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1.  The Alzheimer’s Disease Centers’ Uniform Data Set (UDS): The Neuropsychological Test Battery 
The neuropsychological test battery from the Uniform Data Set (UDS) of the Alzheimer’s Disease Centers (ADC) program of the National Institute on Aging (NIA) 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 3,268 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 (AD) in a relatively well-educated sample. Regression models investigating the impact of age, education, and gender 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 AD and other forms of dementia.
PMCID: PMC2743984  PMID: 19474567
2.  Factor Structure of the National Alzheimer’s Coordinating Centers Uniform Dataset Neuropsychological Battery: An evaluation of invariance between and within groups over time 
The neuropsychological battery from the National Alzheimer’s Disease Coordinating Center (NACC) is designed to provide a sensitive assessment of mild cognitive disorders for multicenter investigations. Comprised of eight common neuropsychological tests (12 measures), the battery assesses cognitive domains affected early in the course of Alzheimer’s disease (AD). We examined the factor structure of the battery across levels of cognition (normal, mild cognitive impairment (MCI), dementia) based on Clinical Dementia Rating (CDR) scores to determine cognitive domains tapped by the battery. Using data pooled from 29 NIA funded Alzheimer’s Disease Centers, exploratory factor analysis was used to derive a general model using half of the sample; four factors representing memory, attention, executive function, and language were identified. Confirmatory factor analysis (CFA) was used on the second half of the sample to evaluate invariance between groups and within groups over one year. Factorial invariance testing included systematic addition of constraints and comparisons of nested models. The general CFA model had a good fit. As constraints were added, model fit deteriorated slightly. Comparisons within groups demonstrated stability over one year. In a range of cognition from normal to dementia, factor structures and factor loadings will vary little. Further work is needed to determine if domains become more or less distinct in severely cognitively compromised individuals.
PMCID: PMC3101374  PMID: 21606904
Factor Analysis; invariance; neuropsychological tests; dementia; Alzheimer’s disease
3.  Distinguishing Neurocognitive Functions in Schizophrenia Using Partially Ordered Classification Models 
Schizophrenia Bulletin  2006;32(4):679-691.
Current methods for statistical analysis of neuropsychological test data in schizophrenia are inherently insufficient for revealing valid cognitive impairment profiles. While neuropsychological tests aim to selectively sample discrete cognitive domains, test performance often requires several cognitive operations or “attributes.” Conventional statistical approaches assign each neuropsychological score of interest to a single attribute or “domain” (e.g., attention, executive, etc.), and scores are calculated for each. This can yield misleading information about underlying cognitive impairments. We report findings applying a new method for examining neuropsychological test data in schizophrenia, based on finite partially ordered sets (posets) as classification models.
A total of 220 schizophrenia outpatients were administered the Positive and Negative Symptom Scale (PANSS) and a neuropsychological test battery. Selected tests were submitted to cognitive attribute analysis a priori by two neuropsychologists. Applying Bayesian classification methods (posets), each patient was classified with respect to proficiency on the underlying attributes, based upon his or her individual test performance pattern.
Twelve cognitive “classes” are described in the sample. Resulting classification models provided detailed “diagnoses” into “attribute-based” profiles of cognitive strength/weakness, mimicking expert clinician judgment. Classification was efficient, requiring few measures to achieve accurate classification. Attributes were associated with PANSS factors in the expected manner (only the negative and cognition factors were associated with the attributes), and a double dissociation was observed in which divergent thinking was selectively associated with negative symptoms, possibly reflecting a manifestation of Kraepelin's hypothesis regarding the impact of volitional disturbances on thought.
Using posets for extracting more precise cognitive information from neuropsychological data may reveal more valid cognitive endophenotypes, while dramatically reducing the amount of testing required.
PMCID: PMC2632274  PMID: 16424379
schizophrenia; neurocognitive deficits; neuropsychological test domains; neuropsychological test data reduction; clustering techniques; Bayesian methods
Experimental aging research  2013;39(5):10.1080/0361073X.2013.839029.
Background/Study Context
Studies have found that executive functioning is affected early in the pathophysiological processes associated with Alzheimer’s disease and vascular dementia. There also exists a range of functioning on executive tasks during normal aging. Although qualitative data are commonly utilized in clinical practice for evaluating subtle changes in cognitive functioning and diagnostic discernment, it is not clear whether error responses used in clinical practice are also evident as normative behavior.
As part of an extensive battery of neuropsychological tests, executive functioning measures (i.e., Trail Making-B, Similarities and Verbal Fluency tests) were administered via standardized administration prescript. Regression analyses were used to determine associations between vascular aging indices and qualitative performance measures. Descriptive statistics are included for 1907 cognitively normal individuals.
Results suggest that while qualitative errors do occur, they are relatively infrequent within a presumably cognitively normal sample. Error commission rates on executive functioning tests are significantly associated with both age and education.
Provided is a baseline profile of errors committed on tests of executive function across a range of age and educational levels. The normative datasets are included, stratified by age and educational achievement, for which to compare qualitative test performance of clinical and research populations.
PMCID: PMC3836045  PMID: 24151914
5.  Abbreviated neuropsychological assessment in schizophrenia 
The aim of this study was to identify the best subset of neuropsychological tests for prediction of several different aspects of functioning in a large (n = 236) sample of older people with schizophrenia. While the validity of abbreviated assessment methods has been examined before, there has never been a comparative study of the prediction of different elements of cognitive impairment, real-world outcomes, and performance-based measures of functional capacity. Scores on 10 different tests from a neuropsychological assessment battery were used to predict global neuropsychological (NP) performance (indexed with averaged scores or calculated general deficit scores), performance-based indices of everyday-living skills and social competence, and case-manager ratings of real-world functioning. Forward entry stepwise regression analyses were used to identify the best predictors for each of the outcomes measures. Then, the analyses were adjusted for estimated premorbid IQ, which reduced the magnitude, but not the structure, of the correlations. Substantial amounts (over 70%) of the variance in overall NP performance were accounted for by a limited number of NP tests. Considerable variance in measures of functional capacity was also accounted for by a limited number of tests. Different tests constituted the best predictor set for each outcome measure. A substantial proportion of the variance in several different NP and functional outcomes can be accounted for by a small number of NP tests that can be completed in a few minutes, although there is considerable unexplained variance. However, the abbreviated assessments that best predict different outcomes vary across outcomes. Future studies should determine whether responses to pharmacological and remediation treatments can be captured with brief assessments as well.
PMCID: PMC2668735  PMID: 18720182
Schizophrenia; Disability; Neuropsychological assessment; Functional capacity; Abbreviated assessments
6.  Reliability and Validity of an Algorithm for the Diagnosis of Normal Cognition, MCI and Dementia: Implications for Multi-Center Research Studies 
The traditional consensus diagnosis (ConsDx) of normal cognition, mild cognitive impairment (MCI), and dementia relies on the reconciliation of an informant-based report of cognitive and functional impairment by a physician (PhyDx), and a neuropsychological diagnosis (NPDx). As this procedure may be labor-intensive and influenced by the philosophy and biases of a clinician, the diagnostic algorithm (AlgDx) was developed to identify individuals as cognitively normal, with MCI or dementia.
The AlgDx combines the PhyDx with the NPDx, using a computational algorithm that provides cognitive diagnoses, as defined by the National Alzheimer Coordinating Center/Uniform Data Set (NACC/UDS) nomenclature. Reliability of the AlgDx was assessed in 532 community-dwelling elderly subjects by its concordance with the ConsDx, and association with two biomarkers, medial temporal atrophy (MTA) scores of brain MRI scans, and ApoE-ε4 genotype.
A high degree of concordance was observed between ConsDx and AlgDx with a weighted Cohen’s kappa of 0.84. Concordance of the AlgDx to the same ConsDx categories ranged from 85% to 92%. Excellent discriminative validity was observed as AlgDx, MTA scores, and APOE-ε4 allele frequencies distinguished amnestic MCI and dementia subjects from normal subjects.
The AlgDx of normal cognition, MCI, and dementia is a valid alternative that reduces time, effort and biases associated with the ConsDx. The inherent reliability of a fixed algorithm, together with its efficiency and avoidance of individual bias, suggests the AlgDx may be used in longitudinal, multi-site clinical trials and population studies of MCI and dementia.
PMCID: PMC2844658  PMID: 20306566
Diagnosis; Algorithmic Diagnosis; Mild Cognitive Impairment; Dementia; Longitudinal Studies
7.  Characteristics of patients misdiagnosed with Alzheimer’s disease and their medication use: an analysis of the NACC-UDS database 
BMC Geriatrics  2013;13:137.
This 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.
Longitudinal 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.
Following 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%.
Findings 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.
PMCID: PMC3878261  PMID: 24354549
Alzheimer disease; Diagnosis; Misdiagnosis; Autopsy; Neuropathology
8.  Estimating Premorbid Cognitive Abilities in Low-Educated Populations 
PLoS ONE  2013;8(3):e60084.
To develop an informant-based instrument that would provide a valid estimate of premorbid cognitive abilities in low-educated populations.
A questionnaire was drafted by focusing on the premorbid period with a 10-year time frame. The initial pool of items was submitted to classical test theory and a factorial analysis. The resulting instrument, named the Premorbid Cognitive Abilities Scale (PCAS), is composed of questions addressing educational attainment, major lifetime occupation, reading abilities, reading habits, writing abilities, calculation abilities, use of widely available technology, and the ability to search for specific information. The validation sample was composed of 132 older Brazilian adults from the following three demographically matched groups: normal cognitive aging (n = 72), mild cognitive impairment (n = 33), and mild dementia (n = 27). The scores of a reading test and a neuropsychological battery were adopted as construct criteria. Post-mortem inter-informant reliability was tested in a sub-study with two relatives from each deceased individual.
All items presented good discriminative power, with corrected item-total correlation varying from 0.35 to 0.74. The summed score of the instrument presented high correlation coefficients with global cognitive function (r = 0.73) and reading skills (r = 0.82). Cronbach's alpha was 0.90, showing optimal internal consistency without redundancy. The scores did not decrease across the progressive levels of cognitive impairment, suggesting that the goal of evaluating the premorbid state was achieved. The intraclass correlation coefficient was 0.96, indicating excellent inter-informant reliability.
The instrument developed in this study has shown good properties and can be used as a valid estimate of premorbid cognitive abilities in low-educated populations. The applicability of the PCAS, both as an estimate of premorbid intelligence and cognitive reserve, is discussed.
PMCID: PMC3605367  PMID: 23555894
9.  Effects of cannabis on cognitive function in patients with multiple sclerosis 
Neurology  2011;76(13):1153-1160.
While neuropsychological deficits have been reported in healthy individuals who use street cannabis, data in patients with multiple sclerosis (MS) are lacking. Given that MS is associated with cognitive deterioration, the aim of this study was to determine the neuropsychological effects of cannabis use in this population.
Two groups, each of 25 patients with MS (cannabis users and nonusers), were administered the Minimal Assessment of Cognitive Function in MS battery of neuropsychological tests, the Hospital Anxiety and Depression Scale (HADS), and the Structured Clinical Interview for the DSM-IV Axis I Disorders (SCID-I). Group-matching and regression analysis were used to control for the effects of age, sex, education, premorbid intelligence, disability, and disease course and duration on cognitive function.
Cannabis users performed significantly more poorly than nonusers on measures of information processing speed, working memory, executive functions, and visuospatial perception. They were also twice as likely as nonusers to be classified as globally cognitively impaired. There were no between-group differences on the HADS measures of depression and anxiety or lifetime SCID-I psychiatric diagnoses.
This cross-sectional study provides empirical evidence that prolonged use of inhaled or ingested street cannabis in patients with MS is associated with poorer performance on cognitive domains commonly affected in this population. Whatever subjective benefits patients may derive from using street cannabis (e.g., pain and spasticity relief) should be weighed against the associated cognitive side effects.
PMCID: PMC3068013  PMID: 21444900
10.  The emergence of cognitive discrepancies in preclinical Alzheimer's disease: A six-year case study 
Neurocase  2009;15(4):278-293.
We present neuropsychological data from an 81-year-old individual who was followed over a six-year period, initially as a healthy control participant. She performed above age-adjusted cutoff scores for impairment on most neuropsychological tests, including learning and memory measures, until the final assessment when she received a diagnosis of probable Alzheimer's disease (AD). Despite generally normal scores on individual cognitive tests, her cognitive profile revealed increasingly large cognitive discrepancies when contrasting verbal versus visuospatial tasks, and complex versus basic-level tasks. The present case provides intriguing evidence that cognitive-discrepancy measures could improve our ability to detect subtle changes in cognition at the earliest, preclinical stages of AD.
PMCID: PMC2875065  PMID: 19382039
Alzheimer's disease; Neuropsychology; Cognition; Discrepancy; Preclinical
11.  Cognitive Dimensions in Alzheimer’s Disease, Mild Cognitive Impairment, and Normal Elderly: Developing a Common Metric 
The aim of this research was to assess similarity in cognitive factor structures underlying neuropsychological test performance of elders belonging to three clinical groups: Alzheimer’s disease (AD), Mild Cognitive Impairment (MCI), and normal elderly. We administered a battery of neuropsychological tests to 214 elderly participants in the groups. First, the underlying cognitive structure of a Combined-Set of AD, MCI, and Control subjects was determined by Principal Components Analysis (PCA), including quantitative relationships (loadings) between the test measures and the factors. The PCA resolved 17 neuropsychological test measures into 6 interpretable factors, accounting for 78% of the variance. This cognitive structure was compared with separate cognitive structures from an AD-Set, an MCI-Set, and a Control-Set (different individuals in each set) in additional PCA using Procrustes factor rotation. Analysis of congruence coefficients between each set and the Combined-Set by a bootstrapping statistical procedure supported the factor invariance hypothesis. These close similarities across groups in their underlying neuropsychological dimensions support the use of a common metric system (the factor structure of a Combined-Set) for measuring neuropsychological factors in all these elderly individuals.
PMCID: PMC2922059  PMID: 20717503
Neuropsychological tests; Principal Components Analysis (PCA); cognitive structures; cognitive dimensions; common metric; Procrustes factor rotation; Alzheimer’s disease; Mild Cognitive Impairment; elderly controls; congruence coefficients
12.  Norms for CERAD Constructional Praxis Recall 
The Clinical Neuropsychologist  2011;25(8):1345-1358.
Recall of the 4-item constructional praxis measure was a later addition to the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) neuropsychological battery. Norms for this measure, based on cognitively intact African Americans age ≥70 (Indianapolis-Ibadan Dementia Project, N=372), European American participants age ≥66 (Cache County Study of Memory, Health and Aging, N=507), and European American CERAD clinic controls age ≥50 (N=182), are presented here. Performance varied by site; by sex, education and age (African Americans in Indianapolis); education and age (Cache County European Americans; and only age (CERAD European American controls). Performance declined with increased age, within age with less education, and was poorer for women. Means, standard deviations, and percentiles are presented separately for each sample.
PMCID: PMC3398459  PMID: 21992077
Consortium to Establish a Registry for Alzheimer’s Disease; elderly; neuropsychology measures; constructional praxis; norms; African American
13.  The Relationship between Perceived Cognitive Dysfunction and Objective Neuropsychological Performance in Persons with Rheumatoid Arthritis 
Arthritis care & research  2013;65(3):481-486.
Research shows a gap between perceived cognitive dysfunction and objective neuropsychological performance in persons with chronic diseases. We explored this relationship in persons with rheumatoid arthritis (RA).
Individuals from a longitudinal cohort study of RA participated in a study visit that included physical, psychosocial, and biological metrics. Subjective cognitive dysfunction was assessed using the Perceived Deficits Questionnaire (PDQ; 0–20, higher scores = greater perceived impairment). Objective cognitive impairment was assessed using a battery of 12 standardized neuropsychological measures yielding 16 indices. On each test, subjects were classified as ‘impaired’ if they performed 1 SD below age-based population norms. Total cognitive function scores were calculated by summing the transformed scores (0–16, higher scores = greater impairment). Multiple linear regression analyses determined the relationship of total cognitive function score with PDQ score, controlling for gender, race, marital status, income, education, disease duration, disease severity, depression, and fatigue.
120 subjects (mean ± SD age: 58.5 ± 11.0 years) were included. Mean ± SD scores of total cognitive function and PDQ were 2.5 ± 2.2 (0–10) and 5.8 ± 3.8 (0–16), respectively. In multivariate analysis, there was no significant relationship between total cognitive function score and PDQ score. However, depression and fatigue (β = 0.31, p < 0.001; β = 0.31, p = 0.001) were significantly associated with PDQ score.
The findings emphasize the gap between subjective and objective measures of cognitive impairment and the importance of considering psychological factors within the context of cognitive complaints in clinical settings.
PMCID: PMC3786333  PMID: 22899659
14.  Predictors of cognitive impairment in advanced Parkinson's disease 
Design: Retrospective cohort analysis.
Methods: 100 patients with idiopathic Parkinson's disease were given a neuropsychological test battery investigating attention, memory, and visuospatial and executive functions. Test performance was compared against normative data, and linear regression determined significant predictors of cognitive impairment from a set of demographic and disease course variables.
Results: Frontal-type cognitive dysfunction was widespread in patients with advanced Parkinson's disease. Attention and memory were mildly to moderately impaired, whereas visuospatial function showed only subtle impairment. Older age and tremor at onset were significant predictors of poor cognitive performance.
Conclusions: The observed cognitive impairment in patients with advanced Parkinson's disease is more than expected for normal aging. Although in apparent contrast with most previous research, reporting a greater risk of cognitive dysfunction in Parkinson's disease patients with predominant akinesia/rigidity, tremor at onset may be a marker for more widespread brain pathology that contributes to an increased risk of cognitive impairment.
PMCID: PMC1738465  PMID: 12754355
15.  Frequency of and risk factors for poor cognitive performance in hemodialysis patients 
Neurology  2013;80(5):471-480.
There are few detailed data on cognition in patients undergoing dialysis. We evaluated the frequency of and risk factors for poor cognitive performance using detailed neurocognitive testing.
In this cross-sectional cohort study, 314 hemodialysis patients from 6 Boston-area hemodialysis units underwent detailed cognitive assessment. The neuropsychological battery assessed a broad range of functions, with established age-, sex-, and education-matched normative scores. Principal component analysis was used to derive composite scores for memory and executive function domains. Risk factors for each domain were evaluated using linear regression adjusting for age, sex, race, and education status. Analyses were repeated in those with Mini-Mental State Examination (MMSE) score ≥24.
Compared with population norms, patients on dialysis had significantly poorer executive function but not memory performance, a finding that persisted in the subgroup with MMSE score ≥24. In adjusted analyses, vascular risk factors and vascular disease were associated with lower executive function (p < 0.01).
There is a high frequency of poor cognitive performance in hemodialysis patients, primarily affecting executive function. Risk factors for worse executive function include vascular risk factors as well as vascular disease. Normal performance on the MMSE does not preclude impaired cognitive function, because individuals with MMSE score ≥24 also have a high frequency of poor cognitive performance.
PMCID: PMC3590049  PMID: 23303848
16.  Accuracy of the Clinical Diagnosis of Alzheimer Disease at National Institute on Aging Alzheimer's Disease Centers, 2005–2010 
The neuropathological examination is considered to provide the gold standard for Alzheimer disease (AD). To determine the accuracy of currently employed clinical diagnostic methods, clinical and neuropathological data from the National Alzheimer's Coordinating Center (NACC), which gathers information from the network of National Institute on Aging (NIA)-sponsored Alzheimer's Disease Centers (ADCs), were collected as part of the NACC 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 neuropathological 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 neuropathological criteria. When a clinical diagnosis was not confirmed by minimum levels of AD histopathology, the most frequent primary neuropathological 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 demented subjects 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 epidemiological studies.
PMCID: PMC3331862  PMID: 22437338
Alzheimer disease; Autopsy; Clinical trials; Diagnosis; Histopathology; Neuropathology; Non-Alzheimer dementia
17.  Comparing measures of decline to dementia in amnestic MCI subjects in the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set 
International psychogeriatrics / IPA  2012;24(10):1553-1560.
Many studies have investigated factors associated with the rate of decline and evolution from mild cognitive impairment 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 Status Examination (MMSE) score, Clinical Dementia Rating sum of boxes score (CDR-SB), and a neuropsychological tests composite score (CS).
A total of 2,899 subjects in the National Alzheimer’s Coordinating Center Uniform Data Set age 65+ years diagnosed with amnestic mild cognitive impairment (aMCI) were included in this analysis. Population-averaged decline to dementia rates were estimated and compared for standardized MMSE, CDR-SB, and Composite scores 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 .49 standard deviations (SD) per year, followed by the MMSE with .22 SD/year, and finally the CS with .07 SD/year. The rate of decline of the three measures differed significantly in a global test for differences (p<.0001). Age at visit, BMI at visit, APOE ε4 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.
PMCID: PMC3614357  PMID: 22717299
neuropsychological testing; Alzheimer’s Disease; cognitive assessment; aging
18.  Recommended Measures for the Assessment of Cognitive and Physical Performance in Older Patients with Dementia: A Systematic Review 
To recommend a set of neuropsychological and physical exercise tests for researchers to assess cognition and physical fitness in clinical trials with older patients with dementia; to create consensus, decrease heterogeneity, and improve research quality.
A literature search (2005–2011) yielded 89 randomized controlled trials. To provide information on test recommendations the frequency of test use, effect size of the test outcome, study quality, and psychometric properties of tests were analyzed.
Fifty-nine neuropsychological tests (cognitive domains: global cognition, executive functioning, memory, and attention) and 10 exercise tests (physical domains: endurance capacity, muscle strength, balance, and mobility) were found.
The Severe Impairment Battery, Mini Mental State Examination, and Alzheimer Disease Assessment Scale – cognitive subscale were recommended to measure global cognition. The Verbal Fluency Test Category/Letters, Clock Drawing Test, and Trail Making Test-B were recommended to measure executive functioning. No specific memory test could be recommended. The Digit Span Forward, Digit Span Backward, and Trail Making Test-A were recommended to measure attention. As physical exercise tests, the Timed Up and Go and Six Meter Walk for mobility, the Six Minute Walk Distance for endurance capacity, and the Tinetti Balance Scale were recommended.
PMCID: PMC3551396  PMID: 23341825
Dementia; Neuropsychological tests; Exercise tests; Tool use; Outcome measures; Systematic review
19.  Executive Functions in Chronic Mesial Temporal Lobe Epilepsy 
There is no consensus as to whether mesial temporal lobe epilepsy (MTLE) leads to executive function deficits. In this study, we adopted an extensive neuropsychological test battery and assessed different executive functions in chronic, unilateral MTLE. Performance of MTLE patients was compared with that of healthy peers and with normative data. Several MTLE patients had scores below cut-off or below the 10th percentile of normative data. Scores of the whole patient group were overall in the average range of normative data. Relative to controls, MTLE patients performed poorly in tests of working memory, cognitive flexibility, categorical verbal fluency, set-shifting, categorization, and planning. These findings raise an important methodological issue as they suggest that executive function deficits in chronic MTLE may be individually variable and that their assessment should include different tests. Deficits in chronic MTLE are not limited to temporal lobe functions, such as memory, but may extend to extra temporal cognitive domains, such as executive functions.
PMCID: PMC3428608  PMID: 22937233
20.  Confirmatory Factor Analysis of the ADNI Neuropsychological Battery 
Brain imaging and behavior  2012;6(4):528-539.
The Alzheimer’s Disease Neuroimaging Initiative (ADNI) is a large multi-center study designed to develop optimized methods for acquiring longitudinal neuroimaging, cognitive, and biomarker measures of AD progression in a large cohort of patients with Alzheimer’s disease (AD), patients with mild cognitive impairment, and healthy controls. Detailed neuropsychological testing was conducted on all participants. We examined the factor structure of the ADNI Neuropsychological Battery across older adults with differing levels of clinical AD severity based on the Clinical Dementia Rating Scale (CDR). Confirmatory factor analysis (CFA) of 23 variables from 10 neuropsychological tests resulted in five factors (memory, language, visuospatial functioning, attention, and executive function/processing speed) that were invariant across levels of cognitive impairment. Thus, these five factors can be used as valid indicators of cognitive function in older adults who are participants in ADNI.
PMCID: PMC3538867  PMID: 22777078
ADNI; neuropsychology; cognition; cognitive change; confirmatory factor analysis
21.  Cognition in Non-Demented Diabetic Older Adults 
Current aging science  2012;5(2):131-135.
Evidence links diabetes mellitus to cognitive impairment and increased risk of Alzheimer's disease (AD) and suggests that insulin therapy improves cognition. With an increasing percentage of the US elderly population at high risk for diabetes and AD, the evidence of an association between diabetes and poor cognition in non-demented elderly may have implications for diagnosis, prevention and treatment of cognitive decline including AD.
In our study, we hypothesized that diabetic elders with normal cognition would demonstrate poorer cognitive outcomes than non-diabetic elders and that diabetic elders receiving diabetes treatment would demonstrate better outcomes than those not receiving treatment.
Data were evaluated from the National Alzheimer's Coordinating Center's Uniform Data Set (UDS). The UDS consists of clinical and neuropsychological assessments of a sample of elderly research subjects recruited from thirty-one Alzheimer's Disease Centers nationwide. The UDS provides a unique opportunity to study cognition in a nationally recruited sample with structured neuropsychological tests.
We examined the impact of diabetes and diabetes treatment on cognitive measures in 3421 elderly research subjects from 2005-2007 with normal cognition. We performed linear regression analyses to compare cognitive scores between diabetic subjects and non-diabetic subjects. Diabetic subjects had lower scores than non-diabetic subjects including attention, psychomotor function and executive function, but no differences in memory or semantic memory language. There was no association between diabetes treatment and cognitive scores.
These subtle but significant cognitive deficits in diabetic subjects compared to non-diabetic subjects may contribute to difficulty with compliance with complex diabetes medication regimens. A specific role of diabetes as a risk for cognitive impairment will require longitudinal study.
PMCID: PMC3659164  PMID: 22023096
Diabetes; Cognition; Alzheimer's; Elderly
22.  Predictors of driving safety in early Alzheimer disease 
Neurology  2009;72(6):521-527.
To measure the association of cognition, visual perception, and motor function with driving safety in Alzheimer disease (AD).
Forty drivers with probable early AD (mean Mini-Mental State Examination score 26.5) and 115 elderly drivers without neurologic disease underwent a battery of cognitive, visual, and motor tests, and drove a standardized 35-mile route in urban and rural settings in an instrumented vehicle. A composite cognitive score (COGSTAT) was calculated for each subject based on eight neuropsychological tests. Driving safety errors were noted and classified by a driving expert based on video review.
Drivers with AD committed an average of 42.0 safety errors/drive (SD = 12.8), compared to an average of 33.2 (SD = 12.2) for drivers without AD (p < 0.0001); the most common errors were lane violations. Increased age was predictive of errors, with a mean of 2.3 more errors per drive observed for each 5-year age increment. After adjustment for age and gender, COGSTAT was a significant predictor of safety errors in subjects with AD, with a 4.1 increase in safety errors observed for a 1 SD decrease in cognitive function. Significant increases in safety errors were also found in subjects with AD with poorer scores on Benton Visual Retention Test, Complex Figure Test-Copy, Trail Making Subtest-A, and the Functional Reach Test.
Drivers with Alzheimer disease (AD) exhibit a range of performance on tests of cognition, vision, and motor skills. Since these tests provide additional predictive value of driving performance beyond diagnosis alone, clinicians may use these tests to help predict whether a patient with AD can safely operate a motor vehicle.
AD = Alzheimer disease; AVLT = Auditory Verbal Learning Test; Blocks = Block Design subtest; BVRT = Benton Visual Retention Test; CFT = Complex Figure Test; CI = confidence interval; COWA = Controlled Oral Word Association; CS = contrast sensitivity; FVA = far visual acuity; JLO = Judgment of Line Orientation; MCI = mild cognitive impairment; MMSE = Mini-Mental State Examination; NVA = near visual acuity; SFM = structure from motion; TMT = Trail-Making Test; UFOV = Useful Field of View.
PMCID: PMC2677513  PMID: 19204261
23.  Neuropsychological Functioning in Bipolar Disorder and Schizophrenia 
Biological psychiatry  2006;62(2):179-186.
Some patients with bipolar disorder (BD) demonstrate neuropsychological deficits even when stable. However, it remains unclear whether these differ qualitatively from those seen in schizophrenia (SZ).
We compared the nature and severity of cognitive deficits shown by 106 patients with SZ and 66 patients with BD to 316 healthy adults (NC). All participants completed a cognitive battery with 19 individual measures. After adjusting their test performance for age, sex, race, education, and estimated premorbid IQ, we derived regression-based T-scores for each measure and the six cognitive domains.
Both patient groups performed significantly worse than NCs on most (BD) or all (SZ) cognitive tests and domains. The resulting effect sizes ranged from 0.37 to 1.32 (mean = 0.97) across tests for SZ patients and from 0.23 to 0.87 (mean = 0.59) for BD patients. The Pearson correlation of these effect sizes was 0.71 (p < 0.001).
Patients with bipolar disorder suffer from cognitive deficits that are milder but qualitatively similar to those of patients with schizophrenia. These findings support the notion that schizophrenia and bipolar disorder show greater phenotypic similarity in terms of the nature than severity of their neuropsychological deficits.
PMCID: PMC2041824  PMID: 17161829
bipolar disorder; schizophrenia; cognitive testing; neuropsychology; biomarker
24.  Prevalence and correlates of neuropsychological deficits in amyotrophic lateral sclerosis. 
OBJECTIVE: To determine the prevalence and correlates of neuropsychological impairment in a large cohort (n = 146) of patients with typical, sporadic (non-familial) amyotrophic lateral sclerosis. METHODS: A battery of neuropsychological tests was administered to patients with amyotrophic lateral sclerosis who were attending a monthly outpatient clinic or who were in hospital undergoing diagnostic tests. RESULTS: Comparing individual patient's scores with relevant normative data, 35.6% of the patients displayed evidence of clinically significant impairment, performing at or below the 5th percentile on at least two of the eight neuropsychological measures. Deficits were most common in the areas of problem solving, attention/mental control, continuous visual recognition memory, word generation, and verbal free recall. Impairment was most prevalent in patients with dysarthria (48.5%), but 27.4% of non-dysarthric patients were also impaired. Impaired patients had more severe or widespread symptoms of amyotrophic lateral sclerosis than non-impaired patients, and had fewer years of education. CONCLUSION: Neither the conventional wisdom that cognition is intact in nearly all patients with amyotrophic lateral sclerosis, nor more recent suggestions that cognition is often at least mildly impaired seems to be correct. A minority of patients with amyotrophic lateral sclerosis displayed evidence of significant impairment. Dysarthria, low education, and greater severity of motor symptoms were risk factors for impairment.
PMCID: PMC1074039  PMID: 8937336
25.  Elevated Blood Pressure and Cognitive Decline in Mild Cognitive Impairment 
Controversy exists regarding whether high blood pressure (BP) is a risk factor for an accelerated decline in persons with mild cognitive impairment (MCI). The purpose of this study was to examine whether elevated BP levels are associated with a faster decline in specific cognitive domains.
Prospective longitudinal cohort.
Uniform Data Set of the NIH-NIA Alzheimer’s Disease Centers.
1385 participants with a diagnosis of MCI and measured BP values at baseline and two annual follow-up visits.
Neuropsychological test scores and Clinical Dementia Rating Sum of Boxes score.
MCI patients with two or three annual occasions of high BP values (≥140 systolic BP or ≥90 diastolic BP) had a significantly faster decline on neuropsychological measures of visuomotor sequencing, set shifting, and naming than those who were normotensive on all three occasions. Elevated systolic BP values were associated as well with a faster decline on the Clinical Dementia Rating Sum of Boxes score.
Hypertension is associated with a faster cognitive decline in persons at risk for dementia.
PMCID: PMC3518855  PMID: 18604484
Mild Cognitive Impairment; Hypertension; Neuropsychology; Cerebrovascular Disease; Dementia

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