Development of the CHARIOT Research Register for the Prevention of Alzheimer's Dementia and Other Late Onset Neurodegenerative Diseases.

BACKGROUND: Identifying cognitively healthy people at high risk of developing dementia is an ever-increasing focus. These individuals are essential for inclusion in observational studies into the natural history of the prodromal and early disease stages and for interventional studies aimed at prevention or disease modification. The success of this research is dependent on having access to a well characterised, representative and sufficiently large population of individuals. Access to such a population remains challenging as clinical research has, historically, focussed on patients with dementia referred to secondary and tertiary services. The primary care system in the United Kingdom allows access to a true prodromal population prior to symptoms emerging and specialist referral. We report the development and recruitment rates of the CHARIOT register, a primary care-based recruitment register for research into the prevention of dementia. The CHARIOT register was designed specifically to support recruitment into observational natural history studies of pre-symptomatic or prodromal dementia stages, and primary or secondary prevention pharmaceutical trials or other prevention strategies for dementia and other cognitive problems associated with ageing. METHODS: Participants were recruited through searches of general practice lists across the west and central London regions. Invitations were posted to individuals aged between 60 and 85 years, without a diagnosis of dementia. Upon consent, a minimum data set of demographic and contact details was extracted from the patient's electronic health record. RESULTS: To date, 123 surgeries participated in the register, recruiting a total of 24,509 participants-a response rate of 22.3%. The age, gender and ethnicity profiles of participants closely match that of the overall eligible population. Higher response rates tended to be associated with larger practices (r = 0.34), practices with a larger older population (r = 0.27), less socioeconomically disadvantaged practices (r = 0.68), and practices with a higher proportion of White patients (r = 0.82). DISCUSSION: Response rates are comparable to other registers reported in the literature, and indicate good interest and support for a research register and for participation in research for the prevention of age-related neurodegenerative diseases and dementia. We consider that the simplicity of the approach means that this system is easily scalable and replicable across the UK and internationally.

Comparison of Site-Based Versus Central Ratings in a Study of Generalized Anxiety Disorder.

Lack of standardization across sites and raters, poor interrater reliability, and possible scoring bias affecting the primary outcome measure contribute to a high failure rate in anxiety trials. Remote centralized raters who are blinded to protocol inclusion and exclusion criteria as well as visit number may standardize assessments across raters and eliminate scoring bias, decreasing placebo response and thereby increasing signal detection. The purpose of the primary study was to test the safety and efficacy of an anxiolytic in a double-blind, placebo-controlled (no active comparator), multicenter trial. However, there was an additional prospective objective to explore site ratings compared with remote centralized ratings in the cohort of subjects on placebo. Site raters assessed subjects 6 times over an 8-week period. The primary outcome measure was the week 8 site-rated Hamilton Anxiety Scale (HAM-A). Remote centralized raters by telephone independently rated these subjects on the HAM-A at baseline and week 6. Of the 122 subjects selected by site raters and therefore randomized, remote centralized raters would have admitted 59 (48%) and excluded 63 (52%), based on their HAM-A ratings. The mean change from baseline in HAM-A total score in the placebo group admitted to the study by site raters was 9.3, significantly higher than the 5.9 point mean change on placebo as measured by the remote centralized raters.The data are consistent with the potential for qualification bias at baseline when rated by sites. The results make a strong case for using strategies to ensure that baseline scoring is truly independent of the pressure to enroll.

Parkinson's Disease Case Ascertainment in the EPIC Cohort: The NeuroEPIC4PD Study.

BACKGROUND/AIMS: Large epidemiological prospective studies represent an important opportunity for investigating risk factors for rare diseases such as Parkinson's disease (PD). Here we describe the procedures we used for ascertaining PD cases in the EPIC (European Prospective Investigation into Cancer and Nutrition) study. METHODS: The following three-phase procedure was used: (1) elaboration of a NeuroEPIC4PD template for clinical data collection, (2) identification of all potential PD cases via record linkage and (3) validation of the diagnosis through clinical record revision, in a population of 220,494 subjects recruited in 7 European countries. All cases were labelled with the NeuroEPIC4PD diagnoses of 'definite', 'very likely', 'probable', or 'possible' PD. RESULTS: A total of 881 PD cases were identified, with over 2,741,780 person-years of follow-up (199 definite, 275 very likely, 146 probable, and 261 possible). Of these, 734 were incident cases. The mean age at diagnosis was 67.9 years (SD 9.2) and 458 patients (52.0%) were men. Bradykinesia was the most frequent presenting motor sign (76.5%). Tremor-dominant and akinetic rigid forms of PD were the most common types of PD. A total of 289 patients (32.8%) were dead at the time of the last follow-up. CONCLUSIONS: This exercise proved that it is feasible to ascertain PD in large population-based cohort studies and offers a potential framework to be replicated in similar studies.

One-year safety and efficacy study of arformoterol tartrate in patients with moderate to severe COPD.

BACKGROUND: Arformoterol tartrate (arformoterol, 15 µg bid) is a nebulized long-acting ß2-agonist approved for maintenance treatment of COPD. METHODS: This was a multicenter, double-blind, randomized, placebo-controlled study. Patients (aged ≥ 40 years with baseline FEV1 ≤ 65% predicted, FEV1 > 0.50 L, FEV1/FVC ≤ 70%, and ≥ 15 pack-year smoking history) received arformoterol (n = 420) or placebo (n = 421) for 1 year. The primary assessment was time from randomization to respiratory death or first COPD exacerbation-related hospitalization. RESULTS: Among 841 patients randomized, 103 had ≥ 1 primary event (9.5% vs 15.0%, for arformoterol vs placebo, respectively). Patients who discontinued treatment for any reason (39.3% vs 49.9%, for arformoterol vs placebo, respectively) were followed for up to 1 year postrandomization to assess for primary events. Fewer patients receiving arformoterol than placebo experienced COPD exacerbation-related hospitalizations (9.0% vs 14.3%, respectively). Twelve patients (2.9%) receiving arformoterol and 10 patients (2.4%) receiving placebo died during the study. Risk for first respiratory serious adverse event was 50% lower with arformoterol than placebo (P = .003). Numerically more patients on arformoterol (13; 3.1%) than placebo (10; 2.4%) experienced cardiac serious adverse events; however, time-to-first cardiac serious adverse event was not significantly different. Improvements in trough FEV1 and FVC were greater with arformoterol (least-squares mean change from baseline vs placebo: 0.051 L, P = .030 and 0.075 L, P = .018, respectively). Significant improvements in quality of life (overall St. George's Hospital Respiratory Questionnaire and Clinical COPD Questionnaire) were observed with arformoterol vs placebo (P < .05). CONCLUSIONS: Arformoterol demonstrated an approximately 40% lower risk of respiratory death or COPD exacerbation-related hospitalization over 1 year vs placebo. Arformoterol was well-tolerated and improved lung function vs placebo. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00909779; URL: www.clinicaltrials.gov.

Establishing the motivations of patients with dementia and cognitive impairment and their carers in joining a dementia research register (DemReg).

BACKGROUND: Connecting willing patients with dementia to suitable clinical research studies has been historically challenging. The United Kingdom Dementia and Neurodegenerative Research Network (DeNDRoN) was established to link patients into high-quality studies. One component is DemReg, a register of dementia patients and their carers who have agreed to be approached regarding future research studies. The limited literature highlights the predominance of altruism mediating research register participation. The objective of this study was to understand the motivations of patients and carers to participate in DemReg. METHODS: There were 107 participants in the study, interviewed using a questionnaire to determine which factors were important in their decision to be on the register. The study compared the proportion of the altruistic motivations articulated with the proportion of the other answers offered. RESULTS: The two most important motivators for registering on DemReg were to help others (44%; p < 0.001) or themselves (29%; p < 0.001) and altruistic motives took precedence over those for personal benefit. Participants were not motivated by the prospect of payment or by concern that they would be letting down their clinician if they did not register. CONCLUSIONS: There are currently major projects within the United Kingdom to increase the number of patients on dementia registers and to further involvement in dementia research. This study, to the best of our knowledge, is the first to assess the motivations of patients and carers for joining a dementia research register in the United Kingdom, and the findings highlight the importance of altruistic motives.

Developing a Dementia Research Registry: a descriptive case study from North Thames DeNDRoN and the EVIDEM programme.

AIM: To describe the development of a dementia research registry, outlining the conceptual, practical and ethical challenges, and to report initial experiences of recruiting people with dementia to it from primary and secondary care. BACKGROUND: Women, the oldest old and ethnic minorities have been under-represented in clinical trials in dementia. Such under-representation biases estimates of absolute effect, absolute harm and cost-effectiveness. Research on dementia should include patient populations that more exactly reflect the population at risk. One of the impediments to this is the lack of a suitable tool for identification of patients suitable for studies. CONSTRUCTION & CONTENTS: A technology development methodology was used to develop a registry of people with dementia and their carers. This involved phases of modelling and prototype creation, 'bench testing' the prototype with experts and then 'field testing' the refined prototype in exemplar sites. The evaluation of the field testing described here is based on a case study methodology. UTILITY: This case study suggests that construction and population of a dementia research registry is feasible, but initial development is complex because of the ethical and organisational difficulties. Recruitment from primary care is particularly costly in terms of staff time and only identifies a very small number of people with dementia who were not already known to specialist services. Recruiting people with dementia through secondary care is a resource intensive process that takes up to six months to complete. Identifying the components of a minimum dataset was easy but its usefulness for pre-screening potential research populations has yet to be established. Acceptance rates are very high in the first clinic to recruit to the registry, but this may reflect the efforts of registry 'champions'. DISCUSSION AND CONCLUSIONS: Easier recruitment may perpetuate potential selection biases and we are not yet able to assess the representativeness of the research-ready population recruited to the registry. The need to recruit from wider populations, through primary and social care, remains. The success of this registry will be measured by the proportion of people from it who are recruited to research projects, and its impact on overall accrual to studies.

Output and aerosol properties of 5 nebulizer/compressor systems with arformoterol inhalation solution.

BACKGROUND: Arformoterol, the (R,R) isomer of formoterol, is approved as an inhalation solution for the treatment of bronchoconstriction in patients with chronic obstructive pulmonary disease. Multiple nebulizer systems are commercially available. Different nebulizers can differ significantly in drug output, which may impact drug delivery and clinical efficacy. This study compared the aerosol properties of arformoterol delivered via 5 commonly used nebulizer systems for the home-care market. METHODS: The delivered dose of arformoterol inhalation solution (15 microg/2 mL) was collected in a glass Dreschel-type apparatus. The delivered amount in fine-droplet fraction was assessed with an Andersen cascade impactor, and droplet size (average median diameter and average percent<5 microm) was evaluated via laser diffraction. Compressor flow rate measurements were taken after 1 min and 6 min by placing the flow meter in line with each system. RESULTS: The Pari LC Plus, Updraft II Opti-Neb, and NebuTech systems delivered similar amounts of the 15-microg nominal dose (from 23% to 25%). The Pari LC Star and Sidestream systems delivered slightly higher doses (31% and 35%, respectively). The nebulizer/compressor systems differed somewhat with respect to droplet size. The NebuTech delivered the lowest fine-droplet fraction (61%) via Andersen cascade impactor, and the smallest percent of droplets<5 microm (40%) via laser diffraction. The Pari LC Star and Sidestream delivered the highest fine-droplet fraction (100% and 93%, respectively), and the greatest percent of droplets<5 microm (84% and 88%). The fine-droplet fractions for the Updraft II Opti-Neb and Pari LC Plus were 93% and 89%, respectively, and the percent of droplets<5 microm was about 67%. Compressor flow rates ranged from 3.2 L/min (Pari LC Plus) to 5.4 L/min (NebuTech). CONCLUSIONS: The results of this study demonstrate that the choice of nebulizer/compressor system can influence the aerosol properties of arformoterol inhalation solution and should be considered when prescribing nebulized medications.

The influence of breathing pattern during nebulization on the delivery of arformoterol using a breath simulator.

BACKGROUND: Patients with obstructive airway conditions, including chronic obstructive pulmonary disease (COPD), use nebulizers for drug delivery. Tidal breathing patterns employed by patients during nebulized drug delivery may vary. It is unclear whether different breathing patterns affect the emitted quantity of nebulized drug. This in vitro study evaluated whether different tidal breathing patterns that encompass a range that could be observed in COPD patients influence the emitted amount of nebulized arformoterol. METHODS: Breath-simulation experiments used a Pari LC Plus nebulizer in combination with the Duraneb 3000 portable aerosol system. Four breathing patterns that could represent a range of tidal volumes and inspiratory and expiratory times observed in patients with COPD were studied. The amount of arformoterol on the inspiratory and expiratory filters, and the residual amount in the nebulizer bowl were determined via high-pressure liquid chromatography. Results are expressed as a percent of the nominal dose (15 microg in 2 mL). RESULTS: The total amount of arformoterol on the inspiratory filter increased with a longer inspiratory phase of tidal breathing (ranging from 8.0% to 13.1%), while the expiratory filter dose remained similar (7.9% to 8.7%). The total emitted dose (expiratory and inspiratory amounts combined) for all patterns was 16.0% to 21.1% of the nominal dose. Retained arformoterol amount (not emitted) ranged from 55.9% to 62.3% of the nominal dose. CONCLUSIONS: These breath-simulation experiments suggest that only about 20% of the nominal 15-microg arformoterol dose was emitted from the nebulizer apparatus with each of the 4 tidal breathing patterns studied, and that a longer inspiratory phase was associated with greater inhaled dose.

A focal adhesion-like process underlies induction of long-term potentiation in the Schaffer collateral-CA1 region of the hippocampus.

In the series of experiments reported here we provide evidence that a focal adhesion-like process underlies the induction of long-term potentiation (LTP) in the Schaffer Collateral-CA1 projection in the hippocampus. Here we show that an integrin binding peptide (RGD) impairs induction of Schaffer Collateral-CA1 LTP in hippocampal slice preparations in vitro. The heparin-binding peptide that binds heparan sulfate proteoglycan (HSPG) and blocks the formation of focal adhesions also impairs induction of LTP. Either the integrin-binding peptide or heparin-binding peptide reduces LTP partially. However, when the two peptides were administered simultaneously, there was no LTP 1 hour after induction. This indicates that these two molecules might function together and that a focal adhesion-like process might be involved in the induction of LTP. Additionally,we report that the RGD effect on LTP is time dependent and occurs only in the first few minutes following LTP induction, that the binding of the RGD peptide in CA1 stratum radiatum increases after LTP induction and that this increased binding depends on Ca(2+). Using electron microscopy we show that integrins are present in synapses.