Psychometric Cognitive Decline Precedes the Advent of Subjective Cognitive Decline in the Evolution of Alzheimer's Disease.

BACKGROUND: We have described the clinical stages of the brain aging and Alzheimer's disease (AD) continuum. In terms of the pre-dementia stages of AD, we introduced the terminology "mild cognitive impairment" (MCI) for the first pre-dementia stage and "subjective cognitive decline" (SCD) for the pre-MCI stage. We now report the characteristics of a pre-SCD condition eventuating in likely AD. OBJECTIVE: The aim of this study was to characterize a pre-SCD condition eventuating in AD. METHOD: Sixty healthy persons with "no cognitive decline" (NCD) were recruited and 47 were followed (mean baseline age, 64.1 ± 8.9 years; mean follow-up time, 6.7 ± 3.1 years). Outcome was determined at the final assessment prior to 2002 as "decliner," if SCD or worse, or "nondecliner" if NCD. RESULTS: After controlling for age, gender, years of education, and follow-up time, there was a between-group difference in the decline rate (p < 0.001). Also, after controlling for demographic variables and follow-up time, the combinatorial psychometric score was lower at baseline in the future decliners (p = 0.035). Of the 9 psychometric variables, after controlling for demographic variables and follow-up time, 3 were significantly lower at baseline in future decliners. Since AD is known to be age related and all subjects in this study were otherwise healthy, we also did an analysis without controlling for age. The combinatorial psychometric score was highly significantly better at baseline in the future nondecliners than in the future decliners (p = 0.008). CONCLUSION: This is ostensibly the first study to link psychometric cognitive decline to the subsequent SCD stage of eventual AD.

Two Year Outcomes, Cognitive and Behavioral Markers of Decline in Healthy, Cognitively Normal Older Persons with Global Deterioration Scale Stage 2 (Subjective Cognitive Decline with Impairment).

BACKGROUND: Little is known with respect to behavioral markers of subjective cognitive decline (SCD), a condition initially described in association with Global Deterioration Scale (GDS) stage 2. OBJECTIVE: Two-year interval behavioral markers were investigated herein. METHODS: Subjects from a published 7-year outcome study of GDS stage 2 subjects were selected. This study had demonstrated a hazard ratio of 4.5 for progression of GDS stage 2, in comparison with GDS stage 1 (no subjective or objective cognitive decline) subjects, after controlling for demographic and temporal variables. Because GDS 2 subjects have previously demonstrated impairment in comparison with healthy persons free of complaints, we herein suggest the terminology "SCD(I)" for these persons. 98 SCD(I) persons, 63 women and 35 men, mean baseline age, 67.12±8.75 years, with a mean educational background of 15.55±2.60 years, and mean baseline MMSE scores of 28.9±1.24 were followed for 2.13±0.30 years. RESULTS: Observed annual decline on the GDS was 6.701% per annum, very close to a 1986 published estimate. At follow up, the MMSE, and 7 of 8 psychometric tests did not decline significantly. Of 21 Hamilton Depression Scale items, 2 improved and the remainder were unchanged. Anxieties declined from multiple perspectives. The Brief Cognitive Rating Scale (BCRS) declined significantly (p < 0.001), with component declines in Remote memory (p < 0.01), and Functioning/self-care (p = 0.01). CONCLUSION: SCD(I) persons decline at an annual rate of approximately 6.7% /year from several recent studies. The BCRS assessments and the Digit Symbol Substitution Test can be sensitive measures for future studies of progression mitigation.

Comprehensive, Individualized, Person-Centered Management of Community-Residing Persons with Moderate-to-Severe Alzheimer Disease: A Randomized Controlled Trial.

BACKGROUND/AIMS: The aim was to examine added benefits of a Comprehensive, Individualized, Person-Centered Management (CI-PCM) program to memantine treatment. METHODS: This was a 28-week, clinician-blinded, randomized, controlled, parallel-group study, with a similar study population, similar eligibility criteria, and a similar design to the memantine pivotal trial of Reisberg et al. [N Engl J Med 2003;348:1333-1341]. Twenty eligible community-residing Alzheimer disease (AD) subject-caregiver dyads were randomized to the CI-PCM program (n = 10) or to usual community care (n = 10). Primary outcomes were the New York University Clinician's Interview-Based Impression of Change Plus Caregiver Input (NYU-CIBIC-Plus), assessed by one clinician set, and an activities of daily living inventory, assessed by a separate clinician set at baseline and at weeks 4, 12, and 28. RESULTS: Primary outcomes showed significant benefits of the CI-PCM program at all post-baseline evaluations. Improvement on the NYU-CIBIC-Plus in the management group at 28 weeks was 2.9 points over the comparator group. The memantine 2003 trial showed an improvement of 0.3 points on this global measure in memantine-treated versus placebo-randomized subjects at 28 weeks. Hence, globally, the management program intervention benefits were 967% greater than memantine treatment alone. CONCLUSION: These results are approximately 10 times those usually observed with both nonpharmacological and pharmacological treatments and indicate substantial benefits with the management program for advanced AD persons.

The BEHAVE-AD assessment system: a perspective, a commentary on new findings, and a historical review.

BACKGROUND: Behavioral and psychological symptoms of dementia (BPSD) and associated disturbances in Alzheimer's disease (AD) are a source of distress and burden for spouses, professional caregivers, and others with responsibilities for the care of individuals with AD. BPSD with behavioral disturbances are also associated with more rapid institutionalization and increased morbidity and mortality for persons with AD. OBJECTIVES: In this review and commentary, we discuss the history of the development of BPSD and behavioral disturbance assessments, which are distinct from those evaluating cognitive and functional symptoms of AD. In particular, we review the informant-based Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD), the related, potentially more sensitive, BEHAVE-AD Frequency-Weighted Severity Scale (BEHAVE-AD-FW), and the direct subject evaluation-based Empirical BEHAVE-AD Rating Scale (E-BEHAVE-AD). The kinds of medications that alleviate behavioral symptoms on these measures as well as the problems and possibilities for further advances with these medications are discussed. Finally, the importance of distinguishing BPSD and behavioral disturbance remediation in AD from the treatment of cognitive decline and other aspects of AD is emphasized in the context of appropriate assessment methodology. The objective of this paper is to provide a framework for further advances in the treatment of BPSD and associated behavioral disturbances in AD and, consequently, a framework for continuing improvements in the lives of individuals with AD and those who share the burden of the disease with the AD person.

Outcome over seven years of healthy adults with and without subjective cognitive impairment.

BACKGROUND: Subjective cognitive impairment (SCI) in older persons without manifest symptomatology is a common condition with a largely unclear prognosis. We hypothesized that (1) examining outcome for a sufficient period by using conversion to mild cognitive impairment (MCI) or dementia would clarify SCI prognosis, and (2) with the aforementioned procedures, the prognosis of SCI subjects would differ significantly from that of demographically matched healthy subjects, free of SCI, termed no cognitive impairment (NCI) subjects. METHODS: A consecutive series of healthy subjects, aged > or =40 years, presenting with NCI or SCI to a brain aging and dementia research center during a 14-year interval, were studied and followed up during an 18-year observation window. The study population (60 NCI, 200 SCI, 60% female) had a mean age of 67.2 +/- 9.1 years, was well-educated (mean, 15.5 +/- 2.7 years), and cognitively normal (Mini-Mental State Examination, 29.1 +/- 1.2). RESULTS: A total of 213 subjects (81.9% of the study population) were followed up. Follow-up occurred during a mean period of 6.8 +/- 3.4 years, and subjects had a mean of 2.9 +/- 1.6 follow-up visits. Seven NCI (14.9%) and 90 SCI (54.2%) subjects declined (P < .0001). Of NCI decliners, five declined to MCI and two to probable Alzheimer's disease. Of SCI decliners, 71 declined to MCI and 19 to dementia diagnoses. Controlling for baseline demographic variables and follow-up time, Weibull proportional hazards model revealed increased decline in SCI subjects (hazard ratio, 4.5; 95% confidence interval, 1.9-10.3), whereas the accelerated failure time model analysis with an underlying Weibull survival function showed that SCI subjects declined more rapidly, at 60% of the rate of NCI subjects (95% confidence interval, 0.45-0.80). Furthermore, mean time to decline was 3.5 years longer for NCI than for SCI subjects (P = .0003). CONCLUSIONS: These results indicate that SCI in subjects with normal cognition is a harbinger of further decline in most subjects during a 7-year mean follow-up interval. Relevance for community populations should be investigated, and prevention studies in this at-risk population should be explored.

The pre-mild cognitive impairment, subjective cognitive impairment stage of Alzheimer's disease.

BACKGROUND: Subjective cognitive impairment (SCI) has been a common, but poorly understood condition, frequently occurring in older persons. METHODS: The past and the emerging literature on SCI and synonymously named conditions is reviewed. RESULTS: Findings include: (1) There is support from at least one longitudinal study for a long-standing concept of SCI as a pre-mild cognitive impairment (MCI) condition lasting approximately 15years. (2) There are complex relationships between SCI and depression and anxiety. (3) Differences in SCI subjects from age-matched non-SCI persons are being published in terms of cognitive tests, hippocampal gray matter density, hippocampal volumes, cerebral metabolism, and urinary cortisol levels. Psychometric and dementia test score differences between SCI and MCI subjects have long been evident. (4) Predictive electrophysiologic features of subsequent decline in SCI subjects are being published. CONCLUSIONS: Studies of therapeutic agents in SCI treatment and resultant Alzheimer's disease prevention appear to be feasible. These trials are also necessary from a public health perspective.