Sensitive Outcome Measures Research Articles

Diffusion imaging changes in grey matter in Alzheimer's disease: a potential marker of early neurodegeneration.

Alzheimer’s disease (AD) is recognized to have a long presymptomatic period, during which there is progressive accumulation of molecular pathology, followed by inexorable neuronal damage. The ability to identify presymptomatic individuals with evidence of neurodegenerative change, to stage their disease, and to track progressive changes will be important for early diagnosis and for prevention trials. Despite recent advances, particularly in magnetic resonance imaging, our ability to identify early neurodegenerative changes reliably is limited. The development of diffusion-weighted magnetic resonance imaging, which is sensitive to microstructural changes not visible with conventional volumetric techniques, has led to a number of diffusion imaging studies in AD; these have largely focused on white matter changes. However, in AD cerebral grey matter is affected very early, with pathological studies suggesting that grey matter changes predate those in white matter. In this article we review the growing number of studies that assess grey matter diffusivity changes in AD. Although use of the technique is still at a relatively early stage, results so far have been promising. Initial studies identified changes in diffusion measures in the hippocampi of patients with mild cognitive impairment, which predated macroscopic volume loss, with positive predictive value for progression to AD dementia. More recent studies have identified abnormalities in multiple neocortical areas (particularly the posterior cingulate) at various stages of disease progression. Studies of patients who carry genetic mutations predisposing to autosomal dominant familial AD have shown cortical and subcortical grey matter diffusivity changes several years before the expected onset of the first clinical symptoms. The technique is not without potential methodological difficulties, especially relating to partial volume effects, although recent advances appear to be reducing such issues. Going forward, further utilization of grey matter diffusion measurements in AD may improve our understanding with regards to the timing and nature of the earliest presymptomatic neurodegenerative changes. This imaging technique may also be useful in comparing and contrasting subtle variations in different disease subgroups, and as a sensitive outcome measure for presymptomatic clinical trials in AD and other neurodegenerative diseases.

Physical Activity and Different Concepts of Fall Risk Estimation in Older People--Results of the ActiFE-Ulm Study.

ObjectivesTo investigate the relationship between physical activity and two measures of fall incidence in an elderly population using person-years as well as hours walked as denominators and to compare these two approaches.DesignProspective cohort study with one-year follow-up of falls using fall calendars. Physical activity was defined as walking duration and recorded at baseline over one week using a thigh-worn uni-axial accelerometer (activPAL; PAL Technologies, Glasgow, Scotland). Average daily physical activity was extracted from these data and categorized in low (0–59 min), medium (60–119 min) and high (120 min and more) activity.SettingThe ActiFE Ulm study located in Ulm and adjacent regions in Southern Germany.Participants1,214 community-dwelling older people (≥65 years, 56.4% men).MeasurementsNegative-binomial regression models were used to calculate fall rates and incidence rate ratios for each activity category each with using (1) person-years and (2) hours walked as denominators stratified by gender, age group, fall history, and walking speed. All analyses were adjusted either for gender, age, or both.ResultsNo statistically significant association was seen between falls per person-year and average daily physical activity. However, when looking at falls per 100 hours walked, those who were low active sustained more falls per hours walked. The highest incidence rates of falls were seen in low-active persons with slow walking speed (0.57 (95% confidence interval (95% CI): 0.33 to 0.98) falls per 100 hours walked) or history of falls (0.60 (95% CI: 0.36 to 0.99) falls per 100 hours walked).ConclusionFalls per hours walked is a relevant and sensitive outcome measure. It complements the concept of incidence per person years, and gives an additional perspective on falls in community-dwelling older people.

2014 Update of the Alzheimer's Disease Neuroimaging Initiative: A review of papers published since its inception

The Alzheimer's Disease Neuroimaging Initiative (ADNI) is an ongoing, longitudinal, multicenter study designed to develop clinical, imaging, genetic, and biochemical biomarkers for the early detection and tracking of Alzheimer's disease (AD). The initial study, ADNI-1, enrolled 400 subjects with early mild cognitive impairment (MCI), 200 with early AD, and 200 cognitively normal elderly controls. ADNI-1 was extended by a 2-year Grand Opportunities grant in 2009 and by a competitive renewal, ADNI-2, which enrolled an additional 550 participants and will run until 2015. This article reviews all papers published since the inception of the initiative and summarizes the results to the end of 2013. The major accomplishments of ADNI have been as follows: (1) the development of standardized methods for clinical tests, magnetic resonance imaging (MRI), positron emission tomography (PET), and cerebrospinal fluid (CSF) biomarkers in a multicenter setting; (2) elucidation of the patterns and rates of change of imaging and CSF biomarker measurements in control subjects, MCI patients, and AD patients. CSF biomarkers are largely consistent with disease trajectories predicted by β-amyloid cascade (Hardy, J Alzheimer's Dis 2006;9(Suppl 3):151–3) and tau-mediated neurodegeneration hypotheses for AD, whereas brain atrophy and hypometabolism levels show predicted patterns but exhibit differing rates of change depending on region and disease severity; (3) the assessment of alternative methods of diagnostic categorization. Currently, the best classifiers select and combine optimum features from multiple modalities, including MRI, [18F]-fluorodeoxyglucose-PET, amyloid PET, CSF biomarkers, and clinical tests; (4) the development of blood biomarkers for AD as potentially noninvasive and low-cost alternatives to CSF biomarkers for AD diagnosis and the assessment of α-syn as an additional biomarker; (5) the development of methods for the early detection of AD. CSF biomarkers, β-amyloid 42 and tau, as well as amyloid PET may reflect the earliest steps in AD pathology in mildly symptomatic or even nonsymptomatic subjects and are leading candidates for the detection of AD in its preclinical stages; (6) the improvement of clinical trial efficiency through the identification of subjects most likely to undergo imminent future clinical decline and the use of more sensitive outcome measures to reduce sample sizes. Multimodal methods incorporating APOE status and longitudinal MRI proved most highly predictive of future decline. Refinements of clinical tests used as outcome measures such as clinical dementia rating-sum of boxes further reduced sample sizes; (7) the pioneering of genome-wide association studies that leverage quantitative imaging and biomarker phenotypes, including longitudinal data, to confirm recently identified loci, CR1, CLU, and PICALM and to identify novel AD risk loci; (8) worldwide impact through the establishment of ADNI-like programs in Japan, Australia, Argentina, Taiwan, China, Korea, Europe, and Italy; (9) understanding the biology and pathobiology of normal aging, MCI, and AD through integration of ADNI biomarker and clinical data to stimulate research that will resolve controversies about competing hypotheses on the etiopathogenesis of AD, thereby advancing efforts to find disease-modifying drugs for AD; and (10) the establishment of infrastructure to allow sharing of all raw and processed data without embargo to interested scientific investigators throughout the world.

WS07.4 MBW and MRI as sensitive markers of stable CF lung disease and at exacerbation in children and adolescents

Objectives MBW and MRI have both been shown to be sensitive outcome measures for CF lung disease. Therefore, we wanted to determine the correlation of the LCI with alterations in the MRI chest score as markers of CF lung disease under stable conditions and at exacerbation. Methods 57 stable children with CF (mean age, 9.5±6.2 years) had chest MRI scans performed. All children with CF and 106 healthy children (mean age, 8.9±4.8 years) underwent age-adapted MBW testing to assess LCI and to calculate LCI z-scores. 36 children (mean age, 13.9±4.4 years) were investigated at time of pulmonary exacerbation either via MRI (n = 10) or MBW (n = 26). Results Mean LCI z-score in healthy children was 0.1±1.2). LCI z-score was significantly higher in stable children with CF (5.4±5.5, P Conclusion LCI z-score and MRI chest score are elevated in CF and show a high correlation. Both methods are feasible and sensitive non-invasive markers of CF lung disease in children with CF under stable conditions and at time of exacerbation.

Does gait speed indicate prosthetic walking potential following lower limb amputation?

Background: Gait speed is an indicator of walking ability, morbidity and mortality; and is a reliable, valid and sensitive outcome measure commonly used in the rehabilitation setting. Gait speed is a quick and efficient assessment method; yet, to date, there has been little investigation of its potential use in populations with lower limb amputation.

Response of the COPD Assessment Tool in Stable and Postexacerbation Pulmonary Rehabilitation Populations.

The COPD Assessment Tool (CAT) has previously been shown to be a sensitive outcome measure for pulmonary rehabilitation (PR) in a stable population, but its utility in a postexacerbation PR population is unknown. The aim of this study was to investigate any differences in response to the CAT between stable and postexacerbation patients undertaking PR. Patients attending a 7-week outpatient PR program completed a CAT questionnaire pre- and postrehabilitation. Patients referred for elective outpatient PR were compared with those who had been referred to PR following a hospital admission for an exacerbation. Two hundred consecutive patients completed the CAT questionnaire: 125 stable patients (74 male, mean age 71.1 ± 8.9 years, forced expiratory volume in 1 second [FEV1] 1.39 L ± 0.6, and body mass index [BMI] 28.5 ± 6.7 kg/m) and 75 postexacerbation patients (23 male, mean age 70.6 ± 8.6 years, FEV1 1.16 L ± 0.5, and BMI 25.8 ± 7.3 kg/m). A statistically significant difference between the stable and postexacerbation patient groups pre-PR CAT score (P = .05) was observed. There was no significant difference in post-PR CAT scores or change in CAT scores between the stable and postexacerbation groups. There was a significant difference in pre- and post-PR walking test results between the groups. The improvement in the Endurance Shuttle Walking Test (ESWT) in the stable group was greater (P < .05). Postexacerbation PR patients had a worse CAT score prior to PR when compared with a stable PR population, but both groups made improvements in CAT following completion of PR.

Robotic and clinical evaluation of upper limb motor performance in patients with Friedreich's Ataxia: an observational study.

BackgroundFriedreich’s ataxia (FRDA) is the most common hereditary autosomal recessive form of ataxia. In this disease there is early manifestation of gait ataxia, and dysmetria of the arms and legs which causes impairment in daily activities that require fine manual dexterity. To date there is no cure for this disease. Some novel therapeutic approaches are ongoing in different steps of clinical trial. Development of sensitive outcome measures is crucial to prove therapeutic effectiveness. The aim of the study was to assess the reliability and sensitivity of quantitative and objective assessment of upper limb performance computed by means of the robotic device and to evaluate the correlation with clinical and functional markers of the disease severity.MethodsHere we assess upper limb performances by means of the InMotion Arm Robot, a robot designed for clinical neurological applications, in a cohort of 14 children and young adults affected by FRDA, matched for age and gender with 18 healthy subjects. We focused on the analysis of kinematics, accuracy, smoothness, and submovements of the upper limb while reaching movements were performed. The robotic evaluation of upper limb performance consisted of planar reaching movements performed with the robotic system. The motors of the robot were turned off, so that the device worked as a measurement tool. The status of the disease was scored using the Scale for the Assessment and Rating of Ataxia (SARA). Relationships between robotic indices and a range of clinical and disease characteristics were examined.ResultsAll our robotic indices were significantly different between the two cohorts except for two, and were highly and reliably discriminative between healthy and subjects with FRDA. In particular, subjects with FRDA exhibited slower movements as well as loss of accuracy and smoothness, which are typical of the disease. Duration of Movement, Normalized Jerk, and Number of Submovements were the best discriminative indices, as they were directly and easily measurable and correlated with the status of the disease, as measured by SARA.ConclusionsOur results suggest that outcome measures obtained by means of robotic devices can improve the sensitivity of clinical evaluations of patients’ dexterity and can accurately and efficiently quantify changes over time in clinical trials, particularly when functional scales appear to be no longer sensitive.

Alzheimer’s Disease Dementia, Amyloid Imaging and Underpinning Fibrillar Aβ Plaque Associated Pathology: Are They Aligned?

The goal of this review is to summarize the literature about Alzheimer's disease (AD) diagnosis at the level of clinical, histopathological examinations and amyloid PET imaging, which is important not only to clinicians, but also to scientists who develop and test new therapies and biomarkers for AD. AD is the most common form of dementia and is characterized by the presence of fibrillar amyloid β (Aβ) in the form of extracellular plaques and hyperphosphorylated tau protein in the form of intracellular neurofibrillary tangles in specific brain regions. The definitive diagnosis of AD requires neuropathological examination of brain tissue. There are several published histopathologic criteria for the diagnosis of AD. These criteria are necessary to distinguish between pathologic changes associated with healthy aging versus those indicative of AD. The most commonly used criteria in clinical pathology practice and research are those developed by the Consortium to establish a registry for AD (CERAD) and by the National Institute on Aging (NIA)-Reagan criteria. Concordance between clinical diagnosis of AD and pathological findings is not exact. Previous clinical-postmortem studies have reported that ~10-15% of AD subjects diagnosed in expert centers show no signs of Aβ pathology. The diagnostic precision of community physicians is lower when rigorously assessed and compared to autopsy. For example, in a community- based brain bank study, only 77% of clinically diagnosed AD subjects received a pathological diagnosis of AD and 52% of those diagnosed with a non-AD dementia actually had pathological AD. It is critical to choose a right pathological assessment approach that can accurately and quantitatively assess the amount of amyloid in the brain. In this review we discussed how to dichotomize a postmortem measure of Aβ load using Aβ immunohistochemistry with the 4G8 antibody, and also assessed the role of amyloid imaging in diagnosis of AD and clinical development of new therapies. Amyloid imaging tests performance has been discussed from available clinical trials assessing diagnostic sensitivity, specificity, and accuracy; this type of technology recognized as a sensitive outcome measure in testing future therapies. The future directions in which field should move forward would require to improve the clinical diagnosis of AD and to validate amyloid imaging probes to be used as regulatory-accepted endpoints in disease-modifying trials.

Feasibility, acceptability and validity of SMS text messaging for measuring change in depression during a randomised controlled trial.

BackgroundDespite widespread popularity, text messaging has rarely been used for data collection in clinical research. This paper reports on the development, feasibility, acceptability, validity, and discriminant utility of a single item depression rating scale, delivered weekly via an automated SMS system, as part of a large randomised controlled trial.Methods755 depressed patients (BDI-II score ≥20) were recruited from primary care into a randomised trial of acupuncture versus counselling or usual care, and invited to opt into a repeated-measures text messaging sub-study. Two weeks following random allocation, trial participants were sent a weekly text message for 15 weeks. Texts were a single question asking, on a scale from 1 to 9, the extent to which they felt depressed. Feasibility and acceptability of the automated SMS system were evaluated according to cost, ease of implementation, proportion consenting, response rates, and qualitative feedback. Concurrent validity was estimated by correlating SMS responses with the Patient Health Questionnaire (PHQ-9). SMS responses were compared between groups over time to explore treatment effects.Results527 (69.8%) trial participants consented to the texting sub-study, of whom 498 (94.5%) responded to at least one message. Participants provided a valid response to an average of 12.5 messages. Invalid responses accounted for 1.1% of texts. The automated SMS system was quick to set-up, inexpensive, and well received. Comparison of PHQ-9 and SMS responses at 3 months demonstrated a moderate to high degree of agreement (Kendall’s tau-b = 0.57, p < 0.0001, n = 220). SMS depression scores over the 15 weeks differed significantly between trial arms (p = 0.007), with participants allocated to the acupuncture and counselling arms reporting improved depression outcomes compared to usual GP care alone, which reached statistical significance ten weeks after randomisation. Overall, the single item SMS scale also appeared more responsive to changes in depression, resulting from treatment, than the PHQ-9.ConclusionsAutomated SMS systems offer a feasible and acceptable means of monitoring depression within clinical research. This study provides clear evidence to support the regular use of a simple SMS scale as a sensitive and valid outcome measure of depression within future randomised controlled trials.Trial registrationCurrent Controlled Trials - ISRCTN63787732 http://www.controlled-trials.com/ISRCTN63787732/ACUDEP Date of registration: 15/12/2009

PRAGMA-CF. A Quantitative Structural Lung Disease Computed Tomography Outcome in Young Children with Cystic Fibrosis.

Chest computed tomography (CT) is the gold standard for demonstrating cystic fibrosis (CF) airway disease. However, there are no standardized outcome measures appropriate for children younger than 6 years. We developed the Perth-Rotterdam Annotated Grid Morphometric Analysis for CF (PRAGMA-CF), a quantitative measure of airway disease, and compared it with the commonly used CF-CT scoring method. CT scans from the Australian Respiratory Early Surveillance Team for CF (AREST CF) cohort in Western Australia were included. PRAGMA-CF was performed by annotating a grid overlaid on 10 axial slices for the presence of bronchiectasis, mucous plugging, or other airway abnormalities (inspiratory scans) and trapped air (expiratory scans). The separate proportions of total disease (%Dis), bronchiectasis (%Bx), and trapped air (%TA) were determined. Thirty scans were used for observer reliability, and 30 paired scans obtained at 1 and 3 years old were used for comparison with a validated standard and biologic plausibility. Intraobserver, intraclass correlation coefficients (95% confidence interval) for %Dis, %Bx, and %TA were 0.93 (0.86-0.97), 0.93 (0.85-0.96), and 0.96 (0.91-0.98), respectively. The change in %Dis (P = 0.004) and %Bx (P = 0.001) with PRAGMA-CF was related to neutrophil elastase presence at age 3, whereas only the change in bronchiectasis score was related to neutrophil elastase (P < 0.001) with CF-CT. Sample-size calculations for various effect sizes are presented. PRAGMA-CF is a sensitive and reproducible outcome measure for assessing the extent of lung disease in very young children with CF.

Motor development following in utero exposure to organochlorines: a follow-up study of children aged 5–9 years in Greenland, Ukraine and Poland

BackgroundPrior studies on the association between prenatal exposure to polychlorinated biphenyls (PCBs) and dichlorodiphenyldichloroethylene (DDE) and child motor development have found contradicting results. Using data collected in the INUENDO cohort in Kharkiv (Ukraine), Warsaw (Poland) and Greenland (N = 1,103) between the years 2002 and 2012, we examined relations of prenatal exposure to 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p′-DDE) and 2,2′,4,4′,5,5′-hexachlorobiphenyl (CB-153) on motor development and developmental milestones; crawling, standing-up and walking.MethodsCB-153 and p,p′-DDE were measured in maternal blood in second or third trimester of pregnancy. Motor development was measured in terms of the parentally assessed screening tool Developmental Coordination Disorder Questionnaire 2007 and developmental milestones were assessed via retrospective parental reports of child age at the first time of crawling, standing-up and walking.ResultsWe saw no associations between tertiles of CB-153 and p,p′-DDE or log-transformed exposures and retrospective reports of the developmental milestones crawling, standing-up and walking in infancy or the motor skills measured as developmental coordination disorder at young school age.ConclusionsIn utero exposure to CB-153 and p,p′-DDE was not associated with parentally retrospectively assessed developmental milestones in infancy or parentally assessed motor skills at young school age. The use of a more sensitive outcome measure may be warranted if subtle effects should be identified.Electronic supplementary materialThe online version of this article (doi:10.1186/s12889-015-1465-3) contains supplementary material, which is available to authorized users.

Clinical neuropathy scales in neuropathy associated with impaired glucose tolerance

AimsDisagreement exists on effective and sensitive outcome measures in neuropathy associated with impaired glucose tolerance (IGT). Nerve conduction studies and skin biopsies are costly, invasive and may have their problems with reproducibility and clinical applicability. A clinical measure of neuropathy that has sufficient sensitivity and correlates to invasive measures would enable significant future research. MethodsData was collected prospectively on patients with IGT and symptomatic early neuropathy (neuropathy symptoms <2years) and normal controls. The seven scales that were examined were the Neuropathy Impairment Score of the Lower Limb (NIS-LL), Michigan Diabetic Neuropathy Score (MNDS), modified Toronto Clinical Neuropathy Scale (mTCNS), Total Neuropathy Score (Clinical) (TNSc), The Utah Early Neuropathy Scale (UENS), the Early Neuropathy Score (ENS), and the Neuropathy Disability Score (NDS). ResultsAll seven clinical scales were determined to be excellent in discriminating between patients with neuropathy from controls without neuropathy. The strongest discrimination was seen with the mTCNS. The best sensitivity and specificity for the range of scores obtained, as determined by using receiver operating characteristic curves, was seen for the mTCNS followed by the TNSc. Most scales show a stronger correlation with measures of large rather than small fiber neuropathy. ConclusionsAll seven scales identify patients with neuropathy. For the purpose of screening potential patients for a clinical study, the mTCNS followed by the TNSc would be most helpful to select patients with neuropathy.

ECG in neonate mice with spinal muscular atrophy allows assessment of drug efficacy.

Molecular technologies have produced diverse arrays of animal models for studying genetic diseases and potential therapeutics. Many have neonatal phenotypes. Spinal muscular atrophy (SMA) is a neuromuscular disorder primarily affecting children, and is of great interest in translational medicine. The most widely used SMA mouse models require all phenotyping to be performed in neonates since they do not survive much past weaning. Pre-clinical studies in neonate mice can be hindered by toxicity and a lack of quality phenotyping assays, since many assays are invalid in pups or require subjective scoring with poor inter-rater variability. We find, however, that passive electrocardiography (ECG) recording in conscious 11-day old SMA mice provides sensitive outcome measures, detecting large differences in heart rate, cardiac conduction, and autonomic control resulting from disease. We find significant drug benefits upon treatment with G418, an aminoglycoside targeting the underlying protein deficiency, even in the absence of overt effects on growth and survival. These findings provide several quantitative physiological biomarkers for SMA preclinical studies, and will be of utility to diverse disease models featuring neonatal cardiac arrhythmias.

ECG in neonate mice with spinal muscular atrophy allows assessment of drug efficacy

Molecular technologies have produced diverse arrays of animal models for studying genetic diseases and potential therapeutics. Many have neonatal phenotypes. Spinal muscular atrophy (SMA) is a neuromuscular disorder primarily affecting children, and is of great interest in translational medicine. The most widely used SMA mouse models require all phenotyping to be performed in neonates since they do not survive much past weaning. Pre-clinical studies in neonate mice can be hindered by toxicity and a lack of quality phenotyping assays, since many assays are invalid in pups or require subjective scoring with poor inter-rater variability. We find, however, that passive electrocardiography (ECG) recording in conscious 11-day old SMA mice provides sensitive outcome measures, detecting large differences in heart rate, cardiac conduction, and autonomic control resulting from disease. We find significant drug benefits upon treatment with G418, an aminoglycoside targeting the underlying protein deficiency, even in the absence of overt effects on growth and survival. These findings provide several quantitative physiological biomarkers for SMA preclinical studies, and will be of utility to diverse disease models featuring neonatal cardiac arrhythmias.

Acute optic neuritis: a clinical paradigm for evaluation of neuroprotective and restorative strategies?

What makes the acute optic neuritis model unique in an era of trials for neuroprotective and myelin repair agents? Acute optic neuritis (AON) is a common, and often the earliest manifestation of central nervous system (CNS) inflammatory demyelinating disorders like multiple sclerosis (MS) and neuromyelitis optica (NMO). It affects at least half the patients with MS and is the presenting feature in 15–20% of patients. Vision loss in AON secondary to NMO tends to be more severe with less potential for recovery and greater axonal degeneration, as measured by optical coherence tomography (OCT) (Bennett et al., 2014). Several unique features of the afferent visual pathway (AVP) make the AON model an ideal system to study disease pathogenesis and evaluate potential neuroprotective and myelin repair strategies.

The presentation, assessment, pathogenesis, and treatment of calcinosis in juvenile dermatomyositis.

Calcinosis is one of the hallmark sequelae of juvenile dermatomyositis (JDM), and despite recent progress in the therapy of JDM, dystrophic calcification still occurs in approximately one third of patients. This review discusses our current, albeit limited, understanding of risk factors for the development of calcinosis in JDM, as well as approaches to assessment, and current views on its pathogenesis. Anecdotal approaches to treating calcinosis associated with JDM, including both anti-inflammatory therapies and agents aimed at inhibiting the deposition of calcium hydroxyapatite, are reviewed. An improved understanding of the pathogenesis of calcinosis, the establishment of standardized measurement tools to assess calcinosis, and randomized controlled trials employing more sensitive outcome measures are needed to develop efficacious therapies for this often disabling complication.

Psychometric evaluation of the Disabilities of the Arm, Shoulder and Hand (DASH) with Dupuytren's contracture: validity evidence using Rasch modeling.

BackgroundDupuytren’s contracture is a progressive, fibroproliferative disorder that causes fixed finger contractures and can lead to disability. With the advances of new therapeutic interventions, the necessity to assess the functional repercussions of this condition using valid, reliable and sensitive outcome measures is of growing interest. The Disabilities of the Arm, Shoulder and Hand (DASH) is one frequently used patient-reported outcome measure but its reliability and validity have never been demonstrated specifically for a population affected with Dupuytren’s contracture. The objective of this study was to evaluate the psychometric properties of the DASH, with focus on validity evidence using the Rasch measurement model.MethodsSecondary analysis was performed on data collected as part of a randomised clinical trial. One hundred fifty-three participants diagnosed with Dupuytren’s contracture completed the DASH at four time points (pre-op, 3, 6 and 12 months post-op). Baseline data were analysed using traditional analysis and to test whether they adhered to the expectations of the Rasch model. Post-intervention data were subsequently included and analyzed to determine the effect of the intervention on the items.ResultsDASH scores demonstrated large ceiling effects at all time points. Initial fit to the Rasch model revealed that the DASH did not adhere to the expectations of the Rasch partial credit model (χ2 = 119.92; p < 0.05). Multiple items displayed inadequate response categories and two items displayed differential item functioning by gender. Items were transformed and one item deleted leading to an adequate fit. Remaining items fit the Rasch model but still do not target well the population under study.ConclusionsThe original version of the 30-item DASH did not display adequate validity evidence for use in a population with Dupuytren’s contracture. Further development is required to improve the DASH for this population.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2474-15-361) contains supplementary material, which is available to authorized users.

Con: are we ready to translate Alzheimer's disease-modifying therapies to people with down syndrome?

BackgroundAdults with Down syndrome develop Alzheimer’s disease neuropathology in an age-dependent manner. This unique feature provides an opportunity to test interventions targeted for prevention of Alzheimer’s disease neuropathology and dementia in Down syndrome.DiscussionIn considering clinical trial designs, however, there are several challenges that we believe will be critical to examine further. These include: accuracy in dementia, mild cognitive impairment and preclinical Alzheimer’s disease diagnoses in Down syndrome; clinical trial outcome measures appropriate for individuals with Down syndrome; in vivo imaging outcome measures (and practical considerations); and contributions of medical co-morbidities to disease progression. Also, when studies are designed, the molecular target may appear to be obvious (for example, targeting beta-amyloid pathology), but chromosome 21 has over 200 additional genes that could influence both positive and negative clinical trial outcomes.SummaryObservational longitudinal studies of aging in Down syndrome will be critically important as there is a need to establish sensitive clinical outcome measures and understand the consequences of gene overexpression in relation to specific interventions.

G.P.125: Manganese enhanced muscle MRI as a sensitive outcome measure of dystrophin restoration in the mdx mouse

A central component of dystrophic pathology in DMD patients as well as mdx mice is a persistent increase in steady-state calcium levels in muscle. Increased calcium load leads to loss of muscle strength, activation of calcium-dependent proteases and may increase muscle cell necrosis. As a key primary event in dystrophic pathology, measurement of calcium levels may offer a sensitive marker of the efficacy of therapeutic agents. Manganese is a divalent cation with very similar chemical properties to calcium and is thought to be taken up by cardiac and skeletal muscle by the same receptors as calcium ions. It is also a contrast agent in T1 weighted MRI, enabling calcium levels in muscle to be measured non-invasively. We have previously shown that manganese-enhanced MRI (MEMRI) contrast is elevated in cardiac pathology in mdx and can track the dynamics of calcium channel blockade in dystrophic models. Here, we have extended this analysis by infusing manganese intravenously and observing the uptake by skeletal muscle using MRI, showing that the mdx mouse has an increased steady-state level of MEMRI contrast in both chest wall and triceps. Furthermore, we treated a cohort ( n = 6) of 12-week old mdx mice with an increasing dosage (64 mg/kg or 133 mg/kg) of phosphorothioate Morpholino oligonucleotides (PMOs) to induce exon skipping. Animals were treated with a series of three i.v. injections spaced two weeks apart, scanned after a further two weeks, and muscle (heart, chest wall and triceps) harvested for dystrophin quantification by IF and Western blotting, as well as for histology. We show that inducing exon skipping, even at very low levels, can be detected by changes in the MEMRI signal in both cardiac and skeletal muscle, even in the absence of discernable changes in histology. These data suggest that muscle MEMRI may be a valuable tool for longitudinal studies on dystrophin restoration in mdx and may have increased sensitivity when compared to more established methods.

Changes in Quality of Life in the First 5 Years of Disease in a Multicenter Cohort of Patients With Systemic Lupus Erythematosus

The Medical Outcomes Study Short Form 36 (SF-36) is recommended to assess quality of life (QOL) in systemic lupus erythematosus (SLE). The aim of the current study was to assess QOL over time in the first 5 years of a multicenter inception cohort of patients with SLE. An inception SLE cohort was assembled according to a standardized protocol between 2000 and 2012. In addition to clinical and laboratory assessments, patients completed the SF-36 at yearly intervals. Only patients who had ≥5 completed QOL questionnaires were included in these analyses. Generalized estimating equation models were run separately for each of the 8 subscales and for the physical and mental component summary scores, adjusting for repeated measures by patients. A total of 495 patients were included. The mean ± SD disease duration at the first visit was 5.3 ± 4.1 months. The mean ± SD age at enrollment was 35.8 ± 13.2 years. All 8 subscales and the 2 summary scores showed improvement in the first 2 years from enrollment. Between years 2 and 5, none of the subscales or summary scores showed any change. Minimum clinically important improvement was achieved by 35-56% of the patients and was influenced by demographic and disease factors. Unlike late-stage lupus, where QOL is stable over time, in patients with early disease, all subscales improve in early followup up to 2 years. Therefore, the SF-36 may be a sensitive outcome measure in early disease in patients with SLE.