The goal of this article is (a) to review a series of measurement standards for group and individual-patient applications of cognitive tests for Alzheimer's disease (AD); and (b) to review the literature and to use specific data from the NORMACODEM (a project of standardization of cognitive and functional tools for AD) to evaluate the measurement standards of the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog). Seven measurement standards for group and individual patient use were evaluated: practicality, extent of measurement, depth of measurement, cross-sectional precision, longitudinal precision, validity, and standardization. The results indicated that ADAS-Cog meets practicality standards, that the scoring method is not difficult, but training is needed to administer the test. In comparison with other rating scales, the ADAS-Cog is regarded as more comprehensive, although it is not a substitute for an extensive neuropsychological test. The ADAS-Cog is not a tool that is suitable for primary care physicians, although it is a valuable screening test that has utility in both early detection (diagnosis) and staging of AD, and is useful in the severity range of Global Dementia stages 1 to 6. Interrater reliability coefficients for the ADAS-Cog satisfy recommended standards, and the test shows good internal consistency and reproducibility. Age and education are associated with the ADAS-Cog score. There is, however, a lack of standardization, which restricts the comparability of study results, and test materials remain unpublished.

The SKT is a simple and short test for assessing cognitive impairment of memory and attention. The test consists of nine subtests, each limited to a maximum performance time of 60 seconds. Thus, total testing time normally does not exceed 10 to 15 minutes. Test scoring and auditing are also accomplished within a short time and are easily learned. The test is useful for staging the severity of cognitive deficits and for assessing the benefits of therapy, especially with patients suffering from dementia. The SKT is highly accepted both by patients, who are motivated by the appealing character of the tasks and their play-like nature, and hospital clinicians and general practitioners (GPs) because of its brevity and simplicity. The SKT was introduced in Germany two decades ago and has been successfully validated. Test versions of the SKT in English and other languages have confirmed its international applicability and validity, a point of particular importance in light of the current attempts to harmonize methods for assessing the efficacy of pharmaceutical products.

We propose a two-step process for the assessment of dementia using standardized instruments. The family physician performs a screening consisting of taking a medical history, gathering information from relatives and friends of the patient, and administering the combined Mini-Mental State Examination (MMSE) and Clock Drawing Test (CDT). Specialists examine patients with suspected dementia to confirm the diagnosis of dementia and, after a thorough differential diagnostic process, provide the family physician with recommendations for treatment. Specialists should perform neurological and psychiatric examinations, imaging (computer-assisted tomography [CT], magnetic resonance imaging [MRI]), and laboratory work-up. The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) core neuropsychological battery is proposed to serve as a minimal data set that is internationally compatible. In addition, we recommend the Nurses' Observation Scale for Geriatric Patients (NOSGER) as a standard tool for functional assessment.

There is increasing awareness of the importance of psychopathological and behavioral changes in dementia and a need for a technique to measure these noncognitive features. Such a schedule should keep screening questions to a minimum, include a severity measure, exclude symptoms resulting from physical illness, be as brief as possible, and not mix domains of psychopathology. To test the reliability, sensitivity, and validity of a newly developed test, 30 carers were interviewed four times during 6 weeks. An obligatory stem question in each category was followed by supplementary questions. The interviewer recorded the presence of each symptom, its severity, when each symptom started, its duration, and whether it was still present. To detect the presence of delusions, the informant was asked about the patient's insight. Satisfactory differences in mean κ values were demonstrated in test-retest and interrater reliability and validity compared with other techniques. This test may be useful to measure the outcome of drug trials, for correlating psychopathological and behavioral changes with autopsy findings and in epidemiological surveys.

The Columbia University Scale for Psychopathology in Alzheimer's disease (CUSPAD) was developed as a short, semistructured instrument that can be administered by a clinician or trained lay interviewer to the relatives or caregivers of patients with probable Alzheimer's disease (AD). The components of the scale focus on symptoms of psychosis, behavioral disturbance, and depression. A simple decision-tree approach is used to identify the presence of specific psychotic features and makes it possible for the instrument to be used by trained lay interviewers. Interrater reliability has been established. Use of this scale in a multicenter longitudinal study of patients with mild to moderate AD revealed that agitation was the most common and persistent symptom, depressed mood with vegetative signs was the least common and least persistent, and paranoid delusions and hallucinations showed moderate persistence over time. Besides its established psychometric properties, the strengths of the CUSPAD include its brevity, clarity in assessing psychotic symptoms, and ease of administration. These features make it useful for cross-sectional and longitudinal evaluation of the symptoms of psychopathology in AD. The main disadvantage is the lack of quantitative ratings of severity for many of the components, making it unsuitable for use in psychopharmacologic trials.

Ham: There seems to be an astonishing range of expectation from this group as to what a general practitioner (GP) will do for his or her patients, ranging from screening only through to being the primary manager. I feel that we are expecting a fairly high level of sophistication from the GPs within an average British, Canadian, or American family practice. I think we need to be aware that, for some time, the core recommendation in the USA has been to assess the patient using the Mini-Mental State Examination (MMSE) or the Clock Test and perhaps two or three other quantitative assessments. Noncognitive features, such as behavior, are harder to quantify and the individual who assesses them must be the patient's primary manager. It will increasingly happen in the USA that as care becomes more managed, a greater emphasis will be put upon primary care.

Our group accomplished two tasks. First, it identified several general issues that were relevant to our discussions and probably also to the discussions of the other groups; and second, it formulated several criteria for the evaluation of instruments for neuropsychological assessment and applied them to generally available instruments.

Inability to perform activities of daily life is inherent to dementia and an essential component of its severity. Examination of this disability is crucial for diagnosis, management of the patient and family, and evaluation of treatment effects. To examine everyday disability in community-dwelling patients with mild dementia, we developed the Interview for Deterioration in Daily living Activities in Dementia (IDDD) at the memory clinic of the Academic Medical Center at Amsterdam. The IDDD is a caregiver-based measure, which consists of 20 concretely worded items, reflecting the initiative to perform and actual performance of self-care and more complex activities. The original version of the IDDD (1988) was an interview measure, but since 1990 a paper-and-pencil version has been used, which has good construct validity and test-retest reliability, as well as good responsiveness to deterioration over 6 months. In the present study, we examined interobserver agreement among 25 caregiver pairs, which consisted of primary and secondary caregivers. Although the reliability of caregiver reports is often questioned, we found substantial to almost perfect agreement at subscale level and acceptable agreement for most of the items. We conclude that the paper-and-pencil version of the IDDD is a suitable instrument for the description and discrimination of disability among patients with mild dementia still living at home. The IDDD may also be a useful method to incorporate in clinical trials and longitudinal studies.

Functional impairment is a core symptom of Alzheimer's disease. The most accurate indicator of functional impairment is the decline in performance of Activities of Daily Living (ADL). Several scales have been used to measure ADL in geriatric and Alzheimer's disease (AD) populations including the Disability Assessment for Dementia (DAD). The key to making a correct differential diagnosis between benign cognitive impairment and dementia is the detection of a decline in functioning. The instrumental ADL (IADL) relevant items of the DAD could provide crucial guidance in the diagnosis of early stage AD for primary care physicians. It is anticipated that the role of primary care physicians, already essential for the management of the AD patient, will expand to include the diagnosis of earlier cases and the prescription of cholinergic drugs as treatment. ADL assessment tools such as the DAD may help their tasks.

Staging methodologies are an essential tool in the assessment of disease severity in progressive dementing illness. Several different instruments have been developed for this purpose. One of the most widely used methodologies is the Global Deterioration Scale/Functional Assessment Staging (GDS/FAST) system. This system has been studied extensively and proven to be reliable and valid for staging dementia in Alzheimer's disease (AD) in diverse settings. One of the major advantages of this system is that it spans, demarcates, and describes the entire course of normal aging and progressive AD until the final substages of the disease process. Other advantages include: (a) greatly enhanced ability to track the longitudinal course of AD, (b) improved clinicopathologic observations of AD interrelationships, and (c) enhanced diagnostic, differential diagnostic, and prognostic information. This article presents a brief overview of the GDS/FAST staging system.

Global staging measures for dementia of the Alzheimer type (DAT) assess the influence of cognitive loss on the ability to conduct everyday activities and represent the “ultimate test” of efficacy for antidementia drug trials. They provide information about clinically meaningful function and behavior and are less affected by the “floor” and “ceiling” effects commonly associated with psychometric test. The Washington University Clinical Dementia Rating (CDR) is a global scale developed to clinically denote the presence of DAT and stage its severity. The clinical protocol incorporates semistructured interviews with the patient and informant to obtain information necessary to rate the subject's cognitive performance in six domains: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. The CDR has been standardized for multicenter use, including the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) and the Alzheimer's Disease Cooperative Study, and interrater reliability has been established. Criterion validity for both the global CDR and scores on individual domains has been demonstrated, and the CDR also has been validated neuropathologically, particularly for the presence or absence of dementia. Standardized training protocols are available. Although not well suited as a brief screening tool for population surveys of dementia because the protocol depends on sufficient time to conduct interviews, the CDR has become widely accepted in the clinical setting as a reliable and valid global assessment measure for DAT.

Whitehouse: In the USA, the Agency for Healthcare Policy and Research has recently issued guidelines for early recognition and assessment of dementia, which I think this group should aim to incorporate in its deliberations. Interestingly, to assess patient function, they selected an instrument from the literature called the FAQ, which as far as I am aware, is not widely known by people in the field. Would anyone like to comment on this test? These guidelines will influence GPs, because they will be made aware of the recommendations by government information leaflets.

Our topic was functional and global evaluations. We discussed the scales per se versus the concept of evaluation. In terms of usefulness for the primary care physician, we concluded that the concept of evaluating functional and global impairment was important, but due to time constraints on general practitioners (GPs), the use of ratings scales was impractical. However, we believed that for those of us with research interests, the rating scales and their psychometric properties are crucial.

There is compelling evidence for the early involvement of the hippocampal formation in the natural history of Alzheimer's disease (AD). The evidence comes from recent neuropathology, neuropsychology, and neuroimaging studies. AD-type histopathologic changes limited to the hippocampus have been described and may be seen in normal aging subjects. The sites of maximal neuronal loss in the hippocampal formation are in the CA1, subiculum, and entorhinal cortex. Minimally cognitively impaired (MCI) individuals (defined by ratings of functional capacity and psychiatric symptomatology) exhibit a neuropsychological profile that is distinct from that of the unimpaired elderly. Pathologic evidence suggests that most of these cases already have AD brain changes accentuated in the hippocampal region, and our own longitudinal studies reveal that 70% of this group develop dementia within a 4-year period. We have developed a negative-angle axial view designed to cut parallel to the anterior-posterior plane of the hippocampus. Using this modified axial plane of section in conjunction with computed tomography (CT) and magnetic resonance imaging (MRI), we estimated the prevalence of hippocampal atrophy in normal aging and across severity levels of cognitively impaired elderly patients. Longitudinal study shows that hippocompal atrophy is a sensitive and specific predictor of future AD for patients with MCI. MRI volume study of AD patients, controls, and MCI patients shows specific hippocampal volume loss in MCI. We conclude that the atrophic changes associated with early AD can be visualized using qualitative techniques and are readily quantifiable with volumetry. This article is not intended to be comprehensive, but to provide an overview of some of the structural neuroimaging data from our laboratory.

In a prospective study of more than 200 cases of dementia and 119 controls, annual technetium-99m–hexamethyl-propylene amineoxime (99m Tc-HMPAO) single-photon emission computed tomography (SPECT) and annual medial temporal lobe (MTL) oriented X-ray computed tomography (CT) have been used to evaluate the diagnostic potential of functional and structural neuroimaging in the differential diagnosis of dementia. Some subjects have had up to 7 annual evaluations. So far, of 151 who have died, 143 (95%) have come to necropsy. Histology is known for 118, of whom 80 had Alzheimer's disease (AD), 24 had other “non-AD” dementias, and 14 controls with no cognitive deficit in life also had no significant central nervous system pathology. To compare the findings in the dementias with the profile of stuctural and functional imaging in the cognitively normal elderly, scan data from 105 living, elderly controls without cognitive deficit have also been included in the analysis. All clinical diagnoses were according to National Institute of Neurological and Communicable Disease and Stroke—Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) and the Diagnostic and Statistical Manual of Mental Disorders (3rd ed., rev.; DSM-III-R) criteria, and all histopathological diagnoses according to the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria. Early data from this cohort have suggested that the combination of both MTL atrophy seen on CT with parietotemporal hypoperfusion on SPECT may predict the pathology of AD. The diagnostic sensitivity, specificity, accuracy, and positive and negative predictive values of the NINCDS-ADRDA and DSM-III-R criteria could be assessed in this cohort against the gold standard of histopathology. The diagnostic potential of CT evidence of MTL atrophy alone, SPECT evidence of parietotemporal hypoperfusion alone, and the combination of both of these scan changes in the same individual could then be compared against the diagnostic accuracy of clinical operational criteria in the pathologically confirmed cases. Furthermore, all of these modalities could be compared with the diagnostic accuracy of apolipoprotein E4 (Apo E4) genotyping to predict AD in the histopathologically confirmed cohort. In this population, NINCDS “probable-AD” was 100% specific, 49% sensitive, and 66% accurate; “possible-AD” was only 61% specific, but 93% sensitive and 77% accurate; and the combination of both “probable-AD” and “possible-AD was 61% specific, 96% sensitive, and 85% accurate. DSM-III-R criteria were 51% sensitive, 97% specific, and 66% accurate. In the same cases and including the 105 living, elderly controls, the diagnostic accuracy of the Oxford Project to Investigate Memory and Aging (OPTIMA) scanning criteria showed CT alone to be 85% sensitive, 78% specific, and 80% accurate; SPECT alone had 89% sensitivity, 80% specificity, and 83% accuracy; and the combination of the two was 80% sensitive, 93% specific, and 88% accurate. The Apo E4 genotype was 74% sensitive but yielded 40% false positives in the histologically confirmed series. The diagnostic accuracy afforded by this method of CT and SPECT used alone is better than that of any established clinical criteria and reveals that the combination of MTL atrophy and parietotemporal hypoperfusion is common in AD, much less common in other dementias, and rare in normal controls. In the NINCDS-ADRDA criteria “possible-AD” cases, the combination of CT and SPECT findings alone were better in all diagnostic indices than the presence of Apo E4 alone in predicting AD. The frequent occurrence of MTL atrophy in AD and also in other “non-AD” dementias later in the course of the disease suggests the concept of medial temporal lobe dementia. This could explain some of the overlap of clinical profiles in the dementias, particularly as the dementia progresses, making clinical differential diagnosis difficult. In this context, the use of SPECT can significantly enhance specificity.