The articles and round table discussions in this issue are all from a special meeting of the International Psychogeriatric Association (IPA) sponsored by the IPA's Pharmacy and Therapeutics Committee, The meeting was entitled “Outcome Methodologies for Pharmacologic Trials in Mild, Moderate, and Severe Alzheimer's Disease” and was held on July 26, 1994, at the New York University Medical Center, New York. NY. The following is a list of the participants in this meeting (with their affiliations as noted at the time of the meeting).

This issue is a product of a special meeting ofthe International Psychogeriatric Association (IPA). The meeting, entitled “Outcome Methodologies for Pharmacologic Trials in Mild, Moderate, and Severe Alzheimer's Disease,” was held under the auspices of the IPA's Pharmacy and Therapeutics Comniittee on July 26, 1994, at the New York University Medical Center in New York City. The purpose of the meeting was to bring together leading scientists, clinicians, and regulatory personnel to address issues surrounding assessment of treatment efficacy in Alzheimer's disease (AD).

To address the issue of mild, moderate, and severe Alzheimer's disease (AD), it is necessary to initially establish some agreement on terminology. In recent decades, these terms have frequently been defined using screening instrument scores with measures such as the Mini-Menal State Examination (MMSE). There are many problems with this approach, perhaps the most salient of which is that it has contributed to the total and tragic neglect of patients with severe AD. An alternative approach to the classification of AD severity is staging. This approach has advanced to the point where moderately severe and severe AD can be described in detail. Procedures for describing this previously neglected latter portion of AD have recently been extensively validated. Staging is also uniquely useful at the other end of the severity spectrum, in differentiating early aging brain/behavior changes, incipient AD, and mild AD. Temporally, with staging procedures, it is possible to track the course of AD approximately three times more accurately than with the MMSE. The net result of the advances in AD delineation is that issues such as prophylaxis, modification of course, treatment of behavioral distrubances, loss of ambulation, progressive rigidity, and the development of contractures in AD patients can now be addressed in a scientifically meaningful way that will hopefully bestow much benefit in AD patients and those who care for them.

This article reviews longitudinal data collected from patients with Alzheimer's disease (AD) that are relevant to the design and interpretation of clinical treatment trials. Longitudinal data from patients tested with the Alzheimer's Disease Assessment Scale demonstrate that cognitive symptoms, including memory loss, dysphasia, and dyspraxia, worsen relentlessly over time with the rate of change depending upon baseline dementia severity. Noncognitive symptoms, such as agitation, depressed mood, and psychosis, are episodic, do not necessarily worsen over time, and tend not to be highly correlated with one another. The reliability of cognitive change measures increases with follow-up duration so that the likelihood of detecting drug effects on the rate of cognitive deterioration is greater with longer treatment trials. Functional measures of activities of daily living are difficult to standardize for AD patients but are important for determining the overall clinical and economic impact of AD treatments.

The Hierarchic Dementia Scale is an instrument for measuring the severity of mental impairment based on Piagetian concepts, neuropsychological findings, and the hierarchic nature of decline in mental function. Performance of 20 specific functions such as orienting reflexes and comprehension can be rapidly pinpointed over a wide range of impairment. The scale is reliable, valid, responsive, safe, inexpensive, and easy to use.

The reliability, validity, and sensitivity to change of the Hierarchic Dementia Scale (HDS) were tested in two cross-sectional studies and one longitudinal study. Results prove the HDS to be a simple-to-conduct method, economical in terms of time, and possessing high reliability and high concurrent and criterion-related validity. The HDS appears capable of use at all stages of dementia and capable of permitting studies of the course well into the advanced stages of the illness.

Two reliability studies were performed on a recently developed cognitive assessment battery for severe dementia. The method, the Modified Ordinal Scales of Psychological Development (M-OSPD), is based on the Piagetian developmental model of sensorimotor functions. Procedures have been adapted from this test battery, which was originally applied to infants and small children, for the assessment of remaining cognitive capacity in severe dementia. Two independent interrater reliability studies were conducted. In these studies, two different raters simulataneously evaluated patients with severe dementia. One interrater reliability study was performed in a nursing home setting (Study 1), and the other reliability study consisted of a sample of community-residing patients (Study 2). The Global Deterioration Scale and the Mini-Mental State Examination were used to assess dementia severity. Study 1 (N = 22) resulted in an intraclass correlation coefficient (ICC) of .99 (p < .01) for the M-OSPD total score. Study 2(N = 19) resulted in an ICC of .96 (p < .01) for the M-OSPD total score. The M-OSPD proved to be a reliable instrument in these studies. This cognitive assessment measure can provide meaningful information regarding the cognitive abilities of late-stage dementia patients. Until recently, these late-stage dementia patients had been considered untestable in studies that utilized conventional psychometric and mental status evaluation measures.

Agitation is inappropriate verbal, vocal, or motor activity, which is common among older persons with dementia. Its assessment is complicated both by communication difficulties and by the complexity of the manifested behaviors. Three general approaches are used to assess agitation: informant ratings, observational methods, and technological devices. Within each category, several assessment instruments exist. The approaches differ as to time sampling, objectivity, and cost. Assessment of agitation in pharmacological studies should include consideration of the specific meaning to the agitated behavior for the older person and for the caregiver, along with an evaluation of the consequences of the behavior. At times, the agitated behavior seems to signal a specific need, and alternative methods for fulfilling that need should be considered. Evaluation studies of pharmaologic agents should include consideration of the impact of these agents on nontarget behaviors, as well as an awareness of the large intraperson and interperson variability in agitated behaviors.

A clinician should not rely entirely upon a caregiver's report regarding behavioral pathology when planning a treatment strategy. Direct observational evaluation instruments as well as caregiver-based assessments are necessary. A new scale for the empirical (observational) evaluation of behavioral symptoms in Alzheimer's disease (AD) and related dementias, the Empirical Behavioral Pathology in Alzheimer's Disease Rating Scale (E-BEHAVEAD) was developed. Interrater reliability of this new assessment instrument was examined. Additionally, the relationship between the observed occurrence of behavioral symptomatology on this new rating instrument was compared with the occurrence using a similarly designed, caregiver-based instrument. The interrater reliability study consisted of two raters who simultaneously evaluated 20 dementia patients. The comparative study employed a cross-sectional design (N = 49). Individuals were evaluated in an outpatient clinic setting. The study population consisted of cognitively normal individuals and dementia patients. Evaluations included the new, observationally based behavioral assessment (the E-BEHAVE-AD), a caregiver-based behavioral assessment (the Behavioral Pathology in Alzheimer's Disease Rating Scale; BEHAVE-AD), a clinical global measure (the Global Deterioration Scale), and a mental status assessment (the Mini-Mental State Examination). The interrater reliability study revealed an intraclass correlation coefficient of .97 (p < .01) for total scores on the new E-BEHAVE-AD rating scale. The correlation coefficient for the amount of agreement on the presence of symptoms in six symptomatic categories between caregiver-based information about the patient's behavioral pathology assessed on the BEHAVE-AD and the clinician's observations assessed with the new E-BEHAVE-AD rating instrument was .51 (p < .01). The New E-BEHAVE-AD rating instrument showed excellent interrater reliability. Furthermore, there was a statistically significant relationship between clinician observation of the occurrence of behavioral pathology assessed using the E-BEHAVE-AD and caregive-reported pathology assessed with the BEHAVE-AD. However the magnitude of the correlation between these measures indicated that the majority of variance was independent and nonoverlapping. Consequently, these data support theoretical models suggesting that the assessment of behavioral pathology in dementia might ideally encompass both direct observational and caregiver-report approaches, using measures such as the E-BEHAVE-AD as well as measures such as the BEHAVE-AD.

To understand the quality of life of persons with Alzheimer's disease (AD), it is necessary for investigators to examine the perspective of the victim of the disease. This requires more than assessment of memory and function; qualitative changes in quality of life as expressed by sucessful, adaptive, and problem behaviors need to be measured. The latter are often expressions of emotional distress that, if properly understood, may allow observers to appreciate the experience of AD from the patient's perspective. Such an approach provides a greater likelihood of preserving “the self” of the patient during intervention.

This article reviews the history of Clinical Global Impressions of Change (CGIC) instruments, their use and limitations in clinical trials of Alzheimer's disease, and the development of the National Institute on Aging's Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change Scale (ADCS-CGIC). Originally, CGICs were simple and unstructured instruments that asked a clinician to rate change over the duration of a clinical trial. The method, however, failed to consistently detect treatment effects, leading to the development of more structured and subsequently validated approaches, such as the Clinician Interview-Based Impression Scale (CIBI) and the ADCS-CGIC. Both are currently used in clinical trials. The implications and importance of choosing an appropriate global rating are discussed.

Alzheimer's disease (AD) is asociated with an increased mortality in comparison with aged control populations. The relationship between the clinical and the temporal course of AD has not been well studied over significant intervals. Community residing patients with probable AD (N = 103, 42 men, mean age = 70.2 ± 8.0 years) were studied at baseline on demographic and clinical variables, including measures of global deterioration (Global Deterioration Scale; GDS), mental status and cognition (e.g., Mini-Mental State Examination; MMSE), and functional impairment (Functional Assessment Staging; FAST). Baseline characteristics included a GDS range of Stage 4, 5, or 6 (38.8%, 39.8%, and 21.4% respectively) and a mean MMSE score of 15.4 ± 5.6. The mean follow-up interval was 4.6 ± 1.4 year. Follow-ups were done blind to baseline measures and when necessary were conducted in residential and nursing home settings. Of locatable subjects (n = 95, 92%), 30 (31.6%) were deceased. Survivors (n = 65) had a mean GDS stage of 6.2 ± 0.9 and a mean MMSE score of 5.1 ± 6.9; 51% had MMSE scores of 0. Increased age and male gender, but not baseline clinical dementia variables, increased the risk of death (ps < .01). Change in clinical variables correlated significantly with time elapsed (r = .32, p < .05, for MMSE change, to r = .48, p < .001, for GDS change). Significant variance in temporal change (i.e., time elapsed) was accounted for by change in two of the five clinical measures studied (i.e., GDS and FAST; multiple r = .53). The results support previous estimates of mean duration of the GDS and FAST stages. For subjects with probable AD followed over approximately 5 years, clinical variables changed significantly over time in survivors. However, the majority of temporal variance in the course of AD remains unexplained.

Rachel Billington: My assignment here is to give the caregiver's view, and I feel that's an awesome responsibility. Because I'm with Alzheimer's Disease International (ADI), I must take a global view of this disease. We recently surveyed our members—all national Alzheimer's societies-and according to 21 early respondents, they have an estimated 15 million people with Alzheimer's disease (AD) in their countries. Total population in those countries is 1.7 billion, and the total world population is 5.7 billion.

John Lyons: I just organized my thoughts on essentially three different domains. If you are pursuing clinical trials, particularly in severely demented individuals, there are three different sets of domains that I believe might be reasonable to think about, and all of these have been touched on today.

Barry Reisberg: We're very fortunate in having here the regulatory persons from the United States, Canada, and Germany, in the persons of Paul Leber, Catherine Petersen, and Ursula Kern. I hope that we can proceed more or less in the fashion that the last round table went, which is your reactions as you've been listening to what you've been hearing today. And also your reactions, more generally, in terms of the field. We'll start with Dr. Kern and then Dr. Petersen and then Dr. Leber.

Barry Reisberg: Alistair Burns, a researcher and a clinician, is very active in the International Psychogeriatric Association (IPA). He comes to us from the U.K., and will add a unique perspective. Sture Eriksson is from Umea, Sweden, and he is a geriatrician. He sees patients and he also has a research perspective and, more particularly for this meeting, he is the chairman ofthe IPA's research committee. Sandy Finkel is the current president of IPA. He's aclinician, he sees patients, and he does research both in nursing home settings and in outpatient, settings. Serge Gauthier is a neurologist. He comes to us from Montreal, Canada, and he is indeed a clinician and also a researcher and he is the director of the Canadian clinical trials consortium. Raymond Levy is the president-elect of the IPA. He is a professor at the Maudsley in London; he remains a clinician and he also has a truly longitudinal view of the field. Laurie Mallery is from Halifax. Nova Scoria. She's a geriatrician. She's very rnuch involved with patients, and she also has become involved in research and is familiar with research issues, and obviously lends a unique perspective.

Dr. Khachaturian highlighted the importance of noncognitive symptoms of Alzheimer's disease (AD) for the care providers versus our current lack of knowledge about these symptoms' origin, their relationship with cognitive loss, and our ability to control them. Our relatively greater understanding of the pathophysiology of cognitive loss is not yet matched with respect to non-cognitive symptoms, explaining the hit-and-miss treatment approaches currently in use. It is thus essential to study the underlying biological basis of noncognitive changes in AD. Nonpharmacological approaches to the management of noncognitive symptoms in later stages of AD such as teaching of coping strategies must be encouraged, because they may have a major impact on the patient and the care providers. There is a relative paucity of instruments and clear outcome variables for noncognitive symptoms, including quality of life, which will have to be defined as related to the patient or to caregivers. Such symptoms should be studied in a holistic way in order to treat the underlying pathophysiological process rather than just suppressing unacceptable behaviors such as agitation. Although noncognitive symptoms in later stages of AD are important, from a national research strategy perspective, priority should be given to delaying onset of symptoms by some 10 years. Humane and ethical considerations must always predominate in research on treatment for later stages of AD.