The value of assessing cognitive function in drug development

This is the final version of the article. Available from the publisher via the NCBI link in this record.This paper reviews the value and utility of measuring cognitive function in the development of new medicines by reference to the most widely used automated system in clinical research. Evidence is presented from phase 1 to 3 of the nature and quality of the information that can be obtained by applying the Cognitive Drug Research computerized assessment system to ongoing clinical trials. Valuable evidence can be obtained even in the first trial in which a novel compound is administered to man. One application of such testing is to ensure that novel compounds are relatively free from cognition-impairing properties, particularly in relation to competitor products. Another is to ensure that unwanted interactions with alcohol and other medications do not occur, or, if they do, to put them in context. In many patient populations, cognitive dysfunction occurs as a result of the disease process, and newer medicines which can treat the symptoms of the disease without further impairing function can often reveal benefits as the disease-induced cognitive dysfunction is reduced. Another major application is to identify benefits for compounds designed to enhance cognitive function. Such effects can be sought in typical phase 1 trials, or a scopolamine model of the core deficits of Alzheimer's disease can be used to screen potential antidernentia drugs. Ultimately, of course, such effects can be demonstrated using properly validated and highly sensitive automated procedures in the target populations. The data presented demonstrate that the concept of independently assessing a variety of cognitive functions is crucial in helping differentiate drugs, types of dementia, and different illnesses. Such information offers a unique insight into how the alterations to various cognitive functions will manifest themselves in everyday behavior. This reveals a major limitation of scales that yield a single score, because such limited information does not permit anything but a quantitative interpretation; and the concept of "more" cognitive function or "less" is manifestly inappropriate for something as complex and diverse as the interplay between cognitive function and human behavior. Finally, the next generations of cognitive testing are described. Testing via the telephone has just been introduced and will have dramatic effects on the logistics of conducting cognitive testing in large patient trials. Testing via the Internet is not far off either, and will come fully into play as the proportion of homes connected to the Internet increases in Europe and North America. There are no sound reasons for not wishing to include cognitive function testing in the development protocol of any novel medicine

Moving beyond the pros and cons of automating cognitive testing in pathological aging and dementia: the case for equal opportunity.

This is the final version of the article. Available from BioMed Central via the DOI in this record.The lack of progress over the last decade in developing treatments for Alzheimer's disease has called into question the quality of the cognitive assessments used while also shifting the emphasis from treatment to prophylaxis by studying the disorder at earlier stages, even prior to the development of cognitive symptoms. This has led various groups to seek cognitive tests which are more sensitive than those currently used and which can be meaningfully administered to individuals with mild or even no cognitive impairment. Although computerized tests have long been used in this field, they have made little inroads compared with non-automated tests. This review attempts to put in perspective the relative utilities of automated and non-automated tests of cognitive function in therapeutic trials of pathological aging and the dementias. Also by a review of the automation of cognitive tests over the last 150 years, it is hoped that the notion that such procedures are novel compared with pencil-and-paper testing will be dispelled. Furthermore, data will be presented to illustrate that older individuals and patients with dementia are neither stressed nor disadvantaged when tested with appropriately developed computerized methods. An important aspect of automated testing is that it can assess all aspects of task performance, including the speed of cognitive processes, and data are presented on the advantages this can confer in clinical trials. The ultimate objectives of the review are to encourage decision making in the field to move away from the automated/non-automated dichotomy and to develop criteria pertinent to each trial against which all available procedures are evaluated. If we are to make serious progress in this area, we must use the best tools available, and the evidence suggests that automated testing has earned the right to be judged against the same criteria as non-automated tests

The impact of lifestyle factors on disease risk and long-term disability progression in multiple sclerosis

The thesis is corrected according to the thesis' errata.Background: Multiple sclerosis (MS) is a disabling inflammatory disease of the central nervous system (CNS) likely caused by genetic susceptible variants and environmental triggers. Low vitamin D levels and smoking are already established risk factors for MS, while obesity and physical activity may also influence the risk. In addition, some of these factors are associated with disease course in MS, but less is known about their potential long-term effects on MS. Objectives: In this thesis, we examined (i) the association between body size and MS risk across different geographical areas (Paper 1), (ii) whether frequency and intensity of physical activity in adolescence may be an independent risk factor for MS (Paper 2) and (iii) whether vitamin D levels, tobacco use and body mass index (BMI) can influence long-term disability progression in MS (Paper 3). Methods and materials: In Paper 1 and 2, we used retrospective self-reported data from a large multinational population-based case-control study on environmental and lifestyle factors in MS (the EnvIMS study). The study on body size and MS risk in Paper 1 was based on self-reported body sizes on a 9-figure scale, at 5-year intervals, from age 5 to age 30 years in Norway and Italy. The study on physical activity (PA) and MS risk in Paper 2 was based on reported average weekly amounts of light and vigorous PA during adolescence in Norway, Sweden and Italy. We used logistic regression models to examine the associations between lifestyle factors and the risk of MS, with adjustment for relevant covariates. For Paper 3, we had available baseline and 10-year follow-up data from 80 patients who initially participated in a randomized study on omega-3 fatty acids treatment in MS (the OFAMS study). In linear regression models, we examined the association between mean baseline levels of serum 25-hydroxyvitamin D (25(OH)D), serum cotinine (a nicotine metabolite) and BMI, and 10-year disability progression given by the 10-year change in Expanded Disability Status Scale (EDSS) score. We also examined the importance of seasonal fluctuations of 25(OH)D on this association. Results: In Paper 1, a large body size (body figure 6-9) was significantly associated with increased MS risk in Norway from age 15- 25 years. The association was strongest at age 25, with an age-adjusted odds ratio (OR) of 2.10 (95% confidence interval (CI): 1.08-4.09) for men and 1.48 (95% CI: 0.94-2.32) for women, compared to a “normal weight” body size 3. Further adjusting for smoking and outdoor activity gave similar estimates. In Italy we found no clear association between body size and the risk of MS, but after disease onset, the controls in both countries reported larger body sizes relative to the cases. In Paper II, the pooled analyses for Norway, Sweden and Italy showed that vigorous PA ≥ 3 hours compared to < 1 hour per week was associated with a reduced risk of MS with an age- and sex-adjusted OR of 0.74 (95% CI: 0.63-0.87). We found similar estimates in country-specific analyses, also after adjusting for other established risk factors. No clear evidence of reverse causation explaining this association was observed in a subgroup analysis, excluding participants with disease onset within 10 years from reported PA. In Paper 3, one standard deviation (SD; 18.7 nmol/L) increase in seasonally adjusted 25(OH)D levels during the OFAMS baseline study was associated with 0.45 point (95% CI: -0.75 to -0.16) less change in EDSS score after 10 years, in a model adjusting for sex, age and baseline EDSS score. There was a significant dose-response relationship across quartiles of 25(OH)D levels (p for trend = 0.024). The association was mainly driven by low 25(OH)D levels during spring and seasonally adjusted levels below 80 nmol/L. For BMI and tobacco use, no significant associations were observed, but we found a trend towards less progression with higher BMI. Conclusions: A large body size during childhood and young adulthood was associated with increased risk of MS among men and women in Norway, but less so in Italy. Higher amounts of regularly vigorous PA were associated with lower MS risk across different geographical areas, also after adjustment for potential confounders. Higher levels of 25(OH)D during a two-year period were associated with less 10-year disability progression, which appeared to be driven by low spring levels. Our findings suggest that healthy lifestyle changes during young ages may influence the risk of developing MS in a beneficial way, and that better long-term outcomes can be achieved by maintaining 25(OH)D levels above 80 nmol/L throughout the year.Doktorgradsavhandlin

The Effects of the Selective Muscarinic M3 Receptor Antagonist Darifenacin, and of Hyoscine (scopolamine), on Motion Sickness, Skin Conductance & Cognitive Function

Aims: The aim of this study was to compare the effects of the selective M3 muscarinic acetylcholine receptor antagonist Darifenacin, oral Hyoscine hydrobromide and Placebo on motion sickness induced by cross-coupled stimulation. Methods: The effects of Darifenacin 10 mg or 20 mg, Hyoscine hydrobromide 0.6 mg and Placebo were assessed in a randomised, double-blind, 4-way cross over trial of 16 healthy subjects. Motion sickness, skin conductance (a measure of sweating) and psychomotor cognitive function tests were investigated. Results: Hyoscine hydrobromide produced significantly increased tolerance to motion versus Placebo (P<0.05 to P<0.01). The motion protection effect of Darifenacin (10 or 20 mg) was approximately one third of that of Hyoscine hydrobromide, but was not significant versus Placebo. Darifenacin and Hyoscine hydrobromide both significantly reduced skin conductance versus Placebo. Darifenacin produced either no effect or an enhanced effect on cognitive function in contrast to Hyoscine hydrobromide where there was significant impairment of psychomotor performance. Conclusion: The results suggest that selective antagonism of the M3 receptor may not be important in the prevention of motion sickness. However selective M3 antagonism does not impair cognitive function. These observations may be important given that long term treatment with non-selective anti-muscarinic agents such as Oxybutynin may lead to an increased incidence of dementia

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

This is the final version of the article. Available from the publisher via the NCBI link in this record.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

Birthweight and urinary incontinence after childbirth: a systematic review and meta-analysis

Urinary incontinence (UI) is common after childbirth. Many cohort and cross-sectional studies have reported data on birthweight, but results have not been pooled. It is unclear how birthweight affects UI after childbirth. The objective is to review the effect of birthweight on UI after childbirth through meta-analyses. Searches were performed in Medline, Embase, Svemed+, ClinicalTrials.gov, Cochrane, and Cinahl in August 2016. Additional reference checking was performed. Included articles evaluated birthweight as a possible risk factor for maternal UI. We included articles that were presented in Norwegian, Danish, Swedish, or English. Two independent reviewers extracted the data and analysed it using Review Manager 5.3 software. Available data from included studies on birthweight (≥4000 g and ≥3500 g, respectively) and UI were combined in meta-analyses. PRISMA and MOOSE guidelines were used. Eighteen studies (N = 30 070) reported data on birthweight >4000 g vs 4000 g compared to weight 3500 g vs 3500 g was also associated with a significantly increased OR of UI (OR 1.26, 95% CI 1.15 – 1.37). High birthweight appears to increase OR of UI after childbirth. Preventative strategies should be targeted towards women at particular risk.publishedVersio

Longitudinal Changes in Global and Domain Specific Cognitive Function in the Very old: Findings from the Newcastle 85+ Study

Objective - Ageing is associated with changes in cognition in some, but not all domains. In young–old adults, defined as persons aged 65–84 years, baseline cognitive function has been shown to impact on cognitive trajectories. Whether similar patterns occur in the very‐old, defined as persons aged 85 years and over, is not known. Methods - Longitudinal changes (5 years' follow‐up) in global and domain specific cognitive function including memory, attention and speed were investigated in participants from the Newcastle 85+ Study (n = 845). At baseline, participants were grouped using Mini‐Mental State Examination cut‐off scores and dementia status into the following: not impaired, mildly impaired or severely impaired/dementia groups. Results - Only a limited number of cognitive measures showed significant decline in performance over time. Where observed, change generally occurred only in the severely impaired group. In the severely impaired group, small differences in baseline age were associated with poorer performance over time on most measures. Education was not protective against cognitive decline in any group. Conclusions - There are individuals who maintain a high level of cognitive function or only show mild impairments even into their ninth decade of life. This group of successful cognitive agers may provide insight for identifying predictors of cognitive integrity in later life. In individuals with severe impairment, cognitive performance shows significant decline over time, especially in measures of attention and speed. Further work to identify those individuals at highest risk of cognitive decline is necessary to implement early support and intervention strategies in this rapidly expanding age group

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