Tracking early decline in cognitive function in older individuals at risk for Alzheimer disease dementia: the Alzheimer's Disease Cooperative Study Cognitive Function Instrument.

IMPORTANCE: Several large-scale Alzheimer disease (AD) secondary prevention trials have begun to target individuals at the preclinical stage. The success of these trials depends on validated outcome measures that are sensitive to early clinical progression in individuals who are initially asymptomatic. OBJECTIVE: To investigate the utility of the Cognitive Function Instrument (CFI) to track early changes in cognitive function in older individuals without clinical impairment at baseline. DESIGN, SETTING, AND PARTICIPANTS: Longitudinal study from February 2002 through February 2007 at participating Alzheimer's Disease Cooperative Study sites. Individuals were followed up annually for 48 months after the baseline visit. The study included 468 healthy older individuals (Clinical Dementia Rating scale [CDR] global scores of 0, above cutoff on the modified Mini-Mental State Examination and Free and Cued Selective Reminding Test) (mean [SD] age, 79.4 [3.6] years; age range, 75.0-93.8 years). All study participants and their study partners completed the self and partner CFIs annually. Individuals also underwent concurrent annual neuropsychological assessment and APOE genotyping. MAIN OUTCOMES AND MEASURES: The CFI scores between clinical progressors (CDR score, ≥0.5) and nonprogressors (CDR score, 0) and between APOE ε4 carriers and noncarriers were compared. Correlations of change between the CFI scores and neuropsychological performance were assessed longitudinally. RESULTS: At 48 months, group differences between clinical progressors and non-progressors were significant for self (2.13, SE=0.45, P<.001), partner (5.08, SE=0.59, P<.001), and self plus partner (7.04, SE=0.83, P<.001) CFI total scores. At month 48, APOE ε4 carriers had greater progression than noncarriers on the partner (1.10, SE=0.44, P<.012) and self plus partner (1.56, SE=0.63, P<.014) CFI scores. Both self and partner CFI change were associated with longitudinal cognitive decline (self, ρ=0.32, 95% CI, 0.13 to 0.46; partner, ρ=0.56, 95% CI, 0.42 to 0.68), although findings suggest self-report may be more accurate early in the process, whereas accuracy of partner report improves when there is progression to cognitive impairment. CONCLUSIONS AND RELEVANCE: Demonstrating long-term clinical benefit will be critical for the success of recently launched secondary prevention trials. The CFI appears to be a brief, but informative potential outcome measure that provides insight into functional abilities at the earliest stages of disease.

White matter tract integrity metrics reflect the vulnerability of late-myelinating tracts in Alzheimer's disease.

Post-mortem and imaging studies have observed that white matter (WM) degenerates in a pattern inverse to myelin development, suggesting preferential regional vulnerabilities influencing cognitive decline in AD. This study applied novel WM tract integrity (WMTI) metrics derived from diffusional kurtosis imaging (DKI) to examine WM tissue properties in AD within this framework. Using data from amnestic mild cognitive impairment (aMCI, n = 12), AD (n = 14), and normal control (NC; n = 15) subjects, mixed models revealed interaction effects: specific WMTI metrics of axonal density and myelin integrity (i.e. axonal water fraction, radial extra-axonal diffusivity) in late-myelinating tracts (i.e. superior and inferior longitudinal fasciculi) changed in the course of disease, but were stable in the initial stages for early-myelinating tracts (i.e. posterior limb of the internal capsule, cerebral peduncles). WMTI metrics in late-myelinating tracts correlated with semantic verbal fluency, a cognitive function known to decline in AD. These findings corroborate the preferential vulnerability of late-myelinating tracts, and illustrate an application of WMTI metrics to characterizing the regional course of WM changes in AD.

Language impairment in Alzheimer's disease and benefits of acetylcholinesterase inhibitors.

Alzheimer's disease is characterized by progressively worsening deficits in several cognitive domains, including language. Language impairment in Alzheimer's disease primarily occurs because of decline in semantic and pragmatic levels of language processing. Given the centrality of language to cognitive function, a number of language-specific scales have been developed to assess language deficits throughout progression of the disease and to evaluate the effects of pharmacotherapy on language function. Trials of acetylcholinesterase inhibitors, used for the treatment of clinical symptoms of Alzheimer's disease, have generally focused on overall cognitive effects. However, in the current report, we review data indicating specific beneficial effects of acetylcholinesterase inhibitors on language abilities in patients with Alzheimer's disease, with a particular focus on outcomes among patients in the moderate and severe disease stages, during which communication is at risk and preservation is particularly important.

Age and apolipoprotein E genotype influence rate of cognitive decline in nondemented elderly.

OBJECTIVE: This study examined the impact of age and apolipoprotein E (APOE) genotype on the rate of cognitive decline in nondemented elderly participants in a simulated Alzheimer's disease (AD) primary prevention treatment trial carried out by the Alzheimer's Disease Cooperative Study. METHOD: Cognitive tests were administered at baseline and at four subsequent annual evaluations to 417 nondemented participants (172 men, 245 women) between the ages of 74 and 93 (M = 79.13 ± 3.34). APOE genotyping was available for 286 of the participants. RESULTS: Four-year decline was evident on measures of orientation, memory, executive function, and language. Faster decline was evident in APOE ε4+ (a genetic risk factor for AD; n = 73) than in ε4- participants (n = 213), even after controlling for education, gender, ethnicity, and baseline functional and cognitive abilities. This discrepancy increased with age, indicating an Age × Genotype interaction. CONCLUSION: These results are consistent with population-based studies, and extend the findings to a carefully screened sample that meets inclusion and exclusion criteria for an AD primary prevention trial. The interaction between age and APOE genotype on rate of decline suggests that preclinical disease may be overrepresented in older ε4+ individuals. Thus, APOE genotype and age should be considered in the design of AD primary prevention treatment trials.

Health-related resource use and costs in elderly adults with and without mild cognitive impairment.

OBJECTIVES: To assess differences in resource use and cost between older adults with and without mild cognitive impairment (MCI) over time. DESIGN: Multicenter, longitudinal study. SETTING: Sixty-eight Alzheimer's Disease Cooperative Study (ADCS) sites in the United States. PARTICIPANTS: Two hundred fifty-nine individuals diagnosed with MCI and 107 cognitively normal elderly adults followed annually for 3 years. MEASUREMENTS: The Resource Use Instrument (RUI) was used to capture medical and nonmedical care use. Generalized linear latent and mixed models were used to estimate differences in resource use and costs in older adults with and without MCI after controlling for clinical and demographic characteristics. RESULTS: At baseline, average annual direct medical cost per person was substantially higher for participants with MCI ($6,499) than for those without ($2,969) P < .001). Informal care use was also substantially higher (33% vs 8.4%, P < .001). Results from multivariate analyses of longitudinal data show that, after controlling for participant and informant characteristics, direct medical costs were 44% higher for participants with MCI than for those without. Participants with MCI were almost five times as likely to use informal care as those without. Number of medical conditions and older age were associated with higher medical cost. Worse functional and cognitive status, older age, being married, and being female were associated with higher likelihood of informal care use. Having an adult child informant was associated with higher likelihood of using informal care. CONCLUSION: The RUI captured differences in resource use and costs between individuals with and without MCI. Clinicians who care for individuals with MCI should address informal care needs early in the disease course.

Identifying amnestic mild cognitive impairment in primary care: a feasibility study.

BACKGROUND AND OBJECTIVE: Amnestic mild cognitive impairment (aMCI), characterized by episodic memory impairment in the absence of clinical dementia, often represents a transitional stage between normal aging and Alzheimer's disease (AD). It is not known if non-expert primary-care physicians (PCPs) can differentiate individuals with no cognitive impairment (NCI), aMCI and mild AD in a primary-care practice setting. This study develops an approach to this question, which is necessary for aMCI to become a treatment target. METHODS: Fourteen experts assessed subjects with memory complaints in terms of their laboratory test results, magnetic resonance imaging findings and scores on the Mini-Mental State Examination, adapted Clinical Dementia Rating Scale and Alzheimer's Disease Assessment Scale-cognitive subscale Delayed Word Recall before designating each subject as having NCI, aMCI or AD. Subjects agreed upon by a consensus committee were assigned to non-expert PCPs who, following brief training, assessed them using the same clinical information and utilizing the same assessment instruments. The chance-corrected inter-rater reliability (expert versus non-expert) measure κ, based on binary outcome (aMCI/not-aMCI), was estimated. RESULTS: The study recruited 119 evaluable subjects (50 aMCI, 27 mild AD and 42 NCI) and demonstrated fair to moderate agreement (κ = 0.423) between experts and non-experts in designation of aMCI. The percent agreement was 72.3%, sensitivity 62.0% and specificity 79.7%. Overall, non-experts under-rated the level of impairment compared with experts. CONCLUSION: This study established the feasibility of making the aMCI designation in the community and identified some likely sources of error. The results suggest that when drugs with clear benefit for aMCI patients are developed, community-based PCPs, with additional, more optimized training, will be able to accurately identify those patients who should receive treatment.

Analyzing the impact of 23 mg/day donepezil on language dysfunction in moderate to severe Alzheimer's disease.

INTRODUCTION: Progressive language impairment is among the primary components of cognitive decline in Alzheimer's disease (AD). Because expressive and receptive language help to maintain emotional connections to caregivers and support the management of AD patients' functional needs, language plays a critical role in patients' emotional and physical health. Using data from a large prospective clinical trial comparing two doses of donepezil in patients with moderate to severe AD, we performed a post hoc analysis to determine whether a higher dose of donepezil was associated with greater benefits in language function. METHODS: In the original randomized, double-blind clinical trial, 1,467 patients with moderate to severe AD (baseline Mini-Mental State Examination (MMSE) score 0 to 20) were randomized 2:1 to receive donepezil 23 mg/day or to continue on donepezil 10 mg/day for 24 weeks. In this post hoc analysis, the Severe Impairment Battery-Language scale (SIB-L) and a new 21-item SIB-derived language scale (SIB[lang]) were used to explore differences in language function between the treatment groups. Correlations between SIB-L and SIB[lang] scores and scores on the severe version of the Alzheimer's Disease Cooperative Study-Activities of Daily Living inventory (ADCS-ADL-sev), the Clinician's Interview-Based Impression of Severity-plus caregiver input/Clinician's Interview-Based Impression of Change-plus caregiver input (CIBIS-plus/CIBIC-plus) and the MMSE were also investigated. RESULTS: At week 24, treatment with donepezil 23 mg/day was associated with an improvement in language in the full intention-to-treat population, whereas language function declined in the group treated with donepezil 10 mg/day (SIB-L treatment difference 0.8, P = 0.0013; SIB[lang] treatment difference 0.8, P = 0.0009). Similar results were observed in a cohort of patients with more severe baseline disease (MMSE score 0 to 16). At baseline and week 24, correlations between the SIB-derived language scales and the ADCS-ADL-sev and CIBIC-plus were moderate, but the correlations were stronger between the language scales and the MMSE scores. CONCLUSIONS: Patients with moderate to severe AD receiving donepezil 23 mg/day showed greater language benefits than those receiving donepezil 10 mg/day as measured by SIB-derived language assessments. Increasing the dose of donepezil to 23 mg/day may provide language benefits in patients with moderate to severe AD, for whom preservation of language abilities is especially critical.ClinicalTrials.gov identifier: NCT00478205.

Tramiprosate in mild-to-moderate Alzheimer's disease - a randomized, double-blind, placebo-controlled, multi-centre study (the Alphase Study).

INTRODUCTION: The aim of the study was to assess the clinical efficacy, safety, and disease-modification effects of tramiprosate (homotaurine, ALZHEMED(TM)) in mild-to-moderate Alzheimer's disease (AD). MATERIAL AND METHODS: Double-blind, placebo-controlled, randomized trial in 67 clinical centres across North America. Patients aged ≥ 50 years, with mild-to-moderate AD (Mini-Mental State Examination score between 16 and 26) and on stable doses of cholinesterase inhibitors, alone or with memantine. INTERVENTION: 78-week treatment with placebo, tramiprosate 100 mg or tramiprosate 150 mg BID. MEASUREMENTS: Alzheimer Disease Assessment Scale - cognitive subscale (ADAS-cog) and Clinical Dementia Rating - Sum of Boxes (CDR-SB) assessments were performed at baseline and every 13 weeks. Baseline and 78-week magnetic resonance imaging (MRI) hippocampus volume (HV) measurements were conducted in a subgroup of patients. RESULTS: A total of 1,052 patients were enrolled and 790 (75.1%) completed the 78-week trial. Patient discontinuation and reasons for withdrawal were similar across groups. Planned analyses did not reveal statistically significant between-group differences. Lack of adequate statistical validity of the planned analysis models led to the development of revised predictive models. These adjusted models showed a trend toward a treatment effect for ADAS-cog (P = 0.098) and indicated significantly less HV loss for tramiprosate 100 mg (P = 0.035) and 150 mg (P = 0.009) compared to placebo. The incidence of adverse events was similar across treatment groups. CONCLUSIONS: The primary planned analyses did not show a significant treatment effect, but were confounded by unexplained variance. Post-hoc analyses showed a significant treatment-related reduction in HV loss. However, there was only a trend towards slowing of decline on the ADAS-cog and no slowing of decline on the CDR-SB. These results must be interpreted in consideration of the limitations of clinical and disease-modification outcome measures and their relationship, the heterogeneity of the disease and the impact of confounding demographic and clinical variables.

Effects of rivastigmine transdermal patch and capsule on aspects of clinical global impression of change in Alzheimer's disease: a retrospective analysis.

BACKGROUND: The Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) scale is widely used in Alzheimer trials. It assesses cognition, activities of daily living (ADLs), behavior and global functioning. To advance the understanding of relationships between the ADCS-CGIC and scores from other commonly used tools, this analysis investigated the ability of each domain to measure change. This was a hypothesis-forming study, designed to provide a basis for possible future research. METHODS: This retrospective analysis used data from a 24-week, randomized, placebo-controlled trial [study ENA713D2320 (IDEAL)] that evaluated rivastigmine patches and capsules in AD patients. RESULTS: At week 24, significant treatment effects versus placebo were seen on the ADCS-CGIC cognitive domain with rivastigmine 17.4 mg/24 h patch (p < 0.01), 9.5 mg/24 h patch (p = 0.02) and capsules (p < 0.01); similarly on the ADCS-CGIC ADL domain. The cognition portion of the CGIC correlated with the Alzheimer's Disease Assessment Scale cognitive subscale and the ADL section with the ADCS-ADL trial measures. Variance ascribable to these tools was small, indicating that CGIC detects changes not measured by the domain-specific tools. CONCLUSIONS: The results of this post hoc analysis suggest that the ADCS-CGIC accurately reflects changes in cognitive and functional domains measured by other tools; it captures changes not assessed by domain-specific instruments. Cognitive alterations show greatest correlation with total CGIC. These results may assist in analyzing and interpreting CGIC results in other trials.

Evaluation of dementia rating scales in Parkinson's disease dementia.

Disease-specific assessments are not currently available for patients with Parkinson's disease dementia (PDD). This study evaluated the criterion-related validity and test-retest reliability of the Alzheimer's Disease Assessment scale cognitive subscale (ADAS-cog) in terms of sensitivity for differentiation between mild and moderate severity impairment in PDD. Six other dementia rating scales and cognitive tests were also examined. A total of 113 patients with PDD or Alzheimer disease were recruited into this 4-week, multicenter study, segregated into 2 severity groups based on Mini-Mental State Examination (MMSE) score. Mean ADAS-cog scores showed a statistically significant separation between mild and moderate severity patients in both dementias (P < .001). For the ADAS-cog, test-retest Spearman correlation coefficients were significant for each dementia type and severity. This study demonstrated the criterion-related validity and test-retest reliability for ADAS-cog in patients with PDD and strong correlations with MMSE. This supports the validity of previous results obtained with these measures in studies of patients with PDD.

Characteristics and performance of a modified version of the ADCS-CGIC CIBIC+ for mild cognitive impairment clinical trials.

INTRODUCTION: The Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) was modified for use in mild cognitive impairment (MCI) trials and tested in the ADCS MCI randomized clinical trial of donepezil, vitamin E, and placebo. We assessed feasibility for its use by determining whether or not: (1) it distinguished a medication effect at 6 months and 12 months, (2) baseline demographic or clinical characteristics predicted change, (3) there was an association between MCI-CGIC and change in other clinical measures in order to evaluate external or concurrent validity. METHODS: We used a generalized estimating equations approach for ordinal outcome data to test the effects of treatment, baseline characteristics, and change in clinical measures on the MCI-CGIC over 12 months, and ordinal logistic regression to assess the association between MCI-CGIC and change in clinical measures at 6 months and 12 months. RESULTS: On the MCI-CGIC overall, 12.9% and 10.6% were rated as having improved, and 31.6% and 39.8% as having worsened over 6 months and 12 months, respectively. The MCI-CGIC did not distinguish the donepezil or vitamin E groups from placebo at 6 and 12 months treatment. Variables at screening or baseline that were associated with worse CGIC scores over 6 and 12 months included white race, greater years of education, worse depression, dementia severity rating, cognitive, and daily activities scores, and lower memory domain scores on a neuropsychological battery. Rate of worsening on the MCI-CGIC over 12 months was associated with change on the Alzheimer Disease Assessment Scale-cognitive and on executive function. Worsening at 6 months and 12 months, separately, were associated with the corresponding change in Alzheimer Disease Assessment Scale-cognitive, Activities of Daily Living, Beck Depression Inventory, Mini-Mental State Examination, Clinical Dementia Rating sum of boxes, memory, and executive function. CONCLUSIONS: Change detected by the MCI-CGIC was associated with baseline clinical severity and with change in clinical ratings over 6 and 12 months, supporting the validity of a CGIC approach in MCI. The effect size of the donepezil-placebo difference was similar to that of other outcomes at 12 months. About 40% of MCI patients were judged worse and about 11% improved, consistent with clinical experience and other ratings.

Age-related non-Gaussian diffusion patterns in the prefrontal brain.

PURPOSE: To characterize age-related MR diffusion patterns of the prefrontal brain cortex microstructure using a new method for investigating the non-Gaussian behavior of water diffusion called diffusional kurtosis imaging (DKI). MATERIALS AND METHODS: Measures of mean diffusivity (MD), fractional anisotropy (FA) and mean kurtosis (MK) were compared in the prefrontal brain cortex of 24 healthy volunteers (adolescents, young adults, and elderly) ranging from age 13 to 85 years. A Mann-Whitney test was used to compare subject groups with respect to the diffusion measures, and linear regression was used to characterize the change in each diffusion measure as a function of age. RESULTS: We found significant age-related changes in the elderly adult group, with increase of MD and decrease of FA. CONCLUSION: The current study demonstrates distinct mean kurtosis patterns for different age-ranges, with significant age-related correlation for mean kurtosis (MK) and MK peak position, showing that diffusional kurtosis is able to characterize and measure age-related diffusion changes for both grey and white matter, in the developing and aging brain.

Synergistic effect of apolipoprotein E epsilon4 and butyrylcholinesterase K-variant on progression from mild cognitive impairment to Alzheimer's disease.

OBJECTIVE: To evaluate the synergistic effects of the apolipoprotein E (APOE) epsilon4 and butyrylcholinesterase K-variant (BCHE-K) alleles on progression to Alzheimer's disease (AD) in individuals with mild cognitive impairment (MCI). METHODS: This was a post-hoc exploratory analysis from a 3-4-year, randomized, placebo-controlled study of rivastigmine in participants with MCI (InDDEx study). Participants who consented to genetic testing were included in the current analyses. The incidence of progression to AD, cognitive decline and changes in MRI brain volumes were investigated in participants from the placebo arm of the InDDEx study. RESULTS: Of the 1018 participants in the overall study, 464 were successfully genotyped for both APOE and butyrylcholinesterase. Of these, 68 (14.7%) carried > or =1 APOE epsilon4 and > or =1 BCHE-K allele. The presence of APOE epsilon4 was associated with a significantly higher incidence of progression to AD whereas the presence of BCHE-K had no independent effect on progression. A synergistic effect of the combined presence of APOE epsilon4 and BCHE-K on the time to clinical diagnosis of AD and on MRI brain volumes was seen. Progression to AD and hippocampal volumetric loss was greatest in participants who carried both APOE epsilon4 and BCHE-K alleles and lowest in BCHE-K carriers without the APOE epsilon4 allele. CONCLUSION: In MCI, the risk of cognitive decline, hippocampal volumetric loss and progression to AD seems to be the greatest in individuals who carry at least one copy of both the BCHE-K and APOE epsilon4 alleles.

Rofecoxib in patients with mild cognitive impairment: further analyses of data from a randomized, double-blind, trial.

A recent clinical trial in patients with Mild Cognitive Impairment (MCI) found an increased rate of possible or probable Alzheimer's disease (AD) diagnoses in patients assigned to rofecoxib compared to placebo. This unexpected finding was difficult to interpret due to methodological issues and a lack of confirmation on secondary endpoints, as well as a lack of confirmation in trials in related populations. We performed additional post hoc analyses to explore explanations for the finding based on possible neuropathological, cardiovascular/cerebrovascular, or cognitive effects of rofecoxib. 1) Neuropathological hypothesis: Of the 189 incident cases of possible or probable AD, 154 were probable AD. In probable AD patients, the treatment hazard ratio was reduced compared to the primary analysis -- a concordant finding would have strengthened a conclusion that rofecoxib accelerated the underlying neuropathology of AD. The treatment hazard ratio was increased in the remaining 35 patients with less certain diagnoses, but there was no single predominant reason for the reduced certainty of diagnosis. 2) Cardiovascular hypothesis: Neither cardiovascular risk status nor mean arterial blood pressure had an overall effect on AD diagnosis or modified the treatment difference. 3) Cognitive side-effects hypothesis: The percentages of patients with non-specific NSAID-type central nervous system adverse events were similar between the treatment groups. In summary, the present analyses are limited by their post hoc nature but provided little support for any of the possible explanations explored. The significance of the observation that rofecoxib increased the rate of conversion from MCI to AD remains uncertain.

Mild cognitive impairment (MCI): a historical perspective.

Descriptions of dementia can be traced to antiquity. Prichard (1837) described four dementia stages and Kral (1962) described a "benign senescent forgetfulness" condition. The American Psychiatric Association's DSM-III (1980) identified an early dementia stage. In 1982, the Clinical Dementia Rating (CDR) and the Global Deterioration Scale (GDS) were published, which identified dementia antecedents. The CDR 0.5 "questionable dementia" stage encompasses both mild dementia and earlier antecedents. GDS stage 3 described a predementia condition termed "mild cognitive decline" or, alternatively, beginning in 1988, "mild cognitive impairment" (MCI). This GDS stage 3 MCI condition is differentiated from both a preceding GDS stage 2, "subjective cognitive impairment" (SCI) stage and a subsequent GDS 4 stage of mild dementia.GDS stage 3 MCI has been well characterized. For example, specific clinical concomitants, mental status and psychological assessment score ranges, behavioral and emotional changes, neuroimaging concomitants, neurological reflex changes, electrophysiological changes, motor and coordination changes, and changes in activities, accompanying GDS stage 3 MCI have been described.Petersen and associates proposed a definition of MCI in 2001 which has been widely used (hereafter referred to as "Petersen's MCI"). Important differences between GDS stage 3 MCI and Petersen's MCI are that, because of denial, GDS stage 3 MCI does not require memory complaints. Also, GDS stage 3 MCI recognizes the occurrence of executive level functional deficits, which Petersen's MCI did not. Nevertheless, longitudinal and other studies indicate essential compatibility between GDS stage 3 MCI and Petersen's MCI duration and outcomes.

Recommendations for best practices in the treatment of Alzheimer's disease in managed care.

BACKGROUND: Alzheimer's disease and related dementias (ADRDs) are increasingly recognized as important causes of impaired cognition, function, and quality of life, as well as excess medical care utilization and costs in the elderly Medicare managed care population. Evidence-based clinical practice guidelines for ADRDs were published in 2001. More recent studies have resulted in the approval of new agents and demonstrated an expanded role for antidementia therapy in various types of dementia, settings of care, stages of disease, and the use of combination therapy. However, these clinical guidelines have not been updated in the past few years. OBJECTIVE: The goal of this article was to provide practical recommendations developed by a panel of experts that address issues of early diagnosis, treatment, and care management of ADRDs. The panel also addressed the societal and managed care implications. METHODS: A panel of leading experts was convened to develop consensus recommendations for the treatment and management of dementia based on currently available evidence and the panel's informed expert opinion. The panel comprised 12 leading experts, including clinical investigators and practitioners in geriatric medicine, neurology, psychiatry, and psychology; managed care medical and pharmacy directors; a health systems medical director; and a health policy expert. In addition, articles were collected based on PubMed searches (2000-2005) that were relevant to the key issues identified. Search terms included Alzheimer's disease, dementia, clinical practice guidelines, clinical trials, screening and assessment, and managed care. RESULTS: ADRDs represent a significant clinical and economic burden to individuals and society, including Medicare managed care organizations (MCOs). Appropriate utilization of antidementia therapy and care management is vitally important to achieving quality of life and care for dementia patients and their caregivers, and for managing the excess costs of Alzheimer's disease. The recommendations address relevant, practical, and timely concerns that are faced on a daily basis by practitioners and by Medicare MCO medical management programs in the care of dementia patients. These consensus recommendations attempt to describe a reasonable current standard for the provision of quality care for patients with dementia. The panel recommendations support the use of screening for cognitive impairment and the use of antidementia therapy for ADRDs in different stages of disease and types of dementia in all clinical settings. The panel members evaluated the use of the 3 marketed cholinesterase inhibitors-donepezil, galantamine, and rivastigmine-as well as the N-methyl-D-aspartate antagonist memantine. Recommendations for using these medications are made with an appreciation of the difficulties in translating the results from investigational clinical trials into clinical practice. CONCLUSIONS: The recommendations of the expert panel represent a clear consensus that nihilism in the diagnosis, treatment, and management of ADRDs is unwarranted, impairs quality of care, and is ultimately not costeffective.

ADCS Prevention Instrument Project: overview and initial results.

One objective of the Alzheimer's Disease Cooperative Study (ADCS) is to develop new or improved instruments and assessment methods for evaluating treatment efficacy in Alzheimer disease (AD) clinical trials. The ADCS Instrument Committee has previously helped to define the state of the art in assessment for AD and Mild Cognitive Impairment clinical trials. We are now entering an exciting era of primary prevention trials to evaluate promising treatments that may delay disease onset and there is a need to develop appropriate instruments for these trials. The ADCS instrument committee has undertaken a project to develop instruments for prevention studies that assess domains known to be important in AD. Prevention trials are long and require large numbers of subjects, making them costly and requiring a high burden of participation for subjects. The current study focused on developing instruments that can be completed at home and in the clinic. The instruments are being evaluated in a cohort of nondemented elderly participating in a 4-year longitudinal study that simulates the design of a primary prevention trial. This report describes the design, baseline characteristics, and some longitudinal outcomes of the study cohort through the completion of the first 2 years of follow-up. We also describe the assessment domains to be measured with our new experimental instruments. This study recruited 644 subjects, 75 years of age and older. Participation in a "book club" that provided free books of interest to elders was offered as a recruitment incentive. Approximately 23% had some mild cognitive symptoms consistent with a Clinical Dementia Rating of 0.5. All subjects received a standardized in-clinic evaluation at baseline, which is repeated annually for 4 years to identify cases suspected of developing dementia and to measure longitudinal change on established clinical assessments. Subjects completed a set of self-administered experimental instruments at home or in the clinic designed to assess cognitive function and behavior, global change, activities of daily living, quality of life, and resource use. An additional "mail-in cognitive function questionnaire" was obtained separately by mail, 1 month before the other assessments. To evaluate the feasibility, efficiency, and validity of the home-based instruments in comparison with acquiring the same information during a clinic visit, subjects were randomized to 1 of 2 conditions in which the baseline and annual follow-up assessments are completed either at home ("home group") or at the study site during their clinic visits ("clinic group"). This initial report describes the ongoing 4-year longitudinal study and provides baseline results, which confirm the feasibility of obtaining home-based clinical information via mail or telephone. Initial results for the experimental instruments and for the book club are reported in separate accompanying articles.

ADCS Prevention Instrument Project: ADCS-clinicians' global impression of change scales (ADCS-CGIC), self-rated and study partner-rated versions.

BACKGROUND: Because primary prevention trials will require large samples and modest treatment effects are expected, the use of standard clinician-administered, clinic-based measures are unlikely to be feasible. There is a need for proxy-administered outcome measures. The goal of the Alzheimer's Disease Cooperative Study (ADCS) Prevention Instrument Project was to conduct a simulated Alzheimer disease prevention trial in 650 nondemented elderly (Ferris et al, 2006). This involved comparison of data acquisition from both home and clinic and the use of both informant-ratings and self-ratings. Important outcomes included clinical global impressions of change (CGIC) as indicators of clinically meaningful change. Such ratings provide verification that the effects of a medication as measured on rating scales are readily observable and clinically meaningful. One objective was to develop self-rated and study partner-rated CGICs optimized for nondemented elderly or people with very early Alzheimer disease. An important consideration was whether global assessments are specific and sensitive measures of change during a prevention trial. METHODS: A self-administered CGIC and a study partner-rated CGIC were developed to be used either in the clinic or at home. Using 3-month follow-up data, we determined its reliability and validity with 317 subject-partner pairs. We compared subject-ratings with partner-ratings, clinic-based with home-based ratings, and ratings based on severity as determined by the Clinical Dementia Rating scale. RESULTS: There were no differences between clinic and home ratings. Overall, 24% of subjects rated themselves, and 10% of study partners rated the subjects, as minimally to markedly improved. Subjects and partners agreed to within 1 point of their ratings 83% of the time on the 7-point scale. There were weak correlations, generally <0.20, with change scores of selected clinical rating scales. DISCUSSION: The CGICs behaved as expected, showing no overall change over 3 months, no difference between administrations at home compared with clinics, and concurrent validity. Some subjects tended to rate themselves better than their partners rated them. These analyses show the potential for using home-based CGICs which can be completed with minimal supervision and allow assessments of potential preventative interventions.