The evaluation of cognitive function in the dementias: methodological and regulatory considerations

Impairment of cognitive function is the central feature of dementia. Although, clinically, the cognitive deficit most often manifests itself as memory problems, a number of other areas of cognition are affected, and memory is but one of the cognitive skills compromised in dementia. Dementia with Lewy bodies, for example, accounts for 15% to 25% of all dementias and does not have memory deficits as a core feature. Our cognitive facilities underlie our abilities to engage successfully in the activities of daily living (ADL) and it follows thai enhancement of cognitive function will facilitate performance of ADL The assessment and understanding of these impairments are crucial to any treatment of the disorder. Unfortunately, the principal instrument used to assess cognitive function in most of the major clinical trials of Alzheimer's disease in recent years, the Alzheimer's Disease Assessment Scale-Cognitive Subsection (ADAS-COG), primarily assesses aspects of memory, which has resulted in other important cognitive deficits in dementia being overlooked. Automated cognitive tests are now available that can identify an earlier onset of improvements in dementia in smaller samples than the ADAS, Regulatory authorities should encourage - or even require - the use of automated procedures alongside the ADAS in pivotal trials to help determine the relative utility of the instruments in the fairest way possible. Whatever the outcome, this will be of long-term benefit to patients, carers, drug developers, clinicians, and regulators in this important area

Effects of levomilnacipran extended-release on major depressive disorder patients with cognitive impairments

Performance-based cognitive data were collected using the Cognitive Drug Research System in a study of levomilnacipran extended-release (ER) 40-120 mg/day (NCT01034462) in adults with major depressive disorder. These data were analyzed post-hoc to explore the relationship between cognitive measures, depression symptoms (Montgomery-Asberg Depression Rating Scale, MADRS), and self-reported psychosocial functioning (Sheehan Disability Scale; SDS). Changes from baseline were analyzed in the intent-to-treat population and subgroups with impaired attention, as indicated by baseline Cognitive Drug Research System scores for Power of Attention and Continuity of Attention. Path analyses evaluated the direct and indirect effects of levomilnacipran ER on SDS total score change. Significantly greater improvements were observed for levomilnacipran ER versus placebo for Power of Attention, Continuity of Attention, MADRS, and SDS score changes; the mean differences were larger in the impaired subgroups than in the overall intent-to-treat population. Path analyses showed that the majority of SDS total score improvement (>=50%) was attributable to an indirect treatment effect through MADRS total score change; some direct effect of levomilnacipran ER on SDS total score improvement was also observed. In adults with major depressive disorder, levomilnacipran ER effectively improved measures of depression and cognition, which contributed toward reductions in self-reported functional impairment

Spatial patterns of larval settlement and early post-settlement survivorship of Mytilus galloprovincialis in a Galician Ría (NW Spain). Effect on recruitment success

10 páginas, 3 figuras, 7 tablasLarval settlement and recruitment play an important role on the population dynamics of marine benthic invertebrates, and are key factors in the management of aquaculture industries. In order to check the current strategies of mussel seed gathering from collector ropes in the Ria of Ares-Betanzos (NW Spain), this work analyses the seasonal and spatial variability of larval settlement and recruitment of the mussel Mytilus galloprovincialis, as well as the relationship between settlement and recruitment. Our results highlight the importance of the hydrographic characteristics of the Ría de Ares-Betanzos on the spatial distribution of larval settlement and on the early post-settlement mortality, which determines recruitment success. The spatial distribution of larval settlement, with higher abundances in the northern-shore but significant larval retention in the southern culture areas, is in agreement with the positive subtidal circulation of this embayment and the larger residence times in the southern shore. The positive subtidal circulation of the Ría favours larval transport from the culture areas located in the south to the northern shore, while the larger residence times allow larval retention in the southern shore. The strong linear relationship between settlement and recruitment suggest density-independent mortality and allowed estimating recruitment abundances and short-term survival rates. The highest and lowest post-settlement mortalities were registered at the most external and sheltered locations respectively, suggesting that the vulnerability to the hydrodynamic stress may be the main cause of early post-settlement mortality of mussel juveniles on suspended substrates. Our results confirm that the sheltered culture polygons located in the inner area of the Ría of Ares-Betanzos are favourable environments for the recruitment of Mytilus galloprovincialis spat, supporting the current strategies of seed gathering from collector ropes in the Ría of Ares-BetanzosThis work was supported by PROINSA-CSIC contract-project (CSIC0704101100001)Peer reviewe

Tea consumption and measures of attention and psychomotor speed in the very old: the Newcastle 85+ longitudinal study

Background: A number of studies have indicated a beneficial effect of tea consumption on the reduction of risk of cognitive impairment and dementia in older aged populations. However, there is a paucity of data on these associations in the very old, defined as individuals aged 85 years and over. We investigated the relationship between tea consumption in the very old and measures of global cognitive function, memory, attention and psychomotor speed. Method: Longitudinal (5-years), population-based cohort study of individuals aged 85+ years in the North East of England, United Kingdom. Participants were community-dwelling and institutionalized men and women recruited through general medical practices (n = 676). Baseline tea consumption and longitudinal measures of global and domain specific (memory, speed and attention) cognitive function were assessed. Linear mixed models, controlling for demographic (e.g. age, sex and education) and health variables were used to determine whether tea consumption was protective against cognitive decline. Results: Tea consumption was not associated with cognitive function at baseline on any measure (unadjusted and adjusted analyses). In the linear mixed effects models adjusted for age, sex, education and disease co-morbidity, higher tea consumption was associated with significantly better attention (focused and sustained attention), and psychomotor speed (complex tasks only) over five-years follow-up. However, there was no association between tea consumption and global cognitive function, memory or performance on simple speed tasks over time. Conclusions: In this cohort study of non-demented very old adults we found that higher (vs. lower) tea consumption was associated with better performance over time on measures of focused and sustained attention and some psychomotor speed tasks. No associations with global cognition, memory or easy speed tasks (simple Reaction Time or Word Recognition) were detected. The results have implications for the development of possible diet-based interventions focused on improving cognitive function in the very old age group. These findings need to be confirmed in a sufficiently powered and well-designed RCT with non-demented very old adults.publishersversionpublishe

A randomized controlled trial of a novel mixed monoamine reuptake inhibitor in adults with ADHD

<p>Abstract</p> <p>Background</p> <p>NS2359 is a potent reuptake blocker of noradrenalin, dopamine, and serotonin. The aim of the study was to investigate the efficacy, safety and cognitive function of NS2359 in adults with a DSM IV diagnosis of ADHD.</p> <p>Methods</p> <p>The study was a multi-centre, double-blind, randomized placebo-controlled, parallel group design in outpatient adults (18–55 years) testing 0.5 mg NS2359 vs. placebo for 8 weeks. Multiple assessments including computerized neuropsychological evaluation were performed.</p> <p>Results</p> <p>There was no significant difference between NS2359 (n = 63) versus placebo (n = 63) on the primary outcome measure reduction in investigator rated ADHD-RS total score (7.8 versus 6.4; p < 0.45). However, in subjects with the inattentive subtype, there were significantly more responders in the NS2359 group compared to placebo (41% versus 7%; p < 0.01). For all secondary variables (ADHD-RS patient rated; The Conners Adult ADHD Scale; The Brown Adult Scale, and CGI-improvement scale) there were no significant differences between the two groups; however, in the inattentive subgroup, the response to treatment was significantly larger than to placebo. NS2359 improved composite factor scores of attention, episodic- and working memory. No serious adverse events were reported with insomnia, headaches and loss of appetite most commonly reported as side effects.</p> <p>Conclusion</p> <p>No overall effect of NS2359 was found on overall symptoms of ADHD. There was also a modest signal of improvement in the inattentive adults with ADHD and cognition warranting further exploration using differing doses.</p

Cognitive performance in relapsing remitting multiple sclerosis: A longitudinal study in daily practice using a brief computerized cognitive battery

<p>Abstract</p> <p>Background</p> <p>There is need for a cognitive test battery that can be easily used in clinical practice to detect or monitor cognitive performance in patients with multiple sclerosis (MS). In order to conduct, in this patient group, a preliminary investigation of the validity and utility of a brief computerized battery, the Cognitive Drug Research (CDR) battery, we longitudinally assessed cognition in patients with relapsing remitting (RR) MS.</p> <p>Methods</p> <p>Forty-three mildly disabled, clinically active RRMS patients were repeatedly assessed with the Digit Symbol Substitution Test (DSST), Paced Auditory Serial Addition Test (PASAT) and five composite scores derived from the CDR computerized cognitive test system (CDR System): Power of Attention, Continuity of Attention, Quality of Working Memory, Quality of Episodic Memory and Speed of Memory. The Multiple Sclerosis Functional Composite (MSFC) and Expanded Disability Status Scale (EDSS) measured disability.</p> <p>Results</p> <p>The composite scores from the CDR battery generally showed excellent test-retest reliability over the repeated assessments, though was low on occasions for the Quality of Working Memory and Quality of Episodic Memory measures. The CDR measures tended to be highly correlated with other measures of cognition (DSST and PASAT) and were also strongly related to disability (EDSS and MSFC). Baseline scores indicated large impairments to visual information processing speed and attention (DSST, Cohen's d 1.1; Power of Attention d 1.4 [reaction time on tasks of focussed and sustained attention]), and a moderate impairment both to sustained attention (Continuity of Attention d 0.6) and complex information processing speed (Speed of memory d 0.7 [reaction time on tasks of working and episodic Memory]), when compared to normative data derived from healthy volunteers enrolled in a series of separate, prior clinical trials. Working memory (Quality of Working Memory) and episodic memory (Quality of Episodic Memory) were unimpaired.</p> <p>Conclusions</p> <p>Preliminary validation of the CDR System indicated that for most, but not all measures psychometric properties were adequate and the measures were related to disability (EDSS and MSFC) and other measures of cognition.</p

Modulation of cognitive performance and mood by aromas of peppermint and ylang-ylang

This study provides further evidence for the impact of the aromas of plant essential oils on aspects of cognition and mood in healthy participants. One hundred and forty-four volunteers were randomly assigned to conditions of ylang-ylang aroma, peppermint aroma, or no aroma control. Cognitive performance was assessed using the Cognitive Drug Research computerized assessment battery, with mood scales completed before and after cognitive testing. The analysis of the data revealed significant differences between conditions on a number of the factors underpinning the tests that constitute the battery. Peppermint was found to enhance memory whereas ylang-ylang impaired it, and lengthened processing speed. In terms of subjective mood peppermint increased alertness and ylang-ylang decreased it, but significantly increased calmness. These results provide support for the contention that the aromas of essential oils can produce significant and idiosyncratic effects on both subjective and objective assessments of aspects of human behavior. They are discussed with reference to possible pharmacological and psychological modes of influence

Cognitive Performance and Morning Levels of Salivary Cortisol and α-Amylase in Children Reporting High vs. Low Daily Stress Perception

The aim of the present study was to assess the effects of daily stress perception on cognitive performance and morning basal salivary cortisol and alpha-amylase levels in healthy children aged 9-12. Participants were classified by whether they had low daily perceived stress (LPS, n = 27) or a high daily perceived stress (HPS, n = 26) using the Children Daily Stress Inventory (CDSI). Salivary cortisol and alpha-amylase were measured at awakening and 30 minutes later. Cognitive performance was assessed using the Cognitive Drug Research assessment system. The HPS group exhibited significantly poorer scores on speed of memory (p < .05) and continuity of attention (p < .05) relative to the LPS group. The HPS group also showed significantly lower morning cortisol levels at awakening and at +30 minutes measures in comparison with the LPS group (p < .05), and mean morning cortisol levels were negatively correlated with speed of memory (p < .05) in the 53 participants. No significant differences were observed between both groups in alpha-amylase levels. These findings suggest that daily perceived stress in children may impoverish cognitive performance via its modulating effects on the HPA axis activit

Tolerability of ORM-12741 and effects on episodic memory in patients with Alzheimer's disease

Introduction ORM-12741 is a novel selective antagonist of alpha-2C adrenoceptors. This trial evaluated the safety and efficacy of ORM-12741 in patients with Alzheimer's disease (AD). Methods A randomized, double-blind, placebo-controlled, exploratory phase 2a trial was conducted in 100 subjects with AD and neuropsychiatric symptoms. Participants were randomized to receive one of two flexible doses of ORM-12741 (30–60 mg or 100–200 mg) or placebo b.i.d. for 12 weeks in addition to standard therapy with cholinesterase inhibitors. Efficacy was assessed primarily with the Cognitive Drug Research (CDR) computerized assessment system and secondarily with the Neuropsychiatric Inventory (NPI). Results A statistically significant treatment effect was seen in one of the four primary CDR system end points, Quality of Episodic Memory (P = .030; not adjusted for multiple comparisons), favoring ORM-12741 over placebo. NPI caregiver distress scores also favored ORM-12741 (P = .034). ORM-12741 was well tolerated. Discussion This is the first clinical trial providing evidence on an acceptable safety profile for ORM-12741 in patients with AD and neuropsychiatric symptoms. In addition, the trial provided hints of potential therapeutic benefit, primarily on episodic memory, in this patient population