Duane Beekly

The Uniform Data Set (UDS): Clinical and cognitive variables and descriptive data from Alzheimer disease centers

A Clinical Task Force, composed of clinical leaders from Alzheimers Disease Centers (ADC), was convened by the National Institute on Aging to develop a uniform set of assessment procedures to characterize individuals with mild Alzheimer disease and mild cognitive impairment in comparison with nondemented aging. The resulting Uniform Data Set (UDS) defines a common set of clinical observations to be collected longitudinally on ADC participants in accordance with standard methods. The UDS was implemented at all ADCs on September 1, 2005. Data obtained with the UDS are submitted to the National Alzheimers Coordinating Center and represent a unique and valuable source of data to support and stimulate collaborative research.

The Alzheimer's Disease Centers' Uniform Data Set (UDS): the neuropsychologic test battery.

The neuropsychologic test battery from the Uniform Data Set (UDS) of the Alzheimers Disease Centers (ADC) program of the National Institute on Aging consists of brief measures of attention, processing speed, executive function, episodic memory, and language. This paper describes development of the battery and preliminary data from the initial UDS evaluation of 3268 clinically cognitively normal men and women collected over the first 24 months of utilization. The subjects represent a sample of community-dwelling, individuals who volunteer for studies of cognitive aging. Subjects were considered “clinically cognitively normal” based on clinical assessment, including the Clinical Dementia Rating scale and the Functional Assessment Questionnaire. The results demonstrate performance on tests sensitive to cognitive aging and to the early stages of Alzheimer disease in a relatively well-educated sample. Regression models investigating the impact of age, education, and sex on test scores indicate that these variables will need to be incorporated in subsequent normative studies. Future plans include: (1) determining the psychometric properties of the battery; (2) establishing normative data, including norms for different ethnic minority groups; and (3) conducting longitudinal studies on cognitively normal subjects, individuals with mild cognitive impairment, and individuals with Alzheimer disease and other forms of dementia.

Meta-analysis confirms CR1, CLU, and PICALM as alzheimer disease risk loci and reveals interactions with APOE genotypes.

OBJECTIVESnTo determine whether genotypes at CLU, PICALM, and CR1 confer risk for Alzheimer disease (AD) and whether risk for AD associated with these genes is influenced by apolipoprotein E (APOE) genotypes.nnnDESIGNnAssociation study of AD and CLU, PICALM, CR1, and APOE genotypes.nnnSETTINGnAcademic research institutions in the United States, Canada, and Israel.nnnPARTICIPANTSnSeven thousand seventy cases with AD, 3055 with autopsies, and 8169 elderly cognitively normal controls, 1092 with autopsies, from 12 different studies, including white, African American, Israeli-Arab, and Caribbean Hispanic individuals.nnnRESULTSnUnadjusted, CLU (odds ratio [OR], 0.91; 95% confidence interval [CI], 0.85-0.96 for single-nucleotide polymorphism [SNP] rs11136000), CR1 (OR, 1.14; 95% CI, 1.07-1.22; SNP rs3818361), and PICALM (OR, 0.89; 95% CI, 0.84-0.94, SNP rs3851179) were associated with AD in white individuals. None were significantly associated with AD in the other ethnic groups. APOE ε4 was significantly associated with AD (ORs, 1.80-9.05) in all but 1 small white cohort and in the Arab cohort. Adjusting for age, sex, and the presence of at least 1 APOE ε4 allele greatly reduced evidence for association with PICALM but not CR1 or CLU. Models with the main SNP effect, presence or absence of APOE ε4, and an interaction term showed significant interaction between presence or absence of APOE ε4 and PICALM.nnnCONCLUSIONSnWe confirm in a completely independent data set that CR1, CLU, and PICALM are AD susceptibility loci in European ancestry populations. Genotypes at PICALM confer risk predominantly in APOE ε4-positive subjects. Thus, APOE and PICALM synergistically interact.

The National Alzheimer's Coordinating Center (NACC) database: The uniform data set

The National Alzheimers Coordinating Center (NACC) is responsible for developing and maintaining a database of participant information collected from the 29 Alzheimers Disease Centers (ADCs) funded by the National Institute on Aging (NIA). The NIA appointed the ADC Clinical Task Force to determine and define an expanded, standardized clinical data set, called the Uniform Data Set (UDS). The goal of the UDS is to provide ADC researchers a standard set of assessment procedures, collected longitudinally, to better characterize ADC participants with mild Alzheimer disease and mild cognitive impairment in comparison with nondemented controls. NACC implemented the UDS (September 2005) by developing data collection forms for initial and follow-up visits based on Clinical Task Force definitions, a relational database, and a data submission system accessible by all ADCs. The NIA requires ADCs to submit UDS data to NACC for all their Clinical Core participants. Thus, the NACC web site (https://www.alz.washington.edu) was enhanced to provide efficient and secure access data submission and retrieval systems.

Apolipoprotein E Genotype and Sex Risk Factors for Alzheimer Disease: A Meta-analysis

Importance It is unclear whether female carriers of the apolipoprotein E (APOE) &egr;4 allele are at greater risk of developing Alzheimer disease (AD) than men, and the sex-dependent association of mild cognitive impairment (MCI) and APOE has not been established. Objective To determine how sex and APOE genotype affect the risks for developing MCI and AD. Data Sources Twenty-seven independent research studies in the Global Alzheimer’s Association Interactive Network with data on nearly 58 000 participants. Study Selection Non-Hispanic white individuals with clinical diagnostic and APOE genotype data. Data Extraction and Synthesis Homogeneous data sets were pooled in case-control analyses, and logistic regression models were used to compute risks. Main Outcomes and Measures Age-adjusted odds ratios (ORs) and 95% confidence intervals for developing MCI and AD were calculated for men and women across APOE genotypes. Results Participants were men and women between ages 55 and 85 years. Across data sets most participants were white, and for many participants, racial/ethnic information was either not collected or not known. Men (OR, 3.09; 95% CI, 2.79-3.42) and women (OR, 3.31; CI, 3.03-3.61) with the APOE &egr;3/&egr;4 genotype from ages 55 to 85 years did not show a difference in AD risk; however, women had an increased risk compared with men between the ages of 65 and 75 years (women, OR, 4.37; 95% CI, 3.82-5.00; men, OR, 3.14; 95% CI, 2.68-3.67; Pu2009=u2009.002). Men with APOE &egr;3/&egr;4 had an increased risk of AD compared with men with APOE &egr;3/&egr;3. The APOE &egr;2/&egr;3 genotype conferred a protective effect on women (OR, 0.51; 95% CI, 0.43-0.61) decreasing their risk of AD more (P valueu2009=u2009.01) than men (OR, 0.71; 95% CI, 0.60-0.85). There was no difference between men with APOE &egr;3/&egr;4 (OR, 1.55; 95% CI, 1.36-1.76) and women (OR, 1.60; 95% CI, 1.43-1.81) in their risk of developing MCI between the ages of 55 and 85 years, but women had an increased risk between 55 and 70 years (women, OR, 1.43; 95% CI, 1.19-1.73; men, OR, 1.07; 95% CI, 0.87-1.30; Pu2009=u2009.05). There were no significant differences between men and women in their risks for converting from MCI to AD between the ages of 55 and 85 years. Individuals with APOE &egr;4/&egr;4 showed increased risks vs individuals with &egr;3/&egr;4, but no significant differences between men and women with &egr;4/&egr;4 were seen. Conclusions and Relevance Contrary to long-standing views, men and women with the APOE &egr;3/&egr;4 genotype have nearly the same odds of developing AD from age 55 to 85 years, but women have an increased risk at younger ages.

A multiancestral genome-wide exome array study of Alzheimer Disease, frontotemporal dementia, and progressive supranuclear palsy

IMPORTANCEnPrevious studies have indicated a heritable component of the etiology of neurodegenerative diseases such as Alzheimer disease (AD), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP). However, few have examined the contribution of low-frequency coding variants on a genome-wide level.nnnOBJECTIVEnTo identify low-frequency coding variants that affect susceptibility to AD, FTD, and PSP.nnnDESIGN, SETTING, AND PARTICIPANTSnWe used the Illumina HumanExome BeadChip array to genotype a large number of variants (most of which are low-frequency coding variants) in a cohort of patients with neurodegenerative disease (224 with AD, 168 with FTD, and 48 with PSP) and in 224 control individuals without dementia enrolled between 2005-2012 from multiple centers participating in the Genetic Investigation in Frontotemporal Dementia and Alzheimers Disease (GIFT) Study. An additional multiancestral replication cohort of 240 patients with AD and 240 controls without dementia was used to validate suggestive findings. Variant-level association testing and gene-based testing were performed.nnnMAIN OUTCOMES AND MEASURESnStatistical association of genetic variants with clinical diagnosis of AD, FTD, and PSP.nnnRESULTSnGenetic variants typed by the exome array explained 44%, 53%, and 57% of the total phenotypic variance of AD, FTD, and PSP, respectively. An association with the known AD gene ABCA7 was replicated in several ancestries (discovery P=.0049, European P=.041, African American P=.043, and Asian P=.027), suggesting that exonic variants within this gene modify AD susceptibility. In addition, 2 suggestive candidate genes, DYSF (P=5.53×10(-5)) and PAXIP1 (P=2.26×10(-4)), were highlighted in patients with AD and differentially expressed in AD brain. Corroborating evidence from other exome array studies and gene expression data points toward potential involvement of these genes in the pathogenesis of AD.nnnCONCLUSIONS AND RELEVANCEnLow-frequency coding variants with intermediate effect size may account for a significant fraction of the genetic susceptibility to AD and FTD. Furthermore, we found evidence that coding variants in the known susceptibility gene ABCA7, as well as candidate genes DYSF and PAXIP1, confer risk for AD.

Comparison of Alzheimer’s disease in American Indians, whites, and African Americans

The recent development of a national Alzheimers disease database makes it possible to compare the course of illness in various ethnic groups.

Design and implementation of a longitudinal multicenter database

Longitudinal data obtained from patients with a clinical diagnosis of Alzheimers disease (AD) and from normal control subjects enrolled in the Consortium to Establish a Registry for Alzheimers Disease (CERAD) were centrally maintained in electronic files at the CERAD Methodology and Data Management Center (MDMC) at the University of Washington, Seattle. In addition to creating and maintaining this database, the MDMC assisted in the design of the data collection forms and studies of the reliability of the data collected. MDMC personnel advised CERAD investigators of the strengths and limitations of available data, created subsets of appropriate data for analysis, provided statistical advice, and in many cases, performed analyses.nnDatabase activities. The database was written in SAS (SAS, Inc., Cary, NC) whose database utilities and statistical procedures are supported by most universities. Thus, SAS data files could be easily transferred to CERAD sites and investigators interested in the data. SAS files can be read by many other software packages, including S-Plus (StatSci, Inc., Seattle, WA) statistical programming software used extensively by MDMC statisticians. SAS also has the standard query language SQL. The SAS products Base, AF, SCL, FSEDIT, and GRAPH were used to create and maintain the database and create reports.nnThe database was relational, with files related by identification code(ID) and visit number. Each subject had a unique six-digit ID number, which also identified the site and subjects status as patient or control subject. For confidentiality, no names or identifying information were used.nnThere was a separate file for each CERAD form, with records for each subject corresponding to initial and annual follow-up visits. Index files were also developed; these indicated which forms had been submitted for each subject, the subjects status (deceased, date entered nursing home, data dropped out, and so forth), and the dates the forms were completed …

THE NATIONAL ALZHEIMER'S COORDINATING CENTER: QUERYING THE DATABASE AND REQUESTING DATA

hemisphere findings, we evaluated the diagnostic utility in adding markers of hemispatial neglect to our previous baseline algorithm. Methods: We used the publicly available DementiaBank dataset (257 interviews from 169 AD patients and 242 interviews with 99 healthy controls). In addition to our baseline algorithm, which included 353 lexical and acoustic markers, we evaluated three approaches to dividing the Cookie Theft image: Halves, strips and quadrants, as seen in figure 1. For each given division, we compiled a list of information units (info-units) that are contained in each region (e.g. the info-units “stool” and “mother” are contained by the left and right halves, respectively). For each region we then recorded four measures from a given transcript: 1) Number of infounits mentioned 2) ratio of info-units to all words 3) ratio of unique info-units to all possible info-units in the region 4) ratio of unique info-units to total mentioned info-units (a measure of redundancy). We also included quadratic interaction terms between regions. We then performed a 10-fold cross validation procedure with a correlation-based feature selection preprocessing phase and trained a logistic regression model using each of the halves, strips, and quadrants approach, and compared against baseline. Results: The halves model [PPV 0.84, 95%CI 0.80-0.86, NPV 0.81(0.74 – 0.88)] and strips model [PPV 0.84 (0.77 – 0.91), NPV 0.82 (0.76 – 0.88)] but not the quadrants model [PPV 0.81 (0.74 – 0.87), NPV 0.81 (0.75 – 0.87)] showed a trend towards improvement from baseline. Conclusions: Including markers of hemispatial neglect to a machine learning algorithm analyzing lexical and acoustic speech features may improve diagnostic accuracy of AD versus healthy controls.

Factors Influencing Successful Lumbar Puncture in Alzheimer Research.

Objective: Lumbar puncture (LP) is increasingly common in Alzheimer disease research; however, agreement to undergo LP varies. We sought to determine factors influencing LP consent at Alzheimer’s Disease Centers (ADCs) in the United States. Methods: A 3-part survey was distributed to each ADC: (1) ADC LP Experience; (2) LP Requestor Experience; and (3) Patient LP Experience (both Initial and Follow-up). In all, 64 LP Requestor, 579 Patient/Initial, and 404 Patient/Follow-up surveys were collected. Logistic regression analyses with generalized estimating equations were used to assess factors associated with LP agreement and post-LP complications. Results: Asians and those viewing LP negatively were less likely to agree to LP. Three hundred fifty-two participants had an LP; LP headache occurred in 11.9% (blood patch required in 1.4%) and 9.9% reported other complications. Younger individuals, women, those diagnosed with mild cognitive impairment, use of a Quincke needle, ⩽20u2009mL cerebrospinal fluid drawn, and hemorrhage during LP were associated with LP headache. Use of gravity flow during LP was associated with fewer other complications (nausea, dizziness, vasovagal response, back pain, neck stiffness, and/or nerve root pain). Conclusions: LP in Alzheimer disease research is generally safe and well tolerated. Factors influencing LP agreement potentially could be studied to advance participant acceptance of the procedure.