Christine Oyugi, BSc Managing Editor, Geriatrics & Aging. Edited by: Karl Farcnik, BSc, MD, FRCPC Psychiatrist, Division of Geriatric Psychiatry, University Toronto, Part-time staff, Toronto Western Hospital, Toronto, ON.

Contributions from: Serge Gauthier, MD, FRCPC Director, McGill Centre for Studies in Aging, Professor of Medicine (Neurology), McGill University, Montreal, QC. Dr. Katarina Rogaeva Research Associate, Centre for Research in Neurodegenerative diseases, University of Toronto, Toronto, ON.

Introduction
With Canada's aging population, dementia has become a growing problem. Eight percent of Canadians who are over the age of 65 suffer from dementia, of these approximately 60% are believed to have Alzheimer disease. Dementia is an age-related disease, with the prevalence increasing from 2.4% of those from 65-74 years of age, to 34.5% of those 85 and older. There are sixty thousand new cases of dementia diagnosed each year, and the costs of providing health care for these patients continue to escalate. It is with these alarming statistics in mind that clinicians gathered to hear the latest developments in the biology of dementias presented during the 11th annual Rotman conference. Various dementias were discussed at the conference including Frontotemporal lobar dementia (FTLD). FTLD is the third most common form of cortical dementia following Alzheimer disease (AD) and Dementia with Lewy Bodies. It is often mistaken for AD, yet it presents strikingly different clinical and histopathological features and therefore, must be managed distinctly. This article will serve as a summary of some of the key points presented during the first day of this conference on Monday, March 19th.

In her opening remarks, Dr. Rogaeva, a Research Associate at the Centre for Research in Neurodegenerative diseases at the University of Toronto, gave a brief overview of the genetic variability and pathobiology of Alzheimer Disease. AD is a neurological disorder that is characterized by a slow degenerative process affecting cognitive function. At a histopathological level, AD patients are characterized by the deposition of senile plaques within the brain, as well as within the walls of cerebral blood vessels. It is believed that through some unknown mechanism, these senile plaques exert a toxic effect on surrounding neurons, resulting in the neuronal degeneration found in AD patients. Other pathology that is seen includes reactive microglia, swollen neurons and intracellular neurofibrillary tangles.

The primary constituent of these senile plaques is the amyloid b peptide (Ab). Two proteases, b-secretase and g-secretase cleave this peptide from a larger precursor protein, b-amyloid precursor protein (b-APP). Essentially, b-secretase cleaves APP to produce an APPsb soluble fragment.

The pathogenesis of AD has been linked to both genetic and environmental factors (See Figure 1).

A number of genes have been identified as influencing the development of AD including APO E, the presenilin genes and b-APP gene. (See Figure 2).

Of these, presenilin 1 (PS1) mutations are said to account for majority of the early-onset familial AD cases. In a study that screened AD patients for PS1 mutations, 11% of the cases had mutations in regions coded by PS1 and, of these, 21 were novel mutations. The study also found that the AD patients who had a positive PS1 test were significantly younger (46 ±11yrs) than were the patients who tested negative for PS1 (60±11yrs).

According to Dr. Rogaeva, screening for presenilin mutations is likely to be successful and cost-efficient if it is targeted to the right groups.

The deposition of Ab in the brains of AD patients is linked to the pathology that is characteristic of the disease. In his talk, Dr. Younkin, Director of Research and Professor of Pharmacology at the Mayo clinic in Jacksonville, explained the role of Ab aggregation in the pathogenesis of AD with a focus on whether it is an essential early event in the disease process. One clue to the role of Ab can be garnered from patients with Down Syndrome or trisomy of chromosome 21. These patients invariably develop AD pathology by age 40 and have been found to have high Ab levels in their plasma. Interestingly, this increase in plasma levels of Ab is seen prior to the onset of symptoms. Studies have shown that all mutations that are linked to AD increase the extracellular concentrations of Ab; this phenomenon occurs prior to the development of the disease and fosters Ab aggregation. Aggregated Ab has been shown to be directly toxic to neurons in culture; for this reason inhibition of b or g-secretase, thereby reducing Ab concentrations, has emerged as a therapeutic target for AD. Clinical trials are currently underway to assess the efficacy of immunization with b-secretase.

Plasma and cerebrospinal fluid (CSF) levels of Ab have been shown to increase with age (over age 65 years). A study comparing patients with typical late-onset AD to age-matched controls found that Ab was increased in AD patients. Some of these patients had levels similar to those found in patients with trisomy 21 or familial AD. What is interesting with late onset AD is that, as the disease progresses, there is a decline in the levels of Ab in the plasma and CSF. The reason for this decline is not well understood, although microglial clearance has been implicated.

Although plasma levels of Ab are not adequate for making a diagnosis of AD, they may be useful as a biomarker for the disease. According to Dr Younkin, in the future, therapies could be targeted to patients with elevated Ab in the same way that patients are treated for elevated cholesterol levels to prevent cardiovascular disease. The study of Ab is only one of many approaches to the study of AD. Other approaches could play important roles in the disease progression and could also be key targets for therapeutic intervention.

Dr. Wilhelmsen, Associate Professor of Neurology at the University of Carlifornia, gave a brief overview on the pathobiology of taupathies. His talk was based on clinical evidence gained from a family with members that suffered from a variety of neurodegenerative diseases. Some of the symptoms observed included: behavioural disinhibition, dementia--which differed from that seen in AD in that there was a relative preservation of language and praxis--and Parkinson's disease, without the typical tremor and non-responsive to L-DOPA. Most members of the family with the disease eventually developed amyotrophy--which is the loss of motor neurons resulting in the development of brisk reflexes, but reduced motor power in the limbs. However, by the time that most patients were dying they were all akinetic, in a fetal position and bed-ridden, making it difficult to recognize that they had typical signs of motor neuron disease. Personality changes were observed in family members including aggressiveness, depression, alcoholism, hyper- and hypo-sexuality, childishness, craving for sweets and hyper-religiosity. Interestingly, they did not respond very well to neuroleptics. The age of onset of symptoms ranged from 25-56 years.

At the time of autopsy, microvascular changes were observed in the anterior temporal cortex of the frontal lobes, between layers II and III. Other pathology includes, rare ballooned neurons, swollen vacuolated anterior horn cells, loss of pigmented cells in the substantia nigra and gliosis in the hippocampus.

Linkage analysis was performed and a link was found to chromosome 17. This analysis was done on several families all of whom had suffered from a variety of disorders including progressive Parkinsonism and dementia with palido-ponto-nigral degeneration (PPD), frontotemporal dementia and primary progressive aphasia (PPA). Several of these families had mutations in the tau gene, which has been implicated in the formation of neurofibrillary tangles in AD. Tau protein deposits have been linked to a variety of neurodegenerative diseases, many of which are frontotemporal dementias or movement disorders, collectively referred to as tauopathies--Pick's disease, progressive supranuclear palsy, and corticobasal degeneration.

What is the function of tau? The tau gene is large and has a complex pattern of alternative spicing. The protein has domains that have been shown to affect the assembly of microtubules. Disruption of this alternative splicing is enough to cause a dysfunction of the tau protein and resulting neurodegeneration. It appears that the regulation of splicing of the gene is important for maintenance of normal brain function. Future research is needed to elucidate whether it is the aggregation of the protein that ultimately results in disease.

Many doctors have never seen a case of progressive supranuclear palsy (PSP). The disease is often misdiagnosed as Parkinson's disease until the patient fails to respond to normal therapy for PD. The prevalence of the disease is less than that for PD. The pathology of PSP is marked by the precipitation of tau protein throughout the midbrain. Although PSP is primarily a sporadic disease, studies show that a precipitating mutation may be required for the disease to occur.

Aggregates of tau protein are seen in many neurodegenerative disorders suggesting that this process may be a common pathway in the pathology of these diseases. Although the importance of the tau gene is known, more research is needed into the interaction of tau with other genes, as well as the regulation and metabolism of tau. Future efforts to develop animal models of tau-mediated neurodegeneration should provide further insights into the onset and progression of tauopathies, as well as Alzheimer disease. This could lead to the discovery of effective therapies for these disorders

The next speaker was Dr. David Westaway who began his review of the latest research in prion diseases. Prion diseases, or transmissible spongiform encephalopathies, are fatal neurodegenerative disorders. These neurodegenerative diseases include scrapie in sheep, mad cow disease in cattle, and Creutzfeldt-Jakob disease (CJD) in humans. Prion diseases may present as genetic, infectious or sporadic disorders, all of which involve the post-translational modification of the prion protein (PrPC) into the disease-causing PrPSc. CJD generally presents as progressive dementia where as the other forms of prion disease typically manifest as ataxia-like disease.

More than 20 mutations of the PrPC gene are now known to cause the inherited human prion diseases, and significant genetic linkage has been established for five of these mutations. However, why or how these mutations cause the protein to change and result in disease is not really understood.

The function of PrPC is still unknown, although there is some evidence that it is involved in the binding of Cu(II) ions. Recent studies suggest that PrPC may function in signal transduction through a pathway involving Fyn tyrosine kinase. Fyn is associated with acetylcholine receptors in muscle cells. It is highly expressed in the limbic system and may have a role in myelination. It was hoped that deletion of the mouse Prnp gene would alter the phenotype such that conclusions could be made with respect to the function of PrPC. Studies in mice show that injection with PrPSc results in death within 150 days. However, Prnp0/0 knockout mice are resistant to prion infection. This provides evidence that cellular PrP is necessary for disease pathogenesis.

Dr. Sandra Black then gave an overview of the use of neuroimaging biomarkers for AD. An ideal test for AD should: reflect the pathophysiology of the disease, allow for pathologic evaluation, allow for early detection, differentiate AD from other dementias, be non-invasive, be affordable, have a sensitivity greater than 80% for detecting AD and a specificity of greater than 80% for distinguishing other dementias. The desired sensitivity and specificity of a biomarker depends on its purpose.

Dr. Black suggested that current clinical techniques can be termed the "bronze standard" for diagnosis. This is based on the combined use of history, and physical and cognitive examination, as well as blood test and neuroimaging to exclude secondary causes. The "gold standard" is based on tissue pathology. Biochemical markers for AD include apolipoprotein E (ApoE) genotyping, and several potential CSF markers including: beta-amyloid, possibly reflecting amyloid deposition and formation of senile plaques; PHFtau protein as a marker for the phosphorylation state of tau, and formation of neurofibrillary tangles; (total) tau protein, a normal axonal protein, used as a marker for ongoing neuronal and axonal degeneration, and the CSF/serum albumin ratio, as a marker for blood-brain barrier damage, used to exclude patients who also have cerebrovascular pathology.

Functional imaging techniques such as PET and SPECT also serve as important diagnostic tools. Recently, functional studies have shown abnormalities in the posterior cingulate and medial temporal regions of patients who show memory impairment and later develop AD. This finding is potentially useful in detecting pre-clinical AD, but it is difficult to apply to individual cases.

With the emerging therapeutic compounds for the treatment of AD, an important role of imaging is in monitoring whether treatment is actually slowing down the progression of atrophy. Several techniques have been proposed to monitor the progression of the atrophy, but currently, none can be performed reliably. It is likely that both quantitative neuroimaging and biochemical profiles (urine and serum) together with clinical neurobehavioural assessments will be needed in order to achieve the required sensitivity for diagnosing and monitoring AD. Dr. Black stressed the urgent need for sensitive and specific tests.

Dr.Serge Gauthier gave the final talk of the day on currently available and future therapies for AD and related conditions. In his opening remarks, Dr. Gauthier stressed that it is important for clinicians to be knowledgeable of the fact that AD is not just one condition, but entails a mild stage AD, moderate AD and severe AD. Different treatments are effective at different stages in the disease.

In typical cases, AD progresses through relatively predictable stages, as described in the Global Deterioration Scale of Reisberg et al., (Reisberg B, Ferris SH, Deleon MJ, Crook T. The global deterioration scale for assessment of primary degenerative dementia. Am J Psychiatry 1994;44:2203-6). The estimated time from diagnosis to death is usually 5-8 years. In typical AD, most patients initially present with a change of mood, which improves over time. They then experience a linear cognitive and functional decline including a loss of autonomy for instrumental and self-care activities of daily living. Most patients have some degree of neuropsychiatric change, including hallucinations, misidentifications (Capgras syndrome), delusions and paranoid ideation, aggression or apathy, wandering and sexual disinhibition. The appearance of early-onset motor or gait disturbances, including asymmetrical grasp responses is atypical and suggests conditions other than AD. Dr. Gauthier described milestone steps in the progression of AD. These are important as they may act as future therapeutic targets (Table 1).

TABLE 1 Milestones in Progression of AD

a) Diagnosable dementia b) Loss of IADL (Instrumental Activities of Daily Living) c) Emergence of neuropsychiatric symptoms d) Nursing home placement e) Loss of basic ADL f) Death

Different stages of AD present different issues in management of the disease. In the early stages of AD the management issues include making an accurate diagnosis, patient and caregiver education, advance power of attorney, advance directives and whether the patient should continue driving. In the moderate stages, the physician should carefully monitor the patient's autonomy. At this stage it is very important to monitor the health and well-being of the caregiver. Management issues in the final, severe stages of AD include cessation of cholinesterase inhibitors and end-of-life decision making.

Taken together the speakers presented a great deal of useful information on the pathobiology of a variety of neurodegenerative diseases. Understanding the genetic and biochemical basis of these diseases may allow for treatments tailored to various disease stages, as well as providing useful biomarkers to enable detection of those patients who are most at risk.

Dementia: Biological and Clinical Advances--Part I

Dementia: Biological and Clinical Advances--Part III

Cognitive Assessment and Neuroimaging of Dementia

Bob Chaudhuri, MD
Department of Psychiatry,
University of Toronto,
Toronto, ON.

Contributions from:

Morris Freedman, MD, FRCPC
Director, Behavioural Neurology
and Senior Scientist,
Rotman Research Institute,
Baycrest Centre for Geriatric Care,
Professor of Medicine (Neurology),
University of Toronto,
Toronto, ON.

Larry Leach, PhD, CPsych
Psychologist, Department of Psychology,
Baycrest Centre for Geriatric Care,
Adjunct Professor,
University of Toronto,
Toronto, ON.

Wendy Meschino, MD, CCFP, FRCPC, FCCMG
Clinical Geneticist,
North York General Hospital,
Toronto, ON.

On Sunday, March 18th, a series of speakers discussed cognitive assessment and neuroimaging in dementia. The speakers included Dr. Morris Freedman, Dr. Larry Leach, Dr. Robert van Reekum, Dr. Sandra E. Black and Dr. Wendy Meschino.

The focus of Dr. Freedman's workshop was the Bedside Assessment of Cognitive Function. He demonstrated cognitive screening tools in dementia and selective supplementary testing from the Behavioural Neurology Assessment that was developed at Baycrest and that is currently being prepared for publication.

Dr. Freedman showed how clock drawing is an easy to administer and sensitive measure of cognitive function. However, not all time settings are equally good for demonstrating deficits. A preferred time to ask the patient to draw is "10 after 11." He gave striking examples in which the clock-drawing test was more sensitive than the Folstein Mini-Mental Status Exam (MMSE). He pointed out that, in conjunction with the clock drawing, mental status testing in the office setting can be effective in defining and tracking the patient's cognitive function.

There are a variety of common clinical problems that are associated with making a diagnosis of dementia.

The first problem is how best to test the patient's memory. Memory is almost always impaired in Alzheimer disease, although poor memory does not necessarily mean AD; intact memory suggests a diagnosis other than AD.

Generally, a patient has a history of memory loss and he or she, and/or the family, is concerned about the possibility of dementia.

The second problem is how best to test the patient's attention. The MMSE uses serial 7s and spelling the word 'world' backwards as tests; however, using months backwards or, in severe cases, having the patient use serial 1s subtraction from one hundred is useful.

A third problem is how to assess language. Dr. Freedman stated that listening to the pattern of spontaneous speech (fluent vs. nonfluent), and testing comprehension, naming and repetition are very useful. Fluent speech suggests a temporal-parietal lesion, and non-fluent points to a frontal lesion. AD produces fluent speech until the later stages.

Auditory comprehension testing involves the assessment of single words, phrases and whole body commands. He suggested that the clinicians also test repetition of single words and phrases, and test naming by showing the patient common objects to name (e.g. pencil and watch). In Alzheimer disease, naming is impaired and repetition is normal in the early stages.

Dr. Freedman outlined testing for ideomotor apraxia, which is the inability to pretend to carry out a motor activity to command (e.g. comb your hair) when the activity is one that can be performed easily in spontaneous situations. To determine if a patient has apraxia, give a verbal command. If the patient fails to respond correctly to the command ask him or her to imitate the action. Finally, ask the patient to use the real object if imitation is impaired.

Visuospatial function is commonly impaired early in the course of AD. Clock drawing is a sensitive test of visuospatial function. Supplementary testing includes drawing to command and copy, such as a house, a flower and a cube.

Dr. Freedman summarized by stating that there are a number of tests of memory. These include asking patients the year, month, day, place, name of the Prime Minister and Premier and immediate and 5 minute 3 word recall words such as cat, apple, table. Attention can be tested through serial 7s and 3s subtraction and by reciting the months backwards. Naming can be tested by asking patients to name objects. Asking the patient to draw a clock, with the time set to 10 after 11, is an effective method to test visuospatial function. Testing similarities and proverb interpretation assesses the ability to manipulate acquired knowledge. It should be noted that the tests of similarities and proverbs may be somewhat confounded by cultural biases. Copying patterns of multiple loops or alternating sequences can be used to assess frontal lobe function. Perseveration on these tasks, and deficits on world list generation of animal names or words beginning with the letter F, are often seen following frontal brain damage.

This workshop reviewed the basic aspects of the mental status exam that make up screening assessment in an office setting. Dr. Freedman concluded that testing cognitive function is very important for the differential diagnosis of dementia.

Dr. Larry Leach presented the next workshop on Neuropsychological Assessment in Dementia. The learning objectives of this lecture were: to determine whether an individual met the basic criteria for dementia; to evaluate the effectiveness of cognitive testing in identifying dementia; and to establish a battery of tests that describes the cognitive profile of a patient with dementia.

The DSM-IV modified definition of dementia was discussed and compared to the definitions provided by Cummings and Benson (1983) and by Strub and Black (1981).^1,2

The test battery domains were discussed in terms of memory, abstract reasoning, perceptual functioning, constructional ability, language, praxis, mood, global intelligence and cognitive functioning.

Common referral questions include: a) "Is impairment present?" b)"What is the pattern of impairment?" c)"What is the etiology?" d) "Is it mood related?" d) "And has there been a change?"

Dr. Leach also discussed diagnostic issues involving the effects of age, education, gender and culture.

The Prevalence of dementia was discussed and found to have an incidence of 2.4% in the population aged 5 to 74, 11.1 % in the population aged 75 to 84, and 34.5% in the population over age 85.

Dr. Leach reached several conclusions regarding the use of the MMSE as a diagnostic tool, including that:

a) It was poor for diagnosing dementia when prevalence is less than .60%;

b) It was adequate for ruling out moderate to severe cognitive impairment when prevalence is below .35%, except for those patients who are over the age of 80 and had a lower educational status. Cut-off scores need to be adjusted according to age and education.

The following criteria for diagnosing 1) Frontal-Temporal Dementia, 2) Lewy-body disease, 3) Vascular Dementia, and 4) Alzheimer Dementia, were discussed. Special tests for dementia were discussed.

Cognitive and neuropsychological tests provide insights into the nature and severity of brain dysfunction as well as brain regions that are dysfunctional in dementia. The pattern of impairment reflects brain regions affected more so than the cause of dysfunction. Therefore, there are practical limitations to diagnosing cause based solely or primarily on the results of mental status examination or neuropsychological assessment. Despite this limitation, the pattern of deficits due to dementia are clearly distinguishable for those cognitive disruptions associated with depression.

Dr. Robert van Reekum followed Dr. Leach with a presentation on the importance of neuropsychiatric evaluation in dementia. He emphasized that changes in mood and behaviour are common in these patients and can cause suffering, impact on disability and handicap, influence diagnosis and have prognostic implications. Perhaps most importantly, these changes in mood and behaviour are treatable. He divided factors that should be assessed into premorbid factors, which included a past history of medical, psychiatric, personal, neurodevelopmental and social factors, and responses to previous treatments, and current factors. The current factors include medical status, arousal antecedents/precipitants/patterns, and cognitive and neurologic status.

A variety of different behaviours are common in patients with dementia. Because the actual dementia may mimic or mask psychiatric disorders, the evaluation of psychiatric illness in this population must take into account the direct effects of CNS disease. Some of the behavioural symptoms of dementia, such as psychosis, may warrant pharmacological intervention. Anxiety, agression, disinhibition and apathy may also warrant treatment.

Finally, Dr. van Reekum stressed the need for structure, reliable and valid Behavioural inventories to improve the consistency of behaviour quantification in these patients. He reviewed one such inventory, the Neuropsychiatric Inventory (NPI).

Dr. Sandra Black presented the pros and cons of the currently available techniques for neuroimaging in dementia. The objectives of this workshop were:

a) To review currently available structural and functional imaging techniques;

b) To review principles for the interpretation of brain-behavior relationships in dementia;

c) To illustrate the above in case examples of patients with dementia.

Currently available techniques for neuroimaging in dementia include magnetic resonance imaging (MRI), positron emission tomography (PET) and CT scan. The relative merits of these techniques were discussed.

CT scanning in dementia has the following strengths: it has excellent spatial resolution; it is relatively cheap and widely available, it rules out major pathologies; and, if applied correctly, medial temp width can be measured. However, it also presents the following weaknesses: there is less contrast; there is a problem of bone artifact; it is less sensitive to pathology; and the patient is exposed to radiation.

Magnetic resonance imaging (MRI) gives excellent spatial resolution, no bone artifact and better contrast with high sensitivity, and is low risk. However, it has a higher cost than does CT scanning and is less readily available and takes longer to image (but this is changing), and there are associated contraindications (pacemaker, aneurysm and claustrophobia).

Positron Emission Tomography (PET) has the strength of being versatile: injected radiolabel can measure regional cerebral blood flow, metabolism or receptors; direct quantification is possible; there is fair resolution; and it can measure brain activation using subtraction. On the downside, it has a high costs associated with it (cyclotron and special team); it is a scarce resource and not widely available; and there is a risk associated with exposure to radiation.

Single Photon Emission Computed Tomography is relatively cheap and widely available, and the injected radio label measures regional brain perfusion; but it only offers relative quantification, gives poor spatial resolution and again has a risk of radiation exposure.

All of these techniques are useful in different ways for the diagnosis of dementia. Examination of blood flow, oxygen utilization, cerebral atrophy and brain function can be demonstrated using these techniques.

The final lecturer was Dr. Wendy Meschino who discussed the use of Genetic Testing for Dementia in Clinical practice. The objectives of the presentation were how to approach a family history of dementia, risk assessment of hereditary dementia, what tests are available, determining when testing is helpful and providing information on how to get testing done. Alzheimer disease risk factors were identified as: increasing age, a positive family history of AD, Down Syndrome, cognitive impairment, head injury, low education level, and aluminum exposure (controversial). Exposure to exogenous estrogen for women and the presence of arthritis may be protective.

The family history of dementia work-up includes:

a) Taking a detailed three-generation pedigree, noting specific symptoms, such as the age of onset and the number of unaffected relatives;

b) Obtaining medical records, including autopsy, to determine whether the patient suffers from AD or some other condition.

Less than 5% of AD is inherited as an autosomal dominant trait. These cases are usually early in onset. Hereditary factors combined with environmental factors (complex inheritance) play a role in a further 15-25% of mostly late-onset cases. The remaining 75% are sporadic, late-onset and indistinguishable in phenotype from hereditary forms.

Dr. Meschino reviewed a list of genes that are now known to cause hereditary dementias. For early-onset AD these include Presenilin 1, APP and Presenilin 2. Presenilin 1, a gene on chromosome 14, accounts for the majority of early-onset cases. The average age of onset is in the 40's. Some cases of frontotemporal dementia (FTD) are associated with mutations in the tau gene. Notch3 mutations have been found in patients with CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy).

There are also a number of genes that are believed to predispose a patient to late-onset AD. These risk modifier genes are: the e4 allele of the APOE gene on Chromosome 19 (e4 has the effect of decreasing the age of onset), and A2M-2 on Chromosome 12 (in some studies associated with an increased risk of developing AD). These are examples of genes which affect susceptibility to disease, but do not directly cause it. Genetic testing for APOE is not recommended for asymptomatic individuals because the test cannot determine whether an individual will or will not develop AD in the future.

Prior to genetic testing, patients should be provided with genetic counselling, especially when undergoing pre-symptomatic testing. Important information to cover in the session includes outlining the differences between hereditary and sporadic AD, late-onset and early-onset AD, and the risk of developing AD in the general population compared to the risk for that individual.

There are a number of important ethical issues that need to be considered when discussing predictive testing. The patient must be able to make an informed choice; that is, there should be no patient coercion. The clinician should outline the various reasons for knowing or not knowing the diagnosis, the effects it may have on the family and the potential that they will be subject to discrimination. In general, requests for prenatal diagnosis for adult-onset diseases are infrequent, and testing in childhood is strongly discouraged.

One of the following criteria should be met before Alzheimer testing is considered:

a) An individual affected with AD, with onset at less than 60 years;

b) A first-degree, unaffected relative of an affected individual, in a family with 2 or more early-onset cases (all affected are deceased);

c) 2 or more living affected family members with onset greater than 60 years (DNA samples needed from both relatives).

As part of this presentation a video clip was shown from a recent CBC Nature of Things episode called Amanda's Choice, in which a young woman from northern Ontario underwent genetic testing for early-onset Alzheimer disease. There was an extensive family history of the disease in her mother's family with onset of the disease in the mid-30's. She was shown receiving her genetic test results from the presenter as well as genetic counselling. The film explored the emotional impact of living at risk for this devastating disease and the effects on her family.

In summary, these workshops were highly educational and practical. From the neuropsychiatric assessments, MRI and PET diagnostic tests for different dementias, to the ethics and practicality of genetic testing, these workshops appealed to the novice and expert alike.

Dementia: Biological and Clinical Advances--Part II

Dementia: Biological and Clinical Advances--Part III

References

1. Cummings JL, Benson DF. Dementia: A Clinical Approach 1983. Butterworths & Company, Canada.
2. Strub RL, Black, FW. The Mental Status Examination in Neurology 1981. Philadelphia: FA Davis.

Wendy S. Meschino, MD, CCFP, FRCPC, FCCMG
Department of Genetics,
North York General Hospital,
Toronto, ON.

The last decade has seen important gene discoveries for early-onset, autosomal dominant forms of Alzheimer disease and other dementias. The genes include presenilin 1, presenilin 2 and amyloid precursor protein (APP) for Alzheimer disease, the tau gene for frontotemporal dementia (FTD) and notch3 for CADASIL. Testing for one or more of these genes is available in research laboratories in Canada and in a private US lab. Testing for presenilin 1 is indicated for patients affected with early-onset (< 60 years) Alzheimer disease. If an affected family member is unavailable (i.e. deceased), testing an unaffected first-degree relative can be considered when there are two or more affected early-onset cases in the family.

Patients requesting pre-symptomatic (predictive) testing should be referred for appropriate genetic counselling, including a full discussion of the risks and benefits of predictive testing. The following points should be considered before proceeding: Is the choice to have testing informed and free from coercion? What are the reasons for knowing or not knowing? What are the potential effects on other members of the family? Is there a potential for insurance, employer or other forms of discrimination?

For the majority of Alzheimer disease (95%), which occurs after age 60, no major dominantly inherited genes have been found. In most cases, the disease occurs sporadically in families. However in approximately 15-25%, the etiology has a complex genetic basis with both inherited and environmental modifying factors. One such genetic modifier is the e4 allele of the apolipoprotein E gene, which has been associated with a decreased age of onset, especially when homozygous. As it is neither necessary nor sufficient for onset of the disease, testing for e4 has limited utility and is not recommended in the pre-symptomatic situation. A search for other late-onset Alzheimer genes is in progress. In this regard, genetic testing on a research basis may be considered when samples can be obtained from two or more affected family members.

Dr. Robert van Reekum, MD, FRCPC
Department of Psychiatry and KLARU,
Baycrest Centre for Geriatric Care,
Assistant Professor,
Department of Psychiatry,
University of Toronto, Toronto, ON.

Neuropsychiatric assessment in dementia is important as changes in mood and behaviour are common, cause suffering, impact on disability and handicap, influence diagnosis, have prognostic implications and are often treatable. Behaviour may be conceptualized as affecting 'the ABCs': affect, behaviour, cognition, disability, economics, family and goals. Important premorbid factors to assess include a past history of medical, psychiatric, personal, neurodevelopmental, social support/stressors and response to previous treatments. Important current factors to assess include medical status (e.g. metabolic, infections, nutrition, pain, medications), arousal (e.g. delirium), antecedents/precipitants/patterns, cognitive status (e.g. insight), neurologic status (e.g. localizing signs, Parkinsonism). Common behaviours in dementia include agitation, wandering, panic attacks/catastrophic reactions, mood disorders, affective lability, hallucinations, delusions, disinhibition, sexual behaviours, compulsions/perseveration and incontinence. CNS disease may mimic or mask psychiatric disorders (e.g. Parkinson's disease causing the slowing seen in depression, expressive aprosodia masking expression of dysphoria) so that the evaluation of psychiatric illness in this population needs to take into account direct effects of CNS disease. Major Depression is not simply sadness, but is a syndrome of behaviours, which are persistent, severe and have an impact. "Mild depression" does not imply the use of low-dose antidepressants. Given the potential for masking and potential for improvement with the treatment, many clinicians "over-diagnosis" this condition (beware of risks due to antidepressants). Psychotic symptoms include hallucinations and delusions (e.g. of stealing) and are often associated with distress and changes in behaviour (e.g. agitation) which warrant pharmacological intervention. There are many anxiety disorders (e.g. panic, social phobia etc.) which are common in dementia and often warrant treatment. Anxiety may affect cognitive performance, as may depression and psychoses. Apathy (decreased interest, initiation and motivation plus flat affect) is also common in the dementias; rule out sleep disorders, metabolic disturbance (e.g. thyroid), decreased arousal (e.g. side effects of medication) and effects of role loss (e.g. institutionalization). Disinhibition (i.e. behavioural impulsivity, affective lability) is also common and contributes to other problems (e.g. aggression). Finally, this presentation stressed the need for the use of structured, reliable and valid Behavioural inventories to improve consistency of communication and quantification of behaviours (e.g. to allow for improved monitoring of the treatment response) and often to save time (e.g. it can be quicker to complete a structured inventory than it is to write a detailed progress note). The Neuropsychiatric Inventory (NPI) was reviewed, and its use encouraged for clinicians working with dementia populations.

Larry Leach, PhD, Cpsych
Psychologist, Department of Psychology,
Baycrest Centre for Geriatric Care,
Adjunct Professor, Department of Psychology,
University of Toronto,
Toronto, ON.

The accurate and reliable assessment of dementia is essential not only for the purpose of diagnosis, but also because recent advances offer promise for treatment. With the advent of new treatments, early diagnosis becomes even more important because those individuals in the early stages of a disease such as Alzheimer are likely to benefit the most from treatment. Dementia is not a disease but rather a constellation of symptoms that reflect brain dysfunction. The most common clinical criteria of dementia (the DSM-IV) requires the presence of dysfunction in memory and one or more other mental functions such as language, reasoning, perception, attention or spatial awareness. In addition, the mental dysfunction must interfere with the performance of daily activities. There are many neurological diseases that can lead to dementia, Alzheimer disease being the most common. Recent statistics published by the Canadian Consensus Conference on Dementia indicate that dementia is present in approximately 8% of Canadians. The prevalence of dementia changes dramatically with age, increasing from 2.4% of Canadians aged 65-74 to 34.5% over the age of 85.

In order to determine if an individual has some form of dementia they must undergo special tests of mental functions referred to as mental status exams or neuropsychological assessments. Such tests much meet three general criteria: they must be reliable; they must be sensitive to dementia; and they must be specific to the dementia. Reliability ensures that results can be repeated within acceptable limits of error. Sensitivity requires that the test must be able to identify individuals who are known to have dementia. Specificity requires that the test must be able to identify individuals who are known not to have dementia. Over the years, various mental status examinations have also been developed to help identify the presence of cognitive impairments that are sufficiently severe to represent a dementia. The reliability, sensitivity and specificity of tests are often documented but unfortunately, one characteristic--the predictive ability--has not always been thoroughly documented or appreciated. The predictive ability involves two complementary characteristics, positive and negative prediction. In contrast to sensitivity and specificity, which reflect how well a test identifies individuals who are known to have (or not to have) dementia, positive and negative predictions reflect the likelihood that a person has the disease given a certain test result. Positive prediction is the probability that a positive test result indicates the presence of dementia. Negative prediction is the probability that a negative test result represents the absence of dementia. Positive or negative prediction is what a clinician should be most concerned with. After all, if a clinician knew that the person has a dementia then there would be no problem. There is one aspect about predictive ability that is not fully appreciated: predictive ability varies with the prevalence of dementia. As disease prevalence increases, positive prediction increases but negative prediction decreases. Conversely, as disease prevalence decreases negative prediction increases while positive prediction decreases. This lack of appreciation of the change in predictive ability of a test with disease prevalence can lead unwary clinicians into a false sense of security with respect to the outcomes of test results.

One of the most commonly used tests of mental status is the Mini-Mental Status Examination (MMSE). This test is the most frequently used diagnostic tool to determine presence of cognitive impairment for the diagnosis of dementia. Although the sensitivity and specificity of the MMSE appear acceptable, evaluation of the positive and negative prediction across different levels of prevalence reveals that the MMSE is less than stellar. For example, a positive test result of an MMSE (based on a cut-off score of 24/30) obtained in a situation where the prevalence of dementia is expected to be 2.4% is only 12% accurate. In other words, 88% of the positive test results would likely come from normal individuals! Furthermore, the sensitivity and specificity of the MMSE has also been shown to vary with age and education of people, but age corrections are seldom applied in many clinical settings. The Mattis Dementia Rating Scale (DRS) has been shown to have excellent sensitivity and specificity; in addition, it has excellent positive and negative predictive ability across a wide range of prevalence of dementia. The MMSE has a large following due to the short amount of time it takes to administer (approximately 10 minutes), but the greater predictive ability of the DRS makes it well worth the 25 minutes it may take to administer.

Although a short test such as the DRS is sensitive to cognitive impairment, it has the shortcoming of failing to identify specific patterns of dysfunction relating to various types of dementia. For this purpose, neuropsychological tests are far superior. A detailed neuropsychological assessment can clearly and reliably define those cognitive domains that are deficient and intact. Furthermore, the neuropsychological tests have been shown to correlate with regional brain dysfunction. Although patterns of dysfunction relate to brain dysfunction they do not always identify cause. Numerous case studies have demonstrated that individuals, who have been diagnosed as having one form of dementia on the basis of patterns of impairment, have been shown to have another cause of dementia at autopsy. This represents a limitation to the present diagnostic techniques based primarily on clinical signs and symptoms. Nevertheless, an appreciation of the extent as well as type of cognitive impairment can prove to be valuable in the treatment of individuals with dementia. Despite this limitation, the pattern of deficits due to dementia are clearly distinguishable from those cognitive disruptions associated with depression.

Bob Chaudhuri, MD
Resident in Psychiatry,
Department of Psychiatry,
University of Toronto.

In 1990, three million members of the US population were 85 years of age or older. By the year 2050, it is expected that the numbers of these very elderly people will reach 20 million. However, the percentage of older people in the US is less than that in most European nations. If one considers developing nations, 250 million Chinese will be over the age of 60 by the year 2020, and the number of people in developing nations over the age of 60 will be greater than that number in all the countries in Europe. Importantly, the number of people over the age of 80 continues to grow in proportion to the nation's population.¹ Given these demographic numbers,² the sequella of aging is relevant to psychiatry in general and geriatric psychiatry specifically. There is no specific Canadian data on this subpopulation.

Dementia is primarily a disease of later life, affecting approximately 5% of people over the age of 65, and in some populations studied, almost 50% of those over the age of 85. The essential features of dementia include the development of multiple cognitive deficits including, memory impairment, disturbance in executive functioning, and at least one of aphasia, apraxia or agnosia.

Eileen P. Sloan, PhD, MD
Resident in Psychiatry,
Department of Psychiatry,
University of Toronto.

Introduction
Agitation is an aspect of dementia that can have serious emotional, medical and health-care system consequences. It results in decreased quality of life for both patient and caregiver and is often cited as the reason for the patient being admitted to a long-term care facility. Within the nursing home setting, agitation may often result in increased use of physical and/or chemical restraints, with concomitant problems such as physical injury and falls. Medical care of the agitated patient can be compromised and nursing staff is required to spend greater amounts of time caring for the agitated patient.

Definition and Prevalence
Allen (1999) points out that "agitation" is not a diagnosis but refers to a constellation of symptoms.¹ Cohen-Mansfield and Billing (1986)² define agitation as "inappropriate verbal, vocal or motor activity unexplained by apparent needs or confusion." These authors divide the symptoms of agitation into three: aggressive behaviours (hitting, kicking, verbal aggression, spitting); inappropriate physically non-aggressive behaviours (pacing, repetitious mannerisms, robing and disrobing); and inappropriate verbal agitated behaviours (screaming, complaining, constant demands for attention).

A. Mark Clarfield

The fact that dementia is finally beginning to receive the attention that it deserves is evidenced by the editors of Geriatrics & Aging wisely deciding to devote most of this issue to the subject. Dementia is primarily associated with memory loss; this means, unfortunately, that professionals often pay far less attention to the other symptoms that can accompany the syndrome. In fact, caregivers tell us that their loved one's problem with memory is usually far less burdensome than are the behavioural symptoms. Two of these symptoms are featured in this issue: agitation, by Dr. Elizabeth Sloan (a resident in Psychiatry at the U of T); and wandering, written by Dr. Bob Chaudhari, of the same department.

Dr. Sloan reminds us that agitation--sometimes accompanied by other symptoms such as screaming and aggression--is not a diagnosis per se but rather consists of a "constellation of symptoms." In geriatric care we are not afraid of such terminology, even if the terms are not always easily found in the index of Harrison's Textbook of Medicine. The same, of course, would hold for falls or incontinence.

As is the case with many of the non-specific ("atypical") presentations of disease in the elderly, Sloan points out, an underlying medical illness must never be overlooked as a possible causal factor. As I like to teach my medical students, "Take a history before prescribing haldol." (Unfortunately, now that the older anti-psychotic medications are increasingly being replaced by less toxic molecules, I'll have to figure out a new alliteration to go with, for example, risperidone--now what starts with an "r"? "rectum", no; "respiratory system"--doesn't ring true.) But I digress.

Dr. Sloan goes on to offer a great deal of good advice and the interested reader is advised to consult the references in her comprehensive bibliography.

Dr. Chaudhuri tackles the related problem of wandering, where he offers an interesting tri-partite classification which I admit that I have not seen before: volitional (depressive), motivational (anxious) and repetitive behavioural (irritable) wandering. Perhaps as a geriatrician, I am used to a more "medical" classification; but the author, not surprisingly as he is a psychiatrist, offers a more psychodynamic approach.

Like Sloan, Dr. Chaudhuri points out that management must take into account the patient's environment. Appropriately, he does not spend much time on a pharmacological approach, which is not usually an effective method unless, of course, your aim is to drug the patient into a stupor.

My own experience is that the wandering (pacing) patient with dementia must be allowed his/her own space. Obviously, as is also the case at the other end of the age spectrum with the toddler, wanderers must be protected against the obvious dangers involved. However, when all is said and done, the milieu extérieur seems to me to be of more importance than the milieu intérieur.

Dr. Clarfield is the Chief of Academic Affairs at the Herzog Hospital in Jerusalem, Director of Geriatrics in the Ministry of Health, and on staff in the Division of Geriatric Medicine, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal.

It is a particular pleasure for me to write the editorial for this month's edition of Geriatrics & Aging. I recently had a mini- reunion with some friends from medical school whom I had not seen in several years. We spent a wonderful evening reminiscing, and I was thrilled to find that my colleagues knew of G&A, and found it very helpful in their clinical practice! I had no idea that the things in which I am involved actually make a difference, although the real credit goes to the full-time editorial staff and the knowledgeable contributors who are so willing to share their expertise. Next, the topic, dementia, is one that is close to my heart. For the last three years, I have been working in the Memory Clinic at the Toronto General Hospital. At first I was shocked at how little I really knew about dementia, but I think I have learned a fair amount in the interim. Now I realize how little anybody really knows about dementia. I have also learned, through personal experience, how different are the professional and personal roles in dementia care. The professionals have it easy!

However, what thrills me most about this edition is our guest editor, A. Mark Clarfield. Mark and I trained together (too many years ago to count), and I still use the example of his dedication to demonstrate what commitment to patient care really means. Prior to his 'half day back for clinic', Mark would come in to the hospital at 6:00 a.m. to ensure that all the needs of his patients had been met. He also left detailed instructions on what his colleagues should do while he was away. I knew Mark would be successful in whatever he decided to do, and it was a thrill that both of us selected careers in geriatric medicine--perhaps inspired by the chief medical resident, Michael Gordon. A decade after training together, we both shared in the Munk Geriatric Award, which was instrumental in shaping our respective careers. Within three years of that award being presented, Mark had written his breakthrough article in the Annals of Internal Medicine, puncturing the myth of the reversible dementia. Mark's work changed the focus in this field from one simply of diagnosis, to one of diagnosis and then the provision of appropriate care, whether the cognitive impairment was reversible or not. This theme of management, regardless of whether the underlying process is modifiable or not, runs through this entire issue of G&A. In our society, health care looks to either high technology or 'magic' bullets. An example of this is the famous article in JAMA several years ago that showed a positive effect for Gingko Biloba in patients with dementia. Although it was a very flawed study, it received widespread media coverage, while an excellent adjacent article on occupational therapy interventions in dementia was completely ignored. Similarly, the possible benefits of vitamin E in preventing nursing home placement has received widespread attention, while the more robust research finding of caregiver education to prevent premature institutionalization is all but ignored.

This edition of G&A has some excellent articles on managing the behavioural problems associated with dementia. Dr. Bob Chaudhuri talks about the treatment of wandering in demented patients, while Dr. Eileen Sloan talks about screaming and agitation. Currently, we try to remember that people with dementia are still people. This means that they must be treated with the same respect for ethical standards that are applied to non-demented people. However, there are specific issues particular to patients with dementia (e.g. to tell or not to tell the diagnosis), that are addressed by Dr. Michael Gordon and Dr. David Goldstein. Dr. Clarfield addresses the issue of treatment in Alzheimer's disease, and Dr. Chris MacKnight highlights the role of the treatment of hypertension in preventing dementia. Margaret MacAdam, from the Baycrest Centre, discusses housing options for patients with dementia. This is particularly appropriate since Baycrest is a world leader in the field. As well, we have our usual assortment of articles. There is an interview with Dr. Judes Poirier, Director of the McGill Centre for Studies in Aging, and articles on the genetics of ALS, atrial fibrillation and hepatocellular carcinoma in the elderly. Enjoy.

Margaret MacAdam, PhD
Senior Vice President and Vice President,
Community Services,
Baycrest Centre for Geriatric Care,
Toronto, ON.

Two of the biggest problems facing patients with cognitive impairment and their families are access to a safe and appropriate physical environment, and access to supportive services throughout the course of the patient's disease. These problems arise because it may become increasingly difficult for the patient to obtain an appropriate level of care in his or her original residence. The options that are currently available to these patients vary widely from province to province but include staying at home, moving to one of the supportive housing projects that are becoming available in many communities, or moving to a long-term care facility. To determine which of these options is most appropriate, one must take into account the needs of the individual patient, his or her prognosis and the resources that are available to the family for maintaining their relative in the community. Because of the progressive nature of many forms of cognitive impairment, housing and care decisions are subject to change during the patient's life span.

The first step in deciding what type of housing is most appropriate is to make an assessment of the individual's needs.