Hannah Hoag, MSc

The loss of memory is considered a normal component of the aging process. As most people age, they lose some short-term memory and experience a decline in their learning ability. However, these changes tend to be relatively benign and the ability of a person to perform day-to-day functions remains intact. In contrast, a person suffering from dementia may be unable to function autonomously.

Memory clinics, such as the Anna and Louis Goldfarb Memory Clinic at the Jewish General Hospital (JGH) in Montreal, were established for the purposes of evaluating, diagnosing and treating those people who suffer from memory deficiencies. Two memory clinics are held at the JGH each week, which allows for the evaluation of 14 to 16 patients per week, and approximately 500 patients per year.

The JGH memory clinic, established in 1991, is now the largest in Canada. The co-directors of the clinic, Dr. Howard Bergman¹ and Dr. Howard Chertkow,² have assembled an interdisciplinary team. This team consists of geriatricians, neurologists, neuropsychologists, nurses, and study and clinic co-ordinators, all of whom, collectively diagnose and treat elderly patients with memory disorders.

There are more than 70 documented disorders that cause dementia. Alzheimer's disease (AD) is the most frequently diagnosed form of dementia, and accounts for approximately 65% of all cases. The prevalence of AD in the population of people over the age 65 is 10 to 15%.

Scientists have found evidence that a recessive gene may be involved in the development of Alzheimer's disease (AD). An Arab Community, Wadi Ara, in northern Israel, has been plagued by an unusually high prevalence of AD; of those aged 85 years and older, 61% had AD. The APOE 4 allele is known to increase the risk for AD in genetically diverse populations, so the researchers examined the frequency of this gene in the Wadi Ara population. DNA samples were collected randomly from participants and their APOE genotype was determined. The findings suggest that the APOE 4 allele is relatively uncommon in the Arabs in Wadi Ara and, in fact, they had the lowest frequency of APOE 4 ever recorded. Thus, the presence of this gene cannot explain the observed high prevalence of AD.

Considering the high rate of intermarriage among close relatives--it has been reported that 44% of all Arab marriages in Israel are consanguineous--the authors speculate that recessive genes for AD must exist and are responsible for the high AD prevalence in the region. Further, they suggest that this, and other similar populations, should be ideal for studying recessive genes for AD because of the large family size and the high rates of inbreeding. Currently, the researchers are continuing their search for the causative gene and for environmental factors that may contribute to the development of the disease.

Source

1. Bowirrat A et al. Neurology 2000, 55:731.

New Cognitive Enhancers Prevent Breakdown of Acetylcholine

Karl Farcnik, BSc, MD, FRCPC
Michelle Persyko, Psy.D, C.Psych
Psychiatrist,
Division of Geriatric Psychiatry,
University Toronto
Part-time staff,
Toronto Western Hospital

Introduction
Acetylcholinesterase (AchE) inhibitors have now become the medications of choice for first-line therapy in the treatment of Alzheimer's Disease (AD).¹ In Canada, there are currently only two drugs that have been approved for the treatment of mild to moderate Alzheimer's Disease; these are donepezil (Aricept)² and rivastigmine (Exelon).³ They have greater central specificity, and a much more favourable side effect profile, than do earlier AchE inhibitors such as tacrine (Cognex). Their role in the treatment of this disease is significant, since research is showing that they impact not only on the cognitive deficits associated with AD, but also help to preserve activities of daily living (ADL) and decrease behavioural problems. Cognition and ADL are both areas that are affected by Alzheimer's disease.⁴ Administration of these medications has been shown to be beneficial throughout the disease process. This paper describes donepezil and also rivastigmine, which is the newest AchE inhibitor that has been approved in Canada.

Miriam Vale
Bachelor of Journalism

The latest, and, perhaps, most newsworthy advances in Alzheimer's research were presented at the popular hot topics session on July 13. The topics that were presented ranged from a discussion of age-related memory deficits in transgenic mice, to use of the drug memantine for the treatment of moderately severe to severe AD.

Dr. David Morgan of the University of South Florida's College of Medicine presented data showing that Ab vaccination blocked cognitive deficits in double transgenic mice carrying mutant amyloid precursor protein (APP) and mutant presenilin 1 (PS1).

The development of transgenic mice models with age-related deficits in learning and memory are quite useful for testing whether therapeutic approaches to AD could potentially reduce or prevent dementia. Using these double transgenic mice, the group found that they could detect the presence of a working memory deficit in mice doing the six-arm radial water maze task. According to Morgan, this test is similar to the registration and recall components of the clinical examination for dementia.

The underwater maze resembles a wheel with six spokes. In this test, the mice must find a hidden underwater platform in one of six channels joined at a central area. The mice must learn the location of the platform over four consecutive learning trials; they are then tested for retention 30 minutes after the last learning trial. The cycle is repeated everyday with only the location of the platform altered so that the mice cannot use reference memory to find it.

The researchers found that 12-month-old and 15-month old mice that had received a course of vaccinations from 4-months of age onwards performed as well as wild-type mice (control mice), in that they learned to navigate the maze with few errors. By contrast, age-matched, non-immunized, transgenic mice were unable to learn the task. The researchers also found that15-month old mice that received a shorter course of the vaccination reached almost the same performance level as the controls. However, the 'short-term' vaccination mice had almost no reduction in their Ab burden when compared to nonimmunized mice, suggesting that the plaques were not responsible per se for the observed cognitive deficits. The radial arm water maze is a sensitive measure of changes in working memory performance because it separates working memory from reference memory. Morgan expects that it may be effective in longitudinal studies

Dr. Barry Reisberg of New York University's School of Medicine, presented his findings from a placebo-controlled six-month trial of the drug memantine for the treatment of patients with moderately severe to severe AD. Memantine is a fast, voltage-dependent NMDA-receptor antagonist. It blocks the NMDA receptor in the presence of the sustained release of low glutamate concentrations and thereby attenuates the function of the NMDA receptor. The presentation only included phase III of the trial, which evaluated the efficacy and tolerability of memantine. The drug, which is already in use in Germany, may also be useful for the treatment of advanced dementia. Pre-clinical data suggest that the drug has symptomatic and neuroprotective properties. The 28-week double-blind trial tested the efficacy of the drug in 32 American centres. The eligibility of patients for the trial was based on their having been diagnosed with AD with a severity rating of five or six on the Global Deterioration Scale. Patients received either 10mg memantine or placebo. Though both treatment groups worsened over the trial period, overall the decline was smaller for the memantine treatment group. It produced statistically significant improvements in clinical global changes, function and cognition. Memantine also appeared to be safe and well tolerated by the study participants. According to Reisberg, "Neuroprotective properties of memantine, in addition to the symptomatic treatment effects reported, may have contributed to these results."

Wafa Harrouk, PhD

Anti-amyloid Approaches to Treating Alzheimer's Disease
Steven T. DeKosky, MD, from the Western Psychiatric Institute of the University of Pittsburgh (Pittsburgh, Pennsylvania, USA), asserted that although current therapeutic strategies are targeted to increase cognition and control behaviour of patients with AD, future treatments are more likely to focus on early detection of the disease. This early treatment will enable clinicians to minimize the symptoms and progression of the disease and to detect pre-symptomatic disease in order to prevent the emergence of the symptoms. In the far future, the restoration of cognitive function in these patients will be the goal.

Dr. DeKosky stated that there are specific and non-specific approaches to altering the progression of the disease. On the specific side, research is focused on 'curing' the disease by aiding the regeneration of lost neurons, whereas on side of the 'non-specific' approach a number of different therapies have been developed. These include any treatment that affects the production of b-amyloid, the use of anti-inflammatories, antioxidants, analogs of estrogen, neurotrophic agents and vitamins. He also discussed the development of a vaccine to accelerate the clearance of b-amyloids, which is discussed in greater detail in a later article. Other approaches have been focused on blocking the aggregation of amyloids.

Target for a New Generation of Therapeutic Agents

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

The small southern Italian village of Nicastro, once again made it into International headlines when researchers at the University of Toronto discovered a new protein, nicastrin, which is involved in Alzheimer's disease (AD). Nicastrin was so named to honour a large family in Nicastro that has been plagued with AD for generations and played a key role in the 1995 discovery of two genes that cause early onset Alzheimer's. The same team, led by Peter St. George Hyslop, has found that nicastrin is a functional component of the g-secretase, which is involved in the formation of toxic plaques found in the brains of AD patients. More importantly, they have found an exposed and highly conserved domain of this protein that affects production of the amyloid-b (Ab) peptide and may serve as a potential target for pharmaceutical modulation of Ab production in patients with AD and other related disorders.

Much of the research into AD has been focused on the mechanism underlying the formation of the (Ab) peptide, which is a key component of the toxic amyloid plaques that are characteristic of brain tissue from patients with AD. In 1995, it was discovered that a mutation in a previously unknown protein could lead to an early-onset form of familial AD. This protein was subsequently discovered to be presenilin, a highly conserved, polytopic membrane protein. However, several studies have demonstrated that although mutations in presenilin may result in overproduction of the toxic Ab derivative, it is unlikely that the protein acts alone.

The Ab peptide is generated from a large precursor protein, the amyloid precursor protein (APP) in a two-step proteolytic pathway. Initially, the protein is cleaved near the cell surface in an extracellular domain either by a b- or a a-secretase to generate C-terminal stubs of the protein. These stubs are then further cleaved in their transmembrane domains by the presenilin-linked g-secretase to generate two different isoforms of the Ab peptide, one that is benign and one that is neurotoxic. The b-secretase enzyme appears to have a benign role; during development it may cleave a protein called Notch, which releases a fragment that activates gene transcription. Unfortunately it has been difficult to determine which proteins are directly responsible for the g-secretase activity, although evidence suggests that the presenilins are involved.

St. George-Hyslop's tream found that nicastrin binds to presenilins 1 and 2 and interacts with the APP carboxy terminal 'stub', the fragment that is produced by the initial, b-secretase cleavage. Mutations in an exposed and conserved domain of nicastrin, increase the production of both forms of the Ab peptide and deletions inhibit their production. The team also found that nicastrin is required for processing of the protein Notch, which is involved in gene activation.

So, nicastrin is structurally part of the g-secretase complex, but how does it interact with the other proteins? The team has suggested that nicastrin may bind to the APP stub and align it in the correct way to presenilin, so that it is cleaved at the right position. Another possibility is that nicastrin regulates the cleavage activity, in which case, compounds that interact with either nicastrin or the presenilins should effectively alter g-secretase and APP turnover; hence a site for pharmaceutical intervention.

Whether or not genetic variants in nicastrin are associated with inherited susceptibility to AD remains to be determined. Research in this field will be ongoing, but in the meantime pharmaceutical companies will no doubt devote a great deal of attention to this little 'Italian' protein.

Miriam Vale
Bachelor of Journalism

What is the most effective way for physicians to utilize the latest treatments for Alzheimer's disease (AD) patients and yet remain mindful of, and willing to deal with, the more mundane issues such as quality-of-life, caregiver support and patient/family education?

This question was the focus of "Bridging Research and Care," the final session of the World Alzheimer's Congress 2000. Topics that were covered included the history of Alzheimer's Disease (AD), traditional versus innovative diagnostic tools, pharmacological and nonpharmacological treatments for AD, the community resources that are available for patients and caregivers, and contemporary ethics for physicians, researchers and care providers.

The final session, entitled "Alzheimer's Disease: Into the Next Millenium", was presented by Dr. Richard W. Besdine, Director of the University of Connecticut Center on Aging. He outlined the roles and responsibilities of physicians dealing with AD patients and reviewed the current pharmacological treatments that are available to them.

First and foremost, argued Besdine, it is the doctor's responsibility to provide a comprehensive assessment of the diagnosis in a careful, compassionate manner. "Honesty is important, but the truth shouldn't bludgeon," he said.

Miriam Vale
Bachelor of Journalism

The early detection of Alzheimer's disease (AD) is one of the hottest research topics in the field. Studies are being conducted around the world with the goal of discovering methods to improve the early detection of AD. Six researchers presented their data on this topic at the Congress on July 10. The bulk of their research focuses on the use of various neuroimaging techniques to detect the areas of the brain which appear to atrophy with disease progression and for the monitoring of metabolic function in the brain. These methods exist as 'stand-alone' techniques but are also used in conjunction with other indicators or predictors of AD, such as the presence of the ApoE e4 allele. Other methods involve the use of neuropsychological testing to try and discriminate between mild cognitive impairment and the onset of AD.

Dr. Marilyn S. Albert from Harvard Medical School presented her team's work on the use of neuropsychological testing for the early detection of AD. The group, which also included Mark B. Moss, from the Boston University School of Medicine and Kenneth Jones of Brandeis University, is studying the prodromal phase of AD before a diagnosis has been made. A total of 146 people (average age=72) were given 17 neuropsychological tests yearly, over a three-year period.

Reviewing the Benefits and Limitations of Psychotropics and Cholinesterase Inhibitors

Wafa Harrouk, PharmD

The following are brief summaries of salient points from presentations in the session on Therapeutic Approaches for the Treatment of Alzheimer's disease, Sunday July 9th, 2000.

Clinical Status of Therapy for Behavioral Disturbances
Dr. Jeffrey L. Cummings, MD, from the Alzheimer's Disease Center, University of California, highlighted some of the most salient therapeutic interventions that are currently available for treatment of behavioural disturbances associated with AD. Alzheimer's disease (AD) is associated with a variety of neuro-psychiatric disturbances, including delusions, hallucinations, anxiety, depression, apathy, irritability, disinhibition, and agitation. Patients may also suffer from aberrant motor behaviours such as rummaging, pacing and wandering. These behavioural disturbances are stressful to the patient as well as to their caregivers. Appropriate treatment of these disturbances would improve the patients' quality of life, alleviate their caregiver's stress, and delay their placement in a nursing home. Relatively few double blind, placebo control trials of psychotrophic medications have been conducted on patients with AD.

Frightening Statistics Kick off the First World Alzheimer's Congress

Miriam Vale
Bachelor of Journalism

We are all aware of the devastating costs, both personal and societal, that are associated with Alzheimer's disease, and most of us are committed to improving our understanding of detection, progression and hopefully, in the near future, its prevention. Currently, a diagnosis of Alzheimer's is equivalent to a death sentence. At this stage, the most important thing a physician can do for his or her patients, and their caregivers, is keep abreast of recent developments in AD, particularly with respect to its early detection, diagnosis and the treatment of its associated behavioural symptoms.

Unfortunately, for many of us, the responsibilities of daily life preclude us from attending conferences, no matter how important they may be. At Geriatrics & Aging, we understand how busy most of you are, and we are committed to ensuring that this will not prevent you from obtaining information that is vital for your patient care decisions. With this in mind we are very pleased to present, in this and our October issue, a series of articles that summarize presentations from the First World Alzheimer's Congress, held in Washington, DC, in July of this year. For those of you who were unable to attend, I hope that this series of articles will provide you with information that you may not otherwise have obtained.