Use of CSF biomarkers in the diagnosis of Alzheimer's disease in clinical practice

INTRODUCTION: The diagnosis of Alzheimer's disease (AD) currently relies on clinical criteria that are primarily based on the presence of an amnestic syndrome of the mesial temporal lobe type. In recent years, new diagnostic tools have been developed, such as the possibility of measuring a set of proteins directly involved in the pathophysiological process of AD. A profile suggestive of AD has been defined, characterized by decreased beta-amyloid peptide, combined with increased Tau protein and phopho-Tau. STATE OF KNOWLEDGE: According to current data available in the medical literature, the potential usefulness of CSF biomarkers in the common forms of AD fulfilling usual clinical criteria remains modest. In contrast however, they could be of significant help in the diagnosis of early-onset AD, in particular in atypical forms with prominent non-memory impairment (involving vision, language or behavior). In addition, due to their close relationship with the pathological process, they bring useful prognosis information upon the aggressiveness of the disease. CONCLUSION AND PERSPECTIVE: Taken together, in the current state of knowledge, use of CSF biomarkers in clinical practice should first be recommended for the assessment of early-onset cognitive disturbances, in particular when initial symptoms are of a non-memory type. Their development, however, offers new avenues in the fields of clinical and pharmacological research.     

Migraine in general practice. A French multicenter study

INTRODUCTION: A national survey has been conducted with 349 general practitioners in order to analyze the management of concerned episodic headache in general practice. METHOD: This survey enabled collection of data from 2537 headache patients. The main data concered IHS diagnosis, severity of headache using the MIGSEV scale, management, practices and the impact on daily living (QVM and HIT-6 scales). RESULTS: Out of the 2537 included patients, 52 percent were migraine sufferers according to IHS criteria (code 1.1/1.2), 34 percent presented with migrainous disorders (code 1.7), and 14 percent were non-migraine headache patients. The distribution of management practices showed that 71 percent of them were given non-specific treatments, 46 percent of them specific treatments and 27 percent of them prophylactic treatments. Analysis of the impact of headache using the QVM or the HIT-6 demonstrated a relationship between diagnosis, migraine severity and disability. Analysis of the correlation between the severity of the last migraine attack as evaluated by the patient and that estimated by the doctor showed that the practitioner tended to underestimate the patient's pain. These results highlight the importance of communication between practitioners and migraine sufferers. CONCLUSION: Training of general practitioners in the use of simple tools such as the HIT-6 scale, should be helpful for a better evaluation of the impact of headache on daily living, and hence should lead to more optimal therapeutic management of headache patients.     

The diagnosis of Alzheimer's disease

Dementia constitutes a growing public health crisis. Early and accurate diagnosis of dementia is essential in order to provide patient and family counseling and appropriate treatment, including with specific antidementia drugs as they become increasingly available. Age-related cognitive decline, as compared with dementia, does not seriously interfere with usual activities. The optimal approach to early detection of dementia is clinical examination that incorporates information from a reliable collateral source about how the patient's cognitive abilities have declined relative to past performance. Alzheimer's disease (AD), the most common cause of dementia, can be diagnosed clinically with high accuracy (=85%) using standardized criteria. Even incipient AD can be detected with clinical methods alone. Although the typical picture of AD is characterized by gradual onset and progression of memory and other cognitive deficits, in other respects the disease is marked by heterogeneity. Early and late-onset AD represent the most easily recognized subtypes. Research continues towards characterizing a biologic marker but, as of yet, no candidate marker surpasses the high diagnostic accuracy of clinical assessments alone. At present, the diagnosis of AD rests primarily in the hands of the clinician.     

Alzheimer's disease: biological diagnosis

The authors discussed the possible clinical chemical diagnosis of Alzheimer's disease in function of the well established biochemical changes in different neurotransmitter systems.     

The neuropsychological diagnosis of Alzheimer's disease

Neuropsychological assessment potentially subserves several functions in subjects in whom Alzheimer's disease (AD) is suspected. Such assessment can detect the presence of brain disease once significant neuronal disruption has occurred. Analysis of the pattern and evolution of cognitive deficits allows inferences to be drawn regarding the likely underlying pathology. Neuropsychological assessment enables delineation of the particular cognitive strengths and weaknesses of individual patients, facilitating the construction of individual management programs. Lastly, cognitive testing provides a cost-effective means of monitoring disease progression and the effects of treatment. This review describes the typical pattern and evolution of cognitive deficits in AD, outlines a number of variant presentations, discusses the differential diagnosis from other dementias, and addresses the issue of progression to clinically probable AD in the cognitively impaired, non-demented elderly. It is anticipated that biomarkers for AD will complement neuropsychological assessment by enabling disease detection before unequivocal cognitive deterioration has ensued, and by improving the accuracy of clinical diagnosis of dementia type. The development of reliable biomarkers will also enable improvements in the sensitivity and accuracy of neuropsychological assessment in AD to be made, more quickly and efficiently than is currently possible using longitudinal studies.     

Antemortem laboratory diagnosis of Alzheimer's disease

The accuracy of diagnosis for AD by conventional clinical and laboratory means is in the order of 80%. Neurophysiological techniques (EEG, evoked potentials) show abnormalities in AD that could prove to be useful for diagnosis after pharmacological challenges. CSF analysis show a reduction of the concentration of various neuropeptides, reduction shared by other types of dementias. Among the existing imaging techniques PET using 18F-fluorodeoxyglucose is the most diagnostic in AD because of the early and often asymmetrical decrease in parietotemporal metabolic activity. Cortical biopsy with histological and biochemical analysis can provide an accurate in vivo diagnosis of AD.     

阿尔茨海默病的不同诊断方法

阿尔茨海默病（AD）是一种进行性发展的神经系统退行性疾病,临床表现为认知和记忆功能不断下降,日常生活能力进行性减退,并伴有各种神经精神症状和行为障碍。目前AD的治疗仍然缺乏非常有效的药物,因此,早期发现、早期诊断对减缓病程进展、降低发病率和患病率具有重要意义。现就AD诊断的相关指标作一综述。     

The clinical diagnosis of Alzheimer's disease

Clinical and pathologic diagnoses are compared in 65 patients who had dementia and who had been studied longitudinally during life. The sensitivity of diagnosis for dementia of the Alzheimer type (DAT) without any other diagnosis was 87%, and the specificity was 78%. The ischemic scale score did not discriminate well between patients with pure multi-infarct dementia and those with both DAT and multi-infarct dementia. However, 35 of 38 cases of pure DAT had a score of 4 or less on the ischemic scale.     

Interrater reliability of Alzheimer's disease diagnosis

To determine interrater reliability of dementia diagnosis, 4 physicians experienced in the evaluation of dementia patients applied 3 sets of diagnostic criteria to each of 62 patients, based on a standardized set of medical record information. All patients had undergone similar examinations and follow-up to establish the initial clinical diagnosis (76% had autopsy). Raters were blind to the diagnosis and to follow-up information after the initial evaluation period. This paper presents interrater agreement (kappa values) for a diagnosis of Alzheimer's disease using the American Psychiatric Association diagnostic criteria from the Diagnostic and Statistical Manual (DSM-III), the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) criteria for the clinical diagnosis of Alzheimer's disease, and the Eisdorfer and Cohen Research Diagnostic Criteria (ECRDC) for primary neuronal degeneration. The NINCDS showed somewhat higher average interrater reliability (kappa = 0.64) than the DSM-III (kappa = 0.55) and considerably higher interrater reliability than the ECRDC (kappa = 0.37). One rater displayed conspicuously lower levels of interrater reliability than the other 3, especially in DSM-III and ECRDC. This study indicates that interrater reliability of DSM-III and NINCDS criteria are comparable. Documentation of interrater reliability and, if necessary, training to improve reliability is an important consideration in research where different observers are diagnosing dementing illnesses.     

Alzheimer's disease diagnosis disclosure in Brazil: a survey of specialized physicians' current practice and attitudes

BACKGROUND: There is little, though growing, interest in the research area of attitudes held among physicians towards disclosing the diagnosis of dementia and Alzheimer's disease (AD), or the current practice on AD disclosure. This study aimed to investigate the practice and attitudes of specialized physicians towards AD diagnosis disclosure in Brazil. METHODS: A questionnaire was devised to survey the current practice and attitudes regarding diagnosis disclosure of AD in Brazil and sent to specialized physicians (170 geriatricians, 300 neurologists and 500 psychiatrists) by electronic mail. RESULTS: From 970 potential respondents, 181 physicians who usually attend AD patients returned the questionnaire. There were no significant differences between the three specialties regarding the frequency with which they informed patients of their AD diagnosis (p = 0.17). The results revealed that only 44.8% of the physicians would regularly inform the patient of the diagnosis, although 85.6% of these use clear terminology. Despite their usual practice, 76.8% would want to know their diagnosis if they themselves were affected by AD. CONCLUSIONS: Disclosure of AD diagnosis is not common among specialized physicians in Brazil and different factors are involved. In the clinical context, discussion on advantages of diagnosis disclosure can be useful for improving the care of AD patients and their families.     

Treatment of Alzheimer's disease: general methodological aspects

The availability of many etiological hypothesis for Alzheimer's disease raise the possibility of treatments aiming at slowing down disease progression. Clinical trial designs and relevant outcomes are available to test these hypothesis. A preventive approach based on individual risk assessment may be possible, which will increase the number of consultations for neurologists in the near future.     

Genetic markers in the diagnosis of Alzheimer's disease

Abbreviations: AD, Alzheimer's disease; AbetaPP, amyloid beta protein precursor; BACE, beta-site AbetaPP cleaving enzyme; PS1, presenilin-1; PS2, presenilin-2; APOE, apolipoprotein E; LRP, low density lipoprotein receptor-related protein; SNPs, single-nucleotide polymorphisms; A2M, alpha-2-macroglobulin. Alzheimer's disease (AD) is the most common neurodegenerative disorder associated with dementia in the elderly population. Its clinical symptoms are manifest with increasing prominence during mid- to late stages of adulthood. In the absence of precise biological indicators that precede or accompany the cognitive decline, diagnostic confirmation of AD requires postmortem detection of histopathological characteristics such as amyloid plaques, neurofibrillary tangles, and extensive cortical atrophy. While the etiology of AD remains incompletely understood, it was recognized early on that the observed familial aggregation of AD implied the presence of one or more inherited susceptibility markers that could be useful in diagnosis and treatment. To date, genetic analyses of these pedigrees have resolved four independent genetic loci linked with inherited susceptibility to AD.     

阿尔茨海默病早期诊断生物学指标研究进展

阿尔茨海默病（AD）是老年人群痴呆的主要病因,本文就目前阿尔茨海默病的主要生物学指标进行综述,包括淀粉样蛋白及β淀粉样蛋白、Tau蛋白、APOEε4与apoE蛋白、炎症因子以及神经递质等有助于预测AD的发病风险并作出早期诊断。     

Positron emission tomography diagnosis of Alzheimer's disease

Positron emission tomography (PET) imaging of [18F]-2-fluoro-2-deoxy-D-glucose (FDG) is accurate in the early detection of Alzheimer's disease (AD) and in the differentiation of AD from the other causes of dementia. FDG-PET imaging is available widely and performed easily. Different patterns of abnormality with the various causes of dementia are well described. Semiquantitative methods of image interpretation are available. Medicare covers FDG-PET imaging for the narrow indication of differentiation of possible AD from frontotemporal dementia.     

Early diagnosis and treatment of Alzheimer's disease

Recently, focus on early detection, diagnosis and treatment of Alzheimer's disease (AD) has been increasing. The rationale is that, as with any other serious illness, early intervention will lead to better outcomes for patients and families. Despite the intuitive appeal of this rationale, there is discussion and even debate regarding the issues surrounding early detection and treatment. This review begins with a futuristic case that is aimed at focusing this discussion/debate and then proceeds to consider each of the issues including: should AD screening be part of routine physical examinations? is the amyloid hypothesis correct?: implications for diagnosis and treatment? can neuroimaging studies be used to detect brain amyloid? can symptomatic medications be combined to facilitate cognition? can cognitive rehabilitation programs facilitate cognition? and can immunotherapy and other plaque-busting therapies modify the progression of AD?