Faculty Bibliography

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/CONCLUSIONS: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.

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.

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. (c) 2014 S. Karger AG, Basel.

Background: A decade ago, the senior author and colleagues published a multicenter study which demonstrated the efficacy of memantine in the treatment of moderate to severe Alzheimer's disease (AD) (Reisberg, et al, N Engl J Med., 2003). This study served as a pivotal trial which supported the US and EU approvals of memantine as the first treatment for advanced AD. The advent of pharmacologic treatment of advanced AD served to highlight the continuing needs of these persons. Therefore, we simulta- neously developed a science of AD management (Reisberg, et al, Int Psychogeriatr, 1999; Reisberg, et al, Am J Alzheimers Dis Other Demen, 2002). After the U.S. approval of memantine treatment we embarked upon a study comparing a Comprehensive, Individualized, Person Centered Management Program (CI-PCM) in persons receiving memantine treatment, with memantine treatment alone. The inclusion criteria, outcome measures and study design were based on our 2003 NEJM memantine study. Subjects were randomized to CIPCM plus memantine treatment (n=10), or memantine treatment alone (controls, n=10). A primary pivotal, outcome measure was the NYU CIBIC-Plus, a global primary outcome used in the 2003 pivotal memantine trial. We recently reported that the CI-PCM+memantine treatment subjects showed significant improvement over the controls on this global outcome measure at all time periods examined (ie, 4, 12 and 28 weeks, p<0.01) (Reisberg, et al, Alzheimer's & Dementia, in press). Herein we describe the source and the meaning of the observed differences. Methods: The NYU CIBIC-Plus (Clinician's Interview Based Impression of Change, Plus Caregiver Input) assessment is comprised of 2 parts: Part 1. A subject interview, and Part 2: A caregiver interview. Part 1 has a cognitive component, a behavioral component total score, and a behavioral global score. Part 2 has a functional disability stage, a behavioral component total score, and a behavioral global score. Differences between the CI-PCM treatment group and the con!

Background: Demonstration of efficacy of memantine treatment for persons with moderate to severe Alzheimer's disease (AD) over 28 weeks (Reisberg, et al., N. Engl. J. Med., 2003) highlighted both treatment possibilities and treatment needs of persons with advanced AD. In prior work, we developed a science of AD management (Reisberg, et al., Am. J. Alzheimers Dis., 2002), based upon scientific observations of the retrogenesis process and other pathologic AD processes (Reisberg, et al., Eur. Arch. Psych. Clin. Neurosci., 1999; Souren, et al., J. Am. Geriatr. Soc., 1995; Franssen, et al., Arch Neurol., 1993). Herein, we investigated the hypothesis that application of this AD management science would result in improved outcomes beyond those with pharmacologic treatment alone. Methods: The same subject selection procedures were applied as in our published, double-blind, memantine trial. These included: community residence, age > 50, probable AD, a Global Deterioration Scale stage of 5 or 6, a Functional Assessment Staging (FAST) level of > 6a, and an MMSE score of 3 to 14. All subjects were titrated to a maintenance dose of memantine, 10 mg bid, as tolerated. Twenty participants were randomized to one of two groups, each comprised of 10 subjects. The intervention group received the CI-PCM program; the control group received financial compensation upon completion of study landmarks. Results: The first results of this study, presented herein, examined the primary outcome measure, the Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus) global scores (New York University version) (Reisberg,Int. Psychogeriatr., 2007). This assessment comprehensively evaluates change in terms of cognition, function and behavior. The results indicated significant improvement in CIBIC-Plus scores in the subjects in the management program versus the subjects receiving financial compensation (p < 0.01 at weeks 4 and 12 and p < 0.001 at week 28), with enhanced benefits throughout the 28 week stud!

Background: Impairment in functional capacities is an integral domain in AD presentation, diagnosis and progression. Among many functional scales for AD assessment, the Functional Assessment Staging scale (FAST) (Table 1) uniquely: (1) charts the entire course of AD, from normal aging to most severe AD; (2) has relevance for AD diagnosis and differential diagnosis; and (3) is brief and easy to utilize. Methods: Reliability, validity, and utility of the FAST have been documented in worldwide studies and clinical settings. Results: The FAST has excellent reliability (e.g., Foster et al., Int J Geriatr. Psychiatry,1988; Sclan and Reisberg, Int. Psychogeriatr., 1992). Concurrent validity has been demonstrated with: cognitive assessments across the severity spectrum (e.g., Reisberg, et al., Int. Psychogeriatr., 1992; Shimada, et al., Psychogeriatrics, 2003; Auer et al., JAGS, 1994); other dementia scales (Na et al., JAD, 2010); and neurologic assessments (Franssen and Reisberg, Int. Psychogeriatr., 1997). Criterion validity investigations have indicated superiority of the FAST in comparison with the MMSE, in tracking the course of AD. E.g., in a 5 year prospective longitudinal study of AD course, the FAST accounted for w 2x the temporal variance of the MMSE (Reisberg, et al., Int. Psychogeriatr., 1996). Also, in a range where the MMSE is zero, the FAST demonstrated very robust relationships to AD neuropathology (e.g., r = 0.9 [p 0.01], with hippocampal cornu ammonis neuronal loss), (Bobinski, et al., J. Neuropathol. Exp. Neurol., 1997). Additionally, in a pivotal trial, associated with worldwide approvals of memantine for AD treatment, FAST scores were sensitive to the intervention, MMSE change was not (Reisberg, et al., N Engl J Med., 2003). The FAST has shown widespread utility (e.g., usage mandated by U.S.A. Medicare since 1998, and the U.S.A. Veterans Administration System, since 2008). Conclusions: As noted in a Korean publication, the FAST is a rapid and easy to use staging tool with excellent validity. it. successfully measure[ s] detailed function throughout the entire course of AD. the FAST is composed of simple . and easy to understand sentences

Background: Subjective Cognitive Impairment (SCI), Global Deterioration Scale stage 2, is common in older persons. A study of otherwise healthy persons found that 54% of SCI subjects followed over 7 years progressed toMild Cognitive Impairment (MCI) or dementia (Reisberg, et al., Alzheimer's & Dementia, 2010).1 Medications may contribute to SCI occurrence, however, their influence on SCI outcome is largely unknown. Therefore, we investigated the impact of medications subsequently associated with dementia risk in our previously characterized cohort.1 Methods: Subjects with SCI at baseline from our 2010 publication1 were studied. These subjects had baseline evaluations between 1/1/1984 and 12/31/1997 and were followed until 12/31/2001. Medication data was available on 143 of 166 subjects. Subjects receiving topical estrogen at the baseline evaluationwere excluded fromthese analyses. At baseline, evaluable subjects (N = 140; 91 women, 49 men) had a mean age of 66.5 +/- 8.4 years; 15.6 +/- 2.7 years of education; and MMSE scores of 29.0 +/- 1.2. Twenty-two women (24.2%) were receiving HRT, comprising estrogen (n = 10) or estrogen-progesterone combination (n = 12). Results: Subjects were followed over 7.0 +/- 3.4 years. Increased age and education were associated with clinical progression in this cohort (OR = 1.06 and 0.78 respectively; p-values < 0.05). Three of ten estrogenonly (30%) subjects progressed (2 to MCI, 1 to dementia); seven of twelve estrogen-progesterone (58.3%) subjects progressed (6 toMCI, 1 to dementia). In the total HRT group, 45.5% progressed, whereas in the control group (no-HRT), 62 of 118 progressed (52.5%), (49 to MCI, 13 to dementia). Age, education and gender did not differ significantly between subjects in the study groups (t-test and chi-square p-values, NS). Multivariate logistic regression for each condition was performed investigating differences in therapy, age, gender and education. Therapy was not associated with progression status. Conclusions: HRT did not influence 7-year outcome in SCI subjects. Therefore, SCI subjects were not particularly sensitive to reported deleterious effects of HRT on progression of cognitive decline. Systematic longitudinal investigation of possible effects of other medications/conditions on progression of SCI to MCI/dementia is required to identify substances that may regulate/prevent this process