A Novel Computerized Cognitive Stress Test to Detect Mild Cognitive Impairment.

BACKGROUND: The Loewenstein Acevedo Scales of Semantic Interference and Learning (LASSI-L) is a novel and increasingly employed instrument that has outperformed widely used cognitive measures as an early correlate of elevated brain amyloid and neurodegeneration in prodromal Alzheimer's Disease (AD). The LASSI-L has distinguished those with amnestic mild cognitive impairment (aMCI) and high amyloid load from aMCI attributable to other non-AD conditions. The authors designed and implemented a web-based brief computerized version of the instrument, the LASSI-BC, to improve standardized administration, facilitate scoring accuracy, real-time data entry, and increase the accessibility of the measure. OBJECTIVE: The psychometric properties and clinical utility of the brief computerized version of the LASSI-L was evaluated, together with its ability to differentiate older adults who are cognitively normal (CN) from those with amnestic Mild Cognitive Impairment (aMCI). METHODS: After undergoing a comprehensive uniform clinical and neuropsychological evaluation using traditional measures, older adults were classified as cognitively normal or diagnosed with aMCI. All participants were administered the LASSI-BC, a computerized version of the LASSI-L. Test-retest and discriminant validity was assessed for each LASSI-BC subscale. RESULTS: LASSI-BC subscales demonstrated high test-retest reliability, and discriminant validity was attained. CONCLUSIONS: The LASSI-BC, a brief computerized version of the LASSI-L is a valid and useful cognitive tool for the detection of aMCI among older adults.

Amnestic Mild Cognitive Impairment is Characterized by the Inability to Recover from Proactive Semantic Interference across Multiple Learning Trials.

BACKGROUND: Difficulties in inhibition and self-monitoring are early features of incipient Alzheimer's disease and may manifest as susceptibility to proactive semantic interference. However, due to limitations of traditional memory assessment paradigms, recovery from interference effects following repeated learning opportunities has not been explored. OBJECTIVE: This study employed a novel computerized list learning test consisting of repeated learning trials to assess recovery from proactive and retroactive semantic interference. DESIGN: The design was cross-sectional. SETTING: Participants were recruited from the community as part of a longitudinal study on normal and abnormal aging. PARTICIPANTS: The sample consisted of 46 cognitively normal individuals and 30 participants with amnestic mild cognitive impairment. MEASUREMENTS: Participants were administered the Cognitive Stress Test and traditional neuropsychological measures. Step-wise logistic regression was applied to determine which Cognitive Stress Test measures best discriminated between diagnostic groups. This was followed by receiver operating characteristic analyses. RESULTS: Cued A3 recall, Cued B3 recall and Cued B2 intrusions were all independent predictors of diagnostic status. The overall predictive utility of the model yielded 75.9% sensitivity, 91.1% specificity, and an overall correct classification rate of 85.1%. When these variables were jointly entered into receiver operating characteristic analyses, the area under the curve was .923 (p<.001). CONCLUSIONS: This novel paradigm's use of repeated learning trials offers a unique opportunity to assess recovery from proactive and retroactive semantic interference. Participants with mild cognitive impairment exhibited a continued failure to recover from proactive interference that could not be explained by mere learning deficits.

Effect of age, ethnicity, sex, cognitive status and APOE genotype on amyloid load and the threshold for amyloid positivity.

The threshold for amyloid positivity by visual assessment on PET has been validated by comparison to amyloid load measured histopathologically and biochemically at post mortem. As such, it is now feasible to use qualitative visual assessment of amyloid positivity as an in-vivo gold standard to determine those factors which can modify the quantitative threshold for amyloid positivity. We calculated quantitative amyloid load, measured as Standardized Uptake Value Ratios (SUVRs) using [18-F]florbetaben PET scans, for 159 Hispanic and non-Hispanic participants, who had been classified clinically as Cognitively Normal (CN), Mild Cognitive Impairment (MCI) or Dementia (DEM). PET scans were visually rated as amyloid positive (A+) or negative (A-), and these judgments were used as the gold standard with which to determine (using ROC analyses) the SUVR threshold for amyloid positivity considering factors such as age, ethnicity (Hispanic versus non-Hispanic), gender, cognitive status, and apolipoprotein E ε4 carrier status. Visually rated scans were A+ for 11% of CN, 39.0% of MCI and 70% of DEM participants. The optimal SUVR threshold for A+ among all participants was 1.42 (sensitivity = 94%; specificity = 92.5%), but this quantitative threshold was higher among E4 carriers (SUVR = 1.52) than non-carriers (SUVR = 1.31). While mean SUVRs did not differ between Hispanic and non-Hispanic participants;, a statistically significant interaction term indicated that the effect of E4 carrier status on amyloid load was greater among non-Hispanics than Hispanics. Visual assessment, as the gold standard for A+, facilitates determination of the effects of various factors on quantitative thresholds for amyloid positivity. A continuous relationship was found between amyloid load and global cognitive scores, suggesting that any calculated threshold for the whole group, or a subgroup, is artefactual and that the lowest calculated threshold may be optimal for the purposes of early diagnosis and intervention.

Association of white matter hyperintensity measurements on brain MR imaging with cognitive status, medial temporal atrophy, and cardiovascular risk factors.

BACKGROUND AND PURPOSE: White matter hyperintensities (WMHs) are frequently characterized as markers of cerebrovascular disease, whereas medial temporal atrophy (MTA) is a recognized marker of Alzheimer disease (AD). Our purpose was to test the reliability of a visual rating system (VRS) in evaluating WMHs and MTA and in distinguishing healthy from cognitively impaired subjects. MATERIALS AND METHODS: Subjects (n = 192) enrolled in the Florida Alzheimer's Disease Research Center were diagnosed with no cognitive impairment, nonamnestic mild cognitive impairment (na-MCI), amnestic MCI (a-MCI), or probable AD. The severity of WMHs was assessed on T2-weighted fluid-attenuated inversion recovery axial MR images, and the severity of MTA was evaluated on 1.5-mm-thick coronal MR images by using a computer-based visual rating system. Cardiovascular risk factor scores were calculated as the sum of 10 independent cardiovascular risk factors. RESULTS: WMH and MTA scores were greater in subjects with probable AD, relative to those with no cognitive impairment and na-MCI. MTA scores differentiated subjects with a-MCI from those with no cognitive impairment and na-MCI. The total WMH score was significantly related to MTA (r = 0.39; P < .001) but not to cardiovascular risk factor scores (r = 0.07; P = not significant). The overall correct classification rate of probable AD versus no cognitive impairment by using MTA scores was 81.8%, improving to 86.5% when combined with WMH scores. CONCLUSIONS: Both MTA and WMH scores distinguished subjects with no cognitive impairment and probable AD. Combining MTA and WMH scores improved the correct classification rate, whereas WMH scores were significantly related to MTA scores, but not to cardiovascular risk factor scores. This finding suggests that among subjects with a-MCI and probable AD, WMHs on MR images are primarily associated with neurodegenerative disease.

Medial temporal lobe atrophy on MRI scans and the diagnosis of Alzheimer disease.

BACKGROUND: Despite convenience, accessibility, and strong correlation to severity of Alzheimer disease (AD) pathology, medial temporal lobe atrophy (MTA) has not been used as a criterion in the diagnosis of prodromal and probable AD. METHODS: Using a newly validated visual rating system, mean MTA scores of three bilateral medial temporal lobe structures were compared for subjects with no cognitive impairment (NCI) (n = 117), nonamnestic mild cognitive impairment (MCI) (n = 46), amnestic MCI (n = 45), and probable AD (n = 53). Correlations between MTA scores and neuropsychological test scores at baseline, and predictors of change in diagnosis at 1-year follow-up were evaluated. RESULTS: With NCI as the reference group, a mean MTA cut score of 1.33 yielded an optimal sensitivity/specificity of 85%/82% for probable AD subjects and 80%/82% for amnestic MCI subjects. MTA and Clinical Dementia Rating Sum of Boxes scores at baseline were independent and additive predictors of diagnosis at baseline, and of transition from NCI to MCI or from MCI to dementia at 1-year follow-up. CONCLUSION: Medial temporal lobe atrophy (MTA) scores 1) distinguish probable Alzheimer disease (AD) and amnestic mild cognitive impairment (MCI) subjects from nonamnestic MCI and no cognitive impairment (NCI) subjects, 2) help predict diagnosis at baseline, and 3) predict transition from NCI to MCI and from MCI to probable AD. MTA scores should be used as a criterion in the clinical diagnosis of AD.

Mild cognitive impairment: directions for future research.

Mild cognitive impairment (MCI), an intermediate state between normal aging and dementia, is characterized by acquired cognitive deficits, without significant decline in functional activities of daily living. Studies conducted on MCI have introduced new concepts regarding the possible distinctions between normal and pathologic aging of the brain. Neuroimaging and genetic testing have aided in the identification of individuals at increased risk for dementia. The measurement of change in cognitive and functional status in MCI remains challenging, because it requires instruments that are more sensitive and specific than those considered adequate for research in dementia. The authors provide an overview of the many methods that have been used to study MCI and directions that may help achieve greater uniformity in methodology. Considerable heterogeneity exists in research methodology used to study the epidemiology, thresholds for cognitive and functional impairment, rate of progression, risk factors, and defining subtypes of MCI. This article emphasizes the need for uniformity in the use of 1) appropriate and sensitive neuropsychological and functional measures to diagnose MCI, 2) reliable methods to determine progression or improvement of cognitive impairment, and 3) instruments in epidemiologic studies to establish population estimates for diverse ethnic and cultural groups. Greater consensus is needed to standardize definitions and research methodology for MCI, so as to make future studies more comparable and more useful for designing effective treatment strategies.

An evaluation of the NINCDS-ADRDA neuropsychological criteria for the assessment of Alzheimer's disease: a confirmatory factor analysis of single versus multi-factor models.

Neuropsychological test batteries are frequently used to assess the nature and severity of cognitive deficits among patients with early Alzheimer's Disease (AD) and related disorders. The NINCDS-ADRDA criteria are among the most widely used guidelines to diagnose dementia (McKhann et al.,1984). These criteria specify eight distinct areas of neuropsychological function that should be evaluated in patients with suspected cognitive impairment. Recent studies have suggested that neuropsychological deficits observed in AD may be explained by a single general factor related to memory deficits or to executive dysfunction. In contrast, the results of other investigations have indicated that multiple qualitatively different factors underlie cognitive abilities in AD. In the present study, we used confirmatory factor analysis to examine the structure of cognitive abilities in AD and to assess the extent to which single and multiple ability factors accurately represent neuropsychological test data obtained from patients with AD. Results indicated that the NINCDS-ADRDA model fit the data better than a single factor model. However, a more parsimonious model specifying memory, verbal abilities, visuospatial skills, executive function, and higher as well as lower functional activities of daily living fit the data better than the NINCDS-ADRDA model. These results have important theoretical and practical implications for diagnostic evaluation.

Caregivers' judgments of the functional abilities of the Alzheimer's disease patient: impact of caregivers' depression and perceived burden.

Research has demonstrated that caregivers of cognitively impaired patients may misjudge aspects of the patient's functional capacities. The nature and directions of these relationships are not well understood, however. Further, the effects that depression and perceived caregiver burden have on the caregivers' ability to render accurate judgments of patient's functional abilities have not been addressed. In this study, the primary caregivers of 128 patients with Alzheimer's disease (AD) were administered a questionnaire regarding the patients' functional capacities. These judgments were subsequently compared to actual functional performance of AD patients on an extended version of the Direct Assessment of Functional Status scale administered in the patients' home environment. A significant proportion of caregivers overestimated AD patients' functional performance in telling time, counting currency, making change for a purchase, brushing teeth, and using eating utensils. Further analyses revealed that self-reported depression, but not perceived burden, was related to the type of caregiver bias errors observed.

Caregivers' judgments of the functional abilities of the Alzheimer's disease patient: a comparison of proxy reports and objective measures.

The assessment of functional capacity is essential for the diagnosis of dementia by DSM-IV criteria and has important implications for patient intervention and management. Although ratings of functional disability by family or other proxy informants are widely used by clinicians, there have been concerns and empirical evidence that potential reporter biases may result in either overestimation or underestimation of specific functional deficits. In this study, we compared family members' judgments of the functional abilities of seventy-two patients diagnosed with Alzheimer's disease (AD). These judgments were compared to actual objective functional performance on an array of real-world tasks using the Direct Assessment of Functional Status (DAFS) scale. The results indicate that caregivers were extremely accurate in predicting the functional performance of AD patients who were not impaired during objective evaluation. In contrast, caregivers significantly overestimated the ability of impaired AD patients to tell time, to identify currency, to make change for a purchase, and to utilize eating utensils. Higher patient MMSE scores were associated with caregivers' overestimation of functional capacity, while the degree of caregivers' depressive symptoms, as measured by the CES-D depression scale, was not related to either overestimation or underestimation of patients' functional performance.

Category fluency test: normative data for English- and Spanish-speaking elderly.

Category fluency tasks are an important component of neuropsychological assessment, especially when evaluating for dementia syndromes. The growth in the number of Spanish-speaking elderly in the United States has increased the need for appropriate neuropsychological measures and normative data for this population. This study provides norms for English and Spanish speakers, over the age of 50, on 3 frequently used measures of category fluency: animals, vegetables, and fruits. In addition, it examines the impact of age, education, gender, language, and depressed mood on total fluency scores and on scores on each of these fluency measures. A sample of 702 cognitively intact elderly, 424 English speakers, and 278 Spanish speakers, participated in the study. Normative data are provided stratified by language, age, education, and gender. Results evidence that regardless of the primary language of the examinee, age, education, and gender are the strongest predictors of total category fluency scores, with gender being the best predictor of performance after adjusting for age and education. English and Spanish speakers obtained similar scores on animal and fruit fluency, but English speakers generated more vegetable exemplars than Spanish speakers. Results also indicate that different fluency measures are affected by various factors to different degrees.

Utility of a modified Mini-Mental State Examination with extended delayed recall in screening for mild cognitive impairment and dementia among community dwelling elders.

The objective of this study was to test the utility of additional delayed recall of the three recall items of the Folstein Mini Mental State Evaluation (MMSE) as a screening measure for mild cognitive impairment and dementia in the elderly. It used a cross-sectional study of subjects, who were administered a brief memory screening battery which included the MMSE and extended delayed recall of the three MMSE recall items at 5 minute intervals. The criteria for cognitive status was determined on the basis of the neurological and neuropsychological evaluation. One hundred and two elderly persons who were recruited through a memory screening program were diagnosed as cognitively normal (N=52), mild cognitively impaired (N=24), or demented (N=26). The observed sensitivity of 83.3% and specificity of 90.4% was achieved across three delayed recall trials in differentiating cases with mild cognitive impairment (without dementia) from individuals with normal cognition and was superior to the total MMSE score alone (sensitivity/specificity: 70.8%/84.6%). Cumulative recall for the three MMSE items across only two delayed recall trials demonstrated a sensitivity of 96.2% and specificity of 90.4% in differentiating between cases of dementia versus cases diagnosed with no cognitive impairment. The three trial delayed recall score enhanced prediction of mild cognitive impairment in at-risk elderly living with the community and may have promise in the development of future screening batteries.

A cross-ethnic analysis of risk factors for AD in white Hispanics and white non-Hispanics.

BACKGROUND: The prevalence of AD appears to vary widely in different ethnic groups. Certain risk factors for AD are well established for the general population, but there is little information regarding the relevance of these risk factors in specific ethnic groups. OBJECTIVE: The authors examined the risk of AD associated with the APOE-epsilon4 allele, the APOE-epsilon2 allele, smoking, alcohol consumption, history of hypertension, low educational level, estrogen replacement therapy, and history of head trauma with loss of consciousness among samples of white non-Hispanics (WNH) (392 AD patients, 202 normal subjects) and white Hispanics (WHIS) (188 AD patients, 84 normal controls). DESIGN: This was a case-control study of patients evaluated at an outpatient memory disorders clinic and control subjects recruited from a free memory screening offered to the community. RESULTS: Increased risk for AD was associated with the APOE-epsilon4 allele after controlling for age, education, and gender among WNH (OR = 3.5; 95% CI = 2.3 to 5.5) and WHIS (OR = 3.1; 95% CI = 1.7 to 5.8). No protective effect was conferred by the APOE-epsilon2 allele, although this relationship approached significance among WNH (p = 0.02). Low levels of education increased the risk for AD among WNH (OR = 3.1; 95% CI = 1.8 to 5.9) but not WHIS. Alcohol use and hypertension approached significance as risk factors in WNH (p < 0.05) but not WHIS. Estrogen replacement treatment approached significance as a protective factor in both ethnic groups (p < 0.05). CONCLUSIONS: Although the APOE-epsilon4 allele is a risk factor for AD among WHIS and WNH, other risk factors such as low education and hypertension appear to be important only for WNH. Risk factors for AD reported or suggested previously that were not confirmed by this study include smoking and head trauma with loss of consciousness.

Depressive symptomatology in first-degree family caregivers of Alzheimer disease patients: a cross-ethnic comparison.

This study investigated the prevalence of depressive symptoms among White Hispanic (WH) and White non-Hispanic (WNH) first-degree family caregivers. We screened 653 primary caregivers of family members with possible or probable Alzheimer disease who presented at our outpatient memory disorders clinic. Caregiver depression was assessed utilizing the Center for Epidemiologic Studies-Depression (CES-D) Scale. Overall, depression (CES-D scores > or = 16) was more common among WH (45%) than among WNH (36%) caregivers (p < 0.05). Elevated CES-D scores among the entire caregiving sample were also linked with being a female spouse (p=0.002), increased level of patient cognitive impairment (p=0.002), and patient psychosis (p=0.002). Risk factors for caregiver depression were identified and compared when the sample was stratified by ethnicity (WH and WNH) and generation (spouses and children). Patient cognitive impairment was a predictor of caregiver depression only among WH spouses and children, whereas patient psychosis was a predictor only among WNH spouses. Female caregiver gender was the most robust risk factor for caregiver depression, being a predictor in all groups except WH children. Implications of this study include the need for increased clinical sensitivity to depression in ethnic minority caregivers, treatment of psychiatric morbidity in dementia caregivers, and respite care for caregivers with high risk for depression.

Interfamilial and intrafamilial phenotypic heterogeneity in familial Alzheimer's disease.

The features of Alzheimer's disease (AD) are very heterogenous, and some component of the variability of AD is likely to be related to genetic factors. To investigate this question, we evaluated 19 clinical neuropsychiatric and brain imaging features in 32 familial Alzheimer's disease (FAD) kindred, primarily of late onset. Within families, patients displayed a high degree of phenotypic heterogeneity (PH), which occurred irrespective of gender, ethnicity, or apolipoprotein E genotype. Overall, an equivalent amount of PH was observed in both the between- (37%) and within-family (31%) groups. However, for onset age and rate of decline between families, there was greater PH than within families (P = .002 and P = .01, respectively). A similar trend was found for severity of cortical atrophy (P = .05). These observations suggest a weak genetic influence, and possibly strong nongenetic influences, on the degree of phenotypic heterogeneity in late-onset FAD. In early-onset AD kindred, a much smaller degree of phenotypic heterogeneity may be expected within families, because genetic influences in phenotypic expression tend to be more prominent in early-onset cases.

Alzheimer's disease: interaction of apolipoprotein E genotype, family history of dementia, gender, education, ethnicity, and age of onset.

We evaluated 197 patients with predominantly late-onset Alzheimer's disease (AD) who belonged to several ethnic groups and analyzed the relationship of age of onset of AD to the presence or absence of several risk factors in this entire group of patients. The apolipoprotein E (apoE) epsilon 4 allele frequency, which was 29% in all patients (compared with the reported population mean of 13.7%, p < 0.001, did not vary significantly between ethnic groups but declined significantly with increasing age. The apoE epsilon 2 allele frequency was 3%, compared with the reported population mean of 7.4% (p = 0.001). The frequency of a positive family history of dementia in first-degree relatives (FH +) (overall 45%) did not vary significantly between ethnic groups. ApoE epsilon 4-positive (epsilon 4+) patients tended to have a higher FH + rate (58%) than apoE epsilon 4-negative (epsilon 4-) patients (40%) (p = 0.02). When the potential risk factors of gender, education, FH+ status, and epsilon 4+ status were examined together in a multiple linear-regression analysis, FH+ and epsilon 4+ status (but not gender or education) were significant (they were both associated with an earlier age of onset of AD). In a post-hoc analysis, we found a reduced age of onset in women, but not men, who were both FH + and epsilon 4+. Additionally, those probands who were epsilon 4+ were more likely to inherit the disease from their mothers than their fathers. The mechanism by which epsilon 4+ and FH+ status operate as risk factors may be by their effect on the age of onset of AD.

A qualitative analysis of semantic intrusive errors in Alzheimer's disease.

Intrusive or perseverative errors as evidenced on tests of memory have been found to occur with greater frequency in patients with Alzheimer's Disease (AD) relative to other disorders and are thought to reflect the cholinergic deficits associated with AD. A particular type of intrusive error, semantic intrusions, has been found to discriminate AD from multi-infarct dementia and normal elderly controls. However, it has been suggested that such errors actually reflect random responding as the result of the disinhibition often observed in AD patients. The present study compared the frequency and types of intrusive errors from a sample of mildly, moderately, and more severely impaired AD patients who had undergone the Fuld Object Memory Evaluation with the "guesses" of elderly controls. Results of this study indicate that the semantic intrusions of AD patients differ both in type and frequency from the guesses of the control subjects.

Neuropsychological test performance and prediction of functional capacities among Spanish-speaking and English-speaking patients with dementia.

Neuropsychological measures have been widely used by clinicians to assist them in making judgments regarding a cognitively impaired patient's ability to independently perform important activities of daily living. However, important questions have been raised concerning the degree to which neuropsychological instruments can predict a broad array of specific functional capacities required in the home environment. In the present study, we examined 127 English-speaking and 56 Spanish-speaking patients with Alzheimer's disease (AD) and determined the extent to which various neuropsychological measures and demographic variables were predictive of performance on functional measures administered within the clinical setting. Among English-speaking AD patients, Block Design and Digit-Span of the WAIS-R, as well as tests of language were among the strongest predictors of functional performance. For Spanish-speakers, Block Design, The Mini-Mental State Evaluation (MMSE) and Digit Span had the optimal predictive power. When stepwise regression was conducted on the entire sample of 183 subjects, ethnicity emerged as a statistically significant predictor variable on one of the seven functional tests (writing a check). Despite the predictive power of several of the neuropsychological measures for both groups, most of the variability in objective functional performance could not be explained in our regression models. As a result, it would appear prudent to include functional measures as part of a comprehensive neuropsychological evaluation for dementia.

Deterioration of functional capacities in Alzheimer's disease after a 1-year period.

There is a paucity of data regarding Alzheimer's disease (AD) patients' longitudinal deterioration in the ability to conduct numerous activities required for daily living. In this study, 52 patients with AD were assessed at baseline and at a 1-year follow-up using the Direct Assessment of Functional Status (DAFS) scale, an objective, well-validated measure of a broad spectrum of functional capacities that is administered within the clinical setting. An important finding was that the level of initial performance on each of the 11 functional tasks measured did not relate to the degree of functional decline in that particular area. Communication skills, such as using the telephone (deterioration among 35.4% of the patients) and preparing a letter for mailing (deterioration among 32.7%), showed the most frequent deterioration among patients upon follow-up. More than half of the AD patients studied demonstrated impairment on one or both of these measures. The pattern of findings indicates that many subtests of the DAFS were sensitive to functional decline after a 1-year period and that the scale has utility in objectively establishing longitudinal patterns of deterioration.

Evaluation of the demented patient.

Approaching the patient with Alzheimer's disease often requires the participation of a team of collaborating physicians and psychologists as well as others both for diagnosis and for management. This article describes the approach to the disease by a neurologist, geriatrician, psychiatrist, and psychologist. Each describes a specific diagnostic approach, and the reader can appreciate the incremental value to assessment and care that emerges from the aggregate.