Shelia Jin

High-Dose B Vitamin Supplementation and Cognitive Decline in Alzheimer Disease: A Randomized Controlled Trial

CONTEXT 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. OBJECTIVE To determine the efficacy and safety of B vitamin supplementation in the treatment of AD. DESIGN, SETTING, AND PATIENTS 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. INTERVENTION 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. MAIN OUTCOME MEASURE Change in the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-cog). RESULTS 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. CONCLUSION This regimen of high-dose B vitamin supplements does not slow cognitive decline in individuals with mild to moderate AD. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00056225.

Longitudinal MRI findings from the vitamin E and Donepezil treatment study for MCI

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 p<0.000). Results of this study support the feasibility of using MRI as an outcome measure of disease progression in multi center therapeutic trials for MCI.

Detailed assessment of activities of daily living in moderate to severe Alzheimer's disease.

Patients with Alzheimers 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.

Smoked cannabis for spasticity in multiple sclerosis: a randomized, placebo-controlled trial

Background: 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. Methods: 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. Results: 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 (p < 0.0001). 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. Interpretation: 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.

Incidence of New-Onset Seizures in Mild to Moderate Alzheimer Disease

OBJECTIVE To estimate the incidence rate and predictors of seizures in patients with mild to moderate Alzheimer disease (AD). DESIGN 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. SETTING Pooled patient-level data from 10 Alzheimer Disease Cooperative Study clinical trials in mild to moderate AD from 1995 to 2010. PATIENTS 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. RESULTS 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 scores <18 compared with Mini-Mental State Examination scores ≥18), and antipsychotic use at baseline (adjusted hazard ratio, 3.47; 95% CI, 1.33-9.08). CONCLUSIONS 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.

Depressed Mood in Informal Caregivers of Individuals With Mild Cognitive Impairment

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 Alzheimers 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.

Assessing Alzheimer's disease patients with the Cohen-Mansfield Agitation Inventory: scoring and clinical implications

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 Alzheimers 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.

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 Alzheimers 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.

The Spanish instrument protocol: Design and implementation of a study to evaluate treatment efficacy instruments for Spanish-speaking patients with Alzheimer's disease

Development of improved outcome measures for Alzheimers disease (AD) clinical trials is a major objective of the Alzheimers Disease Cooperative Study (ADCS), an NIA-sponsored, multisite clinical trials consortium. The ADCS is committed to recruiting and following minority patients in clinical trials. At present, a serious impediment to recruiting non-English-speaking minorities is the lack of instruments with adequate translation. Because Spanish is the second most commonly spoken language in the United States and because persons of Hispanic origin represent approximately 10% of the population, we conducted an instrument development protocol for Spanish-speaking patients. Evaluating treatment efficacy in Spanish-speaking AD patients requires the development of assessments that are comparable to those used for English-speaking participants in clinical trials. The ADCS Instrument Development Project evaluated the sensitivity, reliability, and validity of new or improved measures in each of five assessment domains: (a) cognition (immediate and delayed memory, praxis, attention, and executive function); (b) clinical global change; (c) activities of daily living; (d) behavioral symptoms (agitation and other noncognitive symptoms); and (e) cognition in severely impaired patients. These new treatment efficacy instruments were translated for Spanish speakers and a Spanish Instrument Study was conducted in parallel with the English version of the study. This report describes instrument translation, entry criteria, and recruitment procedures. In addition, the demographic and clinical characteristics of the cohort at baseline are presented and compared to the English-speaking cohort. Implications for the development of comparably sensitive Spanish language instruments are discussed.

Sample Size Requirements for Training to a κ Agreement Criterion on Clinical Dementia Ratings

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 1 or 2 test cases at each severity level; agreement (κ) 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 is at least 0.60. We found that testing raters on 5 or more patients per CDR level (total N=25) will yield the desired confidence in estimated κ, 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 5 patients per CDR stage will provide valid estimation of rater consistency, given the point estimate for κ is roughly 0.80; fewer test cases increases the standard error and unequal distribution of test cases across CDR stages will lower κ and increase error.