5 Steps to Reverse Dementia

Unraveling Alzheimers Disease

Unraveling Alzheimers Disease

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Clinical Diagnosis Of Dementia

Clinical Diagnosis of Dementia A Review 2.3 Dementia Diagnosis, Progression and Retrogression 1 2.4 Staging of Severe Alzheimer's Disease and the Concept of Retrogenesis Doors to be Opened for Research and Clinical Practice 1 2.5 When Diagnosis is Certain, Functional Scores are Robust and Recommendable Markers of the Progression of Alzheimer's Disease 1 2.7 Two Decades of Longitudinal Research in Alzheimer's Disease 1 2.8 Diagnosing Dementia the Need for Improved Criteria 1 2.9 Pitfalls in Diagnosing Alzheimer's Disease 135 2.10 Evaluating the Performance of Measures to Assess Dementia 136 2.11 Dementia as a Diagnostic Entity 139

Definition Of Dementia

Following extensive consultations with experts in some 40 countries, the World Health Organization (WHO) published the Clinical Descriptions and Diagnostic Guidelines for Mental and Behavioural Disorders, as part of the International Classification of Diseases (10th Revision) (ICD-10) 3 . This was followed by the more compact Diagnostic Criteria for Research 4 . A summary of the ICD-10 Diagnostic Guidelines for dementia 3 is that each of the following should be present The diagnostic criteria for dementia are essentially similar in the Diagnostic and Statistical Manual (4th edition) of the American Psychiatric Association (DSM-IV) 5 , although the two systems may give somewhat different prevalence estimates, even when they are applied to the same data from the same population. The evidence so far is that the ICD-10 criteria are more strict and therefore identify fewer cases 6,7 . There are several disorders that may present with clinical features similar to dementia. Some of them may...

The Prevalence And Incidence Of Dementia

To determine how many persons there are in a particular community who have a dementia is a disarmingly simple ambition. But it requires the following a research team, including some clinicians the capacity to identify the true denominator, which is all persons aged, say, 70 years and over, in a defined geographic area, including their year of birth, so that age-specific estimates can be made a method for sampling these elderly persons, so that each has an equal probability of being assessed and an instrument for accurately ascertaining who has the features for dementia specified in ICD-10 or DSM-IV. It is not possible to determine the presence of dementia by interviewing only the elderly person to establish decline in cognitive performance or change in behaviour, collateral information is necessary, usually obtained from a relative. Then, if the study seeks to estimate the prevalence of specific dementias such as AD, further clinical information is needed, ideally obtained by a...

Risk And Protection Factors For Dementia

One way of stemming the rising tide of dementia cases would be to find effective methods of preventing the diseases that result in dementia. A reduction in the prevalence rate for dementia would help to counteract the increase due to an ageing population. We must therefore ask whether prevention of dementia is a possibility. If the causes of dementia in the elderly were understood, it would be possible to use this knowledge to develop preventive strategies. However, even in the absence of a full understanding of its causes, it is possible to base prevention around factors known to increase or decrease the risk of developing dementia. Some risk and protection factors cannot be easily modified and so provide no basis for preventive action. For example, we might know that a family history of dementia increases risk for AD, but there is nothing we can do to modify this risk, at least so far. Gene therapy for dementia remains a distant prospect. Some other factors are modifiable and it is...

Prospects For Prevention Of Dementia

Age-dependent diseases are those in which the disease process is an intrinsic part of ageing. Everyone would develop these diseases if they lived long enough. Age-related diseases, on the other hand, may become more common with age, but are not necessarily related to the ageing process. Age-related diseases can be prevented if an individual is not exposed to the causative agent. By contrast, age-dependent diseases cannot be completely prevented. They can be postponed by slowing down the disease process or avoiding environmental risk factors, but their eventual occurrence is inevitable. With age-dependent diseases the aim of prevention is to extend the period of life free of disablement by delaying disease onset. Whether the major dementing diseases are age-related or age-dependent is still a matter of debate. However, if the age-dependent view is correct, preventive efforts will not reduce the demand for health and welfare programmes to deal with dementia, but might...

Dementia Plenty of Questions Still to Be Answered

No persons are better qualified to address the topic of the review than Henderson and Jorm. Their contribution to research into the epidemiology of dementia has been of the highest order. Here, their opening sentence (Dementia is a disorder of the brain) is a challenging statement, not because what they mean is false, but because it redefines the term. Most clinicians would prefer to state that dementia is a syndrome of mental state phenomena that is caused by one or more disorders of the brain. This is not mere semantic nit-picking, but a syndrome is the only way to arrive at an operational definition of dementia suitable for clinical practice, which is all important. Were we able to biopsy the brain with 100 safety and the certainty of establishing a pathological diagnosis, then dementia as a term would acquire a similar status to heart failure. Nevertheless, it is clear that Henderson and Jorm are seeking to make the point that a disorder of the brain is a sine qua non for...

Rates and Risk Factors for Dementia Evidence or Controversy

Dementia is one of the most common diseases in the elderly, and a major cause of disability and mortality in old age. In their paper, Henderson and Jorm provide a useful overview of this disorder of the brain. This commentary will focus on two essential topics (1) the impact of very mild and mild dementia on the rates of dementia (2) risk factors for dementia the comparison between prevalence and incidence data. The prevalence of dementia in people aged 65 years or more has been estimated in several countries and is between 4 and 6 . However, pre valence estimates of mild dementia have varied considerably, ranging from less than 3 to more than 50 . The fact that some studies made no distinction between mild and moderate severity of dementia, and that the characteristics of the examined populations varied from study to study, has probably contributed to the variance in prevalence estimates of mild dementia 1 . Many screening instruments fail to identify a considerable proportion of...

Dementia the Public Health Challenge

In their review, Henderson and Jorm have set the stage for a full discussion of the multi-faceted nature of the disorders we call dementia. Reliable and valid definitions of the syndrome and its sub-groups are essential in order to understand the scope and impact of these disorders on the world population. As much as a 10-fold difference in prevalence is dependent on the diagnostic criteria for dementia. Moreover, with significant therapeutic advances on the horizon, differentiation of subgroups is essential in order to match target specific treatments. ICD-10 seems to have a much stricter definition for the syndrome than the American DSM-IV classification system. However, other widely used classification systems for Alzheimer's disease (AD) include the National Institute of Neurological and Communicative Disorders-Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) workgroup 1 and the Consortium to Establish a Registry for Alzheimer's disease (CERAD) 2 . For vascular...

Dementia the Challenge for the Next Decade

After a long career in psychiatric research, it is remarkable to note how dementia is now in the forefront of biological, clinical and epidemiological interest rather than remaining an unmentioned, untreatable condition that made some older people senile. Its importance as a source of disability and cost in the developed world has been amply shown in Henderson and Jorm's tables. Even more alarming is the projected increase of prevalence in low-income countries, as the population ages there. At the moment, just under 50 of all world dementia cases are in low-income countries, but by the year 2020 the proportion will rise to approximately 70 1 . The need for education for families, health care agencies and governments about this potential burden is of paramount importance. The subclassification of dementia by categorical diagnosis has proved useful, as it has allowed internationally agreed consensus criteria for each diagnosis to be developed 2,3 . This has led to standardization in...

Recent Progress in the Definition and Epidemiology of Dementia

Dementia is one of the major diseases of our times. The burden of the disorder is immense in terms of direct costs of care for sufferers, but the cost in terms of stress and strain imposed on carers is impossible to measure. It is well recognized that psychological and psychiatric diseases are more feared than some physical afflictions, and dementia is the archetypal example of this, because the symptoms lead to loss of independence and the inability of a person to be in control. Henderson and Jorm provide an unrivalled summary of the salient points in current thinking around dementia in terms of disease definition and epidemiology. There are seven aspects of the disorder which this commentator would like to emphasize. The symptoms of dementia present a continuum between normal ageing and disease 1 . This fact has led people to believe that the syndrome is therefore the inevitable consequence of normal ageing and so nothing can or should be done to mitigate its effects. As a result,...

Is the Prevalence Rate of Alzheimers Disease Increasing in Japan

Local governments in Japan have been greatly concerned with the various problems of the aged, because of the rapid increase in their number. They have conducted surveys to investigate their living conditions and the needs for welfare services for them. In the last two decades, approximately 30 surveys on dementia in the community have been conducted in Japan. The sites of the investigations were distributed all over the country. Surveys were conducted by the two-step method, that is, a screening survey and a secondary survey for diagnosis by a psychiatrist during door-to-door visits. The use of functioning in activities of daily living, behavioural symptoms, and the degree of care required as criteria to screen the elderly with suspected dementia was one of the features in the surveys. In a community survey conducted in 1992 1 , 5000 persons aged over 65 years, randomly selected from approximately 340 000 elderly persons in Kanagawa prefecture, were subjected to a screening survey...

Clinical Diagnosis Of Alzheimers Disease Ad

AD is, epidemiologically, the leading cause of dementia 11 . It is a characteristic clinical and pathological process 9 . Pathologically, it is characterized by the presence in the brain of neurofibrillary tangles, comprised in part of the tau protein, and amyloid (senile) plaques which contain the p-amyloid protein. Although characteristic of AD, these major pathologic elements are not pathognomonic, and can be found both separately and together in both normal aged persons and in other, non-AD, pathologic disorders. The magnitude of occurrence of these major pathologic constituents, their localization in particular brain regions, such as the hippocampus, and the co-occurrence of tau-positive neurofibrillary tangles and senile plaques containing p-amyloid, all assist in the pathologic differentiation of AD from other clinical entities.

The Characteristic Clinical Course of Retrogenic Dementias

Although the characteristic clinical course of AD, as outlined most clearly with the FAST staging procedure, is very different from many other dementing conditions, it is also interesting and of diagnostic relevance that many dementias of diverse etiology occasionally, or more frequently, follow the characteristic FAST sequential progression of AD more or less precisely. The advances in understanding of the etiopathogenic mechanisms of AD provide an explanation for the observed clinical similarities between these ostensibly etiopathogenically diverse, but frequently clinically similar, dementia processes. As described earlier in this review, in AD an etiopathogenic process termed retrogenesis accounts for the pattern of functional losses and of clinical symptomatology. The pathologic basis of this retrogenic process is that the most thinly (recently) myelinated brain regions are the most vulnerable, and the most thickly myelinated brain regions are affected last in the evolution of...

Staging of Severe Alzheimers Disease and the Concept of Retrogenesis Doors to be Opened for Research and Clinical

Among others, there are two most exciting aspects in the paper by Reisberg et al. First, the authors present consistent evidence for the fact that severe Alzheimer's disease (AD) can be precisely described cross-sectionally and during disease progression using the Functional Assessment Staging (FAST). Second, they present the concept of retrogenesis, which implies that subjects with dementia develop backwards, i.e. in the opposite direction to the development during childhood. These two aspects are briefly dealt with in this commentary. Reisberg et al present a comprehensive data set showing the validity of the FAST to assess the severity and, even more importantly, to follow the course of dementia. This is more than can be expected from the Mini-Mental State Examination (MMSE 1 ), which to some extent is still the gold standard in epidemiology and clinical practice for the assessment of the severity of cognitive decline. The fact that there are more severe stages which cannot be...

When Diagnosis is Certain Functional Scores are Robust and Recommendable Markers of the Progression of Alzheimers

Barry Reisberg and co-workers have been studying extensively the natural history and course of dementia of the Alzheimer type (DAT). On their search for robust markers for disease progression, they have been evaluating clinical neurological signs, cognitive tests, microscopic quantitative parameters (hippocampus) and secondary musculoskeletal changes, such as contractures, and the order of loss of functions as the reversal of acquisition of functions during normal development. Using the Functional Assessment Staging (FAST) procedure, they found that functional course is the best marker of disease progression. Two other scales conceived by Reisberg et al, the GDS (Global Deterioration Scale) and the BCRS (Brief Cognitive Rating Scale), also explain a substantial proportion of the variance of cognitive decline in DAT patients. Combination of the scales may improve the significance of the assessed functional stages 1-5 . FAST, GDS and BCRS have been validated and proved to be useful...

Two Decades of Longitudinal Research in Alzheimers Disease

Reisberg and colleagues succinctly summarize more than two decades of intensive longitudinal research on patients with Alzheimer's disease AD . Reisberg's earliest work involved the progression and staging of AD and resulted in the widely used Global Deterioration Scale (GDS) 1 . As a result of reviewing the clinical course of the illness with significant detail, it became clear that patients spent as much as a third to half of the course of the illness in the most advanced stages. Accordingly, Reisberg and colleagues developed the Brief Cognitive Rating Scale (BCRS) 2 and subsequently the Functional Assessment Staging (FAST) 3 . Reisberg et al's paper also summarizes the behavioural and psychological symptoms of dementia (BPSD), describing the clinical symptomatology commonly seen in AD patients 4, 5 . The BEHAVE-AD, which derives from Reisberg's work, has been used extensively in clinical drug trials and has been demonstrated to be a valid and reliable...

Diagnosing Dementia the Need for Improved Criteria

Reisberg et al report that the concept of dementia has entered its third millennium and that the term itself dates back to the first century AD. However, despite marked advances over the past century, the diagnosis of dementia and, particularly, of various dementia subtypes, remains a clinical challenge to this day. The Functional Assessment Staging (FAST) scale provides a detailed framework of the expected evolution of Alzheimer's disease (AD) and can support this diagnosis when the course is typical. Deviations from the FAST scheme can serve as a clue to a non-AD process. Another crucial point is the identification of early disease and of individuals at risk for the development of dementia. Ideally, clinical criteria for dementia should apply universally to all subtypes and should be able to identify initial stages as well as established cases. However, existing criteria for dementia do not always agree. In a study of 1879 elderly subjects, the proportion of subjects with dementia...

Pitfalls in Diagnosing Alzheimers Disease

The dementia syndrome, which, as Reisberg et al remind us, has been known for years, has gained much importance recently for epidemiological reasons. While the number of demented subjects is steadily growing, knowledge of aetiology and pathogenesis is still not sufficient to help the sufferers, and neither medical nor social resources can meet the needs of new cases and their families. In the last decade, however, the state of knowledge has changed significantly. The dogma stating that 50 of dementia is caused by Alzheimer's disease (AD), 20 by vascular changes and 20 by the coexistence of the two, has fallen down. Pick's disease, which had been forgotten for some time, and other fronto-temporal dementias seem to be responsible for about 7 1 , and diffuse Lewy body disease for probably no less than 15 of all dementia cases 2 . Underdiagnosing AD in clinical practice has quite unexpectedly turned into the phenomenon of overdiagnosing this type of dementia. Clinical characteristics of...

Evaluating the Performance of Measures to Assess Dementia

In order to deliver appropriate care to patients with dementia, clinicians need to be able to recognize patients as having a dementia syndrome and then determine the specific cause of dementia. However, nearly three-quarters of patients with moderate to severe dementia are unrecognized by primary care clinicians as having cognitive impairment 1 . Even when recognized, the appropriate evaluation is often lacking 1 . Clinicians also need to be able to accurately assess disease severity in order to select appropriate treatments, therapies and services, as well as to monitor the effectiveness of these interventions. Disease severity can be divided into three domains cognitive function, functional ability and behaviour problems. There are numerous measures used to assess patients with dementia, but no single test has emerged as the established standard 2,3 . Reisberg and colleagues discuss one such measure of disease severity, the Functional Assessment Staging (FAST). Their discussion...

Dementia as a Diagnostic Entity

One classical aspect that has been used to characterize dementia aside from the various cognitive deficits is the presumption of existing structural brain defect. The practical clinical consequence is its irreversibility. Even though Although some dementia cases will show improvement after treatment or supportive effort, in fact, it is assumed to be only a partial improvement caused by reorganization of the remaining functioning part of the brain. The process may, but not necessarily, be progressive and deteriorating as mentioned in Prof. Reisberg's review, the term 'progressive and deteriorating' may be unsuitable in some cases. However, the temporary nature and possibility of complete recovery of the cognitive deficits should negate the diagnostic consideration of dementia (e.g. temporary cognitive deficits found in conditions such as drug intoxication, depression, anxiety, schizophrenia, etc.). As also required by the DSM-IV, dementia as a diagnostic entity should always be...

Neuropsychological And Instrumental Characteristics Of Vascular Dementia Vd

The clinical diagnosis of VD is most frequently based on DSM-IV 76 , or the criteria suggested by the National Institute of Neurological Disorders and Stroke and the Association Internationale pour la Recherche et l'Enseignement en Neurosciences (NINDS-AIREN 77 ). These criteria state that the diagnosis of VD has to be connected with confirming neuroimaging observations in addition to a relevant time relation between cerebrovascular disease and dementia. When neuroimaging examination is lacking, it is possible to use a clinical evaluation of cerebrovascular factors. For instance, it has recently been confirmed that the Hachinski Ischemic Score (HIS 78 ) has a high degree of validity when examined in relation to neuropathologi-cal data 79 . There are a number of reports showing differences between VD and other dementias in specific domains such as personality disturbance, executive dysfunction and motor performance, as well as biologically basic behaviours 80 . However, the conclusion...

Neuropsychological And Instrumental Characteristics Of Frontotemporal Dementia

Table 3.6 Neuropsychological features of frontotemporal dementia profound alteration of personality and social conduct, loss of drive, blunted emotions, lost insight, stereotypic behaviours, reduced speech, cognitive changes due to impairment of mental control 91,92 . In addition to the prototypical FTD, the clinical diagnosis also covers progressive non-fluent aphasia 93 and semantic dementia 94 .

Improving Diagnosis of Dementia

We have come a long way in the last 20 years in our ability to diagnose the different dementing disorders. Indeed, the term dementia is now as much a hindrance as a help. The term was developed to distinguish patients with multiple domains of cognitive impairment from those who had either a focal deficit or a confusional state. The former would lead to an intensive search for a focal lesion, such as a neoplasm, which might have therapeutic implications. The latter, i.e. patients with confusional states and marked impairment of attention, often had an underlying metabolic disorder, the recognition of which was essential. By contrast, patients presenting with multiple domains of cognitive impairment who did not fulfil the criteria for a confusional state or delirium were usually found to suffer from one of the degenerative disorders, such as Alzheimer's disease (AD). The diagnostic process usually stopped at the level of dementia. In order to fulfil the criteria for dementia, there has...

Assessment of Dementia

Within neuropsychology, the assessment of dementia is probably one of the most interesting, fascinating and challenging endeavours. Health care sys tems are required to accurately and efficiently diagnose patients suffering from dementia. This is especially important, since some drug treatment is now available and family members need to be assisted in and prepared for what is ahead of them. It seems obvious that the earlier the diagnosis can be made, the better the health care system is able to react and provide appropriate help. The multidimensional assessment of dementia in general and of Alzheimer's disease (AD) in particular requires well trained personnel and an assessment procedure that will work accurately, efficiently and quickly. However, which neuropsychological instrument should be utilized for the neuropsychological assessment of dementia What are the objectives that need to be met in everyday clinical practice When one examines the available tools and common procedures,...

The Importance of an Early Diagnosis in Alzheimers Disease

Alzheimer's disease (AD) is characterized in many cases by a pre-sympto-matic period with ongoing dysfunctional brain processes for many years Rapid progress has recently been made concerning understanding of the epidemiology, genetics, risk factors and neuropathophysiological processes underlying the development of AD. Some therapeutic agents have been introduced into clinical praxis which appear to have, in at least some patients, symptomatic effects and can even slow down the progression of the disease. It is plausible to assume that drugs to prevent or delay the onset and or course of the disease will be soon available. The present conservative approach to AD requires that the patient fulfils the criteria of dementia, e.g. that the symptoms influence everyday activities and function. The clinical symptoms are thus quite evident when the diagnosis is given. Early treatment will prompt the need for early diagnosis of AD. Identification of early cognitive impairments will probably...

Major Pathologic Features of Alzheimers Disease

A major distinction is to be made between the clinical and pathologic characteristics of dementia of the Alzheimer's type. This chapter concentrates mainly on brain pathology. The postmortem human AD brain is characterized by two types of lesions extracellular senile plaques and intracellular neurofibril-lary tangles (NFTs). In addition, practically all AD patients have amyloid deposits in the walls of blood vessels of the brain, termed cerebral amyloid angiopathy, which is also evident in about 30 of the elderly. In this and the following paragraphs we concentrate on the amyloid pathology and its successful recapitulation in the brain of APP Ld transgenic mice. Then we discuss the completely different situation and the problems encountered in developing transgenic mice with NFT pathology. Fig. 1. Neocortex from Alzheimer's disease patient with numerous argyrophilic plaques. (Bielschowsky's silver method x90.) Fig. 1. Neocortex from Alzheimer's disease patient with numerous...

Pharmacotherapy For Aids Dementia

Before the routine use of zidovudine (AZT), the course of AIDS dementia was often rapid after cognitive decline emerged. Currently, patients receiving zidovudine may exhibit signs of the cognitive and motor changes for months to years before dying 249 . Additionally, health care utilization rates increase as patients with AIDS dementia live longer 250 , placing even more emphasis on the development of safe and effective treatments for this condition. Investigational treatments for AIDS dementia include adjuvant use of anti-inflammatory and neuroprotective agents 251 . This effort is based on evidence that human immunodeficiency virus (HIV) is not the direct cause of CNS damage. Loss of neurons appears related to viral infection of brain macrophages and microglia. A valuable predictor of neurological impairment following HIV infection is the absolute number of immune competent macrophages rather than the level of viral involvement in brain tissue. Additional focus has been on the role...

Dementia Diagnosis Progression and Retrogression

Reisberg has addressed a number of concepts in relation to dementia in his review. He begins with a history of the term dementia, from its Latin roots about 2000 years ago, and goes on to discuss the clinical progression of Alzheimer's disease (AD), in particular the functional decline as charted by the Functional Assessment Staging (FAST) procedure. He argues that the pattern of decline in AD is a reversal of neurodevelopment in childhood and refers to it as retrogenesis, implicating demyelination in the pathogenesis, just as myelination plays a role in development. He puts forward the intriguing concept of the retrogenic dementias''. Dementia. The term dementia has seen may vicissitudes in its long history, and it is quite recently that it acquired its current conceptualization of multifaceted cognitive decline in clear consciousness 1 . Even though the concept of dementia is now firmly established in psychiatric taxonomy, it continues to have many limitations. It lacks...

Alzheimers Like Aftereffects of Brain Injury

Survivors of closed-head injury often have long-lasting neurological aftereffects. These include the development of neurodegenerative disorders.4,5 Traumatic brain injury is now thought to be a significant risk factor for Alzheimer's disease.125 126 Studies in boxers have noted a relationship between the apolipoprotein genotype and the development of Alzheimer's-like dementia.127 In contrast to many studies demonstrating a relationship between traumatic brain injury and later development of neurodegeneration, a recent study in Rotterdam did not concur with previous cross-sectional studies suggesting an interaction with the apolipoprotein genotype and increased risk for Alzheimer's-like dementia following traumatic brain injury,128 but it is in the minority in this regard. Table 1.11 categorizes Alzheimer's changes following brain injury. A leading contemporary theory for the biological basis of Alzheimer's disease is the formation of beta amyloid within the brain. Amyloid is known to...

Dementia Some Controversial Issues

Esquirol began to distinguish between acute, chronic and senile dementia in 1814, and he regarded the last one as resulting from aging and consisting in a loss of the faculties of understanding. In 1906, Alois Alzheimer reported the case of a 51-year-old woman with cognitive impairment, hallucinations, delusions and focal symptoms, whose brain was found on post mortem to show plaques, tangles and arteriosclerotic changes. In the 8th edition of Kraepelin's Textbook, he coined the term Alzheimer's disease'' (AD), as a senium praecox if not perhaps a more or less age-independent unique disease process''. Many authors from that period criticized this new entity (presenile dementia) as something different from classical senile dementia 1 . Henderson and Jorm's review addresses several issues concerning definition, diagnostic criteria, differential diagnosis, types, natural history, incidence prevalence rates and risk factors of dementia that have theoretical and clinical importance. I will...

Dementia Syndromes

Numerous dementia syndromes can occur in the elderly. The most common is Alzheimer's disease (AD), followed by vascular dementia, mixed dementia, Lewy body dementia and then the fronto-temporal dementias. Dementia in Alzheimer's Disease (AD) Until around 1970, AD was thought to be a rare dementia affecting people under 65. At that time, the common senile dementia of the elderly was believed to be due to arteriosclerosis causing a slow strangulation of the brain's blood supply. However, following the important neuropathological study of Tomlinson et al 21 , it was established that persons with senile dementia had the same brain changes as in AD. Following this work, the term senile dementia of the Alzheimer type'' (SDAT) was often used to describe elderly cases with Alzheimer brain changes. However, in recent years the term Alzheimer's disease'' has come to be used to refer to all cases, irrespective of age. The account which follows is based on the Clinical Descriptions and Diagnostic...

Dementia

The prevalence of depression among persons with dementia is high (12 with major depression, compared to 4 of non-demented persons aged 75 yearsC), and depression is associated with increased levels of disability in this population 95 . The high prevalence of depression in nursing homes (where most residents have dementia and many have chronic physical illnesses) has been documented 96, 97 . Clarification concerning the multi-factorial aetiology of such cases, the relative importance of physical health factors, and trials of treatments that differ according to the way the depression presents, is awaited.

With Dementia

By definition, all patients with dementia have both cognitive and functional impairment. Assessment in both domains is a key component of any dementia evaluation, and Prof. Almkvist has provided an excellent overview of the current state of the art in this area. The review highlights several issues of great importance for understanding the use of these assessments, both in clinical practice and in research designed to elucidate pathophysiologic mechanisms of disease. This discussion will amplify Prof. Almk-vist's review in three areas strengths and limitations of neuropsychological Strengths and limitations of neuropsychological tests. There is ample evidence that many elderly persons with dementia remain undiagnosed and untreated. Community-based epidemiologic studies 1 indicate that a very high proportion of all elderly persons living at home meet currently accepted criteria for dementia, but many of them have never received that diagnosis and have never been treated. Clinic-based...

Alzheimer Disease

Alzheimer disease is estimated to affect 10 of Americans older than 65 and as many as half of those older than 85. As with many other common diseases, a subset of Alzheimer cases are familial, and mutations in specific genes have been shown to be responsible for some of these familial cases. Approximately 5-10 of Alzheimer disease cases have early onset (before age 60) and are inherited in autosomal dominant fashion. A small proportion of familial cases are the result of mutations in the chromosome 21 gene that encodes -amyloid precursor protein (BAPP). These mutations lead to improper processing of BAPP and to the buildup of P-amy-loid plaques in the brain (recall that Alzheimer disease is a consistent feature in Down syndrome patients this appears to be caused by the presence of three copies of the BAPP gene in these individuals). Amyloid plaques are thought to be toxic to neurons, resulting in the disease phenotype. Mutations in either of two presenilin genes (one on chromosome 1...

Definition And Epidemiology

OF DEMENTIA 1 of Dementia A Review 1 1.1 The Continuing Evolution of Dementia Epidemiology 34 1.2 Dementia Hope for the Future 36 1.3 Dementia Much Information, Many Unanswered Questions 39 1.4 Vascular Factors and Dementia 42 1.5 Dementia Known and Unknown 45 1.6 Dementia a Public Health Emergency and a 1.7 Dementia Plenty of Questions Still to Be Answered 50 1.8 Rates and Risk Factors for Dementia Evidence 1.9 Dementia the Public Health Challenge 55 1.10 Definition and Epidemiology of Dementia Some 1.11 Dementia the Challenge for the Next Decade 59 1.12 Recent Progress in the Definition and Epidemiology of Dementia 1.13 Dementia Some Controversial Issues 1.14 Is the Prevalence Rate of Alzheimer's Disease Increasing in Japan

Instrumental Diagnosis Of

DEMENTIA 143 Neuropsychological and Instrumental Diagnosis of Dementia A Review 143 3.1 Improving Diagnosis of Dementia 166 3.2 The Contribution of Neuropsychology to the Assessment of Dementia Syndromes 169 of Dementia the Evidence 171 3.4 Some Clinical Aspects and Research Issues in the Neuropsychological Assessment of Dementia 173 the Care of Patients with Dementia 176 3.7 Alzheimer's Disease and Other Degenerative Dementias Need for an Early Diagnosis 182 3.8 Neuropsychological and Instrumental Diagnosis of Dementia in a Clinical Context 184 3.9 Neuropsychological Tests that are Helpful to the Etiological Diagnosis of Dementia 187 3.10 The Importance of an Early Diagnosis in Alzheimer's Disease 189 3.12 Factors Affecting Diagnosis in Dementia 195

Pharmacological Treatment Of

DEMENTIA 199 Pharmacological Treatment of Dementia A Review 199 4.1 Alzheimer's Disease is Treatable 247 4.2 Treatment of Dementia Where Do We Go from 4.3 The Future of Alzheimer's Pharmacotherapeutics 253 4.4 Outcome Measures and Ethical Issues in the Pharmacotherapy of Alzheimer's Disease 256 4.5 From Bench to Bedside How to Treat Dementia 259 4.6 Some Limitations in the Drug Treatment of Alzheimer's Disease 262 4.7 Issues Regarding the Pharmacotherapy of Dementia 266 4.8 Treatment of Cognitive and Non-cognitive Disturbances in Dementia 269 4.9 Are There Concerns about the Real World'' Effectiveness and Safety of Medications for Alzheimer's Disease 272 4.10 Phytoneuropsychotropics in Alzheimer's Disease

Psychosocial Interventions

DEMENTIA 279 Psychosocial Interventions for Dementia A Review 279 5.1 Psychosocial Dimensions of Dementia Care 308 5.3 The Development of Cognitive Neurorehabilitation for Alzheimer's Disease 314 5.4 Psychosocial Interventions and Behavioural Treatments for Dementia 317 5.6 Psychosocial Interventions in Dementia the Nature and Focus of Intervention, Outcome Measurement and Quality of Life 322 for Dementia 325 5.9 Psychosocial Interventions in Dementia Attitudes, Approaches, Therapies and Quality of Life 330 Dementia 337 5.13 Sharing and Supporting Families with Dementia 338 CHAPTER 6 COSTS OF DEMENTIA 341 Costs of Dementia A Review 341 6.1 Dementia the Challenges for Economic Analysis 370 6.2 Costs of Dementia More Questions than Answers 372 6.3 Toward the Economics of Dementia 375 6.4 A Cautionary Commentary on Costs of Dementia Studies 378 6.5 Costs of Dementia Valuable Information for Economic Evaluations 380 6.6 Cost of Illness Study in Dementia a Comment 382 6.7 Dementia Whose...

The Functional Course of AD The Most Robust Marker of AD Clinical Course

Clinically, AD is also a characteristic illness entity, which is recognizable by its onset and course. For several reasons, the characteristic clinical course of AD is most readily appreciated by charting the progressive changes in functioning and daily life activities which occur with the evolution of the disease process. The characteristic functional course of AD is most clearly outlined using the Functional Assessment Staging (FAST) procedure 12 . The FAST course of AD is shown in Table 2.1. Current evidence for the superiority of the FAST staging procedure in tracking the course of AD in dementia patients who are generally free of non-AD related physical pathology is summarized in Table 2.2. Table 2.1 The characteristic functional course of Alzheimer's disease (AD) functional assessment staging (FAST) Table 2.2 Evidence for the superiority of the FAST staging procedure in charting the characteristic clinical course of Alzheimer's disease (AD)

The Etiopathogenic Basis of the Clinical Course of AD

A general relationship between aging, dementia and normal development had been noted for millennia by playwrights and poets and is embodied in vernacular language 59,60 . For example, dotage has been defined in part as childishness of old age'' 2 . Clinicians and scientists have also recognized relationships between senescent dementia and normal development generally 61 and, in more recent times, more specifically 62-68 . However, the precise functional developmental reversal which was noted in the FAST staging considerably advanced clinical and scientific understanding of this relationship. Each FAST stage in AD can be usefully described in terms of a corresponding developmental age (DA). Studies indicated that the reversal of figure drawing (praxic) capacity, of feeding ability, and of other capacities in AD appeared to mirror the normal human developmental pattern and appeared to occur at the DA appropriate point based upon the FAST staging (Table 2.4) 69 . For example,...

Further Implications of the Etiopathogenic Basis of AD for Clinical Diagnosis Additional Clinical Diagnostic Markers of

This temporal course of AD is most clearly charted in terms of the progressive pattern of functional deterioration as described using the FAST staging procedure. Table 2.5 shows the mean duration of the functional stages and substages of AD in patients who are free of significant confounding physical and non-dementia-related mental pathology. Several remarkable aspects of the functional progression of AD should be noted in the context of the retrogenic pattern of deterioration described in the preceding section. One of these remarkable features of AD course is that, in addition to mirroring the order of functional acquisition in normal development, the time course of functional deterioration in AD, until the final 7th stage, mirrors the time course of acquisition of the same functions in normal human development 57,58,86 . Consequently, AD patients lose the ability to manage a complex job and deteriorate to double incontinence over a mean period of approximately 13 years. This is...

Differential Diagnostic Import of the Characteristic Clinical Course of AD

Some entities characterized by dementia, or in which dementia may occur, differ strikingly from the characteristic FAST progression of AD 57,86 . A few examples, which are familiar to all clinicians with a knowledge of brain disease, are stroke and normal pressure hydrocephalus (NPH). For example, a patient may have a stroke and the stroke may result in urinary incontinence. This urinary incontinence may be the only clinically manifest sequela of the cerebrovascular accident (CVA). Alternatively, the CVA with resultant urinary incontinence may also be accompanied by dementia. When this dementia occurs, it may be of any magnitude. For example, the dementia may be of sufficient magnitude to interfere with executive functions, such as organizational skills, and the ability to manage instrumental activities, such as management of personal finances, but not interfere with the ability to choose proper clothing, to put on clothing independently, to bathe without assistance, to toilet without...

AD Risk Factors and Retrogenesis

Many risk factors for the development of AD are now well recognized 11 . Some of these risk factors are the same conditions which may produce dementias of a retrogenic type which can be confused with AD, such as those described in the previous section. For example, low levels of vitamin Bi2 have been associated with increased risk of AD 123 . Other conditions, sometimes biochemically related to vitamin Bi2 deficiency, have also been associated with increased risk for AD. These include folate deficiency and the biochemical markers of chemical Bi2 deficiency, i.e. serum homocysteine and methylmalonic acid 123-126 . In addition to vitamin Bi2 being associated with myelin disturbance, some of these risk factors for AD are independently associated with white matter cerebrovascular pathology 127 as well as peripheral atherosclerosis 128 . Depression also, apart from being associated with an occasionally reversible dementia, appears to be an independent risk factor for AD 129-132 . A broad...

Characteristic Behavioural Changes in AD

Apart from changes in functioning and cognition, characteristic behavioural changes also occur in the course of AD, which have been termed behavioural and psychological symptoms of dementia (BPSD) 148 . These BPSD symptoms are quite diverse, and include (a) paranoid and delusional ideation (b) hallucinatory disturbances (c) activity disturbances (d) aggres-sivity (e) sleep rhythm disturbances and (f) anxieties and phobias. Characteristic symptoms occurring at particular stages of AD can be identified. However, because they are the product of the psychological external and internal environment of the AD patient, as well as the neurochemical milieu in the brain of the AD patient, these BPSD symptoms, although to a greater or lesser extent characteristic of AD, are not pathognomonic. Because the BPSD symptoms of AD appeared to be characteristic but not universally occurring or inevitable, their diagnostic utility was considered limited. However, Lewy body dementia and frontotemporal...

Summary Consistent Evidence

There is abundant and consistent evidence that a characteristic clinical course of the dementia of AD can be described. In AD patients who are free of significant concomitant illness, this characteristic clinical course is most clearly charted in terms of the characteristic sequence of functional changes which occur 12 . Evidence for this characteristic functional course from available studies is overwhelming and appears to be as strong as for any psychiatric clinical process.

Areas Still Open to Research

Known risk factors for AD, and the similarities and differences between the clinical presentation of AD and other dementing disorders, much more research needs to be conducted before these issues can be resolved. Improved etiopathogenic information regarding the dementia process in AD and in other dementias and improved neuroimaging and other investigative techniques should assist in resolving many of these issues in coming years. The term dementia and the differentiation of delirium and dementia have been in wide usage for two millennia 7 . Rapid progress has been possible in recent years, by identifying and differentiating the most important dementing disorders. Study of these entities in coming years can be readily translated not only into improved diagnosis, but also into improved care 70 and into a continually narrowed gap between scientific understanding of the clinical presentation of the dementias and the molecular and pathologic presentation of these prevalent disorders.

Developmental Variance

The clinical diagnosis of dementia is usually not a problem. As Reisberg et al note in their elegantly referenced review, the term dementia has been both used and useful for over two millennia. The existence of two related phenomena with their own equally useful names, delirium and depression'', is noteworthy for clinicians. They alert us to the fact that, although clinical diagnosis of dementia is not usually a problem, patients, especially elderly patients, often have more than one condition. Dementia and delirium, dementia and depression, commonly coexist, thus the job of reductionist classification of a patient's condition to a single entity in everyday practice often is not possible. We have traditionally taught that parsimony is a reasonable goal when diagnosing or classifying a patient's condition into a disease or syndrome. In geriatrics, however, reality suggests an alternative approach. In fact, the problem in clinical diagnosis of all three related phenomena, dementia,...

Findings with the Aid of Functional Assessment Staging FAST

Information is elicited from the patient (as far as possible), relatives and friends regarding the patient's ability to manage his daily life, and his main impediments. Prof. Reisberg states that relevant observations can be made and evidence elicited with the aid of the FAST instrument over a period of some two-thirds of the total course of Alzheimer's disease (AD) or other dementias. Decrease of hippocampal volume and FAST measures. A decrease in the size of hippocampus in AD and to some extent in normal subjects of advanced age has been established for some years. The studies by Bobinski et al 2, 3 carry this knowledge forward with a number of new observations. Brains of 13 subjects with severe AD and of five age-matched normal controls were compared. A number of significant differences emerged. Those graded in the lower part of stage 7 of FAST showed a 36 decrease in hippocampal volume those in higher stages of degeneration a 60 decrease. There was a similar situation in relation...

The Principles Of Neuropsychological Evaluation

The neuropsychological examination is one part of a comprehensive protocol for examination of suspected dementia. In this protocol the subject and a close informant are questioned about present symptoms and medical history. In addition, the patient is examined for somatic, neurological and Dementia, Second Edition. Edited by Mario Maj and Norman Sartorius. 2002 John Wiley & Sons Ltd. isbn fl3-470-84963-0 The main idea of functional diagnosis of all kinds of dementia is the difference principle, which states that it is necessary to examine the possible existence of a difference between pre-morbid and present level of functioning. The difference may concern cognition, personality, behavioural manifestations or activities of daily living (ADLs). The size of the difference and the time course of the change are also important. Finally, the pattern of changes vs. preserved functioning across various cognitive domains, personality characteristics and behaviour has to be carefully outlined.

Premorbid Level of Functioning

The pre-morbid functioning may be assumed as normal when there is no relevant knowledge in the individual patient. It may also be predicted on the basis of demographic data such as age, level of education, profession, interests, history of intellectual or professional development. Such formulae of prediction can be found in the literature (see e.g. 2,3 ). In addition, pre-morbid functioning may be assessed using specific tests such as the New Adult Reading Test (NART, 4 ) or other tests based, for instance, on reading or lexical decisions of word non-word (see e.g. 5 ). Furthermore, pre-morbid functioning may be assessed on the basis of test profiles including functions that are both sensitive and relatively insensitive to change that occurs in dementia. Cognitive abilities that are acquired early in life, over-learned, and not limited by time allotted but rather by knowledge are less sensitive to change compared to those abilities that are acquired recently, less well learned, and...

Evaluation of Results

The interpretation of neuropsychological test results has to consider the size of change (present performance in relation to assumed or assessed premorbid performance), the pattern of performance across cognitive domains, and the pattern of change across time. A very important aspect is whether follow-up data are available if so, the interpretation of a neurop-sychological examination is more powerful. Finally, it has to be pointed out that neuropsychological tests are among the most powerful methods in an examination of suspected dementia, because of the rigorous standardization

Neuropsychological Characteristics

Although AD is said to be characterized by a continuous decline in global cognitive functioning, it is worth noticing that not all cognitive functions are affected. Some abilities seem to be preserved in early AD and, interestingly enough, some functions seem to be preserved even in advanced dementia. Examples of relatively preserved functions in early AD are primary memory, procedural memory and perceptual functions, as well as motor and sensory functions. The pattern of affected and preserved functions, as well as the course of change in these functions, may be understood in terms of neuropathology in AD and of brain-behaviour relationships in general. Table 3.3 Neuropsychological features of Alzheimer's disease across stages of dementia Mild stage of dementia Advanced stage of dementia In contrast, it has been shown repeatedly that short-term memory is preserved in early dementia of the AD type 45,47,52 . Implicit memory as exemplified by priming effects, i.e. the unconscious...

Instrumental Characteristics

The first changes are noted in complex activities, for example at work 60 or in social activities 61 . Much later, when cognitive deterioration has progressed into moderate dementia, there is a change of the ability to perform self-care activities 36 . Not only is the distinction between IADLs and ADLs interesting to observe, but so too is the ability to perform various activities within IADLs and ADLs. As an example, the ability to use cutlery vs. using a comb may vary in a progression-related manner typically the former is most often preserved longer during disease progression than is the latter 62 . However, studies usually demonstrate only a weak to moderate strength of relationship between ADLs IADLs and cognition 37 .

Neuroimaging Findings

Using morphological methods such as MRI, a very good predictive power has been reported for specific measures, i.e. hippocampal atrophy or other measures of the temporal lobes, in relation to development of AD in pre-clinical cases (see e.g. 72-74 ). Also measures of general brain atrophy are associated with dementia 75 .

Incomplete Evidence

The main difficulty with dementia studies is bound to the fact that the dementia diseases are progressive and there are still only very rough indicators of their time course. Second, the behavioural features and symptoms of dementia disorders are dependent on the specific pre-morbid abilities of the individual, and there is no simple way to take into account the pre-morbid abilities when evaluating the present status of cognitive function. Third, the time course of change in cognition, personality and behaviour has

Evaluating the Cognitive Changes of Normal and Pathologic Aging

Increasing interest in normal and pathologic aging has sharpened focus on defining the cognitive changes of dementia compared to those associated with non-demented aging. Prof. Almkvist discusses available methods for detecting these changes in relation to the characteristics of three leading dementing disorders Alzheimer's disease (AD), cerebrovascular dementia and frontotemporal dementia. To detect the earliest symptoms of dementia, detailed and sensitive assessment measures are required. There are no proven biological markers for dementia. The diagnosis thus rests on clinical methods that evaluate cognitive impairment, the core feature of dementia. A critical aspect for diagnosis is that the impairment must represent decline from prior cognitive abilities. The assessment of cognitive status incorporates both clinical and neuropsychologic measures. Although brief cognitive instruments such as the Mini-Mental State Examination (MMSE) 1 are popular and require little training to...

When Should We Use Which Diagnostic Tools

Most patients with dementia are diagnosed and treated exclusively in primary care. Although there is a shared opinion that much can be managed successfully there, barriers contribute to the delivery of inadequate or untimely medical services in primary care settings 1 . As illustrated by the results of our German representative survey, there is a wide gap between expert recommendation and clinical practice in primary care 2,3 . In this situation, screening tools are of special importance and should combine easy application with high sensitivity and specificity and acceptance by the patient and caregiver 4 . As one well-known example, the Clock Drawing Test has been developed for this purpose and combines a memory task with a constructional one. Combined, for example, with the MiniMental State Examination (MMSE), the sensitivity for the diagnosis of dementia, especially Alzheimer's disease (AD), can be increased. The information provided by the caregiver is of special importance, too....

Cholinesterase Inhibitors

There may be a differential response to cholinester-ase inhibitors based upon AD severity. In one analysis of the 30-week tacrine trial 33 , middle-stage patients, defined by MMSE score of 11-17, had a larger effect from tacrine (ADAS-cog change from baseline of 5 units) than patients with a MMSE score of 18-26 (ADAS-cog change from baseline of 2 units) 34 . Similar results were found in analysis of data from clinical trials with other cholinesterase inhibitors 35-37 . Given all the data from the cholinesterase inhibitor trials regarding expanded benefit to other dementia subtypes or more severe AD 37-43 , it is expected that the indications for cholinesterase inhibitor therapy may broaden to include more severe AD, DLB and VD. These benefits appear to be a class effect rather than attributable to the purported differences in mechanism of action between these agents. In a double-blind, placebo-controlled multinational study, the safety and efficacy of...

Treatment of Depression in AD Patients

Few clinical trials of AD patients with depression and several case reports guide antidepressant choice. One non-randomized clinical trial comparing fluoxetine to amitriptyline in depressed AD patients demonstrated efficacy for both agents, with a higher drop-out rate in the tricyclic group 193 . Clomipramine was found to improve mood but diminish cognition in a cross-over study 194 . Similarly, imipramine benefited mood but altered cognition in a depressed group of AD patients 195 . In a case series, 11 of 12 AD patients with depression and psychosis responded to a trial of SSRIs 196 . Citalopram has demonstrated efficacy for depression and affective lability in multicenter studies with depressed AD patients 197 . Not all SSRIs have demonstrated efficacy for depression in demented patients. Fluvoxamine was not effective for depression in a sample of AD and vascular dementia patients with depressive symptoms 198 . In general, SSRIs may be associated with gastrointestinal and sexual...

Effects of Cholinesterase Inhibitors on Disturbed Behaviour in AD

Tacrine to placebo on behavioural items of the ADAS 217 . In a double-blind placebo-controlled trial of metrifonate, a significant superiority of this drug over placebo was found using measures of depression, apathy and hallucinations 218 . The FDA approved cholinesterase inhibitors have all demonstrated effectiveness on behavioural measures for patients with dementia. Donepezil has shown benefit in an open trial of AD patients 219 . Rivas-tigmine has benefitted patients with psychosis associated with Parkinson's disease 220 and DLB 65 . Galanthamine has shown benefit on behavioural measures in AD 221 . Taken together, the effectiveness of the agents on the non-cognitive disturbances associated with dementia probably represents a class effect. Further investigation in this area is necessary to guide prescribing practices.

Reflections on Retrogenesis

Reisberg et al's excellent review on the clinical diagnosis of dementia presents a very powerful and lucid account of the idea of retrogenesis that he and his colleagues have developed over the last few years. In essence, this highlights the similarities between progression in Alzheimer's disease (AD) and reversal of development, such that in cognitive function, functional impairment, behaviour and social interactions, the more severely demented a patient becomes, the more similar he appears to an earlier developmental phase. Apart from being purely observational, this has extended into a theory regarding neurodegenerative processes in AD (particularly reversal of the myelination process) which may have an important bearing on our understanding of dementia and its progression. In particular, Reisberg et al make a very strong case for the use of the particular rating scale there group has championed (the Functional Assessment Staging, FAST) and how this corresponds to severity of...

Methods of Assessment

The Wechsler batteries are not designed for evaluation of dementia, since they do not cover all the changes that occur in dementia syndromes. Therefore, additional tests have to be added in order to get a comprehensive evaluation of dementia. Important cognitive domains not covered by standard batteries are executive functioning, naming, verbal fluency, reasoning, copying, tracking, perceptual abilities, motor skills, and procedural memory. To fulfil the purpose to assess these cognitive domains, specific tests are added at most clinical specialist centres. At some centres, tasks or principles from experimental cognitive psychology have been added to clinical assessment. For instance, the memory-scanning paradigm 14 , the phonological loop idea 15 or examination of priming memory 16 have been used. Although the WMS batteries are widely used for memory assessment, they are lacking the level of task difficulty that is required when assessing individuals in the borderline between...

Clinical Diagnosis Of Dementing Disorder

Dementia is a term which refers to a general mental deterioration 1 , The term has Latin roots. De is a prefix derived from Latin, signifying separation, cessation or contraction, and mens denotes mind 1,2 , Consequently, in dementia there is a contraction of the mind. Chronicity has generally been implicit in the term dementia. Although legal implications of what we now term dementia can be traced to Greek writings of Solon and Plato, the earliest known usage of the term dementia comes from Aurelius Cornelius Celsus, a Roman writer and encyclopedist 3-6 . In a work entitled De Medicina, in the first century a.d., Celsus distinguished delirium and dementia. Roman writers, beginning with Celsus, used the word delirium more or less interchangeably with the Greek-derived term phrenesis (phrenitis, or frenzy), which designated a temporary mental disorder occurring in the course of illness, and featuring excitement and restlessness 7 . Although dementia and delirium continue to be...

Review Contributors

Dr Emile Franssen Aging and Dementia Research and Treatment Center, New York University School of Medicine, New York, NY 10016, USA Professor Barry Reisberg Aging and Dementia Research and Treatment Center, New York University School of Medicine, New York, NY 10016, USA Dr Muhammad A. Shah Aging and Dementia Research and Treatment Center, New York University School of Medicine, New York, NY 10016, USA

Clarification

Henderson and Jorm offer us a comprehensive review of dementia from the perspective of epidemiology. After considering current definitions of dementia itself and its subtypes, the authors review studies and meta-analyses 1 Alzheimer Center, University Hospital of Cleveland, 2074 Abington Road, Cleveland, Ohio 44106, USA that purport to demonstrate the prevalence of disease in different regions of the world. They point out that incidence studies are harder to conduct and thus rarer to find, but nevertheless review the information that is available to us. They conclude by reviewing epidemiological evidence, which suggest that certain factors may increase or decrease the risk of an individual suffering from Alzheimer's disease (AD) during his life. In the middle ground of Henderson and Jorm's review, the field is well covered. However, in the beginning and ending of their paper, there are some conceptual issues that need further clarification. The authors begin with the statement that...

Current Functioning

The current functioning has to be assessed by focusing on those functions in which early changes will appear, which have a differential diagnostic value. It is also important to adapt the level of difficulty to the patient's stage of dementia, because few instruments are adapted to the whole range of dementia development, from very early dementia, across mild and moderate dementia, to severe dementia. To fulfil this purpose, both cognitive functioning and personality have to be evaluated, and various aspects of memory (episodic and semantic, primary, procedural) have to be assessed.

Syndromes

Neuropsychological assessment involves the observation of an individual's behaviour in relation to a given stimulus, selected for its likelihood to provoke an abnormal response in the face of damage to specific neuroana-tomical structures. The theoretical basis of neuropsychological assessment is derived, on the one hand, from cognitive psychology, which is concerned with the development of cognitive tests for the demonstration of theoretical models of normal cognitive functioning, and on the other hand, from behavioural neurology in the tradition of Luria, which aims at the classification of normal and pathological responses to cognitive stimuli with a view to screening central nervous system disorder. Ove Almkvist's review of neuropsychological assessment in dementia emphasizes the importance for diagnosis of considering both normal models of cognitive functioning, such as the dissociation of primary, episodic and procedural memory, and the features of pathological central nervous...

Evidence

Ove Almkvist describes in his review typical neuropsychological and instrumental findings in several dementia syndromes. He concludes that there is some consistent evidence pointing to the specificity of these characteristics for the disease and the degree of dementia severity. Inconsistencies remain, mainly concerning the premorbid abilities of the patient and the lack of sufficient knowledge of the normal ageing process. However, how is the evidence given by the author defined Recently, Tierney 1 reviewed the existing literature on neuropsycholo-gical measurements for diagnosing dementia, using these criteria for guidance. She found only two studies meeting Ia criteria 2,3 and six meeting Ib criteria 4-9 . The study of Incalzi et al 2 was cross-sectional and prospective and included a broad range of elderly patients who were admitted to the same hospital in Italy for minor surgery (two control samples) or to the Neurology or Geriatrics wards (dementia sample). All participants were...

Clinical Context

Almkvist's review is an important summary of many of the significant aspects of making a diagnosis of dementia. Interestingly, however, the concept of dementia associated with Lewy bodies appears to have been excluded from the three most common dementia syndromes. Although it is quite clear to all of us that Alzheimer's disease (AD) is probably the most common cause of dementia, and that vascular and frontotemporal dementias are important and relatively frequent, the Lewy body dementias are considered by some people to be the second most common cause of dementia, and by most people in the field as probably being in the top three. Although this condition is thought by some to be a variant of AD, this is not accepted by all, and specific diagnostic criteria are now available 1 . In my view, dementia associated with Lewy bodies which also has a number of different names, e.g. senile dementia of Lewy body type (SDLT) when it occurs in the elderly, Lewy body dementia, and others is...

Estrogen

Other studies examined the risk of developing or dying with AD. In a cohort of approximately 300 post-menopausal women, the odds of developing AD were increased in women who did not receive ERT (odds ratio 1.82). Duration of estrogen use was not discussed. The population had a relatively high prevalence of vascular dementia 175 . In another cohort of almost 9000 women in a retirement community, earlier age of menarche and longer estrogen use were associated with lower mortality rates from AD and a lower risk of developing AD (odds ratio of 0.65). A methodological limitation of the study was reliance on death certificates for AD diagnosis, reducing diagnostic sensitivity 176 . In the Baltimore Longitudinal Study of Aging, almost 500 women were followed for 16 years and approximately half were estrogen users. The relative risk of developing AD in estrogen users was 0.46 177 . In the Italian Longitudinal Study of Aging, estrogen use was lower among the women who developed AD after...

Transgenesis Applied to Neurology

Ated by Prusiner and colleagues have provided a role for the PrP gene in modulating scrapie infectivity and in the development of species-specific neuropathology (31,32). In a recent extension of this work a direct attempt to model the scrapie-related Gerstmann-Straussler-Scheinker syndrome (GSS) in transgenic mice proved to be extremely successful (33). GSS is a human neurodegenerative disease that has been genetically linked to an amino-acid substitution in the human PrP gene (see ref. 33). Mice expressing a mouse PrP gene construct with an identical mutation develop neuropathology characteristic of GSS, indicating PrP as a potential molecular basis for GSS. Further PrP transgenics are anticipated in the continuing elucidation of prion biology (see ref. 32). The pathology observed in the hamster PrP transgenic mice is particularly interesting with regard to Alzheimer's disease (AD) since characteristic amyloid plaques associated with the production of a protease-resistant PrP are...

From Hippocrates to Kraepelin

The term melancholia survived as the only specifier of morbid mood and disposition until Kraepelin, at the end of the nineteenth century, introduced the term ''manic-depression'' to separate nosologically mood disorders from dementia praecox, known after Bleuler as schizophrenia.

Neostigmine and pyridostigmine are the

Because of its central actions, it was considered to provide modest therapeutic benefit in Alzheimer's disease, but this benefit has not been confirmed in subsequent studies. A newer anticholinesterase, donepezil, has however been confirmed in large studies to provide symptomatic benefit, though there has been no evidence of decreased disease progression.

Diagnosing Schizophrenia A Personal View

In reviewing the ''state-of-the-art'' of diagnosing schizophrenia, one hundred years after the concept of dementia praecox became established, we cannot escape addressing the question what is the entity that we wish to diagnose Is schizophrenia a disease, a syndrome arising as a ''final common pathway'' for a variety of pathological processes, or a loose collection of poorly interrelated symptoms and syndromes of multiple underlying causes, held together by nosographic convention or lack of a better alternative By lumping together hebephrenia, catatonic insanity and dementia paranoides into ''one illness process'', Kraepelin initiated a project for world psychiatry that remains unfinished to validate schizophrenia as a disease entity by emulating the great nineteenth-century medical and neuropatholog-ical precedents, best illustrated by general paresis. The process of discovery was to proceed in stages clinical (grouping the variable symptoms on the basis of a common outcome and thus...

Neuropsychiatric syndromes

There are recognized risk factors for the development of neuropsychiatric disturbances after traumatic brain injury. These include increased age, atherosclerosis, and alcoholism. These interfere with or delay the restorative processes occurring in the central nervous system following brain injury.1 There is not a good classification system for neuropsychiatric disorders seen following traumatic brain injury.2 Moreover, the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), classification of organic mental disorders leaves much to be desired. The clinician will experience great difficulty attempting to classify traumatic brain injury syndromes within the framework of the DSM-IV.124 Except for dementia due to head trauma, all other applicable disorders found in the DSM-IV are classified as disorder due to general medical condition. Thus, there is no scientifically validated way to use the commonly accepted psychiatric classification system, other than in a...

The Side Effects of Hormonal Therapy

As time has progressed, the GnRH agonists have also been shown to have side effects. These include memory loss, parkin-sonism, anemia, and osteoporosis, in addition to the hot flushes and impotence that were obvious from their first use. The most important of the side effects physiologically is osteoporosis, with a loss of bone mass of nearly 10 per annum. Although bispho-sphonates have been shown to be of little effect in prostate cancer in terms of limiting pain and tumor progression, which are the main benefits of their use in breast cancer and myeloma, this group of agents is of significant use in limiting osteoporosis in prostate cancer 11 .

Chapter Summary continued

HIV infection produces a mononucleosis-like acute phase, an asymptomatic latent phase, and then progression to AIDS. Ginical AIDS is characterized by susceptibility to a wide variety of opportunistic infections. AIDS patients are also prone to develop hairy leukoplakia, Kaposi sarcoma, high-grade B-cell lymphomas, cervical cancer, a wasting syndrome, nephropathy, and dementia.

Alternative Therapies

Severely handicapped (aphasia, dementia, or immobility) incontinent patients had normal functioning bladders. Interesting, even these debilitated patients benefited from prompted voiding schedules and fluid restriction. This method of patient management is very labor intensive and works best in a home environment with one-to-one patient attention.

Immunocompromised patients

The increased frequency of Toxoplasma encephalitis in patients with AIDS was reported soon after the start of the HIV epidemic (Roue et al., 1984 Enzensberger et al., 1985 Suzuki et al., 1988), and Toxoplasma encephalitis was an important endstage cause of death in HIV patients before the introduction of HAART (Highly Active Anti-Retroviral Therapy). Toxoplasmosis in patients with AIDS is most often the result of reactivation of latent disease following rupture of cysts in the central nervous system. The frequency of reactivated toxoplasmosis depends on the rate of seroprevalence and, apparently, the concentration of IgG antibodies (Derouin et al., 1996 Hellerbrand et al., 1996). Patients with reactivated toxoplasmosis often present with signs and symptoms of disease in the brain and or the eye (Liesenfeld et al., 1999). Acute acquired infection in AIDS patients has been reported and may involve multiple organs. Toxoplasma encephalitis is the most common presentation of reactivated...

Neurological Disorders

Dementia The aging population worldwide yields concern for an increased prevalence of dementia. Hypothetical reasons exist for lifelong dietary patterns influencing the most common forms of dementia. Harman has elucidated a theory that free radicals might be involved in the onset of dementia.97 Vegetarian diets high in antioxidants may confer protection against free radicals and thus reduce the risk of senile dementia.98 Multi-infarct dementia may also be related to the consumption of cholesterol and different fatty acids. Giem et al.99 investigated the relationship between animal product consumption and evidence of dementia in two sub groups of the Adventist Health Study cohort. To ensure a wide range of dietary exposure, 272 California residents were matched for age, sex, and zip code, which included one pure vegetarian, one lacto-ovo vegetarian, and two heavy meat eaters in each of 68 quartets. The second sub group included 2984 unmatched subjects who resided within the Loma...

Risks of hormone therapy

Dementia (75-84 years of age)* * 7-8 of individuals 75-84 years of age have dementia postmenopausal women have a 1.4-3.0 higher risk of Alzheimer's disease than do men. or decreased mortality among women who had ever used HT or who had used HT for less than five years. Two studies that reported results for use longer than five years yielded conflicting results. The review concluded that benefits include fewer fractures and lower rates of colon cancer, and suggested fewer cases of dementia, which was classified as an uncertain benefit. Harms included increased numbers of CHD events, strokes, thromboembolic events, breast cancer, and cholecystitis.18 Cognition and dementia At the present time, HT is not recommended as primary or secondary prevention for Alzheimer's disease (AD).34 Animal models have suggested biologically plausible mechanisms by which estrogen might be protective against neurodegenerative conditions such as AD.35 The prevention of AD is particularly important for women...

Faceto Face Neuropsychiatrie Screening Methods for Trauma Induced Brain Injury in Adults

Diversity to avoid memory cues.1 Short-term visual memory can be screened by asking the patient to copy simple figures that all persons learn in preschool and elementary school. Asking the patient to copy a square, triangle, and circle and then redraw these after 3 min is a sensitive screening test. Obviously, only the most significantly impaired person will fail this test. On the other hand, since the test is so easy to pass, it is not a useful measure of subtle visual memory loss. By checking orientation, the examiner is actually measuring how the person monitors and incidentally records time (episodic memory). When we arise each morning, we must reorient ourselves to a new day and monitor our place and time throughout the day. We are required to correct for the month every

Production Of The Health Risk Appraisal Functions

The final objective was to produce 'health risk appraisal functions', one for each sex. We selected the Cox regression model of equation (1) as the functional form of the model. To guard against capitalization on chance fluctuation and to ensure meaningful results, we arranged the cluster variables in sets (or levels) in order of their substantive importance and then entered them into a hierarchical regression. Recall, here cluster variables refers to the cluster scores and also to the single variables for those sets of variables in Section 3.1 that contained only one variable. We used p 0 05 for the determination of statistical significance of a cluster variable. If the p-value of a cluster variable was above 0 05 (p > 0 05) upon entry, or was above 0 05 in the presence of other cluster variables, we removed it from the model. The ordering of the sets of cluster variables into levels for entry into the multivariate model was as follows (1) age (2) marital status (3) activity...

Spinocerebellar Ataxias Caused By Polyglutamine Expansions

Autosomal dominant cerebellar ataxias (ADCA) constitute a group of disorders' clinically and molecularly heterogeneous. They are characterized by variable degrees of cerebellar and brainstem degeneration or dysfunction. Neuronal loss variably affects the pons' the inferior olive' the basal ganglia' the cerebellum and its afferent and efferent fibers. Onset is generally during the third or fourth decade but can also occur in childhood or in the old age. Patients usually present with progressive cerebellar ataxia and associated neurological signs' such as ophthalmoplegia' pyramidal or extrapyramidal signs' deep sensory loss and dementia. Attempts to classify subtypes of ADCA were largely unsatisfactory until AE Harding distinguished three phenotypes based on clinical associated signs.1 ADCA type I is the most common subtype and variably combines cerebellar ataxia' dysarthria' ophthal-moplegia' pyramidal and extrapyramidal signs' deep sensory loss' amyotrophy and dementia. However'...

DNA in Dis Diagnostic Medicine

These altered animals are known in general as 'transgenic' or 'knockout' mice, where certain genes have been added to or deleted from, respectively, the normal mouse set of chromosomes. Often very small changes to the total DNA of an organism will produce large changes in its physical appearance, behavior, or intelligence. Transgenic mice have proved useful for creating animal models of human disease, for instance prostate cancer, thyroid deficiency, obesity, lateral sclerosis, or Alzheimer's disease. Such genetically-altered mice may also be used to test new drugs which might potentially cure disease in humans.

Clinical Features

It affects interdigital folds of the hands, inner aspects of the wrist, gluteus, regio axillaris folds, elbows and knees. The vesicular lesions under which the parasite is found are easiest to see on the hands and genitals. The penis, nipples in women, and the soles in babies, are the common areas of involvement (Fig. 42.1) Although the face is rarely affected and is generally not treated, some therapeutic failures have been attributed to scabies of the retrauricular folds. We have also seen babies with paronychia caused by mites, and there are reports that mites hide beneath fingernails (JAMA 1984 252 1318). Vesicles and papules are the response to the parasite and to their eggs and feces. There are scabs and excoriations due to the intense scratching (Figs. 42.2 and 42.3). The incubation period is 3-4 weeks during which the intense pruritus is present, especially at night. With re-infections this period is shorter. Subsequently lichenification and scaling appear on hands, elbows and...

Gastrointestinal Manifestations

Histologically, there is microglial proliferation, slight glial scarring, and perivascular infiltration of lymphocytes, neutrophils and plasma cells. The site most commonly affected is the brainstem, followed by isolated hemispherical involvement in a subgroup of patients usually presenting with hemiparesis and or pyramidal signs, and spinal cord involvement in 4-20 of all cases (only 18 being isolated). A special, although fortunately rare, form of cerebral involvement in BD is the demyelinating variant, which does not have signs of active vasculitis in MRI or cerebrospinal fluid (except elevated protein levels), but nevertheless leads to progressive mental deterioration and dementia 127 . In the other forms, cerebrospinal fluid analysis mostly reveals neutrophilic pleocytosis, but lymphocytic pleocytosis is also common. Elevated protein concentrations with an increased IgG index are usually found, and oligoclonal bands similar to those in multiple sclerosis (MS) may occur and...

Head and Brain Magnetic Resonance Imaging

Many vascular disorders, infections, and cerebral changes associated with dementia can be assessed with this diagnostic tool. In addition to diagnostic applications, MRI can be used to evaluate both radiation and chemotherapy for tumor reduction. Shunt placement, for hydrocephalus, can be monitored with MRI.

Transgenic mice animals and plants

Jimenez-Bermudez, S., Redondo-Nevado, J., Munoz-Blanco, J., Caballer, J.L. et al. (2002) Manipulation of strawberry fruit softening by antisense expression of a pectate lyase gene. Plant Physiology 128, 751-9. The genetic design of strawberries which ripen more slowly than normal. Marquet-Blouin, E., Bouche, F.B., Steinmetz, A., and Muller, C.P. (2003) Neutralizing immunogenicity of transgenic carrot-derived measles virus hemagglutinin. Plant Molecular Biology 51, 459-69. Genetic modification of carrots to carry a measles protein for vaccine purposes. Murray-Kolb, L.E., Takaiwa, F., Goto, F., Yoshihara, T. et al. (2002) Transgenic rice is a source of iron for iron-depleted rats. Journal of Nutrition 132, 95760. Genetic modification of rice to carry more iron for nutritional purposes. Nicoll, J.A., Wilkinson, D., Holmes, C., Steart, P., Markham, H., and Weller, R.O. (2003) Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide. Nature Medicine 9, 448-52....

Clinical Presentation In Patients

Fasciculations, myokymia, myoclonus, chorea, dementia dystonia, cardiac Patients with the SCA1 mutation usually have pyramidal signs with hyperreflexia and gait spasticity82 associated with severe disease progression. An early decrease in saccade velocity and reduced tendon reflexes without extrapyramidal signs is suggestive of SCA2.63'8385 Cognitive changes, whether or not in the context of dementia are also a prominent feature of SCA2 patients.86'87 Both, SCA3 MJD and SCA6 patients frequently present with cerebellar oculomotor signs, such as saccadic smooth pursuit, gaze-evoked nystagmus and diplopia. SCA3 MJD patients frequently have ophthalmoplegia or amyotrophy88 that may be associated with extrapyramidal signs, myokymia and bulging eyes in patients with Portuguese ancestry.89-92 SCA6 patients, however, usually have later onset, slower disease progression and very few neurological signs in addition to cerebellar ataxia during the first decade,64 a profile that closely resembles...

Is Depression in the Older Person Necessarily Associated with Cognitive Impairment and Structural Abnormalities

Alexopoulos et al 29 followed up 57 depressed patients annually over an average period of 3 years. Their survival analysis revealed an almost fivefold increase in the risk of developing dementia over those 3 years for those presenting originally with what was considered to be ''reversible dementia''. They were unable to identify clinical predictors of eventual dementia as neuropsychological and imaging data were not systematically recorded at baseline. The study of Reding et al 30 , however, identified that the presence of cerebrovascular, extrapyramidal or spinocerebellar disorder, together with development of confusion on low doses of tricyclic drugs, were good baseline predictors of future development of dementia. Abas et al 31 found that 70 of her depressive subjects had memory deficits and cognitive slowing, the severity of which was comparable to a group of patients with Alzheimer's disease. However, aphasia and apraxia rarely occurred in depressive subjects, whose poor memory...

Subtypes of Depression in the Elderly

The coexistence or the development of depression in patients with dementia has been observed. A review by Wragg and Jeste 41 noted that depressed mood occurred in 0-80 (mean 41 ) of subjects, while depressive disorder (including dysthymia) was reported in 0-86 (mean 19 ) of subjects. Greenwald et al 42 and Rovner 43 reported a prevalence rate of 17 and 11 , respectively, of major depression in patients with Alzheimer's disease. Further, more severe cognitive impairment was noted to be associated with major depression. Burns et al 44 found depressive symptoms in some two thirds of subjects with Alzheimer's disease, while Kumar 45 found that 50 of carers thought that subjects with dementia were depressed, and Reifler et al 46 and Merriam et al 47 reported a figure of 26 and 86 , respectively. In summary, depression in the elderly has similar core features to depression of the younger adult. However, there are some phenomenological differences. The presentation of depression in the...

Type 2 Transglutaminase and Cell Death

As an active component of the cell death machinery, TG2 is involved in the pathogenesis of several diseases, the enzyme being activated in various disorders 2, 27, 33-35, 55 . TG2 cross-linking activity has been proposed to participate to protein aggregates formation occurring in the major neurodegenerative diseases, including Alzheimer, Parkinson and Huntington's Disease (HD) 56, 57 . In particular, HD is a progressive autosomal-dominant neurodegenerative disorder (incidence 1 in 10,000 individuals), resulting from expanded polyglutamine tracts (beyond 35-40 residues) in the coding region of huntingtin (htt) 58 . The disease is associated with the formation of misfolded ubiquitinated protein aggregates, (neuronal intranuclear inclusions NII), containing all or part of the mutant htt. These protein inclusions have predominantly been detected in the nucleus, but may also be observed in the cytoplasm of striatal and cortical neurons 58 . Several reports suggest that in vitro aggregation...

Treatment Of Depression In Old

In reviewing the efficacy and effectiveness of depression treatments in old age, we shall focus on patients with problems more typical of clinical practice, especially the physically ill, those with comorbid dementia, nursing home residents, non-major depressives and patients with resistant depression.

Depression in Residential Care

Antidepressant treatment is frequently inadequate in residential care, with low rates of prescription and inadequate dosages 190-192 . Treatment studies have to contend with the confounding effects of poor physical health, dementia and old age. Few have been undertaken. The only placebo-controlled trial of antidepressant treatment of major depression in elderly nursing home residents found that nortriptyline was effective in significantly improving depressed mood and reducing suicidality. However, 34 of subjects had adverse events that required termination of treatment, demonstrating the vulnerability of these patients and the need for careful monitoring 175 . In an open-label trial of SSRIs in ''old'' old depressed nursing home residents, good responses were obtained in those with major depressive disorder (93 ), but not in depression associated with dementia (7 ) 193 .

Electroconvulsive Therapy ECT

There have been no prospective studies of ECT in dementia patients with depression. A controlled retrospective series of 21 elderly dementia patients found that there were no significant differences in ECT response in comparison with patients without dementia, although there were higher rates of post-ECT confusion 250 . An earlier literature review found that depression improved in 73 of patients, cognition improved in 29 and cognition worsened, usually transiently, in 21 251 . Thus the outcome of ECT in severe depression associated with dementia appears similar to that found in the elderly without dementia.

The answers are 492 b 493 d 494 c 495 e 496 a

The answer is d. (McPhee, 2 e, pp 155-158 Fauci, 14 e, pp 23482353.) A describes a patient with probable multi-infarct dementia B is a patient with Parkinson's dementia complex or perhaps Lewy body disease C is consistent with the pseudodementia of depression. D is the description most closely associated with Alzheimer's disease although the student should realize that the clinical syndromes may overlap consider ably. Case E describes a long-term alcoholic whose dementia may be multifactorial, with possible direct toxic damage to the brain, possible nutritional deficits, and a social history that might well include episodes of head trauma.

Criteria for Study Validity

Development of objective outcome criteria. Outcomes need to be rated in explicit categories which are objective and can be related to normal clinical practice. This is harder than it sounds. While it may not be too difficult to agree on which patients have remained continuously well since recovery from the index episode and which have died, the threshold for dementia may be hard to operationalize and the distinction between continuous illness and depressive invalidism or multiple relapses can be exceptionally hard to standardize, especially if review assessments are conducted at 1-year intervals or greater and there are no hard data to determine the exact nature and severity of symptoms which affected patients in the interim. Even division into ''good'' and ''bad'' outcome categories is tricky. Many researchers class all but those who remain well after recovery from an index episode as having ''bad'' outcomes, but has a patient who suffers a 4-week relapse of major depression in a...

Psychiatric Hospital and Outpatient Studies

Went on for less than 2 years, 25-68 of subjects had been continuously well after recovery from the index episode (mean 43.7 , 95 CI 36.0-51.3 ), 11-25 had relapsed and then recovered again (mean 15.8 , 13.6-18.0 ), 3-69 had been continuously ill (mean 22.2 , 14.1-30.3 ), and 8-40 had other outcomes such as death or dementia (mean 22.5 , 15.2-29.7 ). Studies which exceeded 2 years in duration found that 18-34 (mean 27.3 , 16.8-37.8 ) of subjects were continuously well after initial recovery, 23-52 (mean 32.5 , 28.8-36.1 ) were well after having at least one relapse, 7-30 (mean 14.2 , 1.8-26.7 ) were continuously ill with depression and 23-39 (mean 30.9 , 20.7-41.2 ) had other outcomes. Poor outcome was inconsistently associated with physical illness, cognitive impairment and depressive severity, whereas social factors apart from severe intervening life events were not associated with outcome. In Post's studies 262, 263 , length of time ill with depression before presentation was a...

Prions And Prion Diseases

Fatal diseases of humans and of other animals. A listing of TSEs is given in Table 7.2. TSEs of humans include kuru, Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker syndrome (GSS), and fatal familial insomnia (FFI). TSEs are characterized by neuronal loss that appears as a spongiform degeneration in sections of brain tissue, often accompanied by amyloid plaques or fibrils. The most prominent symptoms of disease are usually dementia (loss of intellectual abilities) or ataxia (loss of muscle control during voluntary movement) that results from the progressive loss of brain function. The disease always has a fatal outcome. In humans, death usually occurs within 6 months to 1 year of the first appearance of symptoms.