Faculty Bibliography

Because cognitive impairment is the central, defining symptom of Alzheimer disease, cognitive assessments commonly are used as primary or secondary measures of outcome in Alzheimer disease research. The authors review the cognitive functions that decline in this neurodegenerative disease and summarize the necessary features of appropriate cognitive performance tests. The characteristics, strengths, and weaknesses of the major cognitive batteries employed as outcome measures in Alzheimer disease research are reviewed. Finally, the recent contributions to the development of cognitive measures by the Alzheimer's Disease Cooperative Study are presented briefly, followed by discussion of some critical issues for future test development

To determine the association between cognitive dysfunction and motor behavior in older adults, 41 cognitively normal elderly (NL), 25 nondemented patients exhibiting mild cognitive impairment (MI) and at risk for future decline to dementia, and 25 patients with mild (early) Alzheimer's disease (AD) were examined using a wide array of motor/psychomotor and cognitive assessments. The three groups were recruited from an aging and dementia research center and were composed of well-characterized physically healthy volunteers, with similar ages and gender distributions. The outcome measures included 16 motor/psychomotor tests categorized a priori into gross, fine, and complex, as well as eight cognitive tests of memory and language. Relative to the NL group, MI individuals performed poorly on cognitive, fine, and complex motor measures but not on gross motor tests; AD patients performed worse on cognitive and all motor domains. Differences in complex motor function persisted after adjustment for performance on cognitive and on less complex motor tests. Classification analyses showed similar accuracies in discriminating NL from MI and NL from AD cases for both complex motor (79% and 92% accuracy, respectively) and cognitive tests (80% and 93% accuracy, respectively). Less complex motor tests produced poorer accuracies. Among nondemented subjects, education correlated with several cognitive scores but no motor scores. These results indicate that motor impairment is an important aspect of cognitive decline in older adults. Motor/psychomotor assessments were found to be comparably sensitive to traditional tests of cognitive function in identifying persons affected by the earliest stages of AD pathology and may improve identification of at-risk nondemented elderly, especially among diversely educated individuals

We used CT and MR to examine the frequency of occurrence of hippocampal formation atrophy (HA) in a research clinic population of 130 normal elderly, 72 nondemented patients with very mild memory and cognitive impairments (MCI), 73 mild Alzheimer's disease (AD) patients, and 130 patients with moderate to severe AD. HA was found in 29% of the normal elderly group and its frequency of occurrence was strongly related to increasing age. For normal elderly 60-75 years of age, 15% had HA: the proportion rose to 48% in subjects 76-90 years of age. Among the three groups of impaired patients, the frequencies of HA ranged from 78% in the MCI patients to 96% in the advanced AD group. Unlike the normal elderly group, the percentages were not related to age. In both the normal elderly group and MCI group disproportionately more males than females had HA. After controlling for learning and the effects of generalized brain changes as reflected in ventricular size, only in the normal group was HA associated with reduced delayed verbal recall performance. Follow-up examinations for 15 individuals with baseline HA. 4 who at entry were MCI and 11 probable AD, yielded clinical and neuropathologic diagnoses of AD in all cases. The results of the present study indicate that hippocampal formation atrophy is associated with memory and cognitive impairments. Further longitudinal and neuropathologic work is required to validate the relationship between hippocampal formation atrophy and AD

Hippocampal formation (HF) atrophy, although common in normal aging, has unknown clinical consequences. We used MRI to derive HF size measurements at baseline on 44 cognitively normal older adults entering a longitudinal study of memory function (mean age = 68.4 years, mean follow-up = 3.8 years). Only one subject became demented at follow-up. Multiple regression analyses controlling for age, gender, education, and diffuse cerebral atrophy revealed that HF size significantly predicted longitudinal change on memory tests previously found sensitive to decline in normal aging. These results indicate HF atrophy may be a risk factor for accelerated memory dysfunction in normal aging

Alzheimer's disease (AD) is associated 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 years. 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 decreased. 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

Age-Associated Memory Impairment (AAMI) and the broader DSM-IV classification Age-Related Cognitive Decline (ARCD) both represent the well-documented phenomenon of declining cognitive performance with age. Objections to AAMI/ARCD often stem from inappropriate adherence to the ''disease model'' instead of recognizing that cognitive decline is a common behavioral consequence of brain aging. One unsolved problem, however, is the difficulty in assessing individual decline without longitudinal data. Individuals with Mild Cognitive Impairment (MCI) are 3. heterogeneous group whose cognitive performance is between that of individuals with ARCD and early Alzheimer's disease (AD). Research confirms that MCI cases are at increased risk for developing AD within several years, and that cognitive and in vivo brain measures may help identify individuals at risk for accelerated age-associated decline or developing AD. Both ARCD and MCF are appropriate targets for pharmacologic interventions that might slow the rate of decline or delay the onset of 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-Mental 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 disturbances, 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

Objective: The purpose of the study was to develop a standardized instrument, the Behavior Rating Scale for Dementia, for rating psychopathology in patients with probable Alzheimer's disease and to conduct a multicenter pilot study of this instrument. Method: The rating scale was developed collaboratively on the basis of clinical experience and existing instruments. Items were scaled according to frequency of psychopathology and were administered to an informant who was familiar with the subject. The scale was administered in a standardized manner by trained examiners who had met predetermined certification standards. The study group consisted of 303 subjects with probable Alzheimer's disease who had undergone standardized clinical evaluations by the Consortium to Establish a Registry for Alzheimer's Disease. Results: Subjects had an average of 15 problems rated as present in the preceding month. Wide variability in the nature of disturbances was found, with a number of items rated as present since the illness began but not in the east month. Interrater agreement was high. Factor analysis suggested eight preliminary factors that mapped onto clinically relevant domains: depressive features, psychotic features, defective self-regulation, irritability/agitation, vegetative features, apathy, aggression, and affective lability. Conclusions: The Behavior Rating Scale for Dementia provides a standardized, reliable measure that can be administered to caregivers of demented subjects. On the basis of the present study, the scale has been revised slightly. After additional studies in progress, the Behavior Rating Scale for Dementia will be available for general use in assessing a wide range of psychopathology in dementia.