The Effect of Donepezil on Problem-solving Ability in Individuals With Amnestic Mild Cognitive Impairment: A Pilot Study.

BACKGROUND: Clinical trials involving individuals with mild cognitive impairment (MCI) have reported mixed results for the effects of cholinesterase inhibitors on cognitive outcomes. Our previous work demonstrated that a visuospatial problem-solving task was sensitive to non-memory impairments in individuals with MCI. OBJECTIVE: To determine whether the same task is also sensitive to the effects of cholinesterase inhibitors in individuals with amnestic MCI (aMCI). METHOD: We gave 22 individuals with aMCI (clinical dementia rating of 0.5) and Mini-Mental State Examination (MMSE) scores of at least 24 the following measures at baseline and at follow-up 1 year later: Hopkins Verbal Learning Test, Boston Naming Test, Rey Complex Figures Test copying task, anagrams task, and visuospatial problem-solving task. The MMSE was also given at the 1-year follow-up. Twelve of the individuals were drug naïve, having never taken cholinesterase inhibitors before, and donepezil was initiated and titrated to 10 mg daily after baseline in an open-label manner. Ten of the individuals had already been taking donepezil, and there was no change in treatment. We compared the two groups for amount of performance change over 1 year. RESULTS: Individuals for whom donepezil was initiated performed significantly better on the visuospatial problem-solving task after 1 year compared with individuals who had already been taking donepezil. No difference was observed for any of the other variables. CONCLUSION: The visuospatial problem-solving task appeared to be more sensitive than memory measures to the effects of cholinesterase inhibitors in individuals with aMCI, perhaps due to the high attentional demand of the task.

Validity of the Verbal Concept Attainment Test in multiple sclerosis.

OBJECTIVE: As many as 70% of people with multiple sclerosis (MS) have clinically significant cognitive impairment, and most of these individuals exhibit executive dysfunction. Most research concerning executive dysfunction in MS has focused upon nonverbal measures. The Verbal Concept Attainment Test (VCAT) has demonstrated construct validity as an executive function measure in people infected with HIV and in people with focal brain lesions, but its validity among people with MS is unknown. The current study evaluated the VCAT's criterion, diagnostic, and ecological validity in people with MS. METHOD: A comprehensive neuropsychological battery was administered to 44 healthy individuals and 97 people with MS. Based on existing norms, they were classified as impaired or unimpaired, resulting in 65 people with MS categorized as unimpaired and 32 as impaired. They were administered a battery assessing neuropsychological impairment and disability status. RESULTS: The VCAT correlated with most measures of neuropsychological function, but its largest correlations occurred with measures of executive function, working memory, and verbal memory. Regarding classification accuracy, the VCAT achieved satisfactory sensitivity and specificity in identifying neuropsychological impairment in people with MS. The VCAT achieved moderate correlations with measures of disability status. CONCLUSIONS: The data provide evidence for an optimal VCAT cutoff score for establishing neuropsychological impairment in people with MS, and they demonstrate that the VCAT possesses acceptable criterion, diagnostic, and ecological validity. As such, these data support the inclusion of the VCAT in research and clinical practice involving people with MS.

Digitally translated Self-Administered Gerocognitive Examination (eSAGE): relationship with its validated paper version, neuropsychological evaluations, and clinical assessments.

BACKGROUND: The original paper Self-Administered Gerocognitive Examination (SAGE) is a valid and reliable cognitive assessment tool used to identify individuals with mild cognitive impairment (MCI) or early dementia. We evaluated identical test questions in a digital format (eSAGE) made for tablet use with the goals of calibrating it against SAGE and establishing its association with other neuropsychological tests and clinical assessments of cognitive impairment. METHODS: Subjects aged 50 and over who had taken SAGE were recruited from community and clinic settings. Subjects were randomly selected to participate in a clinical evaluation including neuropsychological evaluations. SAGE and eSAGE were administered using a crossover design. Subjects were identified as dementia, MCI, or normal based on standard clinical criteria. Associations were investigated using Spearman correlations, linear regression, and sensitivity and specificity measures. RESULTS: Of the 426 subjects screened, 66 completed the evaluation. eSAGE score correlation to a battery of neuropsychological tests was 0.73 (p < 0.0001) with no significant difference between the paper and digital format. Spearman correlation of SAGE versus eSAGE was 0.88 (p < 0.0001), and they are related by the formula: eSAGE score = -1.05 + 0.99 × SAGE score. Since the slope is very close to 1 (p = 0.86) there is strong evidence that the scaling is identical between eSAGE and SAGE, with no scale bias. Overall, eSAGE scores are lower by an average of 1.21 and the decrease is statistically significant (p < 0.0001). For those subjects familiar with smartphones or tablets (one measure of digital proficiency), eSAGE scores are lower by an average of 0.83 points (p = 0.029). With a score 16 and higher being classified as normal, eSAGE had 90% specificity and 71% sensitivity in detecting those with cognitive impairment from normal subjects. CONCLUSIONS: Tablet-based eSAGE shows a strong association with the validated paper SAGE and a neuropsychological battery. It shows no scale bias compared to SAGE. Both have the advantage of self-administration, brevity, four interchangeable forms, and high sensitivity and specificity in detecting cognitive impairment from normal subjects. Their potential widespread availability will be a major factor in overcoming the many obstacles in identifying early cognitive changes. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02544074 . Registered on 18 March 2015.

Self-administered Gerocognitive Examination (SAGE): a brief cognitive assessment Instrument for mild cognitive impairment (MCI) and early dementia.

OBJECTIVES: To develop a self-administered cognitive assessment instrument to facilitate the screening of mild cognitive impairment (MCI) and early dementia and determine its association with gold standard clinical assessments including neuropsychologic evaluation. METHODS: Adults aged above 59 years with sufficient vision and English literacy were recruited from geriatric and memory disorder clinics, educational talks, independent living facilities, senior centers, and memory screens. After Self-administered Gerocognitive Examination (SAGE) screening, subjects were randomly selected to complete a clinical evaluation, neurologic examination, neuropsychologic battery, functional assessment, and mini-mental state examination (MMSE). Subjects were identified as dementia, MCI, or normal based on standard clinical criteria and neuropsychologic testing. RESULTS: Two hundred fifty-four participants took the SAGE screen and 63 subjects completed the extensive evaluation (21 normal, 21 MCI, and 21 dementia subjects). Spearman rank correlation between SAGE and neuropsychologic battery was 0.84 (0.76 for MMSE). SAGE receiver operating characteristics on the basis of clinical diagnosis showed 95% specificity (90% for MMSE) and 79% sensitivity (71% for MMSE) in detecting those with cognitive impairment from normal subjects. CONCLUSIONS: This study suggests that SAGE is a reliable instrument for detecting cognitive impairment and compares favorably with the MMSE. The self-administered feature may promote cognitive testing by busy clinicians prompting earlier diagnosis and treatment.

The reliability of the modified Balance Error Scoring System.

OBJECTIVE: Study 1 investigated the intraclass reliability and percent variance associated with each component within the traditional Balance Error Scoring System (BESS) protocol. Study 2 investigated the reliability of subsequent modifications of the BESS. DESIGN: Prospective cross-sectional examination of the traditional and modified BESS protocols. SETTING: Schools participating in Georgia High School Athletics Association. INTERVENTION: The modified BESS consisted of 2 surfaces (firm and foam) and 2 stances (single-leg and tandem-leg stance) repeated for a total of three 20-second trials. PARTICIPANTS: Participants consisted of 2 independent samples of high school athletes aged 13 to 19 years. MAIN OUTCOME MEASURES: Percent variance for each condition of the BESS was obtained using GENOVA 3.1. An intraclass reliability coefficient and repeated measures analysis of variance were calculated using SPSS 13.0. RESULTS: Study 1 obtained an intraclass correlation coefficient (r = 0.60) with stance accounting for 55% of the total variance. Removing the double-leg stance increased the intraclass correlation coefficient (r = 0.71). Study 2 found a statistically significant difference between trials 1 and 2 (F(1.65,286) = 4.890, P = 0.013) and intraclass reliability coefficient of r = 0.88 for 3 trials of 4 conditions. CONCLUSIONS: The variance associated with the double-leg stance was very small, and when removed, the intraclass reliability coefficient of the BESS increased. Removal of the double-leg stance and addition of 3 trials of 4 conditions provided an easily administered, cost-effective, time-efficient tool that provides reliable objective information for clinicians to base clinical decisions upon.

Neuropsychological impairment and psychosis in mania.

Deficits involving executive function, working memory, speed of information processing, and new learning occur in many people with mania. Factors that predict impairment remain poorly understood, but there are indications that psychotic features may correspond with increased risk of neurocognitive dysfunction during manic episodes. The current study examined neuropsychological function in 40 inpatients with bipolar I mania, 24 of whom presented with psychotic features. Compared to a control group, the inpatients showed worse executive function, speed of information processing, new learning, and dexterity. Nonetheless, presence of psychotic features failed to distinguish the inpatients with mania. Thus, psychotic features do not appear to increase neurobehavioral morbidity in people with mania, but presence of mania clearly corresponded with neurobehavioral dysfunction. Implications of these data for clinical practice and our understanding of bipolar disorder are discussed.

Self-generated learning in people with multiple sclerosis: an extension of Chiaravalloti and DeLuca (2002).

Although memory impairment is common in people with multiple sclerosis (MS), few interventions have been tested to remediate forgetfulness in MS. Chiaravalloti and DeLuca (2002) examined the memory benefit of self-generated encoding over didactic presentation in people with MS and a control group. They found that self-generated encoding enhanced memory of MS patients and a control group alike. The present study extended this finding by examining self-generated encoding in memory-impaired MS patients as well. A control group and MS patients with and without memory impairment learned word-pairs that were either self-generated or didactically presented. All groups remembered more self-generated words than those that were read aloud, and severity of memory impairment failed to moderate this memory benefit. Implications of these findings for cognitive rehabilitation and the nature of memory impairment in MS are discussed.

Problem solving ability in patients with mild cognitive impairment.

BACKGROUND AND OBJECTIVE: It is important to determine which patients with mild cognitive impairment (MCI) are at risk for progression to dementia. The presence of mild impairments not restricted to the domain of memory may suggest such progression. Our goal is to determine how well a visuospatial problem solving task assessing the cumulative burden of frontal and posterior damage differentiates MCI patients from matched controls. METHODS: Twenty-six patients with MCI [Clinical Dementia Rating (CDR) score of 0.5] and mini-mental state examination (MMSE) scores of at least 24/30, were compared with 20 age and education level matched controls without cognitive impairment. All patients were given the MMSE, Hopkins Verbal Learning Test (HVLT), Boston Naming Test (BNT), Rey Complex Figures copying (RCF), anagrams, and visuospatial problem solving battery (VPS). The VPS is a complex problem solving task, which we predicted would better discriminate patient groups than the relatively simpler tasks. RESULTS: Differences existed between groups on most tasks, but logistic regression revealed that the VPS discriminated the 2 groups better than the other nonmemory cognitive tests. CONCLUSIONS: The VPS, a problem solving task assessing the cumulative burden of frontal and posterior damage is more sensitive for detecting nonmemory impairments in MCI than other tasks. Future research will be needed to determine if impairment in the VPS is a sensitive predictor of progression to dementia or treatment response.

The effect of propranolol on cognitive flexibility and memory in acute cocaine withdrawal.

Upregulated noradrenergic activity occurs early in cocaine withdrawal. Our previous work revealed impaired cognitive flexibility in acute cocaine withdrawal, a cognitive domain that appears to be modulated by noradrenergic activity. Therefore, we wished to determine the effect of beta-adrenergic antagonists on cognitive performance in acute cocaine withdrawal. Eleven subjects acutely withdrawing from cocaine were tested in this pilot study on tasks of cognitive flexibility as well as word fluency, attention, verbal memory, and spatial memory, off and on propranolol in a double-blinded manner. Propranolol significantly benefited certain aspects of cognitive flexibility in acute cocaine withdrawal, and improved some measures of verbal fluency and verbal recall. Cocaine withdrawal treatment is characterized by high failure rates. Further research is needed to determine the role this finding of a reversible cognitive impairment in cocaine withdrawal has in treatment.

The stability of neurocognitive patterns in HIV infected men: classification considerations.

For the neuropsychological impairment which takes place in HIV-1 infection, various classification systems, based on either neuropathological criteria, severity of the disorder or functional criteria, have been suggested in the literature. This study identifies the patterns of neurocognitive disorders in HIV-1 infection and investigates their stability at one-year follow-up. Two hundred and seventeen HIV-1-positive subjects in various stages of infection and 55 HIV-1-negative subjects were evaluated. Our results suggest that there is considerable diversity in the neuropsychological functioning of HIV patients but the patterns are relatively stable, functionally distinct, and differ with respect to the severity of the deficit. The overall pattern is consistent with existing neuropsychological knowledge on HIV infection. Comparison of the patterns identified in this study with other classification systems posed several problems, however, and these problems may have important implications for the theory and methodology of neuropsychological HIV research.

The relationship between age and cognitive function in HIV-infected men.

Several studies have identified increased age as a risk factor for the development of cognitive impairment in human immunodeficiency virus (HIV)-infected subjects, but few have examined the potential synergistic effect of age and HIV serostatus on cognitive decline. The authors examined the possible combined effect of age and HIV serostatus on cognitive decline in 254 subjects stratified by age group and HIV status. After controlling for the effect of education, there were significant effects for serostatus and age group on overall cognitive impairment and a number of neuropsychological measures but no interaction effects. These data suggest that older seropositive individuals are not at an increased risk for HIV-related cognitive impairment when normal age-related cognitive changes are considered.

Marijuana use and cognitive function in HIV-infected people.

The effect of marijuana use on cognitive function is controversial. Although marijuana use is common in HIV-infected individuals for recreational and medicinal purposes, there have been no studies of the impact of marijuana on cognitive function in these subjects. Marijuana also has known immunologic effects, which increases the relevance in HIV-infected patients. We examined the interaction of HIV disease-stage and marijuana use in 282 subjects, stratified by disease stage and frequency of marijuana use. After controlling for the effects of depression, anxiety, and alcohol use, a significant interaction was observed on an overall measure of cognitive impairment. The effect of marijuana use was greatest in subjects with symptomatic HIV infection. Further inspection suggested that this effect was due primarily to performance on memory tasks. These data suggest that although there is minimal impact of marijuana on uninfected individuals or those at early stages of HIV infection, there is a synergistic effect of HIV and marijuana use in patients with advanced HIV disease. This is consistent with other data suggesting that the subtle effects of some conditions may become more manifest in the setting of immunocompromise.

Effect of anxiolytics on cognitive flexibility in problem solving.

OBJECTIVE: Our purpose is to examine the effect of different classes of anxiolytics on cognitive flexibility. BACKGROUND: Situational stressors and anxiety impede performance on "creativity" tests requiring cognitive flexibility. Noradrenergic agents have been shown to modulate cognitive flexibility as assessed by performance on anagrams. To determine whether these findings on noradrenergic modulation of cognitive flexibility are specific to the noradrenergic system or are a nonspecific anxiety effect, we compared the effects of propranolol, lorazepam, and placebo on the anagram task. METHODS: Subjects attended 3 test sessions. Prior to each session, subjects were given 1 of the 3 drugs. As in previous research, the natural log of the solution latency of each test item was summed for each test session and compared across drug conditions. RESULTS: For subjects able to solve the anagrams, solution times after propranolol, but not lorazepam, were significantly lower than after placebo. CONCLUSIONS: Therefore, this suggests that the phenomenon of noradrenergic modulation of cognitive flexibility does not result from a nonspecific anxiolytic effect, but rather is specific to the noradrenergic system.

The effect of previous alcohol abuse on cognitive function in HIV infection.

OBJECTIVE: The authors' goal was to study the potential effect on cognitive function of an interaction of HIV infection and a history of alcohol abuse. METHOD: The subjects were 30 HIV-negative and 50 HIV-positive men with and without a past history of alcohol abuse. Thirty-three of the men (12 HIV negative and 21 HIV positive) had a past history of alcohol abuse, and 47 (18 HIV negative and 29 HIV positive) had never abused alcohol. Each subject's history of alcohol use was obtained by using a syndromal approach based on the Structured Clinical Interview for DSM-III-R and a quantitative approach. Each subject was given a battery of neuropsychological tests assessing verbal reasoning, reaction time, intelligence, memory, and dexterity. The subjects were then compared on a summary neuropsychological impairment rating. RESULTS: There were no significant differences in CD4 level, age, education, depression, anxiety, or other drug abuse history between the HIV-positive and HIV-negative groups with and without a history of alcohol abuse. Significant effects on cognitive function were found for past alcohol abuse and HIV infection, with significant interactions in verbal reasoning, auditory processing, and reaction time. This demonstrates that HIV infection and a history of alcohol abuse have independent effects on some aspects of higher cognitive function but may have synergistic effects on other cognitive domains. In the HIV-negative subjects there were no differences in cognitive function between subjects with and without a history of alcohol abuse. Among the HIV-positive subjects, those with a history of alcohol abuse performed more poorly on tests of verbal IQ, verbal reasoning, and reaction time. CONCLUSIONS: There are both additive and interactive effects of previous alcohol abuse and HIV infection on cognition. Individuals with a history of past alcohol abuse may be at greater risk for cognitive dysfunction in the context of HIV infection.

The relationship between stressful life events and cognitive function in HIV-infected men.

Previous studies have demonstrated an impact of stress on immune function, and recent studies have suggested an adverse effect of stress on the brain. However, no previous study has examined the impact of stress on cognitive function. This article examines the relationship between stress and cognitive function in 82 HIV-negative subjects and 251 HIV-positive subjects. Subjects completed a comprehensive neuropsychological examination, measures of anxiety and depression, and a measure of stressful life events. After controlling for the impact of anxiety, depression, age, and education, stressful life events were related to cognitive impairment only among the HIV-positive subjects. The data were interpreted in the context of previous studies that have demonstrated an adverse effect of stress on the brain and suggest that this adverse impact may be expressed in the setting of a compromised immune system. Furthermore, this analysis suggests several implications for patient management.

Effects of past noninjection drug abuse upon executive function and working memory in HIV infection.

Interactive effects of past noninjection drug abuse/dependence and HIV disease status upon measures of executive function were assessed in a group of 294 homosexual men. Participants were stratified according to HIV status and substance use diagnoses, thereby yielding a 4 (seronegative, asymptomatic seropositive, symptomatic seropositive, and AIDS defining illness) x 2 (never abused drugs, previous substance use disorder) design. Significant main effects of HIV status were found on the Wisconsin Card Sorting Test, Ruff Figural Fluency Test, Trail Making Test B, and total number of impaired performances. Analyses revealed that men with AIDS defining illness performed worse than the other three groups. Drug use history had no significant effect upon neurobehavioral function, and effect sizes for drug abuse history were small. The data suggest that prior drug use yields little if any residual cognitive impairment in HIV infection.

Central beta-adrenergic modulation of cognitive flexibility.

Situational stressors and anxiety impede performance on creativity tests requiring cognitive flexibility. Preliminary research revealed better performance on a task requiring cognitive flexibility, the anagram task, after propranolol (beta-adrenergic antagonist) than after ephedrine (beta-adrenergic agonist). However, propranolol and ephedrine have both peripheral and central beta-adrenergic effects. In order to determine whether noradrenergic modulation of cognitive flexibility is a centrally or peripherally mediated phenomenon, we compared the effects of propranolol (peripheral and central beta-blocker), nadolol (peripheral beta-blocker), and placebo on anagram task performance. Solution latency scores for each subject were compared across the drug conditions. Anagram solution latency scores after propranolol were significantly lower than after nadolol. This suggests a centrally mediated modulatory influence of the noradrenergic system on cognitive flexibility.

Neuropsychological impairment among manic, depressed, and mixed-episode inpatients with bipolar disorder.

Previous research has demonstrated broad neurobehavioral abnormalities in bipolar affective disorder (cf. G. Cassens, L. Wolfe, & M. Zola, 1990). However, there have been no comparisons of neuropsychological function across patients with manic, depressed, or mixed subtypes. In the present study, 37 manic, 24 mixed-episode, and 25 depressed bipolar I inpatients and 34 control subjects were administered a brief battery of neuropsychological tests. The multivariate and univariate effects of participant group on the neuropsychological measures were uniformly significant (p < .05). Planned contrasts revealed that the bipolar participants performed worse than the controls, and few differences existed between the 3 patient groups. Additionally, the bipolar groups were impaired on 50% of the test battery. These abnormalities were unlikely attributable to differences in psychiatric symptomatology, medical illness, comorbid psychiatric diagnoses, or medication status. Findings imply that acute mood disturbance during bipolar disorder yields significant neurobehavioral dysfunction.