Chris Edgar

Benefits of rivastigmine on attention in dementia associated with Parkinson disease

In a 24-week, randomized, double-blind, placebo-controlled, multicenter study of rivastigmine, 487 patients with dementia associated with Parkinson disease underwent assessment of attention on the Cognitive Drug Research computerized cognitive assessment system before dosing and 16 and 24 weeks later. Significant benefits of rivastigmine over placebo were seen on all aspects of attention assessed: sustained attention, focused attention, consistence of responding, and central processing speed.

The evolutionary genetic underpinnings of schizophrenia: the developmental instability model.

The importance of genes in the etiology of schizophrenia is well known, but the manner in which the relevant genomic factors influence neural development and the nature of selection forces operating on these factors are poorly understood. In several prominent papers, Crow has provided a unique and comprehensive theory that attempts to deal with these issues. A central aspect of his theory is that a single gene leads to reduced cerebral lateralization, increased ventricular size, and risk for developing schizophrenia. He relies greatly on Annetts right shift theory of individual variation in handedness. An alternative approach, based on the construct of developmental instability, provides a different way to conceptualize genetic influences, selection forces, and atypical lateralization in schizophrenia. We suggest that the developmental instability model has stronger empirical support and is better grounded in contemporary evolutionary genetics.

Exploratory pilot study assessing the risk of cognitive impairment or sedation in the elderly following single doses of solifenacin 10 mg

Objectives: To assess the cognitive effects of single doses of solifenacin 10 mg compared with placebo (primary objective) and oxybutynin immediate release (IR) 10 mg (secondary objective) in elderly subjects. Methods: Single-centre, randomised, double-blind, placebo-controlled study in 12 healthy elderly volunteers, with three crossover periods separated by two 14-day washout periods. Each sequence consisted of a single dose of solifenacin 10 mg in one period, oxybutynin IR 10 mg in another and placebo in another. Aspects of attention, information processing, working memory, episodic memory and self-rated mood and alertness were tested using the validated Cognitive Drug Research computerised assessment system. Results: There was no evidence from absolute mean values or changes from baseline to suggest that solifenacin 10 mg impaired cognition or self-ratings of mood and alertness versus placebo. Post-hoc ANCOVA showed no statistically significant cognitive deterioration with solifenacin versus placebo, when measured at a time point closest to the probable Cmax of solifenacin. Oxybutynin was associated with statistically significant impairments in several measures of cognitive function at a time point corresponding with its probable Cmax. Conclusion: In this pilot study, single 10 mg doses of solifenacin did not show any clear propensity to impair cognitive function in a healthy elderly population.

The cognitive and psychomotor effects of remacemide and carbamazepine in newly diagnosed epilepsy.

An international trial comparing remacemide hydrochloride with carbamazepine was undertaken in individuals with newly diagnosed epilepsy using a novel double-blind, parallel-group, double triangular sequential design. Patients with two or more partial or generalized tonic-clonic seizures in the previous year were randomized to remacemide or carbamazepine and titrated to a target dose of 600 mg/day. Subsequent dosage adjustments were allowed while maintaining the blind. Repeated assessments of neuropsychological function and mood were carried out using computerized and conventional measures. The trial was completed 20 months after initiation, following the second interim analysis. Efficacy as measured by seizure recurrence showed remacemide to be inferior to carbamazepine. Baseline cognitive and neuropsychological measures showed impairment across the whole patient population. Cognitive/neuropsychological performance at 8, 24, and 48 weeks was compared with that at baseline. Significant deterioration was seen on measures of information processing speed and attention after treatment with carbamazepine. The study data provide evidence for the utility and sensitivity of a number of cognitive assessments, which may be employed in future trials of antiepileptic drugs.

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

BackgroundThere 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.MethodsForty-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.ResultsThe 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, Cohens 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.ConclusionsPreliminary 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.

Performance on a pattern separation task by Alzheimer’s patients shows possible links between disrupted dentate gyrus activity and apolipoprotein E ∈4 status and cerebrospinal fluid amyloid-β42 levels

IntroductionEmerging evidence suggests that decreased adult hippocampal neurogenesis represents an early critical event in the course of Alzheimer’s disease (AD). In mice, adult neurogenesis is reduced by knock-in alleles for human apolipoprotein E (ApoE) ∈4. Decreased dentate gyrus (DG) neural progenitor cells proliferation has been observed in the triple-transgenic mouse model of AD (3xTg-AD); this reduction being directly associated with the presence of amyloid-β (Aβ) plaques and an increase in the number of Aβ-containing neurons in the hippocampus. Cognitive tasks involving difficult pattern separations have been shown to reflect DG activity and thus potentially neurogenesis in both animals and man. This study involved the administration of a pattern separation paradigm to Alzheimer’s patients to investigate relationships between task performance and both ApoE status and cerebrospinal fluid (CSF) Aβ42 levels.MethodsThe CDR System pattern separation task involves the presentation of pictures that must later be discriminated from closely similar pictures. This paper presents pattern separation data from 66 mild to moderate AD patients, of which 50 were genotyped and 65 in whom CSF Aβ42 was measured.ResultsApoE ∈4 homozygotes were not compromised on the easy pattern separations compared with the other patients, but they were statistically significantly poorer at the difficult separations. In all patients CSF Aβ42 correlated significantly with the ability to make the difficult discriminations, but not easier discriminations. Pattern separation speed correlated negatively with CSF Aβ42, and thus the association was not due to increased impulsivity.ConclusionsThese are, to our knowledge, the first human pattern separation data to suggest a possible genetic link to poor hippocampal neurogenesis in AD, as well as a relationship to Aβ42. Therapies which target neurogenesis may thus be useful in preventing the early stages of AD, notably in ApoE ∈4 homocygotes.

Nabilone produces marked impairments to cognitive function and changes in subjective state in healthy volunteers

This was a double-blind, randomised, placebo-controlled, crossover study of the acute cognitive and subjective effects of nabilone 1—3 mg in healthy male volunteers. The Cognitive Drug Research computerised system (CDR system) was used to assess changes in attention, working and episodic memory. In addition, a number of self-ratings were conducted including those of mood, alertness and perceived drug effects. Impairments to attention, working and episodic memory and self-ratings of alertness were evident. Volunteers also experienced a number of subjective drug effects. These data demonstrate that acute doses of nabilone in the range 1—3 mg produce clear cognitive and subjective effects in healthy volunteers, and therefore they may be used as reference data in the future study of peripherally acting cannabinoids believed to be free from such effects.

Computerized cognition assessment during acetylcholinesterase inhibitor treatment in Alzheimer’s disease

Wesnes K, Edgar C, Andreasen N, Annas P, Basun H, Lannfelt L, Zetterberg H, Blennow K, Minthon L. Computerized cognition assessment during acetylcholinesterase inhibitor treatment in Alzheimer’s disease.
Acta Neurol Scand: 2010: 122: 270–277.
© 2009 The Authors Journal compilation

Defining therapeutic benefit for people with schizophrenia: focus on negative symptoms.

Schizophrenia is a complex, heterogeneous, multidimensional disorder within which negative symptoms are a significant and disabling feature. Whilst there is no established treatment for these symptoms, some pharmacological and psychosocial interventions have shown promise and this is an active area of research. Despite the effort to identify effective interventions, as yet there is no broadly accepted definition of therapeutic success. This article reviews concepts of clinical relevance and reports on a consensus conference whose goal was to apply these concepts to the treatment of negative symptoms. A number of key issues were identified and discussed including: assessment of specific negative symptom domains; defining response and remission for negative symptoms; assessment of functional outcomes; measurement of outcomes within clinical trials; and the assessment of duration/persistence of a response. The group reached a definition of therapeutic success using an achieved threshold of function that persisted over time. Recommendations were agreed upon with respect to: assessment of negative symptom domains of apathy-avolition and deficit of expression symptoms; thresholds for response and remission of negative symptoms based on level of symptomatology; assessing multiple domains of function including social occupation, activities of daily living, and socialization; the need for clinical trial data to include rate of change over time and converging sources of evidence; use of clinician, patient and caregiver perspectives to assess success; and the need for establishing criteria for the persistence of therapeutic benefit. A consensus statement and associated research criteria are offered as an initial step towards developing broad agreement regarding outcomes of negative symptoms treatment.

Reliability, validity and ability to detect change of the PANSS negative symptom factor score in outpatients with schizophrenia on select antipsychotics and with prominent negative or disorganized thought symptoms

The PANSS is a valid instrument assessing schizophrenia symptom severity. Analyses have identified a five-factor solution. The negative symptom factor (NSFS) is robust, having been replicated in multiple analyses. The score has superior content validity versus the negative subscale. Aspects of validity in patients with predominant negative symptoms have yet to be established. The present data are from a Phase IIb study of add-on bitopertin therapy in schizophrenia outpatients with prominent negative or disorganized thought symptoms treated with antipsychotics. Analyses were conducted to evaluate reliability, validity and sensitivity to change. Test-retest screening to baseline was high (ICC=0.93). This was maintained in-study, for patients with no change in CGI negative symptom severity (CGI-S-N). Internal consistency at baseline was adequate (α=0.71) and increased at later assessments. Pearson correlation at baseline showed a good association between NSFS and CGI-S-N (0.63), but not overall CGI-S (0.31). Association with PSP at baseline was moderate (-0.39) and for change at Week eight good (-0.65). NSFS responders (≥20% improvement) at Week eight showed a significant improvement in function. The analyses demonstrated reliability, validity and ability to detect change of the NSFS, in schizophrenia patients with prominent negative or disorganized thought symptoms.