Weight-Based Teasing and Metabolic Syndrome Components among Adolescent Military Dependents at Risk for Adult Obesity.

Background: Among adults, weight stigma is associated with markers of poor cardiometabolic health. Although weight-based teasing (WBT) is common among youth with high body weight, few studies have examined its associations with cardiometabolic markers. Owing to unique stressors (e.g., parental deployment and frequent moves), military-dependent youth may be at particularly high risk for obesity, WBT, and poor cardiometabolic health. We, therefore, assessed associations between WBT and cardiometabolic health markers among adolescent military dependents presenting for a weight gain prevention trial. Methods: Participants underwent fasting phlebotomy; had fasting weight, height, and waist circumference measured; and completed assessments of WBT, anxiety, and loss-of-control eating. Multivariate analysis of covariance, adjusting for relevant covariates including demographics and body composition, was used to examine differences in metabolic syndrome (MetS) components (waist circumference, systolic and diastolic blood pressure, high-density lipoprotein cholesterol, triglycerides, and glucose) between youth reporting WBT and youth reporting no WBT. Bootstrapped models examined whether WBT mediated the relationship between BMIz and MetS components. Results: Data from 142 youth (57.7% female; 14.4 ± 1.6 years; 51.2% non-Hispanic White, 20.9% non-Hispanic Black; BMIz: 1.9 ± 0.4) were analyzed. WBT was not significantly associated with any MetS component. Relationships were observed between BMIz and all MetS components (except systolic blood pressure and glucose), although WBT did not significantly mediate these relationships (p's > 0.05). Conclusions: This study did not find support for a relationship between WBT and MetS components in adolescent military dependents at risk for adult obesity. Prospective research is needed to determine whether associations between WBT and adverse cardiometabolic outcomes emerge primarily in adulthood.

Permanent change of station moves and disordered-eating attitudes and behaviors in prevention-seeking adolescent military-dependents.

OBJECTIVE: Military-dependent youth appear to be at greater risk for disordered-eating than their civilian counterparts. Permanent change of station moves (PCS-moves), typically occurring every 2-3 years, are commonly experienced by adolescent military-dependents. However, the links between PCS-moves and disordered-eating in this population have not been explored. We hypothesized that stress arising from PCS-moves may contribute to the development and/or exacerbation of disordered-eating. METHODS: One-hundred-forty-nine adolescent military-dependents with overweight or obesity (59.7% female; 46.3% non-Hispanic White; 14.4±1.5 years; BMI-z: 1.9±0.4) completed measures before commencing an adulthood obesity and binge-eating disorder prevention trial for adolescents at-risk for both conditions due to BMI percentile ≥85th and loss-of-control (LOC)-eating and/or elevated anxiety symptoms. Disordered-eating attitudes and LOC-eating were assessed by semi-structured interview, and emotional eating was self-reported. Adjusting for relevant covariates, multiple linear regressions examined the unique association of PCS-move frequency with disordered-eating attitudes and disinhibited-eating behaviors. RESULTS: PCS-move frequency was not significantly associated with either LOC-eating frequency (ß = 0.09, p = .27) or emotional eating (ß = -0.04, p = .62). However, PCS-move frequency was positively associated with disordered-eating attitudes (ß = 0.17, p = .04), which appeared to be primarily driven by shape concerns (ß = 0.21, p = .01). DISCUSSION: Findings indicate that frequency of PCS-moves is related to disordered-eating attitudes, but not behaviors. Longitudinal research is needed to understand if PCS-moves prospectively relate to the onset and/or exacerbation of disordered-eating, and the relevance of disordered-eating attitudes as opposed to disinhibited-eating behaviors.

Sex differences in metabolic syndrome components in adolescent military dependents at high-risk for adult obesity.

BACKGROUND: Metabolic syndrome in adolescence has been associated with adverse cardiometabolic outcomes in adulthood. Preliminary data suggest that boys may have worsened metabolic syndrome components compared to girls. Yet, little is known about the physical health of military dependents, a potentially at-risk population. OBJECTIVE: Examine sex differences in metabolic syndrome components in a sample of adolescent military dependents. METHODS: Participants were adolescents (N = 139; 14.4 ± 1.6 years; 45.3% male; 41.0% non-Hispanic White, 19.4% non-Hispanic Black; BMI-z: 1.9 ± 0.4) at-risk for adult obesity and binge-eating disorder due to an age- and sex-adjusted BMI ≥85th percentile and loss-of-control eating and/or elevated anxiety. A multivariate analysis of covariance was conducted to compare objectively measured metabolic syndrome components across boys and girls. Covariates were age, race, loss-of-control eating status, anxiety symptoms, and BMI-z. RESULTS: Metabolic syndrome components differed by sex (P = .01). Boys had higher systolic blood pressure (P = .049), lower high-density lipoprotein cholesterol (P = .01), and higher glucose (P = .001) than girls. Waist circumference, diastolic blood pressure, and triglycerides did not differ between boys and girls (P > .05). CONCLUSIONS: Future research should prospectively examine these relationships into adulthood. If the current findings are supported, prevention programs should consider targeting cardiometabolic health particularly among male adolescent military dependents.

Associations between Family Weight-Based Teasing, Eating Pathology, and Psychosocial Functioning among Adolescent Military Dependents.

Weight-based teasing (WBT) by family members is commonly reported among youth and is associated with eating and mood-related psychopathology. Military dependents may be particularly vulnerable to family WBT and its sequelae due to factors associated with their parents' careers, such as weight and fitness standards and an emphasis on maintaining one's military appearance; however, no studies to date have examined family WBT and its associations within this population. Therefore, adolescent military dependents at-risk for adult obesity and binge-eating disorder were studied prior to entry in a weight gain prevention trial. Youth completed items from the Weight-Based Victimization Scale (to assess WBT by parents and/or siblings) and measures of psychosocial functioning, including the Beck Depression Inventory-II, The Rosenberg Self-Esteem Scale, and the Social Adjustment Scale. Eating pathology was assessed via the Eating Disorder Examination interview, and height and fasting weight were measured to calculate BMIz. Analyses of covariance, adjusting for relevant covariates including BMIz, were conducted to assess relationships between family WBT, eating pathology, and psychosocial functioning. Participants were 128 adolescent military dependents (mean age: 14.35 years old, 54% female, 42% non-Hispanic White, mean BMIz: 1.95). Nearly half the sample (47.7%) reported family WBT. Adjusting for covariates, including BMIz, family WBT was associated with greater eating pathology, poorer social functioning and self-esteem, and more depressive symptoms (ps ≤ 0.02). Among military dependents with overweight and obesity, family WBT is prevalent and may be linked with eating pathology and impaired psychosocial functioning; prospective research is needed to elucidate the temporal nature of these associations.

Clinical meaningfulness of Alzheimer's Disease Assessment Scale-Cognitive subscale change in relation to goal attainment in patients on cholinesterase inhibitors.

INTRODUCTION: The clinical meaningfulness of Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) subscale change is disputed. We compared 2- to 4-point ADAS-Cog changes with changes in Goal Attainment Scaling (GAS) and everyday function across initial ADAS-Cog scores and treatment responses. METHODS: This exploratory analysis evaluated mild-moderate Alzheimer's disease patients treated with donepezil (12 months) or galantamine (8 months). Clinical meaningfulness was defined as concomitant ADAS-Cog and GAS changes of ±3 points and/or functional improvement. RESULTS: Patients with ≥3-point ADAS-Cog improvement significantly improved on GAS but not on standard tests of everyday function. ADAS-Cog "no change" (≤±3 points) was seen with mean GAS improvement. Initial ADAS-Cog improvement made endpoint improvement (ADAS-Cog 3 points and GAS 1 point) more likely (odds ratio = 6.9; 95% confidence interval = 2.5-19.5). In contrast, initial deterioration made endpoint improvement unlikely (0.33; 0.14-0.64). DISCUSSION: ADAS-Cog improvement and no change were each associated with GAS improvement. Initial ADAS-Cog worsening was unlikely to result in later improvement. CLINICAL TRIAL REGISTRATION NUMBER: ISRCTN26167328.

Resting-State Cardiac Workload is Related to Both Increased Neocortical Aggregation of Amyloid-ß and Relative Impairments in Spatial Working Memory in Pre-Clinical Alzheimer's Disease.

We sought to determine whether there is any association between a cardiac workload marker, rate pressure product (RPP), working memory, and cortical amyloid-ß (Aß) burden in 63 cognitively normal midlife adults (Mage = 62.8 years; range = 55 to 75 years) at risk for Alzheimer's disease (AD). The results show a small-to-moderate relationship between increasing cardiac workload (at rest) and neocortical amyloidosis in individuals at the preclinical stage of AD. Moreover, increasing RPP was linearly related to increasing relative impairments on a spatial working memory task (R2 = 0.30), but only for those individuals with neuroimaging evidence suggestive of preclinical AD. These results support a relationship between the aggregation of Aß protein plaques in the neocortex, increased cognitive impairment, and more inefficient myocardial oxygen use in the absence of significant metabolic demands.

Considerations for the assessment of suicidal ideation and behavior in older adults with cognitive decline and dementia.

INTRODUCTION: Better understanding of suicide risk and its management in older adults with cognitive impairment and/or dementia remain significant unmet public health needs. Urgency to address them derives from concern that CNS treatments for dementia may impact suicide risk. Regulatory guidances requiring assessment of emergent suicidal ideation and behavior (SI/SB) at every clinical trial visit emphasize the need for understanding their prevalence. METHODS: The literature regarding SI/SB in older persons with cognitive impairment or dementia was reviewed by an Alzheimer's Association Taskforce with emphasis on epidemiology, classification, assessment, and regulatory requirements. RESULTS: Gaps in our knowledge were identified, challenges discussed and recommendations for future work provided. DISCUSSION: Currently available SI/SB data from geriatric persons with dementia do not provide adequate understanding of its epidemiology, identification, assessment, or management. The growing public health burden of this population requires greater attention from clinicians and researchers on tactics and assessment tools to meet these needs.

Suicidal ideation and behavior assessment in dementia studies: An Internet survey.

INTRODUCTION: The AARR task force on suicidal ideation and behavior (SI/SB) in dementia conducted an online survey on the extent of SI/SB in individuals diagnosed with mild cognitive impairment (MCI) or dementia who were participating in clinical trials. METHODS: Investigators with experience in conducting SI/SB assessments in clinical trial subjects with MCI or dementia were invited to complete a global 19-item online survey. RESULTS: A total of 204 evaluable responses were collected with the majority from North America and Europe (83.4%) and the remainder from Asia, Latin America, and Mideast/Africa. The mean (SD) number of subjects personally assessed by the respondents in the past year with MCI, mild-moderate dementia, or severe dementia was 12.8 (26.2), 31.2 (39.6), and 10.1 (34.7), respectively. The mean number of subjects in each diagnostic group with suicidal ideation (SI), suicidal behavior (SB), or completed suicide (CS) was on average quite low (0.3 to 1.1 for SI, 0.1 to 0.2 for SB, and 0.0 to 0.2 for CS). Confidence in subject self-reports of SI/SB over different time periods declined with increasing severity of cognitive impairment and with increasing duration of the recall time period assessed. Of respondents, 56% and 75% had low confidence in self-ratings of SI/SB from subjects with severe dementia over the past 24 hours and the past week to 1 month, respectively. Ratings of the reliability of information collected on SI/SB also decreased with increasing severity of cognitive impairment. Approximately 70% of respondents rated the reliability of the information they obtained from all sources (patient, caregiver, and others) for subjects with MCI as high, but only about half (42.0% to 55.3%) and less than a quarter (17.4% to 24.3%) rated the reliability of information obtained for subjects with mild to moderate dementia or severe dementia as high, respectively. DISCUSSION: These results support the usefulness of prospective SI/SB assessments in MCI and mild dementia, raise questions about the reliability of assessments in moderate dementia, and confirm their lack of clinical utility in severe dementia. The results highlight the need for development of validated assessment instruments adapted to the stage of cognitive decline of the patients under study and may be the most effective in the earliest stages of the disease.

Disruption of cholinergic neurotransmission exacerbates Aß-related cognitive impairment in preclinical Alzheimer's disease.

Disruption in cholinergic neurotransmission is one of the earliest neuropathological changes in preclinical Alzheimer's disease (AD) and may be associated with abnormal beta-amyloid (Aß) accumulation. Therefore, disruption of cholinergic neurotransmission with scopolamine may unmask otherwise undetectable cognitive deficits in preclinical AD. To compare the effects of low-dose (0.20 mg s.c.) scopolamine on cognition between Aß+ and Aß- cognitively normal (CN) older adults using the Groton Maze Learning Test (GMLT). CN older adults completed the GMLT predose and then received scopolamine (0.20 mg) subcutaneously. Participants were reassessed 1-, 3-, 5-, 7-, and 8-hours post dose. All participants underwent positron emission tomography neuroimaging for Aß using (18)F-florbetapir within 6 weeks of their baseline visit. Rhode Island Hospital Clinical Research Center, Providence, USA. CN older adults (n = 63), with a family history of AD and subjective memory complaints were enrolled (15 were classified as Aß+ and 48 were classified as Aß-). Cognition was assessed using the computerized GMLT at all predose and post-dose time points. At 5-hours post dose, the Aß+ group performed significantly worse than the Aß- group on all measures of learning efficiency and working memory and/or executive function (Cohen's d = 1.13-1.56). When participants were classified as having an abnormal response to scopolamine (based on change score at 5-hours post dose >0), 100% were correctly classified as Aß+ and 67% as Aß-. The results of this study suggest that diminished cholinergic tone likely occurs in preclinical AD, and as such, the use of a cholinergic stress test to perturb an already compromised neurotransmitter system may be an effective way of identifying CN older adults who are in this preclinical stage of AD.

Assessing cognition and function in Alzheimer's disease clinical trials: do we have the right tools?

Several lines of evidence from Alzheimer's disease (AD) research continue to support the notion that the biological changes associated with AD are occurring possibly several decades before an individual will experience the cognitive and functional changes associated with the disease. The National Institute on Aging-Alzheimer's Association revised criteria for AD provided a framework for this new thinking. As a result of this growing understanding, several research efforts have launched or will be launching large secondary prevention trials in AD. These and other efforts have clearly demonstrated a need for better measures of cognitive and functional change in people with the earliest changes associated with AD. Recent draft guidance from the US Food and Drug Administration further elevated the importance of cognitive and functional assessments in early stage clinical trials by proposing that even in the pre-symptomatic stages of the disease, approval will be contingent on demonstrating clinical meaningfulness. The Alzheimer's Association's Research Roundtable addressed these issues at its fall meeting October 28-29, 2013, in Washington, D.C. The focus of the discussion included the need for improved cognitive and functional outcome measures for clinical of participants with preclinical AD and those diagnosed with Mild Cognitive Impairment due to AD.

2014 Report on the Milestones for the US National Plan to Address Alzheimer's Disease.

With increasing numbers of people with Alzheimer's and other dementias across the globe, many countries have developed national plans to deal with the resulting challenges. In the United States, the National Alzheimer's Project Act, signed into law in 2011, required the creation of such a plan with annual updates thereafter. Pursuant to this, the US Department of Health and Human Services (HHS) released the National Plan to Address Alzheimer's Disease in 2012, including an ambitious research goal of preventing and effectively treating Alzheimer's disease by 2025. To guide investments, activities, and the measurement of progress toward achieving this 2025 goal, in its first annual plan update (2013) HHS also incorporated into the plan a set of short, medium and long-term milestones. HHS further committed to updating these milestones on an ongoing basis to account for progress and setbacks, and emerging opportunities and obstacles. To assist HHS as it updates these milestones, the Alzheimer's Association convened a National Plan Milestone Workgroup consisting of scientific experts representing all areas of Alzheimer's and dementia research. The workgroup evaluated each milestone and made recommendations to ensure that they collectively constitute an adequate work plan for reaching the goal of preventing and effectively treating Alzheimer's by 2025. This report presents these Workgroup recommendations.

Microdosing of scopolamine as a "cognitive stress test": rationale and test of a very low dose in an at-risk cohort of older adults.

BACKGROUND: Abnormal ß-amyloid (Aß) is associated with deleterious changes in central acetylcholinergic tone in the very early stages of Alzheimer's disease (AD), which may be unmasked by a cholinergic antagonist. We aimed to establish an optimal "microdose" of scopolamine for the development of a "cognitive stress test." METHODS: Healthy older adults (n = 26, aged 55-75 years) with two risk factors for AD, but with low cortical Aß burden, completed the Groton Maze Learning Test (GMLT) at baseline and then received scopolamine (0.20 mg subcutaneously). Participants were reassessed at 1, 3, 5, 7, and 8 hours postinjection. RESULTS: There were significant differences, of a moderate magnitude, in performance between baseline and 3 hours postinjection for total errors, rule break errors, and the GMLT composite (d ≈ 0.50) that were all unrelated to body mass. CONCLUSIONS: A very low dose of scopolamine leads to reliable cognitive impairment at 3 hours postdose (Tmax) and full cognitive recovery within 5 hours, supporting its use as a prognostic test paradigm to identify individuals with potential preclinical AD. This paradigm is being implemented in a larger cohort of healthy adults, with high or low Aß, to identify pharmacodynamic differences between groups.

Revisiting the framework of the National Institute on Aging-Alzheimer's Association diagnostic criteria.

In 2011, the National Institute on Aging and the Alzheimer's Association (NIA-AA) proposed revising the criteria for diagnosing Alzheimer's disease (AD), which had been established more than 25 years earlier by the National Institute on Neurologic and Communicative Disorders and Stroke (NINCDS) and the Alzheimer's Disease and Related Disorders Association (ADRDA), now called the Alzheimer's Association. The NIA-AA initiative also built upon research criteria for AD proposed by the International Working Group (IWG) in 2007 and updated in 2010. These efforts to revise the criteria reflect the need to improve diagnostic accuracy, facilitate clinical trials, and establish a common set of criteria that are universally accepted across domains of clinical practice, research, and drug development. To ensure that the proposed NIA-AA criteria remain as current as possible, the Alzheimer's Association Research Roundtable convened a meeting in Washington, DC, on October 1 and 2, 2012, bringing together international stakeholders from industry, academia, and regulatory agencies to identify areas of agreement and research gaps respective of NIA-AA criteria and IWG recommendations.

Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer's Association Research Roundtable Workgroup.

Amyloid imaging related abnormalities (ARIA) have now been reported in clinical trials with multiple therapeutic avenues to lower amyloid-ß burden in Alzheimer's disease (AD). In response to concerns raised by the Food and Drug Administration, the Alzheimer's Association Research Roundtable convened a working group to review the publicly available trial data, attempts at developing animal models, and the literature on the natural history and pathology of related conditions. The spectrum of ARIA includes signal hyperintensities on fluid attenuation inversion recoverysequences thought to represent "vasogenic edema" and/or sulcal effusion (ARIA-E), as well as signal hypointensities on GRE/T2* thought to represent hemosiderin deposits (ARIA-H), including microhemorrhage and superficial siderosis. The etiology of ARIA remains unclear but the prevailing data support vascular amyloid as a common pathophysiological mechanism leading to increased vascular permeability. The workgroup proposes recommendations for the detection and monitoring of ARIA in ongoing AD clinical trials, as well as directions for future research.

Global issues in drug development for Alzheimer's disease.

The number of clinical trials for Alzheimer's disease conducted outside the United States in a broad array of countries is increasing. As the number of compounds ready for clinical testing increases, and as trials become longer and more complex, this trend is expected to grow. The cultural and ethical context of global clinical trials, potential benefits for those involved, and practical approaches to obstacles generated by these global trials were discussed at a meeting of the Alzheimer's Association Research Roundtable. Regulatory issues, including regional differences in study registration procedures, rules for collecting and reporting serious adverse events, requirements for national identity of study populations, and regulatory audits were also discussed by individuals who are knowledgeable about global clinical trials for Alzheimer's disease.

Predicting cognitive decline in Alzheimer's disease: an integrated analysis.

BACKGROUND: Numerous patient- and disease-related factors increase the risk of rapid cognitive decline in patients with Alzheimer's disease (AD). The ability of pharmacological treatment to attenuate this risk remains undefined. METHODS: Pooled data from 14 randomized clinical studies of donepezil in the treatment of AD (N = 3748) were analyzed to identify predictors of fast decline and determine the effect of donepezil on the risk of fast decline. RESULTS: Young age and more severe baseline cognitive, global, or behavioral status were identified as independent predictors of faster decline in placebo-treated patients. Multivariate models indicated that donepezil treatment was associated with a 39% to 63% reduction in the risk of faster decline. CONCLUSIONS: These results correspond with previous findings, indicating relationships between age or baseline disease severity and rates of cognitive decline. Furthermore, they suggest that symptomatic therapy for AD could reduce the likelihood of faster decline in treated patients.

Effects of donepezil on activities of daily living: integrated analysis of patient data from studies in mild, moderate and severe Alzheimer's disease.

BACKGROUND: We aimed to develop a standardization method to pool data recorded on different activities of daily living (ADL) scales in order to reduce variability of functional outcome data from Alzheimer's disease (AD) clinical trials and to better evaluate the effect of donepezil treatment on function in patients with AD. METHODS: Based on pre-specified criteria, six studies were selected from among all donepezil clinical trials in AD. Individual items from nine ADL scales used in these trials were mapped to a standardized functional scale comprising 12 domains (six basic, six instrumental); scores were transformed to a 0-100 scale. External validation of this scale yielded a concordance rate of 90.8%. For each domain, mean change from baseline to 24 weeks in the placebo and donepezil groups was compared for the total population and for subgroups stratified by baseline disease severity. Study settings included outpatient, assisted living, and skilled nursing facilities. Participants comprised 2183 patients (donepezil, 1261; placebo; 922) with baseline Mini-mental State Examination (MMSE) scores 5-26. RESULTS: Significant treatment differences favoring donepezil were observed for five items (two instrumental and three basic). Patients with moderate AD at baseline (MMSE 10-17) demonstrated the greatest treatment effect. CONCLUSION: Functional data were successfully pooled using standardizing methodology. A beneficial effect of donepezil treatment on function was demonstrated using this standardized functional scale. Similar analyses from studies with other anti-dementia drugs may help to determine the generalizability of these findings and potentially encourage use of functional assessment as a clinical tool.

Randomized, placebo-controlled, clinical trial of donepezil in vascular dementia: differential effects by hippocampal size.

BACKGROUND AND PURPOSE: We sought to assess the efficacy and safety of donepezil in patients with vascular dementia (VaD) fulfilling National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l'Enseignement en Neurosciences criteria. METHODS: This international, multicenter, 24-week trial was conducted from March 2003 to August 2005. Patients (N=974; mean age, 73.0 years) with probable or possible VaD were randomized 2:1 to receive donepezil 5 mg/d or placebo. Coprimary outcome measures were scores on the Vascular-Alzheimer Disease Assessment Scale-Cognitive Subscale and Clinician's Interview-Based Impression of Change, plus carer interview. Analyses were performed for the intent-to-treat population with the last-observation-carried-forward method. RESULTS: Compared with placebo, donepezil-treated patients showed significant improvement from baseline to end point on the Vascular-Alzheimer Disease Assessment Scale-Cognitive Subscale (least-squares mean difference, -1.156; 95% CI, -1.98 to -0.33; P<0.01) but not on the Clinician's Interview-Based Impression of Change, plus carer interview. Patients with hippocampal atrophy who were treated with donepezil demonstrated stable cognition versus a decline in the placebo-treated group; in those without atrophy, cognition improved with donepezil versus relative stability with placebo. Results on secondary efficacy measures were inconsistent. The incidence of adverse events was similar across groups. Eleven deaths occurred in the donepezil group (1.7%), similar to rates previously reported for donepezil trials in VaD, whereas no deaths occurred in the placebo group. CONCLUSIONS: Patients treated with donepezil 5 mg/d demonstrated significant improvement in cognitive, but not global, function. Donepezil was relatively well tolerated; adverse events were consistent with current labeling. Mortality in the placebo group was unexpectedly low. The differential treatment response of VaD patients by hippocampal size suggests that hippocampal imaging warrants further investigation for understanding VaD.

The long-term efficacy and tolerability of donepezil in patients with vascular dementia.

OBJECTIVE: To determine the long-term tolerability and efficacy of donepezil in patients with vascular dementia (VaD). METHODS: International, multicentre, open-label, 30-week extension study of two 24-week, randomised, double-blind, placebo-controlled studies. Participants were ambulatory adults (59% female; mean age, 74.7 +/- 0.3) with a diagnosis of possible or probable VaD and without a diagnosis of Alzheimer's disease, who were medically stable and had completed one of two double-blind studies. All patients received donepezil 5 mg/day for the first 6 weeks, then 10 mg/day (clinician approval required). Assessments were performed at week 6 and every 12 weeks thereafter. The main outcome measure was the Alzheimer's disease Assessment Scale-cognitive subscale (ADAS-cog). Safety/tolerability measures included adverse events (AEs) and physical and laboratory evaluations. RESULTS: Of 1219 eligible patients, 885 (72.6%) were enrolled, of which 707 (79.9%) completed the study; 127 (14.4%) patients discontinued due to AEs. A mean reduction (0.6-1.15 points) from double-blind study baseline score to week 54 (end of open-label study) on the ADAS-cog was observed for patients who received donepezil continuously for 54 weeks. ADAS-cog scores remained stable in the group that initiated donepezil treatment during the extension study. Most common donepezil-related AEs were nausea (occurring in 5.3%) and diarrhoea (8.8%); no unexpected AEs attributable to donepezil occurred. CONCLUSION: These data suggest that donepezil improves cognition for up to 54 weeks in patients with VaD. Patients initiating donepezil in this extension study did not perform as well on the primary outcome measure as those initiating donepezil in the double-blind study.