to die during the first 12 months following a hip fracture when compared to age and sex matched controls without hip fractures. Given this and other serious consequences, there is much interest in discovering factors that can prevent or slow the rate of development of this disease.¹

Pathophysiology of Osteoporosis
Osteoporosis is the generalized, progressive diminution in bone tissue mass per unit volume which causes skeletal weakness, even though the remaining bone is normal morphologically. It is well known that factors that decrease bone mineral density (BMD) and increase the risk of osteoporotic fractures include family history, white race, female gender, estrogen deficiency, low dietary levels of calcium and vitamin D, limited physical activity or immobility and medications such as corticosteroids.^1,2 Currently, there has been an increased interest in determining the role that genetic factors play in the pathogenesis of osteoporosis.

Internet Databases Offer Easy Access to Relevant Genetic Information

Kathleen Jaques Bennett, BSc, BSc, MSc

Familial hypertrophic cardiomyopathy (FHCM) is an inherited disorder that results in the thickening and stiffening of the myocardium, primarily in the left ventricle.¹ This disorder runs in families and may appear late in life. FHCM is produced by mutations in at least eight autosomal genes that are responsible for the synthesis of the sarcomeric filament proteins. These genes vary in terms of where the mutations are located.² FHCM is present in less than 0.5% of the population and has been associated with sudden death.³ The disorder varies both in its severity and in its clinical features, with more variants still being identified. There is some phenotypic heterogeneity with FHCM but the disorder is highly correlated in its physical expression to the mutation and its location, especially within families. Internet-based databases now exist to describe the characteristics of FHCM, specific mutations and loci, the epidemiology and the type of hypertrophy and the prognosis.⁴ FHCM has been a disorder associated with young people but was recently identified as having a late-onset variant that develops after age 50. This late-onset FHCM results from mutations in the gene for cardiac myosin-binding protein C (MBP-C) and cardiac troponin T (TNN-T).

Dr. Mary Tierney
Senior Scientist and Director of
Geriatric Research
Sunnybrook and Women's College Health Sciences Centre

Alzheimer's disease (AD) is the most common cause of dementia, accounting for more than 64% of dementia cases in Canada. It is a progressive neurodegenerative disorder that currently afflicts more than 161,000 Canadians and is expected to affect approximately 800,000 by the year 2030.

A recent accumulation of laboratory, epidemiological and small clinical-trial studies suggest that estradiol, the principal gonadal hormone in females, may delay or prevent the onset of AD, and may also improve cognition in women with the disease. These observations raise the possibility that women taking postmenopausal hormone replacement thera-py (HRT) may be at significantly lower risk for AD. Thus, there is a compelling and urgent need for randomized, placebo-controlled clinical trials to determine whether estrogen replacement can prevent or delay the course of AD. This urgency is made greater by recent studies that have identified cognitive tests and genetic risk factors that enable earlier diagnosis of AD and enable the identification of those most at risk for the disease. For example, our previous research has shown that two neuropsychological tests and two demographic covariates (referred to below as the Alzheimer predictive index) predicted, over a two-year period, with 80% accuracy, the onset of AD in memory-impaired individuals without dementia.

Sheldon Singh, BSc

Since the mid-19th century, it has been postulated that lithium, a small mono-valent cation, may be useful in the treatment of mania and depression. However, it was not until 1949, when Cade tested the effects of lithium on 10 patients with mania and depression, that its dramatic benefits were noted.¹ Today, lithium is the most extensively studied psychotropic medication. It has remained part of the treatment regimen for mood disorders and is the standard by which newer agents are frequently measured.²

This article will give an overview of the use of lithium in bipolar affective disorder with special consideration to the use of lithium in the elderly population.

Mechanism of Action of Lithium
Bipolar affective disorder or manic-depression is a very serious psychiatric disorder, characterized by abrupt switches from mania to depression. The etiology of this disturbance has not been identified. Research indicates that excess catecholamine activity may be present in the manic phase. It has been postulated that since anticholinergic agents cause mania, a decrease in the cholinergic system may also be involved in the manic phase. However, since the cholinergic system is also implicated in the depressive phase, the exact mechanism of catecholamine and cholinergic involvement in bipolar disorder remains to be elucidated.

Genetic Identification Promises Individually-tailored Treatments

Julia Krestow, BSc MSc

Mental illness is a term describing a group of disorders, all of which profoundly affect an individual's ability to think, feel, and act, and which result in a substantially diminished capa-city to cope with the ordinary demands of life. Mental illness can strike irrespective of age, gender, or race.¹ Although mental disorders were recognized as illnesses in the mid-18th century, suspicion and fear often overshadowed understanding. Gradually, advances in the fields of psychiatry, behavioural science, neuroscience, biology, and genetics have replaced trepidation with knowledge. Some common mental illnesses are schizophrenia, bipolar affective disorder and depression.

Researchers and clinicians have worked for decades to reduce the suffering of those with disabling disorders, and current treatments can alleviate symptoms for many. Unfortunately, there is no curative treatment, and the treatments which do exist can have side effects. Research has long shown that the risk of developing mental illness increases if another family member is similarly affected; this suggests a strong hereditary component. Exciting developments in molecular genetics and the neurosciences explain the cautious optimism in terms of insight gained into the causes of mental disorders.

Two Theories Linking DNA Damage and Aging: Free Radical/Oxidation vs. Telomere Shortening

Ruwaida Dhala-Vakil, BSc, MSc

There are many factors involved in human aging, and significant progress has been made in this field over the last few decades. Recent evidence from cloned calves suggests that scientists may not merely be able to reverse the cellular damage accumulating with age--they may, in fact, be able to prolong cell life. The cells from these cloned animals lived longer in culture and had longer telomeres than their normal counterparts. If this extension of the cellular life span can be translated into longer life for the entire organism, the calves may live fifty percent longer than normal.¹ Additionally, studies on antioxidants show that transgenic Drosophila (the fruit fly), which overexpress antioxidant genes, live 34% longer than controls.² This article will focus on both the free radical/oxidation theory of aging, and the role of telome-rase in aging.

Free Radical/Oxidation Theory of Aging
In 1956, Denham Harman suggested that there is an age-related accumulation of reactive oxygen species (ROS) which causes damage to cellular components. The damage is targeted to the proteins and DNA in the nucleus and mitochondria, as well as to the proteins and lipids in the cell membrane, and the proteins of the cytoplasm. Mitochondrial DNA is located near the inner mitochondrial membrane, close to the sites where free radicals form.