Cognitive function in multiple sclerosis: A long-term look on the bright side.

BACKGROUND: Multiple sclerosis (MS) may lead to cognitive decline over-time. OBJECTIVES: Characterize cognitive performance in MS patients with long disease duration treated with disease modifying drugs (DMD) in relation to disability and determine the prevalence of cognitive resilience. METHODS: Cognitive and functional outcomes were assessed in 1010 DMD-treated MS patients at least 10 years from onset. Cognitive performance was categorized as high, moderate or low, and neurological disability was classified according to the Expanded Disability Status Scale (EDSS) as mild, moderate or severe. Relationship between cognitive performance and disability was examined. RESULTS: After a mean disease duration of 19.6 (SD = 7.7) years, low cognitive performance was observed in 23.7% (N = 239), moderate performance in 42.7% (N = 431), and 33.7% (N = 340) had high cognitive performance, meeting the definition of cognitively resilient patients. Within the group of patients with low cognitive performance, severe disability was observed in 50.6% (121/239), while in the group of patients with high cognitive performance, mild disability was observed in 64.4% (219/340). Differences between the group of patients with high cognitive performance and severe disability (4.5%) and the group of patients with low cognitive performance and mild disability (5.0%) were not accounted for by DMD treatment duration. CONCLUSIONS: The majority of DMD treated MS patients did not have cognitive decline that could impair their quality of life after disease of extended duration.

Fasting plasma glucose in young adults free of diabetes is associated with cognitive function in midlife.

Background: Evidence for an association of fasting plasma glucose (FPG) with cognitive function in adults free of diabetes is scarce and based on middle-aged and older adults. We examined the association of FPG, measured at age 30, and of change in FPG from age 30 to 43, with cognitive function at age 50. Methods: 505 nondiabetic participants of the population-based Jerusalem Lipid Research Clinic (LRC) cohort study had baseline FPG, 2-h post-oral challenge plasma glucose (OGTT) and insulin determined at ages 28-32, and FPG and OGTT again at ages 41-46. Subsequently at ages 48-52, global cognitive function and its five specific component domains were assessed with a NeuroTrax computerized test battery, using multiple linear regression and multivariable logistic models. Results: Hyperglycemia (FPG ≥ 5.6 mmol/l vs. <5.6 mmol/l) at baseline was associated with poorer global cognitive function in midlife (predominantly in the visual spatial and attention domains), independent of socio-demographic characteristics, life style variables, body mass index (BMI), and inflammatory and biochemical variables (standardized Beta = -0.121, P = 0.002, plinear trend(FPG continuous) =0.016). Similarly, increased odds for low-ranked (lowest fifth) global cognition was evident (ORper mmol/l FPG=2.31, 95% CI = 1.30-4.13, P = 0.005). Baseline OGTT, insulin resistance (HOMA-IR) and change in FPG and OGTT over 13 years were not associated with cognition. Conclusion: A higher FPG in young adults was associated with lower cognitive performance in midlife. Although we cannot dismiss the possibility of reverse causation, hyperglycemia at a young age may be a modifiable risk factor for low-ranked cognitive function in midlife.

Body Mass Index, Height and Socioeconomic Position in Adolescence, Their Trajectories into Adulthood, and Cognitive Function in Midlife.

BACKGROUND: Whether life course anthropometric indices relate to cognitive function in midlife remains insufficiently explored. Rarely was socioeconomic position (SEP) adequately accounted for. OBJECTIVE: To examine the association of the cumulative life course burden of high-ranked body mass index (BMI), its trajectory, and stature with cognitive function in midlife. METHODS: Weight and height were measured from age 17 across a 33-year follow-up. 507 individuals completed a NeuroTrax computerized cognitive assessment at ages 48-52. Life course SEP was assessed by multiple methods. Using mixed models we calculated the area under the curve (AUC), representing both the life-course burden of BMI (total AUC) and trends in BMI (incremental AUC) from age 17 to midlife. The associations of BMI and height with global cognition and its five component domains were assessed by multiple regression. RESULTS: Higher BMI in late adolescence and total AUC over the life course were associated with poorer global cognition (Standardized beta (Beta) = -0.111, p = 0.005 and Beta = -0.105, p = 0.018, respectively), adjusted for childhood and adulthood SEP, and demographic characteristics. The associations with higher adolescent and midlife BMI were both restricted to those with low childhood SEP (p < 0.05 for interaction). Short adolescent stature was related to poorer cognition (Beta = 0.115, p = 0.040), whereas late final growth in women was associated with better cognition (Beta = 0.213, p = 0.007). CONCLUSION: An adverse association of higher BMI with cognitive function began in adolescence and was restricted to low childhood SEP. Taller stature in both sexes and late growth in women were associated with better midlife cognitive performance.

Increased attrition of leukocyte telomere length in young adults is associated with poorer cognitive function in midlife.

Evidence for an association of leukocyte telomere length (LTL) with cognitive function, predominantly in older adults, is inconsistent. No report has examined the association of LTL dynamics (age-specific LTL and its attrition rate) with cognitive function. We aimed to examine the association of LTL dynamics over 13 years in young adulthood with cognitive function in midlife. 497 individuals who had LTL measured at ages 28-32 and 41-46 years were assessed at ages 48-52 for global cognitive function and its five specific component domains with a NeuroTrax computerized test battery. Multivariable regression and logistic models were applied for cognition treated as a continuous and categorical variable, respectively. We found that LTL attrition (adjusted for sex, baseline LTL and potential confounders including socioeconomic variables) was inversely associated with global cognition (standardized ß = -.119, p = .004) and its component domains: information processing speed (ß = -.102, p = .024), visual-spatial function (ß = -.102, p = .017) and memory (ß = -.093, p = .045), but less so for the attention and executive domains. The multivariable-adjusted odds ratio for low global cognition comparing the upper versus lower thirds of LTL attrition was 2.12 (95 % CI 1.11-4.08, p for trend = .023). There was no association of baseline or follow-up LTL with cognition. No effect modification was evident for sex, smoking or inflammatory markers. In conclusion, faster LTL attrition in young adulthood was associated with poorer global and domain-specific cognitive function in midlife, suggesting that more rapid LTL attrition may be predictive of cognitive aging in healthy young adults.

Increase in the Inflammatory Marker GlycA over 13 Years in Young Adults Is Associated with Poorer Cognitive Function in Midlife.

BACKGROUND: Inflammatory markers are elevated in patients with dementia. Evidence for an association between inflammation and cognitive function in dementia-free individuals is sparse, inconsistent, and predominantly restricted to the elderly. Assessment of inflammatory markers in young adults as predictors of cognitive function in midlife, well before the onset of overt dementia, is lacking. Furthermore, rarely has the relation with longitudinal change in inflammatory markers been examined. OBJECTIVE: To examine the association of the inflammatory markers C-reactive protein (CRP), fibrinogen, white blood cell count (WBC) and GlycA, a novel NMR-determined biomarker of systemic inflammation, measured in young adulthood and of GlycA change over 13 years follow-up with cognitive function in midlife. METHODS: 507 participants of the Jerusalem Lipid Research Clinic (LRC) study were assessed at 3 time points over 18-22 years. First, the inflammatory variables GlycA, CRP, fibrinogen, and WBC were measured in blood samples drawn at ages 28-32. Then, in blood samples drawn a mean 13 years later (range, 12-16 years) at ages 41-46, GlycA was again measured (in 484 individuals). Subsequently at ages 48-52, on average 7 years later, global cognitive function and its five specific component domains were assessed with a NeuroTrax computerized test battery. Multiple regression and multivariable logistic models were applied. RESULTS: Inverse unadjusted associations were shown for baseline levels and longitudinal change in inflammatory markers and measures of cognition. Multiple regression models were adjusted for age at cognitive assessment, sex, socio-demographic characteristics, baseline measures of leisure-time vigorous activity, smoking status and body mass index (BMI) at ages 28-32, change in smoking status and BMI between ages 28-32 and 41-46, and depression assessed at the time of cognitive testing. The highest quintile of GlycA change, but not the baseline inflammation measures, was inversely related to global cognition (standardized ß = -.109, p = .011) as well as to the information processing speed and memory domains (standardized ß = -.124, p = .008 and-.117, p = .014, respectively). The multivariable-adjusted odds ratio for low ranked global cognitive function (lowest fifth) comparing the extreme quintiles of GlycA change was 4.8 (95%CI, 1.7-13.5, p = .003; p for trend = .031). CONCLUSIONS: In this longitudinal study of a novel systemic inflammatory marker in a population-based cohort of young adults, GlycA increase over 13 years, but not baseline measures of inflammation, was associated with poorer cognitive function in midlife.

Lower cognitive performance in healthy G2019S LRRK2 mutation carriers.

OBJECTIVE: To assess cognitive abilities of healthy first-degree relatives of Ashkenazi patients with Parkinson disease (PD), carriers of the G2019S mutation in the LRRK2 gene. METHODS: In this observational study, 60 consecutive healthy first-degree relatives (aged 50.9 ± 6.2 years; 48% male; 30 G2019S carriers) were assessed using a computerized cognitive program, the Montreal Cognitive Assessment questionnaire, the Unified Parkinson's Disease Rating Scale Part III, and the Geriatric Depression Scale. RESULTS: G2019S carriers scored significantly lower on the computerized executive function index (p = 0.04) and on specific executive function tasks (Stroop test, p = 0.007). CONCLUSION: Carrying the LRRK2 G2019S mutation was associated with lower executive performance in a population at risk for PD.

Selection of deep brain stimulation candidates in private neurology practices: referral may be simpler than a computerized triage system.

OBJECTIVE: The objective of this study is to compare a computerized deep brain stimulation (DBS) screening module (Comparing Private Practice vs. Academic Centers in Selection of DBS Candidates [COMPRESS], NeuroTrax Corp., Bellaire, TX, USA) with traditional triage by a movement disorders specialized neurologist as the gold standard. METHODS: The COMPRESS consists of a combination of the Florida Surgical Questionnaire for Parkinson disease (FLASQ-PD), a cognitive assessment battery provided by MindStreams® (NeuroTrax Corp.), and the Geriatric Depression Scale and the Zung Anxiety Self-Assessment Scale. COMPRESS resulted in the classification of patients into three categories: "optimal candidate,""probable candidate," and "not a good candidate." Similar categorical ratings made by a referring private practice neurologist and by a trained movement disorders specialist were compared with the ratings generated by COMPRESS. RESULTS: A total of 19 subjects with Parkinson's disease were enrolled from five private neurological practices. The clinical impressions of the private practice neurologist vs. those of the movement disorders specialist were in agreement approximately half the time (10/19 cases). The movement disorders specialist and COMPRESS agreed on 15/19 cases. A further comparison between outcomes from the entire COMPRESS module and the FLASQ-PD questionnaire by itself resulted in high agreement (18/19 cases in agreement). CONCLUSIONS: The COMPRESS agreed with an in-person evaluation by a movement disorders neurologist approximately 80% of the time. The computerized COMPRESS did not provide any screening advantage over the short FLASQ-PD paper questionnaire. Larger studies will be needed to assess the utility and cost effectiveness of this computerized triage method for DBS.

Validity of a short computerized assessment battery for moderate cognitive impairment and dementia.

BACKGROUND: Computerized cognitive assessment tools have been developed to make precise neuropsychological assessment readily available to clinicians. Mindstreams batteries for mild impairment have been validated previously. We examined the validity of a Mindstreams battery designed specifically for evaluating those with moderate cognitive impairment. METHODS: 170 participants over the age of 60 years performed the computerized battery in addition to standard clinical evaluation. The battery consists of six technician-administered tests and one patient-administered interactive test sampling the cognitive domains of orientation (to time and place), memory, executive function, visual spatial processing, and verbal function. Staging was according to the Clinical Dementia Rating Scale (CDR) on the basis of clinical data but independent of computerized cognitive testing results, thus serving as the gold standard for evaluating the discriminant validity of the computerized measures. RESULTS: Seven participants received a global CDR score of 0 (not impaired), 76 were staged as CDR 0.5 (very mildly impaired), 58 as CDR 1 (mildly impaired), 26 as CDR 2 (moderately impaired), and 3 as CDR 3 (severely impaired). Mindstreams Global Score performance was significantly different across CDR groups (p < 0.001), reflecting poorer overall battery performance for those with greater impairment. This was also true for the domain summary scores, with Executive Function (d = 0.67) and Memory (d = 0.65) distinguishing best between CDR 0.5 and 1, and Orientation best differentiating among CDR 1 and 2 (d = 1.20). CONCLUSIONS: The Mindstreams battery for moderate impairment differentiates among varying degrees of cognitive impairment in older adults, providing detailed and distinct cognitive profiles.

Computerized cognitive assessment of mild cognitive impairment in urban African Americans.

Few objective cognitive assessment tools have been validated for mild cognitive impairment (MCI) in African Americans despite higher prevalence of disease. This preliminary study evaluated discriminant validity of a computerized cognitive assessment battery for MCI in an urban African American cohort. Twenty-seven participants with MCI and 22 cognitively healthy individuals completed a multidomain battery (Mindstreams, NeuroTrax Corp, New Jersey). Mild cognitive impairment participants performed more poorly than cognitively healthy participants in all domains, with significant differences in memory (P = .003; d = 0.96), executive function (P = .046; d = 0.64), and overall battery performance (P = .041; d = 0.63). Adjustment for intelligence quotient (IQ) yielded significant differences in memory (P < .001; d = 1.34), executive function (P = .007; d = 0.86), attention (P = .014; d = .80), and overall performance (P = .001; d = 1.09). Such a validated battery may help to address an important clinical need in this population.

Adjustment of cognitive scores with a co-normed estimate of premorbid intelligence: implementation using mindstreams computerized testing.

Neuropsychological assessment is critically dependent upon comparison to a standard normative database. While generally appropriate for individuals of near-average intelligence, high-intelligence individuals may be erroneously scored as unimpaired and low-intelligence individuals as impaired on cognitive measures. The current paper describes an approach for minimizing such misclassifications that is standardized and practical for clinical use. A computerized test of nonverbal reasoning co-normed with cognitive measures is used for automatic adjustment of normalized cognitive scores. This premorbid estimate showed good construct validity, and adjustment raised cognitive scores for low-intelligence individuals, and lowered cognitive scores for high-intelligence individuals similarly across demographic (age, education, computer experience) and clinical (cognitively healthy, mild cognitive impairment, dementia) subgroups. Adjustment was typically up to three normalized units for scores on the premorbid estimate of +/-1 SD and 6 normalized units for scores of +/-2 SD. The present approach shows promise as a practical solution for assessment of high- and low-intelligence individuals.

Practicality of a computerized system for cognitive assessment in the elderly.

BACKGROUND: Early detection and diagnosis are critical to dementia care. However, many early cases remain undiagnosed as a result of the impracticality of neuropsychological testing, particularly in primary care. Mindstreams is an office-based computerized system for measuring cognitive function in multiple domains, with demonstrated validity, test-retest reliability, and sensitivity to treatment effects. This study evaluated its feasibility for assessment of the elderly. METHODS: Usability data were collected after each of 2,888 consecutive initial-visit testing sessions at the first 11 clinical centers to use Mindstreams. The chi(2) goodness-of-fit test was employed to determine whether patients and supervisors more often rated tests easy versus hard to use. Separate analyses were run for non-computer users, patients older than 75 years, and poor performers (< or =1 standard deviation on overall battery performance). RESULTS: For all patients (n = 2,888; age, 64.7 +/- 18.2 years), 83% rated the tests easy to use (P < .001). Seventy-three percent of non-computer users, 70% of patients older than 75, and 69% of poor performers rated them easy to use (Ps < .001). Supervisor ratings and ease of understandability ratings were similar. For all patients, 76% of supervisor ratings indicated no patient frustration (P < .001). Seventy-eight percent of ratings for non-computer users, 76% for patients older than 75, and 74% for poor performers indicated no frustration (Ps < .001). CONCLUSIONS: Mindstreams was easily employed, including in patients with considerable cognitive impairment, supporting its practicality for in-office cognitive assessment of the elderly. The availability of such valid and practical assessment suggests the feasibility of integrating the technology within a clinical algorithm for improved detection of cognitive decline.

A novel multidomain computerized cognitive assessment for attention-deficit hyperactivity disorder: evidence for widespread and circumscribed cognitive deficits.

Multidomain assessment may enhance the diagnosis of cognitive impairment in children with attention-deficit hyperactivity disorder (ADHD). A set of novel Web-enabled computerized tests has recently been shown to be valid for identifying mild cognitive impairment and characterizing the cognitive profile associated with various disorders. It was anticipated that these tests would be well suited for use in children with ADHD. The authors tested this idea in a pilot study of 15 children (12 males, 3 females; mean age, 11 years 10 months; range, 9-15 years) with ADHD and 15 age-, education-, and gender-matched controls. The profile of cognitive impairment in ADHD children off methylphenidate across 6 cognitive domains (memory, executive function, visual-spatial skills, verbal function, attention, and motor skills) was described relative to controls. The effect of treatment with methylphenidate was examined by comparing the ADHD children on methylphenidate and on placebo (administered in a double-blind randomized fashion) relative to controls and by comparing the ADHD children on methylphenidate relative to placebo. Significant impairment in ADHD was evident in memory, visual-spatial, verbal, and attention domains, and near-significant impairment was observed in executive function and motor skills. On methylphenidate but not placebo, performance was comparable to controls in immediate verbal memory, psychomotor accuracy, visual-spatial, verbal rhyming, and overall battery performance. Significant improvement with administration of methylphenidate relative to placebo was evident for psychomotor accuracy, verbal rhyming, and overall battery performance. Hence, on the limited basis of this pilot study, the set of computerized tests studied appears to be useful for measuring cognitive function in ADHD; however, additional studies are needed to confirm this.

Effects of pharmacological therapy on gait and cognitive function in depressed patients.

OBJECTIVE: To investigate the relationship among affective status, cognitive function, and gait in depressed patients and to evaluate the effects of treatment of depression on gait and cognitive function. METHODS: Nineteen patients recently diagnosed with clinical depression (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria) were recruited from a psychiatric outpatient clinic. Evaluation included the Hamilton Depression Rating Scale (HAM-D), the Mini-Mental State Examination, a computerized neuropsychological battery (Mindstreams, NeuroTrax Corp, New York, NY), and Barthel's Index of Instrumental Activities of Daily Living. Temporal parameters of gait were quantified using a stopwatch and force-sensitive insoles. All assessments were performed at baseline and after approximately 10 weeks of treatment with antidepressants. RESULTS: The patients' mean age was 68.6 +/- 9.1 years (15 women). Therapy significantly (P < 0.001) improved the affective state (HAM-D scores). There were small but significant improvements in gait speed (P = 0.033), stride time variability (P = 0.036), and gait asymmetry (P = 0.038). With the exception of the hand-eye coordination index, all tested cognitive domains also improved significantly. Baseline depression scores correlated with changes in depression: patients with higher HAM-D scores at baseline had more significant improvement in their affect (P < 0.001). Changes in HAM-D were not significantly correlated with changes in gait or changes on computerized tests of cognitive function (P > 0.10). CONCLUSIONS: Depressive symptoms are associated with gait and cognitive impairment. Moreover, the present results suggest that these domains improve in response to antidepressant medication.

A clinical construct validity study of a novel computerized battery for the diagnosis of ADHD in young adults.

The cognitive profile of adult attention deficit hyperactivity disorder (ADHD) remains understudied despite difficulty in diagnosis. Further, no battery of neuropsychological tests has been shown valid in adult ADHD. Continuous performance tests are widely used for ADHD but provide limited information on cognitive functioning in general. The present study evaluated the construct and discriminant validity of Mindstreams (NeuroTrax Corp., NY), a computerized battery assessing multiple cognitive domains. Twenty-nine young male adults with ADHD diagnosis completed a Mindstreams battery, including a multi-stage continuous performance ('Expanded Go-NoGo') test, and the Conners' CPT-II (Multi-Health Systems Inc., NY). Discriminant validity was assessed by comparisons with cognitively healthy controls of comparable age and education. Expanded Go-NoGo and corresponding CPT-II outcomes were significantly correlated in ADHD participants, and the Expanded Go-NoGo test exhibited excellent discriminant validity, with ADHD participants performing more poorly than controls. ADHD participants also performed more poorly on Stroop and Staged Information Processing Speed tests.

A common cognitive profile in elderly fallers and in patients with Parkinson's disease: the prominence of impaired executive function and attention.

The present study examined the cognitive profile of elderly fallers relative to healthy elderly controls and patients with Parkinson's disease (PD), a positive-control group, using a computerized battery. Fallers performed more poorly than controls on executive function, attention, and motor skills, but performed comparably on memory, information processing and the Mini-Mental State Examination. A similar profile was evident for PD patients. However, unlike PD patients, fallers were abnormally inconsistent in their reaction times. These findings indicate that elderly fallers may have a unique cognitive processing deficit (i.e., variability of response timing) and underscore the importance of executive function and attention as potential targets for fall risk screening and interventions.

Comprehensive computerized assessment of cognitive sequelae of a complete 12-16 hour fast.

Food deprivation has been shown to deleteriously affect human cognition, but findings are equivocal, and few studies have examined several cognitive domains. In this study, the authors used computerized testing to describe the profile of shifts in cognition attributable to short-term religious fasting. Multiple cognitive domains were evaluated at midday and late afternoon following complete abstention from eating and drinking beginning at midnight. Cross-domain, fasting-related deficits were found for tasks requiring perception of spatial relations. Fasting-related information processing deficits were found for response time but not accuracy for test levels of intermediate difficulty. Time-of-day effects often reflected poorer afternoon performance. These findings provide a detailed profile of cognitive consequences of food deprivation, affected by time of day, task demands, and type of outcome.

Effect of rivastigmine on tremor in patients with Parkinson's disease and dementia.

The purpose of this study was to assess whether rivastigmine, a cholinergic agent, affects tremor features when given to improve cognition in demented Parkinson's disease (PD) patients. Demented PD patients (n = 26; Mini-Mental State Examination score, 13-25; age, 75.2 +/- 4.9 yr) were given rivastigmine (mean dose, 8.0 mg/day) for 12 weeks. They underwent tremor assessment before and during treatment. Global Tremor Score (GTS) was based on eight items specific to tremor in the Unified Parkinson's Disease Rating Scale. Tremor amplitude was also measured using accelerometers during the ON state in both hands in 19 patients. Drug therapy for other PD symptoms was unchanged. The mean group baseline GTS was 1.2 +/- 1.6 points, increasing to 1.6 +/- 2.4 points after treatment (mean increase, 0.4 +/- 1.2 points; P > 0.05). The GTS increased by 3.2 +/- 1.9 points (range, 1-5) in 7 patients (26.9%) and decreased by 1 +/- 0 points in 3 patients (11.5%). Accelerometric assessment showed a significant increase of the average tremor amplitude in the right hand (0.08 +/- 0.03 xg at baseline; 0.12 +/- 0.02 xg at Week 12 of treatment, P = 0.02). Left-hand tremor amplitude did not change. Rivastigmine caused only slight worsening of tremor in demented PD patients, while improving cognition.

Effects of methylphenidate on cognitive function and gait in patients with Parkinson's disease: a pilot study.

Twenty-one patients with Parkinson's disease were studied before and 2 h after the administration of a single dose of 20 mg of methylphenidate. In response to methylphenidate, attention significantly improved, whereas memory and visual-spatial performance were unchanged. Gait speed, stride time variability, and Timed Up and Go times (demonstrated measures of fall risk) significantly improved. These findings suggest a new potential pharmacologic means of enhancing mobility and decreasing fall risk in Parkinson's disease.

Dual-tasking effects on gait variability: the role of aging, falls, and executive function.

The objectives of the present study were to test the hypothesis that the dual-tasking effect on gait variability is larger in healthy older adults than it is in healthy young adults; that this effect is larger in idiopathic elderly fallers than it is in healthy older adults; and that the dual-tasking effects on gait variability are correlated with executive function (EF). Young adults and older adults who were classified as fallers and nonfallers were studied. Gait speed, swing time, and swing time variability, a marker of fall risk, were measured during usual walking and during three different dual-tasking conditions. EF and memory were evaluated. When performing dual tasks, all three groups significantly decreased their gait speed. Dual tasking did not affect swing time variability in the young adults and in the nonfallers. Conversely, dual tasking markedly increased swing time variability in the fallers. While memory was similar in fallers and nonfallers, EF was different. The faller-specific response to dual tasking was significantly correlated with tests of EF. These findings demonstrate that dual tasking does not affect the gait variability of elderly nonfallers or young adults. In contrast, dual tasking destabilizes the gait of idiopathic elderly fallers, an effect that appears to be mediated in part by a decline in EF.