Alzheimer's Coordinating Center Uniform Research Articles

Characteristics of patients misdiagnosed with Alzheimer’s disease and their medication use: an analysis of the NACC-UDS database

BackgroundThis study compared individuals whose clinical diagnosis of Alzheimer’s disease (AD) matched or did not match neuropathologic results at autopsy on clinical and functional outcomes (cognitive impairment, functional status and neuropsychiatric symptoms). The study also assessed the extent of potentially inappropriate medication use (using potentially unnecessary medications or potentially inappropriate prescribing) among misdiagnosed patients.MethodsLongitudinal data from the National Alzheimer’s Coordinating Center Uniform Data Set (NACC-UDS, 2005–2010) and corresponding NACC neuropathological data were utilized to compare 88 misdiagnosed and 438 accurately diagnosed patients.ResultsFollowing adjustment of sociodemographic characteristics, the misdiagnosed were found to have less severe cognitive and functional impairment. However, after statistical adjustment for sociodemographics, dementia severity level, time since onset of cognitive decline and probable AD diagnosis at baseline, the groups significantly differed on only one outcome: the misdiagnosed were less likely to be depressed/dysphoric. Among the misdiagnosed, 18.18% were treated with potentially inappropriate medication. An additional analysis noted this rate could be as high as 67.10%.ConclusionsFindings highlight the importance of making an accurate AD diagnosis to help reduce unnecessary treatment and increase appropriate therapy. Additional research is needed to demonstrate the link between potentially inappropriate treatment and adverse health outcomes in misdiagnosed AD patients.

Choosing Alzheimer's disease prevention clinical trial populations

To assist investigators in making design choices, we modeled Alzheimer's disease prevention clinical trials. We used longitudinal Clinical Dementia Rating Scale Sum of Boxes data, retention rates, and the proportions of trial-eligible cognitively normal participants age 65 and older in the National Alzheimer's Coordinating Center Uniform Data Set to model trial sample sizes, the numbers needed to enroll to account for drop out, and the numbers needed to screen to successfully complete enrollment. We examined how enrichment strategies affected each component of the model. Relative to trials enrolling 65-year-old individuals, trials enriching for older (minimum 70 or 75) age required reduced sample sizes, numbers needed to enroll, and numbers needed to screen. Enriching for subjective memory complaints reduced sample sizes and numbers needed to enroll more than age enrichment, but increased the number needed to screen. We conclude that Alzheimer's disease prevention trials can enroll elderly participants with minimal effect on trial retention and that enriching for older individuals with memory complaints might afford efficient trial designs.

Characteristics of people misdiagnosed with Alzheimer's disease and their medication use: An analysis of the National Alzheimer's Coordinating Center Uniform Data Set database

Characteristics of people misdiagnosed with Alzheimer's disease and their medication use: An analysis of the National Alzheimer's Coordinating Center Uniform Data Set database

Comparing measures of decline to dementia in amnestic MCI subjects in the National Alzheimer's Coordinating Center (NACC) Uniform Data Set

Many studies have investigated factors associated with the rate of decline and evolution from mild cognitive impairment (MCI) to Alzheimer's disease (AD) dementia in elderly patients. In this analysis, we compared the rates of decline to dementia estimated from three common global measures of cognition: Mini-Mental State Examination (MMSE) score, Clinical Dementia Rating sum of boxes (CDR-SB) score, and a neuropsychological tests composite score (CS). A total of 2,899 subjects in the National Alzheimer's Coordinating Center Uniform Data Set aged 65+ years diagnosed with amnestic mild cognitive impairment (aMCI) were included in this analysis. Population-averaged decline to dementia rates was estimated and compared for standardized MMSE, CDR-SB, and CS using Generalized Estimating Equations (GEE). Associations between rate of decline and several potential correlates of decline were also calculated and compared across measures. The CDR-SB had the steepest estimated slope, with a decline of 0.49 standard deviations (SD) per year, followed by the MMSE with 0.22 SD per year, and finally the CS with 0.07 SD per year. The rate of decline of the three measures differed significantly in a global test for differences (p < 0.0001). Age at visit, body mass index (BMI) at visit, Apolipoprotein E (APOE) ɛ4 allele status, and race (black vs. white) had significantly different relationships with rate of decline in a global test for difference among the three measures. These results suggest that both the rate of decline and the effects of AD risk factors on decline to dementia can vary depending on the evaluative measure used.

Accuracy of the Clinical Diagnosis of Alzheimer Disease at National Institute on Aging Alzheimer Disease Centers, 2005–2010

The neuropathologic examination is considered to provide the gold standard for Alzheimer disease (AD). To determine the accuracy of currently used clinical diagnostic methods, clinical and neuropathologic data from the National Alzheimer's Coordinating Center, which gathers information from the network of National Institute on Aging (NIA)-sponsored Alzheimer Disease Centers (ADCs), were collected as part of the National Alzheimer's Coordinating Center Uniform Data Set (UDS) between 2005 and 2010. A database search initially included all 1198 subjects with at least one UDS clinical assessment and who had died and been autopsied; 279 were excluded as being not demented or because critical data fields were missing. The final subject number was 919. Sensitivity and specificity were determined based on "probable" and "possible" AD levels of clinical confidence and 4 levels of neuropathologic confidence based on varying neuritic plaque densities and Braak neurofibrillary stages. Sensitivity ranged from 70.9% to 87.3%; specificity ranged from 44.3% to 70.8%. Sensitivity was generally increased with more permissive clinical criteria and specificity was increased with more restrictive criteria, whereas the opposite was true for neuropathologic criteria. When a clinical diagnosis was not confirmed by minimum levels of AD histopathology, the most frequent primary neuropathologic diagnoses were tangle-only dementia or argyrophilic grain disease, frontotemporal lobar degeneration, cerebrovascular disease, Lewy body disease and hippocampal sclerosis. When dementia was not clinically diagnosed as AD, 39% of these cases met or exceeded minimum threshold levels of AD histopathology. Neurologists of the NIA-ADCs had higher predictive accuracy when they diagnosed AD in subjects with dementia than when they diagnosed dementing diseases other than AD. The misdiagnosis rate should be considered when estimating subject numbers for AD studies, including clinical trials and epidemiologic studies.

Neuropsychiatric Profiles in Dementia

We compared patterns of neuropsychiatric symptoms across 4 dementia types [Alzheimer disease (AD), vascular dementia (VAD), dementia with Lewy bodies (DLB), and Parkinson disease dementia], and 2 mixed groups (AD/VAD and AD/DLB) in sample of 2,963 individuals from the National Alzheimer's Coordinating Center Uniform Data Set between September 2005 and June 2008. We used confirmatory factor analysis to compare neuropsychiatric symptom severity ratings made by collateral sources on the Neuropsychiatric Inventory Questionnaire for people with Clinical Dementia Rating scores of 1 or higher. A 3-factor model of psychiatric symptoms (mood, psychotic, and frontal) was shared across all dementia types. Between-group comparisons revealed unique neuropsychiatric profiles by dementia type. The AD group had moderate levels of mood, psychotic, and frontal symptoms whereas VAD exhibited the highest levels and Parkinson disease dementia had the lowest levels. DLB and the mixed dementias had more complex symptom profiles. Depressed mood was the dominant symptom in people with mild diagnoses. Differing psychiatric symptom profiles provide useful information regarding the noncognitive symptoms of dementia.

Psychosis in Alzheimer′s Disease in the National Alzheimer′s Disease Coordinating Center Uniform Data Set: Clinical Correlates and Association with Apolipoprotein E

Approximately 50% of late-onset Alzheimer's disease (AD) patients develop psychosis (AD+P), a heritable phenotype associated with more rapid cognitive decline. Prior studies conflict regarding whether apolipoprotein E (APOE) ϵ4 alleles are associated with AD+P, possibly due to small sample sizes, inconsistent diagnostic criteria, and different methodologies to assess psychosis. We used the National Alzheimer's Coordinating Center Uniform Data Set to evaluate the largest uniformly characterized sample of AD+P subjects studied to date for the association of APOE ϵ4 genotype, along with other demographic and clinical variables. Greater cognitive impairment and depressive symptoms were associated with AD+P, while the Caucasian race was protective. Neither APOE ϵ4 carrier status nor allele number was associated with psychosis. The AD+P phenotype is not associated with the APOE ϵ4 genotype. AD+P may represent a useful phenotype for the discovery of non-APOE ϵ4 genetic variation contributing to the risk of AD.

A web-based normative calculator for the uniform data set (UDS) neuropsychological test battery

IntroductionWith the recent publication of new criteria for the diagnosis of preclinical Alzheimer's disease (AD), there is a need for neuropsychological tools that take premorbid functioning into account in order to detect subtle cognitive decline. Using demographic adjustments is one method for increasing the sensitivity of commonly used measures. We sought to provide a useful online z-score calculator that yields estimates of percentile ranges and adjusts individual performance based on sex, age and/or education for each of the neuropsychological tests of the National Alzheimer's Coordinating Center Uniform Data Set (NACC, UDS). In addition, we aimed to provide an easily accessible method of creating norms for other clinical researchers for their own, unique data sets.MethodsData from 3,268 clinically cognitively-normal older UDS subjects from a cohort reported by Weintraub and colleagues (2009) were included. For all neuropsychological tests, z-scores were estimated by subtracting the raw score from the predicted mean and then dividing this difference score by the root mean squared error term (RMSE) for a given linear regression model.ResultsFor each neuropsychological test, an estimated z-score was calculated for any raw score based on five different models that adjust for the demographic predictors of SEX, AGE and EDUCATION, either concurrently, individually or without covariates. The interactive online calculator allows the entry of a raw score and provides five corresponding estimated z-scores based on predictions from each corresponding linear regression model. The calculator produces percentile ranks and graphical output.ConclusionsAn interactive, regression-based, normative score online calculator was created to serve as an additional resource for UDS clinical researchers, especially in guiding interpretation of individual performances that appear to fall in borderline realms and may be of particular utility for operationalizing subtle cognitive impairment present according to the newly proposed criteria for Stage 3 preclinical Alzheimer's disease.

Utility of the Functional Activities Questionnaire for Distinguishing Mild Cognitive Impairment From Very Mild Alzheimer Disease

Current criteria for mild cognitive impairment (MCI) require "essentially intact" performance of activities of daily living (ADLs), which has proven difficult to operationalize. We sought to determine how well the Functional Activities Questionnaire (FAQ), a standardized assessment of instrumental ADLs, delineates the clinical distinction between MCI and very mild Alzheimer disease (AD). We identified 1801 individuals in the National Alzheimer's Coordinating Center Uniform Data Set with MCI (n=1108) or very mild AD (n=693) assessed with the FAQ and randomized them to the development or test sets. Receiver-operator curve (ROC) analysis of the development set identified optimal cut-points that maximized the sensitivity and specificity of FAQ measures for differentiating AD from MCI and were validated with the test set. ROC analysis of total FAQ scores in the development set produced an area under the curve of 0.903 and an optimal cut-point of 5/6, which yielded 80.3% sensitivity, 87.0% specificity, and 84.7% classification accuracy in the test set. Bill paying, tracking current events, and transportation (P's<0.005) were the FAQ items of greatest diagnostic utility. These data suggest that the FAQ exhibits adequate sensitivity and specificity when used as a standardized assessment of instrumental ADLs in the diagnosis of AD versus MCI.

Unified Parkinson’s Disease Rating Scale‐Motor Exam: inter‐rater reliability of advanced practice nurse and neurologist assessments

This paper is a report of a study to establish the inter-rater reliability of advanced practice nurse and neurologist neurological assessments which included ratings with the Unified Parkinson's Disease Rating Scale-Motor Exam. Around the world, advanced practice nurses are performing tasks once completed only by physicians. To promote consumer and provider confidence, it is important to establish that nurse and physician ratings using assessment tools are similar. In addition in research settings, when different raters are used, establishment of inter-rater reliability for study assessments is needed. Advanced practice nurses and neurologists independently recorded findings on neurological examinations of 46 participants in a study conducted between August 2007 and January 2008. An intraclass correlation coefficient was calculated to estimate overall agreement between the nurse and neurologist ratings. Agreement for individual items measured on a dichotomous scale was assessed by calculating Cohen's kappa. There was substantial agreement between advanced practice nurses and neurologists on the mean Unified Parkinson's Disease Rating Scale-Motor Exam ratings (intraclass correlation coefficient = 0.65) and the U.S. National Alzheimer's Coordinating Center Uniform Data Set neurological examination ratings of unremarkable findings (kappa = 0.74) and of gait disorder (kappa = 0.73). Moderate agreement (kappa = 0.53) was reached for the rating of whether all Unified Parkinson's Disease Rating Scale-Motor Exam items were normal. These findings are consistent with studies of the inter-rater agreement of the Unified Parkinson's Disease Rating Scale-Motor Exam and support the conduct of neurological assessments by advanced practice nurses.

Polypharmacy and Potentially Inappropriate Medication Use Among Community-dwelling Elders With Dementia

This cross-sectional study examines the association between total prescription medication use and potentially inappropriate medication use (PIRx) among community-dwelling elderly patients with and without dementia. Data (September 2005 to September 2007) were from the National Institute on Aging-funded National Alzheimer's Coordinating Center Uniform Data Set. The study analyzed the Uniform Data Set initial visits of 4518 community-dwelling subjects aged 65 years and above with and without dementia (2665 and 1853, respectively). PIRx was defined using a partial list of the 2003 Beers criteria. Generalized linear mixed models were applied to estimate the association between PIRx and polypharmacy. In both groups (with and without dementia), subjects who received PIRx on average took more medications than those taking no PIRx. As the total number of medications used increased, the odds of having PIRx also increased, controlling for dementia diagnosis and other subject characteristics. Our key findings were consistent after considering 2 definitions of PIRx (with or without oral estrogens) and accounting for missing data. In summary, the total number of medications used is associated with PIRx among Alzheimer's Disease Centers community-dwelling elderly patients with and without dementia, with polypharmacy increasing the risk of PIRx. Ensuring appropriate medication use in this population is clinically important because of the significant risks for institutionalization.