Faculty Bibliography
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279
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.
PMID: 25341459
ISSN: 1552-5260
CID: 1316462
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. (c) 2014 S. Karger AG, Basel.
PMCID:4216810
PMID: 24714384
ISSN: 1420-8008
CID: 886392
Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease
Eleven susceptibility loci for late-onset Alzheimer's disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer's disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 x 10(-8)) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.
PMCID:3896259
PMID: 24162737
ISSN: 1061-4036
CID: 948132
Addition of a comprehensive, individualized, person centered management program, to memantine alone produces a 900% increment in a pivotal trial global measure over medication treatment alone in advanced alzheimer's disease [Meeting Abstract]
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!
EMBASE:71278551
ISSN: 0893-133x
CID: 752862
Memantine and comprehensive, individualized, person-centered management (CI-PCM) of Alzheimer's disease: A randomized controlled trial [Meeting Abstract]
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!
EMBASE:71416480
ISSN: 1552-5260
CID: 953762
Independent and epistatic effects of variants in VPS10-d receptors on Alzheimer disease risk and processing of the amyloid precursor protein (APP)
Genetic variants in the sortilin-related receptor (SORL1) and the sortilin-related vacuolar protein sorting 10 (VPS10) domain-containing receptor 1 (SORCS1) are associated with increased risk of Alzheimer's disease (AD), declining cognitive function and altered amyloid precursor protein (APP) processing. We explored whether other members of the (VPS10) domain-containing receptor protein family (the sortilin-related VPS10 domain-containing receptors 2 and 3 (SORCS2 and SORCS3) and sortilin (SORT1)) would have similar effects either independently or together. We conducted the analyses in a large Caucasian case control data set (n=11,840 cases, 10,931 controls) to determine the associations between single nucleotide polymorphisms (SNPs) in all the five homologous genes and AD risk. Evidence for interactions between SNPs in the five VPS10 domain receptor family genes was determined in epistatic statistical models. We also compared expression levels of SORCS2, SORCS3 and SORT1 in AD and control brains using microarray gene expression analyses and assessed the effects of these genes on gamma-secretase processing of APP. Several SNPs in SORL1, SORCS1, SORCS2 and SORCS3 were associated with AD. In addition, four specific linkage disequilibrium blocks in SORCS1, SORCS2 and SORCS3 showed additive epistatic effects on the risk of AD (P
PMCID:3669917
PMID: 23673467
ISSN: 2158-3188
CID: 627142
Variants in the ATP-binding cassette transporter (ABCA7), apolipoprotein E 4,and the risk of late-onset Alzheimer disease in African Americans
IMPORTANCE: Genetic variants associated with susceptibility to late-onset Alzheimer disease are known for individuals of European ancestry, but whether the same or different variants account for the genetic risk of Alzheimer disease in African American individuals is unknown. Identification of disease-associated variants helps identify targets for genetic testing, prevention, and treatment. OBJECTIVE: To identify genetic loci associated with late-onset Alzheimer disease in African Americans. DESIGN, SETTING, AND PARTICIPANTS: The Alzheimer Disease Genetics Consortium (ADGC) assembled multiple data sets representing a total of 5896 African Americans (1968 case participants, 3928 control participants) 60 years or older that were collected between 1989 and 2011 at multiple sites. The association of Alzheimer disease with genotyped and imputed single-nucleotide polymorphisms (SNPs) was assessed in case-control and in family-based data sets. Results from individual data sets were combined to perform an inverse variance-weighted meta-analysis, first with genome-wide analyses and subsequently with gene-based tests for previously reported loci. MAIN OUTCOMES AND MEASURES: Presence of Alzheimer disease according to standardized criteria. RESULTS: Genome-wide significance in fully adjusted models (sex, age, APOE genotype, population stratification) was observed for a SNP in ABCA7 (rs115550680, allele = G; frequency, 0.09 cases and 0.06 controls; odds ratio [OR], 1.79 [95% CI, 1.47-2.12]; P = 2.2 x 10(-9)), which is in linkage disequilibrium with SNPs previously associated with Alzheimer disease in Europeans (0.8 < D' < 0.9). The effect size for the SNP in ABCA7 was comparable with that of the APOE 4-determining SNP rs429358 (allele = C; frequency, 0.30 cases and 0.18 controls; OR, 2.31 [95% CI, 2.19-2.42]; P = 5.5 x 10(-47)). Several loci previously associated with Alzheimer disease but not reaching significance in genome-wide analyses were replicated in gene-based analyses accounting for linkage disequilibrium between markers and correcting for number of tests performed per gene (CR1, BIN1, EPHA1, CD33; 0.0005 < empirical P < .001). CONCLUSIONS AND RELEVANCE: In this meta-analysis of data from African American participants, Alzheimer disease was significantly associated with variants in ABCA7 and with other genes that have been associated with Alzheimer disease in individuals of European ancestry. Replication and functional validation of this finding is needed before this information is used in clinical settings.
PMCID:3667653
PMID: 23571587
ISSN: 0098-7484
CID: 627152
Initial assessment of the pathogenic mechanisms of the recently identified Alzheimer risk Loci
Recent genome wide association studies have identified CLU, CR1, ABCA7 BIN1, PICALM and MS4A6A/MS4A6E in addition to the long established APOE, as loci for Alzheimer's disease. We have systematically examined each of these loci to assess whether common coding variability contributes to the risk of disease. We have also assessed the regional expression of all the genes in the brain and whether there is evidence of an eQTL explaining the risk. In agreement with other studies we find that coding variability may explain the ABCA7 association, but common coding variability does not explain any of the other loci. We were not able to show that any of the loci had eQTLs within the power of this study. Furthermore the regional expression of each of the loci did not match the pattern of brain regional distribution in Alzheimer pathology. Although these results are mainly negative, they allow us to start defining more realistic alternative approaches to determine the role of all the genetic loci involved in Alzheimer's disease.
PMCID:3578142
PMID: 23360175
ISSN: 0003-4800
CID: 335882
Relating Memory to Functional Performance in Normal Aging to Dementia Using Hierarchical Bayesian Cognitive Processing Models
Determining how cognition affects functional abilities is important in Alzheimer disease and related disorders. A total of 280 patients (normal or Alzheimer disease and related disorders) received a total of 1514 assessments using the functional assessment staging test (FAST) procedure and the MCI Screen. A hierarchical Bayesian cognitive processing model was created by embedding a signal detection theory model of the MCI Screen-delayed recognition memory task into a hierarchical Bayesian framework. The signal detection theory model used latent parameters of discriminability (memory process) and response bias (executive function) to predict, simultaneously, recognition memory performance for each patient and each FAST severity group. The observed recognition memory data did not distinguish the 6 FAST severity stages, but the latent parameters completely separated them. The latent parameters were also used successfully to transform the ordinal FAST measure into a continuous measure reflecting the underlying continuum of functional severity. Hierarchical Bayesian cognitive processing models applied to recognition memory data from clinical practice settings accurately translated a latent measure of cognition into a continuous measure of functional severity for both individuals and FAST groups. Such a translation links 2 levels of brain information processing and may enable more accurate correlations with other levels, such as those characterized by biomarkers.
PMCID:3387504
PMID: 22407225
ISSN: 0893-0341
CID: 166780
SORL1 is genetically associated with late-onset Alzheimer's disease in Japanese, Koreans and Caucasians
To discover susceptibility genes of late-onset Alzheimer's disease (LOAD), we conducted a 3-stage genome-wide association study (GWAS) using three populations: Japanese from the Japanese Genetic Consortium for Alzheimer Disease (JGSCAD), Koreans, and Caucasians from the Alzheimer Disease Genetic Consortium (ADGC). In Stage 1, we evaluated data for 5,877,918 genotyped and imputed SNPs in Japanese cases (n = 1,008) and controls (n = 1,016). Genome-wide significance was observed with 12 SNPs in the APOE region. Seven SNPs from other distinct regions with p-values <2x10(-5) were genotyped in a second Japanese sample (885 cases, 985 controls), and evidence of association was confirmed for one SORL1 SNP (rs3781834, P = 7.33x10(-7) in the combined sample). Subsequent analysis combining results for several SORL1 SNPs in the Japanese, Korean (339 cases, 1,129 controls) and Caucasians (11,840 AD cases, 10,931 controls) revealed genome wide significance with rs11218343 (P = 1.77x10(-9)) and rs3781834 (P = 1.04x10(-8)). SNPs in previously established AD loci in Caucasians showed strong evidence of association in Japanese including rs3851179 near PICALM (P = 1.71x10(-5)) and rs744373 near BIN1 (P = 1.39x10(-4)). The associated allele for each of these SNPs was the same as in Caucasians. These data demonstrate for the first time genome-wide significance of LOAD with SORL1 and confirm the role of other known loci for LOAD in Japanese. Our study highlights the importance of examining associations in multiple ethnic populations.
PMCID:3614978
PMID: 23565137
ISSN: 1932-6203
CID: 627162
