Search

BackgroundThe COVID-19 pandemic disrupted Alzheimer disease randomized clinical trials (RCTs)forcing investigators to make changes in the conduct of such trials while endeavoring to maintain their validity. Changing ongoing RCTs carries risks for biases and threats to validity. To understand the impact of exigent modifications due to COVID-19 we examined several scenarios in symptomatic and disease modification trials that could be made.MethodsWe identified both symptomatic and disease modification Alzheimer disease RCTs as exemplars of those that would be affected by the pandemic and considered the types of changes that sponsors could make to each. We modeled three scenarios for each of the types of trialsusing existing datasets, adjusting enrollment, follow-ups, and dropouts to examine the potential effects COVID-19-related changes.Simulations were performed that accounted for completion and dropout patterns using linear mixed effects models, modeling time as continuous and categorical. The statistical power of the scenarios was determined.ResultsTruncating both symptomatic and disease modification trials, led to underpowered trials.By contrast, adapting the trials byextending the treatment period, temporarily stopping treatment, delaying outcomes assessments, and performing remote assessment allowed for increased statistical power nearly to the level originally planned.DiscussionThese analyses support the idea that disrupted trials under common scenarios are better continued and extended even in the face of dropouts, treatment disruptions, missing outcomes, and other exigencies, and that adaptations can be made that maintain the trials validity. We suggest some adaptive methods to do this noting that some changes become under-powered to detect theoriginal effect sizes and expected outcomes. These analyses provide insight to better plan trials that are resilient to unexpected changes to the medical, social, and political milieu.

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

Objective. In preclinical reproductive studies, leflunomide was found to be embryotoxic and teratogenic. Women treated with leflunomide are advised to avoid pregnancy; those who become pregnant are advised to reduce fetal exposure through a cholestyramine drug elimination procedure. The present study was undertaken to investigate pregnancy outcomes in women who received leflunomide and were treated with cholestyramine during pregnancy. Methods. Sixty-four pregnant women with rheumatoid arthritis (RA) who were treated with leflunomide during pregnancy (95.3% of whom received cholestyramine), 108 pregnant women with RA not treated with leflunomide, and 78 healthy pregnant women were enrolled in a prospective cohort study between 1999 and 2009. Information was collected via interview of the mothers, review of medical records, and specialized physical examination of infants. Results. There were no significant differences in the overall rate of major structural defects in the exposed group (3 of 56 live births [5.4%]) relative to either comparison group (each 4.2%)(P 0.13). The rate was similar to the 3–4% expected in the general population. There was no specific pattern of major or minor anomalies. Infants in both the leflunomideexposed and non–leflunomide-exposed RA groups were born smaller and earlier relative to infants of healthy mothers; however, after adjustment for confounding factors, there were no significant differences between the leflunomide-exposed and non–leflunomide-exposed RA groups. Conclusion. Although the sample size is small, these data do not support the notion that there is a substantial increased risk of adverse pregnancy outcomes due to leflunomide exposure among women who undergo cholestyramine elimination procedure early in pregnancy. These findings can provide some reassurance to women who inadvertently become pregnant while taking leflunomide and undergo the washout procedure.

Patients with Alzheimer's Disease (AD) who have reached a stage of moderate to severe dementia are capable of completing a restricted range of cognitive tests and performing a limited range of activities of daily living (ADL). As part of an initiative to develop instruments to evaluate AD, we analyzed data describing the performance of a large number of ADL and scores on cognitive and global assessment measures in a cohort of patients with AD with moderate to severe cognitive impairment, defined as a Mini-Mental State Examination score ranging from 0–15 (out of 30). From the large pool of ADL, 19 met criteria of applicability, reliability, good scaling, concordant validity, and sensitivity to detect change in performance over 6–12 months. A total score derived from these 19 ADL ratings, comprising a scale termed the Alzheimer Disease Cooperative Study ADL-sev, correlated strongly with measures of cognition and of global dementia severity. Patients with moderate to severe AD showed a decline on the ADL-sev and cognitive measures over 6 and 12 months, consistent with the progression of AD. Detailed evaluation of ADL may provide a useful index to evaluate patients with moderate to severe AD and may complement cognitive assessment, especially for characterizing change in interventional or therapeutic studies. (JINS, 2005,11, 446–453.)

We explored the applicability of the standard scoring of the Cohen-Mansfield Agitation Inventory (CMAI), a widely used nursing-home derived instrument, to community-dwelling persons with Alzheimer's disease (AD). Item responses to the CMAI were gathered from participants in two large clinical studies, one of which specifically included patients with behavioral disturbances. Confirmatory factor analysis in these two groups of well-characterized AD patients suggested that conventional CMAI subscoring did not adequately describe the responses of these two groups. Exploratory factor analysis indicated that the four CMAI subscores, based on a verbal-physical and aggressive-non-aggressive conceptualization of behavioral disturbance, did not fit community dwelling persons with AD. Based on cross-sectional and longitudinal analyses, there was suggestive evidence for three behavioral clusters, but these clusters did not achieve statistical significance Overall, the CMAI seemed best suited to describe the overall level rather than the specific subtypes of behavioral dyscontrol in community-dwelling persons with AD.

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.

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.

In a longitudinal, multicenter study of 4,954 men at risk for human immunodeficiency virus infection and acquired immunodeficiency syndrome, data from the first 9.5 years of follow-up (April 1984 through September 1993) were used to determine differences between those who remained in the study and those who dropped out. Demographic variables (age, race, education, employment, and study center), health status (human immunodeficiency virus type 1 serostatus and depression), and behavioral characteristics (alcohol drinking, drug use, and anal-receptive intercourse) were analyzed. Strategies for promoting retention included having frequent contact with participants, generating trust, keeping participants well-informed, utilizing multiple resources for follow-up, and providing flexible methods of participation. After 9.5 years of follow-up, vital status was known for 4,385 (88.5%) of the participants. Results from multiple logistic regression showed that race, age, education, and smoking were each significantly associated with nonparticipation (p < 0.001). A high level of retention was maintained in this well-educated and highly motivated cohort of homosexual/bisexual men. Extensive follow-up methods may improve case-finding. Nonwhite race, younger age, less education, and smoking were important predictors of dropping out. These findings identify specific groups for targeting follow-up efforts to reduce potential bias due to dropout.

Spasticity is a common and poorly controlled symptom of multiple sclerosis. Our objective was to determine the short-term effect of smoked cannabis on this symptom.We conducted a placebo-controlled, crossover trial involving adult patients with multiple sclerosis and spasticity. We recruited participants from a regional clinic or by referral from specialists. We randomly assigned participants to either the intervention (smoked cannabis, once daily for three days) or control (identical placebo cigarettes, once daily for three days). Each participant was assessed daily before and after treatment. After a washout interval of 11 days, participants crossed over to the opposite group. Our primary outcome was change in spasticity as measured by patient score on the modified Ashworth scale. Our secondary outcomes included patients' perception of pain (as measured using a visual analogue scale), a timed walk and changes in cognitive function (as measured by patient performance on the Paced Auditory Serial Addition Test), in addition to ratings of fatigue.Thirty-seven participants were randomized at the start of the study, 30 of whom completed the trial. Treatment with smoked cannabis resulted in a reduction in patient scores on the modified Ashworth scale by an average of 2.74 points more than placebo (p0.0001). In addition, treatment reduced pain scores on a visual analogue scale by an average of 5.28 points more than placebo (p = 0.008). Scores for the timed walk did not differ significantly between treatment and placebo (p = 0.2). Scores on the Paced Auditory Serial Addition Test decreased by 8.67 points more with treatment than with placebo (p = 0.003). No serious adverse events occurred during the trial.Smoked cannabis was superior to placebo in symptom and pain reduction in participants with treatment-resistant spasticity. Future studies should examine whether different doses can result in similar beneficial effects with less cognitive impact.

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.

Blood levels of homocysteine may be increased in Alzheimer disease (AD) and hyperhomocysteinemia may contribute to disease pathophysiology by vascular and direct neurotoxic mechanisms. Even in the absence of vitamin deficiency, homocysteine levels can be reduced by administration of high-dose supplements of folic acid and vitamins B(6) and B(12). Prior studies of B vitamins to reduce homocysteine in AD have not had sufficient size or duration to assess their effect on cognitive decline.To determine the efficacy and safety of B vitamin supplementation in the treatment of AD.A multicenter, randomized, double-blind controlled clinical trial of high-dose folate, vitamin B(6), and vitamin B(12) supplementation in 409 (of 601 screened) individuals with mild to moderate AD (Mini-Mental State Examination scores between 14 and 26, inclusive) and normal folic acid, vitamin B(12), and homocysteine levels. The study was conducted between February 20, 2003, and December 15, 2006, at clinical research sites of the Alzheimer Disease Cooperative Study located throughout the United States.Participants were randomly assigned to 2 groups of unequal size to increase enrollment (60% treated with high-dose supplements [5 mg/d of folate, 25 mg/d of vitamin B(6), 1 mg/d of vitamin B(12)] and 40% treated with identical placebo); duration of treatment was 18 months.Change in the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-cog).A total of 340 participants (202 in active treatment group and 138 in placebo group) completed the trial while taking study medication. Although the vitamin supplement regimen was effective in reducing homocysteine levels (mean [SD], -2.42 [3.35] in active treatment group vs -0.86 [2.59] in placebo group; P.001), it had no beneficial effect on the primary cognitive measure, rate of change in ADAS-cog score during 18 months (0.372 points per month for placebo group vs 0.401 points per month for active treatment group, P = .52; 95% confidence interval of rate difference, -0.06 to 0.12; based on the intention-to-treat generalized estimating equations model), or on any secondary measures. A higher quantity of adverse events involving depression was observed in the group treated with vitamin supplements.This regimen of high-dose B vitamin supplements does not slow cognitive decline in individuals with mild to moderate AD.clinicaltrials.gov Identifier: NCT00056225.

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.

Background Individuals diagnosed as having mild cognitive impairment (MCI) have a high likelihood of progressing to dementia within 3 to 5 years, but not all individuals with MCI progress to dementia. Prognostic uncertainty suggests the need for additional measures to assist the clinician. Objective To assess the added value of qualitative measures of medial temporal atrophy (MTA) to estimate the relative risk of progressing from MCI to dementia. Design A 3-year, double-blind, placebo-controlled Alzheimer's Disease Cooperative Study initially designed to evaluate the efficacy of donepezil hydrochloride or vitamin E vs placebo to delay progression of MCI to dementia. Setting Memory assessment centers. Patients A total of 190 individuals with MCI. Main Outcome Measures Ratings of MTA performed using magnetic resonance images obtained at baseline. Log-rank tests and Cox proportional hazards ratios examining the significance of MTA estimates in predicting progression of MCI to dementia. Results A mean MTA score greater than 2.0 was associated with a greater than 2-fold increased likelihood of progression to dementia during the observation period (hazards ratio, 2.30; 95% confidence interval, 1.09-4.92; P = .03) after controlling for age, education, sex, and baseline Mini-Mental State Examination score. Conclusions Adjusted estimates of MTA were associated with significantly increased risk of developing dementia within 3 years, suggesting that obtaining a magnetic resonance image during the evaluation of MCI may offer additional independent information about the risk of progression to dementia. Given the relatively high prevalence of MCI in the general population, use of this method as part of routine clinical evaluation may help identify individuals who might benefit from increased surveillance and future treatment. Trial Registration clinicaltrials.gov Identifier:NCT00000173.

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.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.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.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.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.

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 Mild cognitive impairment is a transitional state between the cognitive changes of normal aging and early Alzheimer’s disease. methods In a double-blind study, we evaluated subjects with the amnestic subtype of mild cognitive impairment. Subjects were randomly assigned to receive 2000 IU of vitamin E daily, 10 mg of donepezil daily, or placebo for three years. The primary outcome was clinically possible or probable Alzheimer’s disease; secondary outcomes were cognition and function. results A total of 769 subjects were enrolled, and possible or probable Alzheimer’s disease developed in 212. The overall rate of progression from mild cognitive impairment to Alzheimer’s disease was 16 percent per year. As compared with the placebo group, there were no significant differences in the probability of progression to Alzheimer’s disease in the vitamin E group (hazard ratio, 1.02; 95 percent confidence interval, 0.74 to 1.41; P=0.91) or the donepezil group (hazard ratio, 0.80; 95 percent confidence interval, 0.57 to 1.13; P=0.42) during the three years of treatment. Prespecified analyses of the treatment effects at 6-month intervals showed that as compared with the placebo group, the donepezil group had a reduced likelihood of progression to Alzheimer’s disease during the first 12 months of the study (P=0.04), a finding supported by the secondary outcome measures. Among carriers of one or more apolipoprotein E e 4 alleles, the benefit of donepezil was evident throughout the three-year follow-up. There were no significant differences in the rate of progression to Alzheimer’s disease between the vitamin E and placebo groups at any point, either among all patients or among apolipoprotein E e 4 carriers. conclusions Vitamin E had no benefit in patients with mild cognitive impairment. Although donepezil therapy was associated with a lower rate of progression to Alzheimer’s disease during the first 12 months of treatment, the rate of progression to Alzheimer’s disease after three years was not lower among patients treated with donepezil than among those given placebo.

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.

To estimate the incidence rate and predictors of seizures in patients with mild to moderate Alzheimer disease (AD).Cohort study of patients with mild to moderate AD in clinical trials. Risk factors for potential seizures were evaluated by stratified descriptive statistics and univariable and multivariable Cox proportional hazards regressions.Pooled patient-level data from 10 Alzheimer Disease Cooperative Study clinical trials in mild to moderate AD from 1995 to 2010.Three thousand seventy-eight subjects randomized to the treatment or placebo arms of 10 AD clinical trials. Screening Mini-Mental State Examination scores ranged between 10 and 28.Eighteen seizures were reported in 3078 randomized subjects, with an incidence rate of 484 per 100 000 person-years (95% CI, 287-764). Statistically significant independent risk factors for seizure were younger age (adjusted hazard ratio, 0.80; 95% CI, 0.69-0.93 per every 5 years of age), greater cognitive impairment at baseline (adjusted hazard ratio, 2.79; 95% CI, 1.06-7.33 for Mini-Mental State Examination scores18 compared with Mini-Mental State Examination scores ≥18), and antipsychotic use at baseline (adjusted hazard ratio, 3.47; 95% CI, 1.33-9.08).Seizure rates in patients with mild to moderate AD in clinical trials are similar to rates observed in longer observational cohort studies, but they are greater than expected in the general elderly population. Younger age, greater degree of cognitive impairment, and history of antipsychotic use were independent risk factors for new-onset seizures in AD.

Background Mild cognitive impairment (MCI) represents a transitional state between the cognitive changes of normal aging and very early dementia and is becoming increasingly recognized as a risk factor for Alzheimer disease (AD). The Memory Impairment Study (MIS) is a multicenter clinical trial in patients with MCI designed to evaluate whether vitamin E or donepezil is effective at delaying the time to a clinical diagnosis of AD. Objective To describe the baseline characteristics of patients with MCI recruited for the MIS and compare them with those of elderly controls and patients with AD in another clinical trial. Design Descriptive and comparative study of patients with MCI participating in a multicenter clinical trial. Setting Memory disorder centers in the United States and Canada. Patients A total of 769 patients with MCI, 107 cognitively normal elderly controls, 122 patients with very mild AD (Clinical Dementia Rating [CDR] 0.5), and 183 patients with mild AD (CDR 1.0) were evaluated. Patients in the MIS met operational criteria for amnestic MCI. Controls were recruited in parallel with the MCI group, underwent the same assessments, and had a CDR of 0. Main Outcome Measures Clinical, neuropsychologic, functional, neuroimaging, and genetic measures. Results Mean ± SD Alzheimer's Disease Assessment Scale–Cognitive Subscale scores were 5.6 ± 3.3 for controls, 11.3 ± 4.4 for patients with MCI, 18.0 ± 6.2 for the AD CDR 0.5 group, and 25.2 ± 8.8 for the AD CDR 1.0 group. Compared with controls, patients with MCI were most impaired on memory tasks, with less severe impairments in other cognitive domains. Patients with MCI were more likely than controls but less likely than patients with AD to carry the apolipoprotein E ϵ4 allele. Patients with MCI had hippocampal volumes that were intermediate between those of controls and patients with AD. Conclusions Patients with MCI had a predominant memory impairment with relative sparing of other cognitive domains and were intermediate between clinically normal individuals and patients with AD on cognitive and functional ratings. These results demonstrate the successful implementation of operational criteria for this unique group of at-risk patients in a multicenter clinical trial.

ContextLaboratory evidence that inflammatory mechanisms contribute to neuronal injury in Alzheimer disease (AD), along with epidemiological evidence, suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) may favorably influence the course of the disease.ObjectiveTo determine whether treatment with a selective cyclooxygenase (COX) -2 inhibitor (rofecoxib) or a traditional nonselective NSAID (naproxen) slows cognitive decline in patients with mild-to-moderate AD.DesignMulticenter, randomized, double-blind, placebo-controlled, parallel group trial, with 1-year exposure to study medications.SettingForty ambulatory treatment centers affiliated with the Alzheimer's Disease Cooperative Study consortium.ParticipantsParticipants with mild-to-moderate AD (Mini-Mental State Examination score of 13-26) were recruited from December 1999 to November 2000 using clinic populations, referrals from community physicians, and local advertising. Stable use of cholinesterase inhibitors, estrogen, low-dose aspirin, and vitamin E was allowed. Participants with inflammatory diseases that might respond to the study medications were excluded. Of 474 participants screened, 351 were enrolled.InterventionsOnce-daily rofecoxib, 25 mg, or twice-daily naproxen sodium, 220 mg, or placebo.Main Outcome MeasuresThe primary outcome measure was the 1-year change in the Alzheimer Disease Assessment Scale-Cognitive (ADAS-Cog) subscale score. Secondary outcome measures included the Clinical Dementia Rating scale sum-of-boxes, the Neuropsychiatric Inventory, the Quality of Life-AD, and the time to attainment of significant end points (4-point decline from baseline ADAS-Cog score, 1-step worsening on the global Clinical Dementia Rating scale, 15-point decline on the ADCS activities of daily living inventory, institutionalization, or death).ResultsThe 1-year mean (SD) change in ADAS-Cog scores in participants treated with naproxen (5.8 [8.0]) or rofecoxib (7.6 [7.7]) was not significantly different from the change in participants treated with placebo (5.7 [8.2]). Results of secondary analyses showed no consistent benefit of either treatment. Fatigue, dizziness, and hypertension were more commonly reported in the active drug groups, and more serious adverse events were found in the active treatment group than in the placebo group.ConclusionThe results of this study indicate that rofecoxib or low-dose naproxen does not slow cognitive decline in patients with mild-to-moderate AD.

ContextSeveral reports from small clinical trials have suggested that estrogen replacement therapy may be useful for the treatment of Alzheimer disease (AD) in women.ObjectiveTo determine whether estrogen replacement therapy affects global, cognitive, or functional decline in women with mild to moderate AD.DesignThe Alzheimer's Disease Cooperative Study, a randomized, double-blind, placebo-controlled clinical trial conducted between October 1995 and January 1999.SettingThirty-two study sites in the United States.ParticipantsA 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.InterventionsParticipants 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 MeasuresThe 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.ResultsThe 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).ConclusionsEstrogen 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.