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.

Viability of neocortical function shown in behavioral activation state PET studies in Alzheimer disease.

Twenty subjects with mildly to moderately severe Alzheimer disease (AD) and 14 normal elderly control subjects were studied using [18F]fluorodeoxyglucose and positron emission tomography (PET) to investigate regional cerebral glucose metabolism during both a resting state and a behavioral activation state, utilizing a reading memory task (RMT). The RMT produced significant global metabolic activation of 15 +/- 15% in normal subjects and 11 +/- 13% in AD subjects. The occipital regions were preferentially activated, but all regions in both groups were also significantly activated. The RMT did not allow a better discrimination of AD patients from normal controls on the basis of regional metabolic deficits. Regions in the AD group that were individually classified as hypometabolic during rest also exhibited metabolic activation. The apparent viability of hypometabolic regions in AD patients challenges current hypotheses regarding the cause of abnormal metabolism in AD.

Cerebrocerebellar relationship during behavioral activation: a PET study.

The effect of behavioral activation on cerebral and cerebellar glucose metabolism was studied in normal subjects when performing either a verbal memory task or a tactile somatosensory task. Each subject was also studied in a resting state control condition, either 1 h earlier or later than the activation task. Compared to the resting state, both tasks produced asymmetrical metabolic activation, which was opposite in direction within the cerebral and cerebellar hemispheres. In both tasks, the difference of activation of CMRglc in the right and left hemispheres in the cerebellum was negatively correlated with that in the sensory-motor region. This apparently coupled metabolic activation of one cerebellum and areas within the opposite cerebral hemisphere represents the inverse of the crossed cerebellar diaschisis phenomenon commonly observed when a vascular lesion affects one cerebral hemisphere and hypometabolism occurs in the opposite cerebellum. Because these correlations were selective and concordant with known anatomical connections, and were found in two different tasks, they suggest strong functional connections between these specific brain regions.

Cognition in early human immunodeficiency virus infection.

Relatively little is known about cognitive changes in early human immunodeficiency virus (HIV) infection. This study examined cognitive functioning in 46 HIV-positive gay men relative to an age and education equivalent group of 13 HIV-negative gay men. The HIV-positive men were asymptomatic except for lymphadenopathy or T4 counts less than 700. The cognitive battery measured language, memory, visuospatial, information processing speeds, reasoning, attention, and psychomotor processes. The HIV-positive group was significantly slower in processing information and performed significantly less well than the HIV-negative group on certain verbal memory measures. Deviations of 1 as well as 2 SDs from the norm/control group mean on four or more tests were observed in 43% and 22% of the HIV-positive subjects, respectively, compared with 8% and none of the HIV-negative subjects, respectively. The results suggest that cognitive inefficiency occurs in a subsample of individuals during early HIV infection.

Neuroanatomic differences between dyslexic and normal readers on magnetic resonance imaging scans.

The areas of six bilateral brain segments in the right and left hemispheres, on a horizontal brain section, and the area of subdivisions of the corpus callosum, on a midsagittal brain section, were measured on magnetic resonance images obtained from 21 dyslexic and 29 control subjects. In the entire group, the frontal half of the horizontal brain section showed asymmetry, with the right side being larger, whereas posteriorly only the occipital polar segment was asymmetrical, with the left side being larger. Dyslexic subjects exhibited asymmetry, with the right side greater than the left side, in contrast to the relatively symmetrical pattern that is normally observed in the midposterior segment that corresponds to the angular gyrus. In the corpus callosum, dyslexic subjects were found to have a larger splenium than nondyslexic subjects, and dyslexic female subjects were found to have a larger splenium than dyslexic male subjects. Because transcallosal pathways connecting the left and right angular gyrus regions traverse through the splenium of the corpus callosum, the above findings in dyslexic subjects suggest an anatomic abnormality in the angular gyrus region.

Predominant left hemisphere metabolic dysfunction in dementia.

Thirty-one patients with probable Alzheimer's disease and 11 patients with memory disorders, attributable to multiple cerebral infarctions, were studied using 18-F-fluorodeoxyglucose-positron emission tomography scans. Asymmetry in cerebral glucose metabolism within these diagnostic groups was assessed by comparison with the metabolic rates obtained in age-equivalent healthy control subjects. A significantly greater number of individuals in both patient groups exhibited predominant left rather than right hemisphere hypometabolism. In addition, for patients with Alzheimer's disease, the degree of asymmetry was not related to either the severity or duration of dementia. These findings could be explained by greater susceptibility of the left hemisphere to degenerative or ischemic brain disease, by a specific sampling effect, or most likely, by greater metabolic deficits resulting from left rather than right hemisphere impairment.

Brain-reactive antibodies and the AIDS dementia complex.

To determine the role of autoantibodies in the development of the AIDS dementia complex, brain-reactive antibodies (BRAs) were assayed in 30 sera samples obtained from AIDS patients. Eighteen samples were obtained from AIDS patients with neuropsychological complications, and 12 samples were obtained from patients without any neuropsychological involvement. BRAs were analyzed using strips of nitrocellulose electroblots as a source of antigen, and were prepared from a sample of normal human parahippocampal tissue subjected to SDS-PAGE. Fourteen of 18 patients with neuropsychological complications and 4 of 12 patients without such complications were positive for BRAs to a protein with Mr of 45,000-50,000.

A comparison of familial and sporadic Alzheimer's disease.

Using a liberal criterion, a conservative probability-based criterion, and a criterion for autosomal dominant inheritance, we classified 36%, 13.5%, and 6.4% of 311 patients, respectively, as having familial Alzheimer's disease (FAD). The mean age of onset was over 70 years for all three categories of FAD. FAD and sporadic Alzheimer's disease (SAD) cases did not differ in clinical features, incidence of risk factors for dementia, or MRI or PET features. We observed earlier age of onset of AD to be related positively to longer duration of disease. Except for the autosomal dominant AD group, there was an earlier age of onset in FAD probands. The inheritance of AD from mothers was from 1.7 to 3.6 times more frequent than from fathers. Among SAD patients only, we found a preponderance of women, who were more frequently affected than would be expected from the male/female ratio in the general population of the same average age. Language performance tended to be less affected in FAD than in SAD patients, contrary to some previous reports.

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.

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.

MR signal abnormalities in memory disorder and dementia.

MR imaging of the brain, performed in 86 normal subjects and 113 patients with objective memory disorder or dementia, demonstrated white- and gray-matter areas of high signal intensity on long TR images (short and long TE). Hyperintensities were analyzed with respect to size (on a scale of 0-3) and location: lesions were periventricular, subcortical, or cortical. The patients with memory disorder and dementia were categorized as having probable/possible Alzheimer disease, a combination of Alzheimer disease and multiinfarct cognitive disorder, or multiinfarct cognitive disorder alone on the basis of clinically determined Hachinski ischemic scores. Significant correlations were found between age and scores for periventricular lesions (r = .40, p less than .0005) and subcortical lesions (r = .39, p less than .0005) in normal subjects. Correlations were also found between the Hachinski ischemic score and scores for periventricular lesions (r = .21, p less than .01), subcortical lesions (r = .27, p less than .0002), and cortical lesions (r = .32, p less than .0005) in subjects with memory disorder/dementia. Comparing multiinfarct cognitive disorder, Alzheimer disease, and normal groups, the mean scores for periventricular lesions were 12.0 +/- 4.6, 7.6 +/- 4.8, and 3.4 +/- 2.6, while mean scores for subcortical lesions were 10.8 +/- 12.2, 4.1 +/- 6.4, and 0.8 +/- 1.2, respectively. Periventricular lesions were present in 99-100% of patients with Alzheimer disease and multiinfarct cognitive disorder. On the other hand, subcortical lesions, which were identified in 100% of patients with multiinfarct cognitive disorder, were present in only about half of the patients with Alzheimer disease.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Induction of depressive affect after prolonged exposure to a mildly depressed individual.

Scores on the Beck Depression Inventory (BDI) were periodically obtained from the roommates of college students who exhibited a persistent mild depression over a 3-month period. For comparative purposes, BDI scores were also obtained from roommates of individuals who were transiently depressed and from subjects with nondepressed roommates. In comparison with control subjects, the roommates of persistently depressed persons displayed a progressive increase in BDI score over the course of the study.

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.

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.

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.

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.