Frequency of behavioral symptoms characterizes agitation in Alzheimer's disease.

This study describes two well-characterized groups of Alzheimer's disease (AD) patients with similar levels of cognitive functioning, but with different overall behavioral disturbance levels. We sought to determine the nature of this difference-whether AD patients with higher levels of behavioral disturbance (n = 148) differ from less disturbed AD patients (n = 235) in terms of (a) the range of symptoms exhibited, (b) the frequency of occurrence of these symptoms, or (c) both of these. We defined and operationalized 'diversity of behaviors' and 'frequency' with respect to the item-level responses on the Cohen-Mansfield agitation inventory (CMAI). We found that, in these two samples of AD patients, differences occurred in the frequency of 10 out of 21 behaviors, rather than in a variety of endorsed behaviors. These 10 behaviors, observed at different frequencies in both groups, may be useful for monitoring change in studies of drugs or behavioral interventions for behavioral disturbance in persons with AD.

On the use of surrogate respondents for controls in a case-control study of Alzheimer's disease.

OBJECTIVE: To examine the presence and extent of bias introduced by using surrogate respondents for healthy controls in a case-control study of Alzheimer's disease (AD). DESIGN: Comparative study of matched responses to questionnaire ascertaining lifestyle issues. SETTING: University Hospitals/Case Western Reserve University Alzheimer Center. PARTICIPANTS: Controls (n = 50) were identified through the Research Registry. Surrogates (n = 50) were their healthy relatives or friends. MEASUREMENTS: Answers in the areas of demographic and occupational history, smoking habits, medical history, dietary intake, and leisure and work activities were recorded. The analysis was based on methods for paired data. Continuous variables were analyzed, focusing on paired differences between self and surrogate responses. RESULTS: For occupations and exposures, over 80% of the surrogates agreed with the subjects on over 80% of the questions. On smoking history, over 90% of the surrogates agreed with the subjects on over 70% of the questions. On leisure and work activities, over 70% of the surrogates agreed with the subjects on over 50% of the questions. There was less agreement regarding medical history. For continuous variables, most paired t-tests of zero mean difference between self and surrogate responses resulted in nonrejection of this hypothesis. Computed mean differences were not always positive or always negative. CONCLUSION: We did not find systematic under- or overreporting by the surrogates of the controls. Therefore, if there are biases in the responses of surrogates of the AD cases in our case-control study, they would not be canceled out by using surrogates for the controls.

Patients with Alzheimer's disease have reduced activities in midlife compared with healthy control-group members.

The development of Alzheimer's disease (AD) later in life may be reflective of environmental factors operating over the course of a lifetime. Educational and occupational attainments have been found to be protective against the development of the disease but participation in activities has received little attention. In a case-control study, we collected questionnaire data about 26 nonoccupational activities from ages 20 to 60. Participants included 193 people with probable or possible AD and 358 healthy control-group members. Activity patterns for intellectual, passive, and physical activities were classified by using an adaptation of a published scale in terms of "diversity" (total number of activities), "intensity" (hours per month), and "percentage intensity" (percentage of total activity hours devoted to each activity category). The control group was more active during midlife than the case group was for all three activity categories, even after controlling for age, gender, income adequacy, and education. The odds ratio for AD in those performing less than the mean value of activities was 3.85 (95% confidence interval: 2.65-5.58, P < 0.001). The increase in time devoted to intellectual activities from early adulthood (20-39) to middle adulthood (40-60) was associated with a significant decrease in the probability of membership in the case group. We conclude that diversity of activities and intensity of intellectual activities were reduced in patients with AD as compared with the control group. These findings may be because inactivity is a risk factor for the disease or because inactivity is a reflection of very early subclinical effects of the disease, or both.

Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: a randomized controlled trial. Alzheimer's Disease Cooperative Study.

CONTEXT: Several reports from small clinical trials have suggested that estrogen replacement therapy may be useful for the treatment of Alzheimer disease (AD) in women. OBJECTIVE: To determine whether estrogen replacement therapy affects global, cognitive, or functional decline in women with mild to moderate AD. DESIGN: The Alzheimer's Disease Cooperative Study, a randomized, double-blind, placebo-controlled clinical trial conducted between October 1995 and January 1999. SETTING: Thirty-two study sites in the United States. PARTICIPANTS: A total of 120 women with mild to moderate AD and a Mini-Mental State Examination score between 12 and 28 who had had a hysterectomy. INTERVENTIONS: Participants were randomized to estrogen, 0.625 mg/d (n = 42), or 1.25 mg/d (n = 39), or to identically appearing placebo (n = 39). One subject withdrew after randomization but before receiving medication; 97 subjects completed the trial. MAIN OUTCOME MEASURES: The primary outcome measure was change on the Clinical Global Impression of Change (CGIC) 7-point scale, analyzed by intent to treat; secondary outcome measures included other global measures as well as measures of mood, specific cognitive domains (memory, attention, and language), motor function, and activities of daily living; compared by the combined estrogen groups vs the placebo group at 2, 6, 12, and 15 months of follow-up. RESULTS: The CGIC score for estrogen vs placebo was 5.1 vs 5.0 (P = .43); 80% of participants taking estrogen vs 74% of participants taking placebo worsened (P = .48). Secondary outcome measures also showed no significant differences, with the exception of the Clinical Dementia Rating Scale, which suggested worsening among patients taking estrogen (mean posttreatment change in score for estrogen, 0.5 vs 0.2 for placebo; P = .01). CONCLUSIONS: Estrogen replacement therapy for 1 year did not slow disease progression nor did it improve global, cognitive, or functional outcomes in women with mild to moderate AD. The study does not support the role of estrogen for the treatment of this disease. The potential role of estrogen in the prevention of AD, however, requires further research.

Determinants of attrition in a natural history study of Alzheimer disease.

The aim of the present study was to identify determinants of attrition in a natural history study of a tertiary care sample of patients with Alzheimer disease (AD) and control subjects. A longitudinal study was performed with 978 patients with AD and 466 control subjects age 50 years and older enrolled at 25 sites of the Consortium to Establish a Registry for Alzheimer's Disease between January 1987 and January 1992; subjects were followed annually for up to 78 months. Both descriptive statistics and polytomous logistic regressions were run to identify determinants of attrition. Of the 1,444 subjects enrolled, 10.5% dropped out after initial evaluation, 31.0% provided at least two waves of data, and 58.4% provided complete follow-up. Inadequate involvement by the site, non-white status, and patient's spouse not enrolled in the study were predictive of dropout; cessation of participation because of death (which may have precluded dropout) predicted continuation in the study. Age, level of education, severity of dementia, and rapidity of progression of disease did not predict dropout. Level-of-site commitment was the most significant determinant of continued participation in this natural history study of AD, followed by white race, and the inclusion of both husband and wife where one is a patient and the other a control subject.

Assessment of agitation in Alzheimer's disease: the agitated behavior in dementia scale. Alzheimer's Disease Cooperative Study.

OBJECTIVES: To develop and evaluate the psychometric properties of a new measure of agitation, the Agitated Behavior in Dementia scale (ABID). The ABID consists of 16 items designed specifically to evaluate frequency of and caregiver reaction to common agitated behaviors in community-residing dementia patients. DESIGN: The ABID was administered at the baseline assessment of a multi-site controlled treatment study to reduce agitation in Alzheimer's Disease (AD). Reliability was assessed by evaluating internal consistency and test-retest correlations. Validity was assessed by examining correlations with other constructs, including demographics, cognitive status, and overall behavioral disturbance. SETTING: Twenty-one sites across the US, comprising the Alzheimer's Disease Cooperative Study, contributed subjects to the investigation. PARTICIPANTS: A total of 148 community-residing AD patients, living with a spouse or adult relative who acted as an informant. Mean age was 75 years, and mean Mini-Mental State Exam (MMSE) score was 13. MEASUREMENTS: Cognitive status was assessed using the MMSE. Behavioral disturbance was assessed using the Behavior Rating Scale for Dementia of the Consortium to Establish a Registry for Alzheimer's Disease, the Revised Memory and Behavior Problems Checklist, and the Cohen-Mansfield Agitation Inventory. RESULTS: Reliability of the ABID was excellent, with internal consistency of 0.70 and test-retest reliability of 0.60 to 0.73. Validity was confirmed by correlations with related measures and lack of correlation with unrelated constructs. CONCLUSIONS: The ABID is brief, easy to administer, and provides objectively anchored observations of problems. It is a promising measure for studies of community-residing AD patients.

Variability in annual Mini-Mental State Examination score in patients with probable Alzheimer disease: a clinical perspective of data from the Consortium to Establish a Registry for Alzheimer's Disease.

OBJECTIVE: To determine the variability in annual Mini-Mental State Examination scores of patients with Alzheimer disease enrolled in the Consortium to Establish a Registry for Alzheimer's Disease (CERAD). PATIENTS: A total of 372 patients with probable Alzheimer disease with 1 or more years of follow-up. SETTING: Twenty-one CERAD clinical sites throughout the United States. RESULTS: An average annual decline of 3.4 points in CERAD patients returning for longitudinal reassessments was close to the SD of the measurement error of 2.8 points for the Mini-Mental State Examination. There was wide variability in individual rates of decline. Even with 4 years of follow-up, 15.8% of the patients had no clinically meaningful decline in Mini-Mental State Examination score (defined as a change in initial score >3, ie, 1 SD of measurement error). Validity of measurements of the rate of change in Mini-Mental State Examination scores improved with longer observation intervals and was reliable for most patients when observations were separated by 3 or more years. CONCLUSIONS: Although the Mini-Mental State Examination is a useful screening instrument to assess level of cognitive function, it has limited value in measuring the progression of Alzheimer disease in individual patients for periods less than 3 years because of a large measurement error and substantial variation in change in annual score.

Growth of rat mesangial cells on oxidized extracellular matrix increases inducible nitric oxide synthase activity.

Biochemical modification of extracellular matrix (ECM) proteins can alter the function in overlying cells. We tested the hypothesis that metal-catalyzed oxidation of native ECM and individual matrix proteins modulates the activity of inducible nitric oxide synthase (iNOS) in cultured rat mesangial cells (RMC). Oxidized modification of native ECM resulted in a 32% increase in iNOS activity (P<0.01) without influencing the response to supplemental L-arginine or to the addition of the iNOS inhibitor, L-NAME. Immunoblot analysis indicated that enhanced iNOS activity was not associated with a parallel rise in the cytosolic content of iNOS. Synthesis of type IV collagen was unaffected by growth of RMC on oxidized native ECM. Oxidation of three normal constituents of the mesangial matrix - type IV collagen, laminin, and fibronectin - also stimulated iNOS activity in overlying RMC by 18-32% (P<0.05). Growth of RMC on oxidized type I collagen or Vitrogel had no effect on NO production. We conclude that oxidized modification of the mesangial matrix promotes increased iNOS activity and NO production by mesangial cells. Further work is required to determine whether this response limits glomerular injury or promotes damage to the mesangium in oxygen free radical-mediated diseases such as chronic renal failure, atherosclerosis and diabetes.

A comparison of the Cohen-Mansfield agitation inventory with the CERAD behavioral rating scale for dementia in community-dwelling persons with Alzheimer's disease.

In a group of 242 community-dwelling patients with Alzheimer's disease (AD), a longitudinal comparison was made of two caregiver-administered instruments for assessment of behavioral disturbance; the Cohen-Mansfield Agitation Inventory (CMAI) and the CERAD Behavioral Rating Scale for Dementia (BRSD). We examined records of the 206 patients with baseline and 12-month follow-up data for the CMAI and the BRSD who also had tests of cognitive (Mini-mental State; MMSE) and global function (Clinical Dementia Rating; CDR and Functional Assessment Staging; FAST). Among 114 AD subjects, the correlation between total CMAI at baseline and 1 month readministration was 0.83 (p < 0.0001). In the same subjects, stratified into 5 groups by MMSE scores, the correlations between BRSD baseline and 1-month scores ranged from 0.70-0.89 (p < 0.0001). There was high correlation between total scores of both instruments at baseline and 12 months. In addition, all CMAI subscales except Verbally Aggressive correlated significantly with total BRSD score at both time points. At baseline, BRSD subscales for irritability/aggression, behavioral dysregulation and psychotic symptoms and at 12 months, irritability/aggression and behavioral dysregulation correlated with total CMAI scores. Neither scale changed significantly over 1 year, but there was wide individual variation. CMAI and BRSD scores correlated with 1-year change in the FAST, but not with MMSE or CDR (which weighs cognition heavily), suggesting that behavioral disturbance may be more strongly related to ability to manage activities of daily living (executive function) than to other aspects of cognition. The CMAI and BRSD appear to be interchangeable as measures of agitation, with the CMAI possibly more useful for patients who lack language and the BRSD more sensitive to apathy and depression.

Delirium in Alzheimer disease.

Advanced age and dementia are well-known risk factors for delirium, and most studies of delirium have concentrated on hospitalized populations. We reviewed the records of 199 community-dwelling Alzheimer disease (AD) patients and identified 43 (22%) who had had episodes of delirium during their dementing illness. These patients were matched for age, gender, and disease duration to AD patients without previous episodes of delirium. Variables examined included causes of delirium, Mini-Mental State Examination scores, Clinical Dementia Rating scores. Blessed Activities of Daily Living (ADL) scores, years of education, neuropsychological performance, and incidence of behavioral symptoms on the Brief Psychiatric Rating Scale. In six of 198 (3%) patients delirium was an initial symptom of AD. Conditions associated with onset of delirium were urinary tract infections, stressful events, surgery, medical illnesses, and medications. No significant differences were found between groups on neuropsychological testing. Patients with previous episodes of delirium had worse ADL scores and higher disease-course incidences of hallucinations and paranoid delusions, mostly occurring during the delirious episode. We conclude that delirium is common in AD, but it is an unusual initial symptom and it occurs in diverse clinical settings. Measures of behavioral symptoms and ADLs are more likely to reflect the impact of delirium on clinical status than measures of cognition or stage of dementia.

Assessing patterns of agitation in Alzheimer's disease patients with the Cohen-Mansfield Agitation Inventory. The Alzheimer's Disease Cooperative Study.

As part of the effort of the NIA Alzheimer's disease cooperative study to develop improved instruments for quantifying effects in Alzheimer's disease (AD) clinical trials, patterns of agitated behaviors were evaluated with the Cohen-Mansfield Agitation Inventory (CMAI) in 241 AD patients and 64 healthy elderly controls with valid baseline assessment on the CMAI. The test-retest reliability of the CMAI over 1 month was good (r = 0.74 to 0.92). Physically and verbally nonaggressive behaviors were most often reported, whereas physically aggressive behaviors were rare. Frequency of agitated behaviors increased with dementia severity, especially for patients with a Mini-Mental Status Exam score of 0-4. Agitation tended to increase in the evening with dementia severity for the more impaired patients. Amount of agitation did increase after 12 months in all but controls and mildly demented patients. The CMAI shows promise for evaluating a unique aspect of behavior and may be useful in assessing the effects of cognitive enhancers and other types of psychotropic drugs on behavior in dementia patients.

Evaluation of risk factors for Alzheimer's disease in elderly east Africans.

A number of biological risk factors have been implicated for Alzheimer's disease (AD). The investigation of prevalence rates of AD in crosscultural populations has much potential in validating these factors. We previously assessed brain amyloid beta (A beta) protein deposition and other lesions associated with AD as possible markers for preclinical AD in elderly nondemented East Africans. In further analysis, we demonstrate that 17-19% of elderly East African subjects without clinical neurological disease exhibited neocortical A beta deposits and minimal neurofibrillary changes at necropsy that was qualitatively and quantitatively similar to that in an age-matched elderly control sample from Cleveland, OH. A beta deposits varied from numerous diffuse to highly localized neuritic plaques and were predominantly reactive for the longer A beta 42 species. In parallel studies, we evaluated another recently implicated factor in AD, the apolipoprotein E genotype. We found relatively high frequencies of the apolipoprotein E-epsilon 4 allele in elderly nondemented East Africans. The frequencies were comparable to those in other African populations but higher than in subjects from developed countries. Our limited study suggests that elderly East Africans acquire cerebral lesions found in AD subjects but the apolipoprotein E-epsilon 4 allele may not be a highly specific factor for the disease among East Africans.

Apolipoprotein E polymorphism in elderly east Africans.

Current advances have shown the apolipoprotein E (APOE)-epsilon 4 allele to be highly associated with late-onset familial and sporadic Alzheimer's disease (AD) in Western populations. The association of APOE allele frequencies and dementia remain unknown in populations from developing countries. We recently initiated a project to examine APOE frequencies in non-demented and demented elderly East Africans. Blood DNA collected from two hospital-based populations showed that the APOE allele frequencies in a group of non-demented 67 Tanzanians over the age of 65 years were found to be 14% for epsilon 2, 61% for epsilon 3 and 25% for epsilon 4. By comparison, the frequency of APOE-epsilon 4 in an age-matched demented group was also 25%. Assessment of APOE genotypes in the group of elderly Kenyan subjects from Nairobi also revealed high frequencies of the epsilon 4 allele with no clear difference in frequency between demented and non-demented subjects. Our preliminary observations suggest that elderly East Africans with no apparent clinical AD possess relatively high APOE-epsilon 4 allele frequencies compared to normal ageing subjects from Western countries including African-Americans. These results appear similar to those reported in a recent study in Nigerian Africans where a lack of correlation between APOE-epsilon 4 allele frequency and Alzheimer type of dementia was noted, and imply that APOE-epsilon 4 allele may not necessarily be a risk factor in some populations of Africa.

Measures of psychiatric symptoms in Alzheimer patients: a review.

This review of instruments for the identification and quantification of psychiatric symptoms in Alzheimer disease (AD) is intended as a reference source for clinicians and researchers concerned with evaluating, quantifying, and managing psychiatric symptoms in AD. We review 16 clinician- and caregiver-rated scales selected from >30 scales on the basis of their face validity, their psychometric properties, the frequency of their use, and their promise as assessment instruments. Instruments are described in terms of the population on which they were developed, the symptoms assessed, informant, by whom administered, time to administer, time interval covered, number of items, measurement of frequency and severity, assessment of impact on caregiver, reliability, validity, and scoring. Recommendations are made concerning the best use of each scale. We summarize in table form the sources of information for instruments, characteristics of the instruments by domain, and potential use of instruments for quantification or management of symptoms and for estimation of caregiver burden. There are a number of reliable and valid scales for the assessment of psychiatric symptoms in AD, each with specific assets and liabilities. Knowledge of the specifics of these scales will enable clinicians and researchers to select the best instruments for their particular needs and to design more effective instruments.

Clinical and neuropsychological differences between patients with earlier and later onset of Alzheimer's disease: A CERAD analysis, Part XII.

To determine whether the age of the onset of Alzheimer's disease (AD) is related to the expression and rate of decline of this disorder, we examined the clinical and neuropsychological performance of 421 patients entered into the Consortium to Establish a Registry for Alzheimer's Disease and followed annually for up to 4 years. Statistical analyses were based on multivariable logistic regression analysis for dichotomous clinical measures and multivariable linear regression analysis for psychometric measures. All analyses examined the effect of age after controlling for gender, education, and stage of dementia. Clinical information obtained on entry into the study indicated that younger patients performed more poorly on measures of language and concentration, and older patients performed more poorly on measures of memory and orientation. On neuropsychological measures at entry, younger patients, performed more poorly on praxis and had significantly higher scores of confrontation naming. Younger age predicted a significantly faster rate of progression for all neuropsychological measures. These findings support the concept of age-related clinical subtypes of AD.

The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part XI. Clinical milestones in patients with Alzheimer's disease followed over 3 years.

The rate of cognitive decline, measured by psychometric testing, is widely used to track the progression of Alzheimer's disease (AD). As an alternative approach, we studied clinical measures as markers of the progression of dementia in 343 community-dwelling patients with probable AD enrolled in the multi-center Consortium to Establish a Registry for Alzheimer's Disease (CERAD) project. Subjects received standardized evaluations at entry and at annual follow-up. Decline on the Clinical Dementia Rating, loss of instrumental activities of daily living, failure to recall three words on the Mini-Mental State Examination (MMSE), and decline of the total MMSE score to below 10 were high-risk milestones, with cumulative frequencies exceeding 50% at 3 years. Loss of dressing and toileting activities occurred at intermediate rates, while loss of eating ability was rare. The risk of reaching clinical milestones and the annual rate of cognitive decline on the MMSE were directly correlated. Clinical milestones are useful indices of the progression of dementia in patients with AD.

The factor structure of the Brief Psychiatric Rating Scale in Alzheimer's disease.

The factor structure of the Brief Psychiatric Rating Scale (BPRS) is well established with young psychiatric patients. A study by Overall and Beller showed, however, that its factor structure was different with geropsychiatric patients. Although the BPRS has been used in assessing the behavioral characteristics of patients with probable Alzheimer's disease (AD), its factor structure has not been established with these patients. The present study investigated the factor structure of the BPRS among patients with clinically diagnosed AD by (NINCDS/ADRDA) criteria. The scale had limited usefulness with outpatients with mild AD. The factor structure obtained was similar to that found with other patient groups, but a unique factor, including the items Tension and Uncooperativeness, probably reflects the behavioral and psychological agitation characteristic of some AD patients. We recommend caution be taken in generalizing data from younger psychiatric samples to older adult patients with dementia.

Neuropsychology and Alzheimer's disease.

This article discusses the usefulness of neuropsychological testing in AD, as an adjunct to the diagnosis, as a means of the evaluation of progression, and response to treatment. Clinical neuropsychological tests that have direct relevance to AD are reviewed, with particular emphasis on recently developed tests of memory function.