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BACKGROUND Acetylcholinesterase inhibitors (AChEIs) and memantine are commonly prescribed medications for Alzheimer's disease (AD). Their concurrent use in AD randomized clinical trials (RCTs) is generally allowed but their effect in outcome measures is unsettled. OBJECTIVE To evaluate whether use of AChEIs and/or memantine across AD RCTs are associated with different rates of cognitive/functional decline. METHODS We pooled data from 5 RCTs of mild to moderate AD conducted by the Alzheimer's Disease Cooperative Study (ADCS) between 2002-2013. 1,423 participants with MMSE of 14-26 and completion of 12-18 months follow-up visits were analyzed. Trials did not randomize with respect to AChEIs or memantine. We defined 4 groups: AChEI (27%), memantine (16%), AChEIs+memantine (46%), and non-users (11%). Outcome measures were change in ADAS-cog-11, ADCS-ADL, and MMSE from baseline to 18 months. Fisher's exact test, Wilcoxon signed rank, and Spearman's tests were used to identify confounding variables. Mixed model repeated measures were used for adjustments and pairwise tests for comparing change in scores. RESULTS Age, apolipoprotein E, and initial MMSE were identified as covariates. Memantine and/or AChEIs users had greater impairment at entry than non-users. There was a significant decline on the ADAS-cog-11 in the memantine (estimate -4.2 p

The assessment of change over time is an important health issue: it is a way of testing new medical treatments and of investigating the natural courses of aging and disease. Of considerable import and interest in clinical research is the definition of “clinically meaningful” change. The definition of clinically meaningful change is challenged on at least two fronts, one statistical and the other clinical. Statistically, there are two important problems associated with measuring change. First, there are limits to the amount of change possible when scores or ratings at the first of two timepoints in question are very high or very low. This differential sensitivity to change due to extreme scores is a characteristic of many assessment instruments, and it makes interpretation of some change scores impossible. Second is the issue of the reliability of the raw change score. Several authors1–3 have argued that the errors associated with measurements at each timepoint greatly complicate the computation, interpretation, and subsequent testing of change scores. Clinical impediments to defining meaningful change arise because (1) there is little information available on the performance of control populations on many instruments and (2) there is little information on the longitudinal use of many instruments and the types of changes to be expected (although see Green et al.4). An example of a domain in which measuring change over time is important but difficult is behavioral problems arising during the course of Alzheimer’s disease (AD). There are many different tests being used to study various aspects of behavioral symptoms in AD; however, the relationship between changes on any two of these tests is unknown. Complicating interpretation of change on behavioral measures is the finding of waxing and waning4 or recurrence5 of behavioral symptoms, rather than sustained change, in persons with AD. Rasmusson and colleagues6 reviewed concisely several mechanisms for defining cognitive changes in AD. In commenting on the issue of predicting decline, the assumption is that decline will be the only change. This assumption is valid over the very long term, but a substantial proportion of AD patients may remain stable or show cognitive improvement over a 12-month period. The distribution of cognitive change in the short term can also cover the spectrum from improvement through no change to worsening.7 Similarly, no-change, worsening, and improving have all been observed with different behavioral measures in studies of persons with AD.4,8,9 There are clearly many contingencies and difficulties in defining change in behavioral symptoms, as well as in other domains. Although degenerative disease inevitably results in decline, truly sustained change in AD, especially behavioral change, may be observed only over very long periods of study. Therefore, change scores observed in clinical trials may not be unidirectional. It would be helpful to have a simple way of characterizing change over the short or long term. Another impediment to defining change is that on many instruments, change in the total score has no fixed meaning. Currently, no norms exist for the behavior assessment instruments used widely in research of patients with AD, such as the Behavior Rating Scale for Dementia (BRSD)10 and the Cohen-Mansfield Agitation Inventory (CMAI),11 although standardization data are available for the BRSD from a large sample of individuals with AD.12,13 Statistical means to assess change in behavioral symptom frequency do exist,3 but mapping clinical meaning on to a statistically significant change over a study period is not straightforward.14,15 Only the actual quantification of change is required to determine differences in change across treatment groups, but this approach may lead to the identification of a treatment as effective when the actual change, while statistically significant, is clinically meaningless.16 Therefore, this study sought to qualify change in an effort to differentiate clinically meaningful change from fluctuation and, at the same time, identify stability (no change) caused by the absence of symptoms from that caused by the continued presence of symptoms. Bereiterl points out that the unreliability of change scores comes from the respective unreliabilities of test scores at times 1 and 2 (echoed by Overall and Woodward2). To increase the reliability of a change score, Bereiter proposed focusing analysis on the item level. The model described here follows from this proposal by computing change on a per-item basis and then qualifying this change to facilitate the decision as to whether the observed change is clinically meaningful. In order to define clinically meaningful change, with the example of a behavioral measurement for persons with AD, we defined the types of changes we expect to carry the most clinical meaning based on the possible changes we can observe between two visits. We classified changes depending on whether the symptom never appeared, emerged, disappeared, increased or decreased in frequency, or remained at a constant level over 1 year. To test this approach, we applied it to changes in the reported frequencies of the specific behaviors assessed in the BRSD over 12 months in a group of well characterized AD patients living in the community. The BRSD total and subscores, as well as each item, have well established validity and reliability.9,10,12,13.

The Clinical Dementia Rating (CDR) is a valid and reliable global measure of dementia severity. Diagnosis and transition across stages hinge on its consistent administration. Reports of CDR ratings reliability have been based on one or two test cases at each severity level; agreement (kappa) statistics based on so few rated cases have large error, and confidence intervals are incorrect. Simulations varied the number of test cases, and their distribution across CDR stage, to derive the sample size yielding a 95% confidence that estimated kappa is at least .60. We found that testing raters on five or more patients per CDR level (total N=25) will yield the desired confidence in estimated kappa, and if the test involves greater representation of CDR stages that are harder to evaluate, at least 42 ratings are needed. Testing newly-trained raters with at least five patients per CDR stage will provide valid estimation of rater consistency given the point estimate for kappa is roughly .80; fewer test cases increases the standard error and unequal distribution of test cases across CDR stages will lower kappa and increase error.

This study estimates the prevalence of depressed mood in caregivers of individuals with mild cognitive impairment (MCI) and assesses whether demographics, stressors, intrapsychic strain, and gain are associated with depressed mood. A secondary analysis of baseline data from the Alzheimer's Disease Cooperative Study MCI trial was conducted using a cross-sectional, correlational design. Descriptive statistics to estimate the prevalence of caregiver depressed mood and univariate and block-wise logistic regression analyses were used. The prevalence of depressed mood in 769 caregivers was 24.6% (95% confidence interval, 21.5-27.7). The odds of being depressed were significantly higher in younger, nonspousal caregivers with less education, who cared for MCI patients with lower activities of daily living functioning, and who perceived greater relational deprivation, higher levels of self-loss, and personal gain. Controlling for relevant variables, relational deprivation and caregiver education continued to be significantly associated with depressed mood. Relational deprivation may be important for future interventions.

The validity and reliability of clinic-based and telephone-based versions of a 4 word delayed recall test were evaluated in nondemented elderly individuals (n=644) participating in a simulated primary prevention clinical trial. There was no significant difference in the average scores achieved by participants tested in clinic (mean=3.40) or by telephone (mean=3.47) and the 2 groups had similar distributions of scores. Delayed recall scores were significantly, but weakly, correlated with scores on a rigorous verbal memory task, were lower in participants in Clinical Dementia Rating stage 0.5 than in those in Clinical Dementia Rating stage 0, and were lower in those with subjective memory complaints than in those without complaints. There was only fair correspondence between scores achieved at initial testing and 3 months later for both versions of the test. There were no differences in the average scores achieved by men or women, those older (age 80 to 93) or younger (age 75 to 79) than age 80, or those with white or nonwhite ethnicity. Participants with low education scored significantly lower than those with high education. Results suggest that clinic-based and telephone-based versions of the Four Word Delayed Recall Test are valid and reliable and can be used to screen for possible memory deficits in elderly individuals. However, the psychometric properties of the test are relatively weak and do not support the general use of the test for clinical and research purposes if the use of a more rigorous memory test with a wider range of possible scores is feasible.

Objective: To evaluate the feasibility of longitudinal assessment and the psychometric properties of both established and new outcome measures used in clinical trials of patients with dementia in a cohort of Spanish-speaking elders in the United States. Methods: This is a prospectively collected multicenter study comparing patients with Alzheimer disease (AD) (N = 77) and elderly controls (N = 17) who are primary Spanish speakers. Spanish-speaking individuals with AD (SSI AD) were selected to represent predefined categories of impairment as determined by a Mini-Mental State Examination score. Controls were selected to approximately match by age and education (SSI C). Subjects were administered a series of Spanish translations of established outcome measures (Mini-Mental State Examination, Clinical Dementia Rating, Geriatric Dementia Scale), and Functional Assessment Staging (FAST)] and new outcome measures developed for United States in clinical trials to assess cognition, function, behavioral disturbance, and clinical global change. Half of the subjects were assessed at 1 and 2 months to evaluate reliability; all subjects were assessed at 6 and 12 months. Comparisons were made between patients and controls and between the Spanish-speaking cohort and a similar English-speaking cohort. Results: The 12-month completion rate was 77%, with a trend toward greater impairment in those with full retention. Both established and new measures demonstrated good internal consistency and test-retest reliability in this cohort. All but one measure of cognition demonstrated excellent discriminability between AD subjects and controls. The SSI AD cohort declined significantly on measures of cognition, function, and clinical global change over the 12-month assessment period. The SSI AD and English AD (ESI AD) cohorts declined equivalently on the most common outcomes in clinical trials of AD (delayed recall, clinical global change). Likewise, the most common behavioral changes were also similar in the ESI and SSI groups. However, the annual change was lower in SSI AD than in the ESI AD on several other measures of cognition and function. Conclusions: These results support the recruitment of Spanish-speaking patients and the use of Spanish language translations for use in the clinical trials for AD.

The vitamin E and donepezil trial for the treatment of amnestic mild cognitive impairment (MCI) was conducted at 69 centers in North America; 24 centers participated in an MRI sub study. The objective of this study was to evaluate the effect of treatment on MRI atrophy rates; and validate rate measures from serial MRI as indicators of disease progression in multi center therapeutic trials for MCI. Annual percent change (APC) from baseline to follow-up was measured for hippocampus, entorhinal cortex, whole brain, and ventricle in the 131 subjects who remained in the treatment study and completed technically satisfactory baseline and follow-up scans. Although a non-significant trend toward slowing of hippocampal atrophy rates was seen in APOE is an element of 4 carriers treated with donepezil; no treatment effect was confirmed for any MRI measure in either treatment group. For each of the four brain atrophy rate measures, APCs were greater in subjects who converted to AD than non-converters, and were greater in APOE is an element of 4 carriers than non-carriers. MRI APCs and changes in cognitive test performance were uniformly correlated in the expected direction (all p0.000). Results of this study support the feasibility of using MRI as an outcome measure of disease progression in multi center therapeutic trials for MCI.

Background The Prevention Instrument project of the Alzheimer's Disease Cooperative Study (ADCS) seeks to develop instruments to assess treatment efficacy including potential economic benefit. The Resource Use Inventory (RUI) is an instrument that has been used to capture resource utilization and costs in populations with Alzheimer disease (AD). However, resource utilization and costs for healthy, cognitively intact elderly as they begin to demonstrate cognitive deterioration are not well understood. In addition, the loss that relates to the subjects' own time as they transition through cognitive impairment is not well documented. Objectives To evaluate the utility of the RUI in a sample of cognitively intact elderly individuals living in the community and enrolled in AD prevention trials. Methods The RUI was administered to 644 subjects and their study partners either at home or in the clinic. For half of each sample, 3-month retesting was carried out. The RUI consisted of 9 questions. The first part of the RUI captured subjects' use of direct medical care (eg, hospitalizations) and nonmedical care (eg, home health aides). The second part of the RUI captured the time caregivers spend providing care to the subjects. The third part of the RUI captured subjects' participation in volunteer work and employment. The assessment interval for each question was the past 3 months. Results The percentage of RUI forms returned incomplete or inaccurate for both in-clinic and at-home groups was extremely low. There were no differences in utilization rates between in-clinic and at-home group for all items in the RUI. Except for use of outpatient procedures, tests, or treatments, there were no differences in utilization rates between subjects who filled out the RUI with the help of their study partners or by themselves. Items in the RUI were sensitive to subjects' cognitive and functional status and demographic characteristics. Conclusions Home-based completion of the RUI by participants in an AD prevention study is feasible, and seems to provide data that are reliable and valid. The instrument will be useful for tracking resource and time use through transition from healthy to cognitive impairment.