Negative variance components and intercept-slope correlations greater than one in magnitude: How do such "non-regular" random intercept and slope models arise, and what should be done when they do?

Statistical models with random intercepts and slopes (RIAS models) are commonly used to analyze longitudinal data. Fitting such models sometimes results in negative estimates of variance components or estimates on parameter space boundaries. This can be an unlucky chance occurrence, but can also occur because certain marginal distributions are mathematically identical to those from RIAS models with negative intercept and/or slope variance components and/or intercept-slope correlations greater than one in magnitude. We term such parameters "pseudo-variances" and "pseudo-correlations," and the models "non-regular." We use eigenvalue theory to explore how and when such non-regular RIAS models arise, showing: (i) A small number of measurements, short follow-up, and large residual variance increase the parameter space for which data (with a positive semidefinite marginal variance-covariance matrix) are compatible with non-regular RIAS models. (ii) Non-regular RIAS models can arise from model misspecification, when non-linearity in fixed effects is ignored or when random effects are omitted. (iii) A non-regular RIAS model can sometimes be interpreted as a regular linear mixed model with one or more additional random effects, which may not be identifiable from the data. (iv) Particular parameterizations of non-regular RIAS models have no generality for all possible numbers of measurements over time. Because of this lack of generality, we conclude that non-regular RIAS models can only be regarded as plausible data-generating mechanisms in some situations. Nevertheless, fitting a non-regular RIAS model can be acceptable, allowing unbiased inference on fixed effects where commonly recommended alternatives such as dropping the random slope result in bias.

Predicting progression to Alzheimer's disease dementia using cognitive measures.

OBJECTIVES: It is important to determine if cognitive measures identified as being prognostic in dementia research cohorts also have utility in memory clinics. We aimed to identify measures with the greatest power to predict future Alzheimer's disease (AD) dementia in a clinical setting where expensive biomarkers are not widely available. METHODS: This study utilized routine Memory Clinic data collected over 18 years. From 2214 patients assessed in the clinic, we selected 328 patients with an initial diagnosis of subjective cognitive decline or mild cognitive impairment. We compared two types of statistical model for the prediction of AD dementia. The first model included baseline cognitive test scores only, while the second model also included change scores between baseline and the first follow-up. RESULTS: Baseline scores on tests of global cognitive function (Mini-mental state examination and Cambridge Cognitive Examination-Revised), verbal episodic memory and psychomotor speed were the best predictors of conversion to AD dementia. The inclusion of cognitive change scores over 1 year of follow-up improved predictive accuracy versus baseline scores alone. CONCLUSIONS: We found that the best cognitive predictors of AD dementia in a clinical setting were similar to those previously identified using research cohorts. Taking change in cognitive function into account enabled the onset of AD dementia to be predicted with greater accuracy.

How important is the linearity assumption in a sample size calculation for a randomised controlled trial where treatment is anticipated to affect a rate of change?

BACKGROUND: For certain conditions, treatments aim to lessen deterioration over time. A trial outcome could be change in a continuous measure, analysed using a random slopes model with a different slope in each treatment group. A sample size for a trial with a particular schedule of visits (e.g. annually for three years) can be obtained using a two-stage process. First, relevant (co-) variances are estimated from a pre-existing dataset e.g. an observational study conducted in a similar setting. Second, standard formulae are used to calculate sample size. However, the random slopes model assumes linear trajectories with any difference in group means increasing proportionally to follow-up time. The impact of these assumptions failing is unclear. METHODS: We used simulation to assess the impact of a non-linear trajectory and/or non-proportional treatment effect on the proposed trial's power. We used four trajectories, both linear and non-linear, and simulated observational studies to calculate sample sizes. Trials of this size were then simulated, with treatment effects proportional or non-proportional to time. RESULTS: For a proportional treatment effect and a trial visit schedule matching the observational study, powers are close to nominal even for non-linear trajectories. However, if the schedule does not match the observational study, powers can be above or below nominal levels, with the extent of this depending on parameters such as the residual error variance. For a non-proportional treatment effect, using a random slopes model can lead to powers far from nominal levels. CONCLUSIONS: If trajectories are suspected to be non-linear, observational data used to inform power calculations should have the same visit schedule as the proposed trial where possible. Additionally, if the treatment effect is expected to be non-proportional, the random slopes model should not be used. A model allowing trajectories to vary freely over time could be used instead, either as a second line analysis method (bearing in mind that power will be lost) or when powering the trial.

Selective Thumb Carpometacarpal Joint Denervation Versus Trapeziectomy and Ligament Reconstruction With Tendon Interposition for Painful Arthritis: A Prospective Study With 2 Years of Follow-Up.

PURPOSE: Thumb carpometacarpal (CMC) joint denervation is a relatively novel method for the management of osteoarthritis-associated pain by selective transection of articular nerve branches of the CMC joint. This study compared functional/patient-reported outcomes after CMC denervation with those after trapeziectomy and ligament reconstruction with tendon interposition (T + LRTI) over a 2-year follow-up period. We hypothesized that the outcomes of denervation and T + LRTI would be similar over the course of the study and at the final 2-year follow-up. METHODS: Adults with Eaton stage 2-4 disease, no evidence of CMC subluxation, and no history of thumb injury/surgery were included. Pain scores, brief Michigan Hand Questionnaire (bMHQ), Kapandji score, 2-point discrimination, and grip/key/3-point pinch strength were measured at 3-, 6-, 12-, and 24-months after surgery. On average, T + LRTI patients underwent 7 weeks of splinting, with release to full activity at 3 months; denervation patients were placed in a soft postoperative dressing for 2 weeks, with release to full activity as tolerated at 3 weeks. RESULTS: Thirty-three denervation and 20 T + LRTI patients were included. Preoperative characteristics were similar between both groups. Two denervation patients underwent secondary T + LRTI during the study period; one denervation patient underwent fat grafting to the CMC joint at an outside institution. Data prior to secondary surgeries were included in the analysis. The average tourniquet times (minutes) for denervation and T + LRTI were 43.5 ± 11.8 and 82.7 ± 14.2 minutes, respectively. For denervation and T + LRTI, the postoperative bMHQ scores were significantly higher than those at baseline at all time points. No significant differences were found between both groups for bMHQ, sensation, or strength measures. CONCLUSIONS: Carpometacarpal denervation is well tolerated, with shorter tourniquet times and faster return to full activity than T + LRTI. For the study cohort, the conversion rate to T + LRTI at 2 years was 9%. Both procedures demonstrated durable improvement in bMHQ compared with the preoperative state with similar long-term outcomes over 2 years of follow-up. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic II.

Plasma phospho-tau181 in presymptomatic and symptomatic familial Alzheimer's disease: a longitudinal cohort study.

Blood biomarkers have great potential to advance clinical care and accelerate trials in Alzheimer's disease (AD). Plasma phospho-tau181 (p-tau181) is a promising blood biomarker however, it is unknown if levels increase in presymptomatic AD. Therefore, we investigated the timing of p-tau181 changes using 153 blood samples from 70 individuals in a longitudinal study of familial AD (FAD). Plasma p-tau181 was measured, using an in-house single molecule array assay. We compared p-tau181 between symptomatic carriers, presymptomatic carriers, and non-carriers, adjusting for age and sex. We examined the relationship between p-tau181 and neurofilament light and estimated years to/from symptom onset (EYO), as well as years to/from actual onset in a symptomatic subgroup. In addition, we studied associations between p-tau181 and clinical severity, as well testing for differences between genetic subgroups. Twenty-four were presymptomatic carriers (mean baseline EYO -9.6 years) while 27 were non-carriers. Compared with non-carriers, plasma p-tau181 concentration was higher in both symptomatic (p < 0.001) and presymptomatic mutation carriers (p < 0.001). Plasma p-tau181 showed considerable intra-individual variability but individual values discriminated symptomatic (AUC 0.93 [95% CI 0.85-0.98]) and presymptomatic (EYO ≥ -7 years) (AUC 0.86 [95% CI 0.72-0.94]) carriers from non-carriers of the same age and sex. From a fitted model there was evidence (p = 0.050) that p-tau181 concentrations were higher in mutation carriers than non-carriers from 16 years prior to estimated symptom onset. Our finding that plasma p-tau181 concentration is increased in symptomatic and presymptomatic FAD suggests potential utility as an easily accessible biomarker of AD pathology.

Plasma amyloid-ß ratios in autosomal dominant Alzheimer's disease: the influence of genotype.

In vitro studies of autosomal dominant Alzheimer's disease implicate longer amyloid-ß peptides in disease pathogenesis; however, less is known about the behaviour of these mutations in vivo. In this cross-sectional cohort study, we used liquid chromatography-tandem mass spectrometry to analyse 66 plasma samples from individuals who were at risk of inheriting a mutation or were symptomatic. We tested for differences in amyloid-ß (Aß)42:38, Aß42:40 and Aß38:40 ratios between presenilin 1 (PSEN1) and amyloid precursor protein (APP) carriers. We examined the relationship between plasma and in vitro models of amyloid-ß processing and tested for associations with parental age at onset. Thirty-nine participants were mutation carriers (28 PSEN1 and 11 APP). Age- and sex-adjusted models showed marked differences in plasma amyloid-ß between genotypes: higher Aß42:38 in PSEN1 versus APP (P < 0.001) and non-carriers (P < 0.001); higher Aß38:40 in APP versus PSEN1 (P < 0.001) and non-carriers (P < 0.001); while Aß42:40 was higher in both mutation groups compared to non-carriers (both P < 0.001). Amyloid-ß profiles were reasonably consistent in plasma and cell lines. Within the PSEN1 group, models demonstrated associations between Aß42:38, Aß42:40 and Aß38:40 ratios and parental age at onset. In vivo differences in amyloid-ß processing between PSEN1 and APP carriers provide insights into disease pathophysiology, which can inform therapy development.

Major Depression and Survival in People With Cancer.

OBJECTIVE: The question of whether depression is associated with worse survival in people with cancer remains unanswered because of methodological criticism of the published research on the topic. We aimed to study the association in a large methodologically robust study. METHODS: We analyzed data on 20,582 patients with breast, colorectal, gynecological, lung, and prostate cancers who had attended cancer outpatient clinics in Scotland, United Kingdom. Patients had completed two-stage screening for major depression as part of their cancer care. These data on depression status were linked to demographic, cancer, and subsequent mortality data from national databases. We estimated the association of major depression with survival for each cancer using Cox regression. We adjusted for potential confounders and interactions between potentially time-varying confounders and the interval between cancer diagnosis and depression screening, and used multiple imputation for missing depression and confounder data. We pooled the cancer-specific results using fixed-effects meta-analysis. RESULTS: Major depression was associated with worse survival for all cancers, with similar adjusted hazard ratios (HRs): breast cancer (HR = 1.42, 95% confidence interval [CI] = 1.15-1.75), colorectal cancer (HR = 1.47, 95% CI = 1.11-1.94), gynecological cancer (HR = 1.36, 95% CI = 1.08-1.71), lung cancer (HR = 1.39, 95% CI = 1.24-1.56), and prostate cancer (HR = 1.76, 95% CI = 1.08-2.85). The pooled HR was 1.41 (95% CI = 1.29-1.54, p < .001, I2 = 0%). These findings were not materially different when we only considered the deaths (90%) that were attributed to cancer. CONCLUSIONS: Major depression is associated with worse survival in patients with common cancers. The mechanisms of this association and the clinical implications require further study.

Power and sample-size calculations for trials that compare slopes over time: Introducing the slopepower command.

Trials of interventions that aim to slow disease progression may analyze a continuous outcome by comparing its change over time-its slope-between the treated and the untreated group using a linear mixed model. To perform a sample-size calculation for such a trial, one must have estimates of the parameters that govern the between- and within-subject variability in the outcome, which are often unknown. The algebra needed for the sample-size calculation can also be complex for such trial designs. We have written a new user-friendly command, slopepower, that performs sample-size or power calculations for trials that compare slope outcomes. The package is based on linear mixed-model methodology, described for this setting by Frost, Kenward, and Fox (2008, Statistics in Medicine 27: 3717-3731). In the first stage of this approach, slopepower obtains estimates of mean slopes together with variances and covariances from a linear mixed model fit to previously collected user-supplied data. In the second stage, these estimates are combined with user input about the target effectiveness of the treatment and design of the future trial to give an estimate of either a sample size or a statistical power. In this article, we present the slopepower command, briefly explain the methodology behind it, and demonstrate how it can be used to help plan a trial and compare the sample sizes needed for different trial designs.

The association between anthropometric measures of adiposity and the progression of carotid atherosclerosis.

BACKGROUND: Few reports are available on the contribution of general and abdominal obesity to the progression of carotid atherosclerosis in late adulthood. This study investigated the impact of four simple anthropometric measures of general and abdominal obesity on the progression of carotid atherosclerosis and the extent to which the association between adiposity and the progression of plaque burden is mediated by cardiometabolic markers. METHODS: Four thousand three hundred forty-five adults (median age 60) from the population-based Tromsø Study were followed over 7 years from the first carotid ultrasound screening to the next. The progression of carotid atherosclerosis was measured in three ways: incidence of plaques in previously plaque-free participants; change in the number of plaques; and total plaque area (TPA). We used generalised linear models to investigate the association between each adiposity measure - body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR) - and each outcome. Models were adjusted for potential confounders (age, sex, smoking, education, physical activity). The pathways through which any associations observed might operate were investigated by further adjusting for cardiometabolic mediators (systolic blood pressure, cholesterol, and HbA1c). RESULTS: There was little evidence that adiposity was related to the formation of new plaques during follow-up. However, abdominal adiposity was associated with TPA progression. WHtR showed the largest effect size (mean change in TPA per one standard deviation (SD) increase in WHtR of 0.665 mm2, 95% confidence interval 0.198, 1.133) while BMI showed the smallest. Effect sizes were substantially reduced after the adjustment for potential mediators. CONCLUSIONS: Abdominal obesity indirectly measured with WC seems more strongly associated with the progression of TPA than general obesity. These associations appear to be largely mediated by known cardiometabolic markers.

The prevalence of depression in general hospital inpatients: a systematic review and meta-analysis of interview-based studies.

BACKGROUND: Comorbid depression in the medically ill is clinically important. Admission to a general hospital offers an opportunity to identify and initiate treatment for depression. However, we first need to know how common depression is in general hospital inpatients. We aimed to address this question by systematically reviewing the relevant literature. METHODS: We reviewed published prevalence studies in any language which had used diagnostic interviews of general hospital inpatients and met basic methodological quality criteria. We focussed on interview-based studies in order to estimate the proportion of patients with a diagnosis of depressive illness. RESULTS: Of 158 relevant articles, 65 (41%) describing 60 separate studies met our inclusion criteria. The 31 studies that focussed on general medical and surgical inpatients reported prevalence estimates ranging from 5% to 34%. There was substantial, highly statistically significant, heterogeneity between studies which was not materially explained by the covariates we were able to consider. The average of the reported prevalences was 12% (95% CI 10-15), with a 95% prediction interval of 4-32%. The remaining 29 studies, of a variety of specific clinical populations, are described. CONCLUSIONS: The available evidence suggests a likely prevalence high enough to make it worthwhile screening hospital inpatients for depression and initiating treatment where appropriate. Further, higher quality, research is needed to clarify the prevalence of depression in specific settings and to further explore the reasons for the observed heterogeneity in estimates.

Presymptomatic atrophy in autosomal dominant Alzheimer's disease: A serial magnetic resonance imaging study.

INTRODUCTION: Identifying at what point atrophy rates first change in Alzheimer's disease is important for informing design of presymptomatic trials. METHODS: Serial T1-weighted magnetic resonance imaging scans of 94 participants (28 noncarriers, 66 carriers) from the Dominantly Inherited Alzheimer Network were used to measure brain, ventricular, and hippocampal atrophy rates. For each structure, nonlinear mixed-effects models estimated the change-points when atrophy rates deviate from normal and the rates of change before and after this point. RESULTS: Atrophy increased after the change-point, which occurred 1-1.5 years (assuming a single step change in atrophy rate) or 3-8 years (assuming gradual acceleration of atrophy) before expected symptom onset. At expected symptom onset, estimated atrophy rates were at least 3.6 times than those before the change-point. DISCUSSION: Atrophy rates are pathologically increased up to seven years before "expected onset". During this period, atrophy rates may be useful for inclusion and tracking of disease progression.

Community health promotion and medical provision for neonatal health-CHAMPION cluster randomised trial in Nagarkurnool district, Telangana (formerly Andhra Pradesh), India.

BACKGROUND: In the mid-2000s, neonatal mortality accounted for almost 40% of deaths of children under 5 years worldwide, and constituted 65% of infant deaths in India. The neonatal mortality rate in Andhra Pradesh was 44 per 1,000 live births, and was higher in the rural areas and tribal regions, such as the Nagarkurnool division of Mahabubnagar district (which became Nagarkurnool district in Telangana in 2014). The aim of the CHAMPION trial was to investigate whether a package of interventions comprising community health promotion and provision of health services (including outreach and facility-based care) could lead to a reduction of the order of 25% in neonatal mortality. METHODS AND FINDINGS: The design was a trial in which villages (clusters) in Nagarkurnool with a population < 2,500 were randomised to the CHAMPION package of health interventions or to the control arm (in which children aged 6-9 years were provided with educational interventions-the STRIPES trial). A woman was eligible for the CHAMPION package if she was married and <50 years old, neither she nor her husband had had a family planning operation, and she resided in a trial village at the time of a baseline survey before randomisation or married into the village after randomisation. The CHAMPION intervention package comprised community health promotion (including health education via village health worker-led participatory discussion groups) and provision of health services (including outreach, with mobile teams providing antenatal check-ups, and facility-based care, with subsidised access to non-public health centres [NPHCs]). Villages were stratified by travel time to the nearest NPHC and tribal status, and randomised (1:1) within strata. The primary outcome was neonatal mortality. Secondary outcomes included maternal mortality, causes of death, health knowledge, health practices including health service usage, satisfaction with care, and costs. The baseline survey (enumeration) was carried out between August and November 2007. After randomisation on 18 February 2008, participants, data collectors, and data analysts were not masked to allocation. The intervention was initiated on 1 August 2008. After an inception period, the assessment start date was 1 December 2008. The intervention ended on 31 May 2011, and data collection was completed on 30 November 2011. Primary analyses followed the intention to treat principle. In all, 14,137 women were enrolled in 232 control villages, and 15,532 in 232 intervention villages. Of these, 4,885 control women had 5,474 eligible pregnancies and gave birth to 4,998 eligible children. The corresponding numbers in intervention villages were 5,664 women, 6,351 pregnancies, and 5,798 children. Of the live-born babies, 343 (6.9%) in the control arm and 303 (5.2%) in the intervention arm died in their first 28 days of life (risk ratio 0.76, 95% CI 0.64 to 0.90, p = 0.0018; risk difference -1.59%, 95% CI -2.63% to -0.54%), suggesting that there were 92 fewer deaths (95% CI 31 to 152) as a result of the intervention. There were 9 (0.16%) maternal deaths in the control arm compared to 13 (0.20%) in the intervention arm (risk ratio 1.24, 95% CI 0.53 to 2.90, p = 0.6176; 1 death was reported as a serious adverse event). There was evidence of improved health knowledge and health practices including health service usage in the intervention arm compared to the control arm. Women in the intervention arm were more likely to rate their delivery and postnatal care as good or very good. The total cost of the CHAMPION interventions was US$1,084,955 ($11,769 per life saved, 95% CI $7,115 to $34,653). The main limitations of the study included that it could not be masked post-randomisation and that fetal losses were not divided into stillbirths and miscarriages because gestational age was not reliably reported. CONCLUSIONS: The CHAMPION trial showed that a package of interventions addressing health knowledge and health seeking behaviour, buttressing existing health services, and contracting out important areas of maternal and child healthcare led to a reduction in neonatal mortality of almost the hypothesized 25% in small villages in an Indian state with high mortality rates. The intervention can be strongly justified in much of rural India, and is of potential use in other similar settings. Ongoing changes in maternal and child health programmes make it imperative that a similar intervention that establishes ties between the community and health facilities is tested in different settings. TRIAL REGISTRATION: ISRCTN registry ISRCTN24104646.

Design optimization for clinical trials in early-stage manifest Huntington's disease.

OBJECTIVES: The purpose of this study was to inform the design of randomized clinical trials in early-stage manifest Huntington's disease through analysis of longitudinal data from TRACK-Huntington's Disease (TRACK-HD), a multicenter observational study. METHODS: We compute sample sizes required for trials with candidate clinical, functional, and imaging outcomes, whose aims are to reduce rates of change. The calculations use a 2-stage approach: first using linear mixed models to estimate mean rates of change and components of variability from TRACK-HD data and second using these to predict sample sizes for a range of trial designs. RESULTS: For each outcome, the primary drivers of the required sample size were the anticipated treatment effect and the duration of treatment. Extending durations from 1 to 2 years yielded large sample size reductions. Including interim visits and incorporating stratified randomization on predictors of outcome together with covariate adjustment gave more modest, but nontrivial, benefits. Caudate atrophy, expressed as a percentage of its baseline, was the outcome that gave smallest required sample sizes. DISCUSSION: Here we consider potential required sample sizes for clinical trials estimated from naturalistic observation of longitudinal change. Choice among outcome measures for a trial must additionally consider their relevance to patients and the expected effect of the treatment under study. For all outcomes considered, our results provide compelling arguments for 2-year trials, and we also demonstrate the benefits of incorporating stratified randomization coupled with covariate adjustment, particularly for trials with caudate atrophy as the primary outcome. The benefits of enrichment are more debatable, with statistical benefits offset by potential recruitment difficulties and reduced generalizability. © 2017 International Parkinson and Movement Disorder Society.

Treatments for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP): an overview of systematic reviews.

BACKGROUND: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a chronic progressive or relapsing and remitting disease that usually causes weakness and sensory loss. The symptoms are due to autoimmune inflammation of peripheral nerves. CIPD affects about 2 to 3 per 100,000 of the population. More than half of affected people cannot walk unaided when symptoms are at their worst. CIDP usually responds to treatments that reduce inflammation, but there is disagreement about which treatment is most effective. OBJECTIVES: To summarise the evidence from Cochrane systematic reviews (CSRs) and non-Cochrane systematic reviews of any treatment for CIDP and to compare the effects of treatments. METHODS: We considered all systematic reviews of randomised controlled trials (RCTs) of any treatment for any form of CIDP. We reported their primary outcomes, giving priority to change in disability after 12 months.Two overview authors independently identified published systematic reviews for inclusion and collected data. We reported the quality of evidence using GRADE criteria. Two other review authors independently checked review selection, data extraction and quality assessments.On 31 October 2016, we searched the Cochrane Database of Systematic Reviews, the Database of Abstracts of Reviews of Effects (in theCochrane Library), MEDLINE, Embase, and CINAHL Plus for systematic reviews of CIDP. We supplemented the RCTs in the existing CSRs by searching on the same date for RCTs of any treatment of CIDP (including treatment of fatigue or pain in CIDP), in the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, and CINAHL Plus. MAIN RESULTS: Five CSRs met our inclusion criteria. We identified 23 randomised trials, of which 15 had been included in these CSRs. We were unable to compare treatments as originally planned, because outcomes and outcome intervals differed. CorticosteroidsIt is uncertain whether daily oral prednisone improved impairment compared to no treatment because the quality of the evidence was very low (1 trial, 28 participants). According to moderate-quality evidence (1 trial, 41 participants), six months' treatment with high-dose monthly oral dexamethasone did not improve disability more than daily oral prednisolone. Observational studies tell us that prolonged use of corticosteroids sometimes causes serious side-effects. Plasma exchangeAccording to moderate-quality evidence (2 trials, 59 participants), twice-weekly plasma exchange produced more short-term improvement in disability than sham exchange. In the largest observational study, 3.9% of plasma exchange procedures had complications. Intravenous immunoglobulinAccording to high-quality evidence (5 trials, 269 participants), intravenous immunoglobulin (IVIg) produced more short-term improvement than placebo. Adverse events were more common with IVIg than placebo (high-quality evidence), but serious adverse events were not (moderate-quality evidence, 3 trials, 315 participants). One trial with 19 participants provided moderate-quality evidence of little or no difference in short-term improvement of impairment with plasma exchange in comparison to IVIg. There was little or no difference in short-term improvement of disability with IVIg in comparison to oral prednisolone (moderate-quality evidence; 1 trial, 29 participants) or intravenous methylprednisolone (high-quality evidence; 1 trial, 45 participants). One unpublished randomised open trial with 35 participants found little or no difference in disability after three months of IVIg compared to oral prednisone; this trial has not yet been included in a CSR. We know from observational studies that serious adverse events related to IVIg do occur. Other immunomodulatory treatmentsIt is uncertain whether the addition of azathioprine (2 mg/kg) to prednisone improved impairment in comparison to prednisone alone, as the quality of the evidence is very low (1 trial, 27 participants). Observational studies show that adverse effects truncate treatment in 10% of people.According to low-quality evidence (1 trial, 60 participants), compared to placebo, methotrexate 15 mg/kg did not allow more participants to reduce corticosteroid or IVIg doses by 20%. Serious adverse events were no more common with methotrexate than with placebo, but observational studies show that methotrexate can cause teratogenicity, abnormal liver function, and pulmonary fibrosis.According to moderate-quality evidence (2 trials, 77 participants), interferon beta-1a (IFN beta-1a) in comparison to placebo, did not allow more people to withdraw from IVIg. According to moderate-quality evidence, serious adverse events were no more common with IFN beta-1a than with placebo.We know of no other completed trials of immunosuppressant or immunomodulatory agents for CIDP. Other treatmentsWe identified no trials of treatments for fatigue or pain in CIDP. Adverse effectsNot all trials routinely collected adverse event data; when they did, the quality of evidence was variable. Adverse effects in the short, medium, and long term occur with all interventions. We are not able to make reliable comparisons of adverse events between the interventions included in CSRs. AUTHORS' CONCLUSIONS: We cannot be certain based on available evidence whether daily oral prednisone improves impairment compared to no treatment. However, corticosteroids are commonly used, based on widespread availability, low cost, very low-quality evidence from observational studies, and clinical experience. The weakness of the evidence does not necessarily mean that corticosteroids are ineffective. High-dose monthly oral dexamethasone for six months is probably no more or less effective than daily oral prednisolone. Plasma exchange produces short-term improvement in impairment as determined by neurological examination, and probably produces short-term improvement in disability. IVIg produces more short-term improvement in disability than placebo and more adverse events, although serious side effects are probably no more common than with placebo. There is no clear difference in short-term improvement in impairment with IVIg when compared with intravenous methylprednisolone and probably no improvement when compared with either oral prednisolone or plasma exchange. According to observational studies, adverse events related to difficult venous access, use of citrate, and haemodynamic changes occur in 3% to17% of plasma exchange procedures.It is uncertain whether azathioprine is of benefit as the quality of evidence is very low. Methotrexate may not be of benefit and IFN beta-1a is probably not of benefit.We need further research to identify predictors of response to different treatments and to compare their long-term benefits, safety and cost-effectiveness. There is a need for more randomised trials of immunosuppressive and immunomodulatory agents, routes of administration, and treatments for symptoms of CIDP.

Visuospatial Processing Deficits Linked to Posterior Brain Regions in Premanifest and Early Stage Huntington's Disease.

OBJECTIVES: Visuospatial processing deficits have been reported in Huntington's disease (HD). To date, no study has examined associations between visuospatial cognition and posterior brain findings in HD. METHODS: We compared 119 premanifest (55> and 64<10.8 years to expected disease onset) and 104 early symptomatic (59 stage-1 and 45 stage-2) gene carriers, with 110 controls on visual search and mental rotation performance at baseline and 12 months. In the disease groups, we also examined associations between task performance and disease severity, functional capacity and structural brain measures. RESULTS: Cross-sectionally, there were strong differences between all disease groups and controls on visual search, and between diagnosed groups and controls on mental rotation accuracy. Only the premanifest participants close to onset took longer than controls to respond correctly to mental rotation. Visual search negatively correlated with disease burden and motor symptoms in diagnosed individuals, and positively correlated with functional capacity. Mental rotation ("same") was negatively correlated with motor symptoms in stage-2 individuals, and positively correlated with functional capacity. Visual search and mental rotation were associated with parieto-occipital (pre-/cuneus, calcarine, lingual) and temporal (posterior fusiform) volume and cortical thickness. Longitudinally, visual search deteriorated over 12 months in stage-2 individuals, with no evidence of declines in mental rotation. CONCLUSIONS: Our findings provide evidence linking early visuospatial deficits to functioning and posterior cortical dysfunction in HD. The findings are important since large research efforts have focused on fronto-striatal mediated cognitive changes, with little attention given to aspects of cognition outside of these areas. (JINS, 2016, 22, 595-608).

Assessing atrophy measurement techniques in dementia: Results from the MIRIAD atrophy challenge.

Structural MRI is widely used for investigating brain atrophy in many neurodegenerative disorders, with several research groups developing and publishing techniques to provide quantitative assessments of this longitudinal change. Often techniques are compared through computation of required sample size estimates for future clinical trials. However interpretation of such comparisons is rendered complex because, despite using the same publicly available cohorts, the various techniques have been assessed with different data exclusions and different statistical analysis models. We created the MIRIAD atrophy challenge in order to test various capabilities of atrophy measurement techniques. The data consisted of 69 subjects (46 Alzheimer's disease, 23 control) who were scanned multiple (up to twelve) times at nine visits over a follow-up period of one to two years, resulting in 708 total image sets. Nine participating groups from 6 countries completed the challenge by providing volumetric measurements of key structures (whole brain, lateral ventricle, left and right hippocampi) for each dataset and atrophy measurements of these structures for each time point pair (both forward and backward) of a given subject. From these results, we formally compared techniques using exactly the same dataset. First, we assessed the repeatability of each technique using rates obtained from short intervals where no measurable atrophy is expected. For those measures that provided direct measures of atrophy between pairs of images, we also assessed symmetry and transitivity. Then, we performed a statistical analysis in a consistent manner using linear mixed effect models. The models, one for repeated measures of volume made at multiple time-points and a second for repeated "direct" measures of change in brain volume, appropriately allowed for the correlation between measures made on the same subject and were shown to fit the data well. From these models, we obtained estimates of the distribution of atrophy rates in the Alzheimer's disease (AD) and control groups and of required sample sizes to detect a 25% treatment effect, in relation to healthy ageing, with 95% significance and 80% power over follow-up periods of 6, 12, and 24months. Uncertainty in these estimates, and head-to-head comparisons between techniques, were carried out using the bootstrap. The lateral ventricles provided the most stable measurements, followed by the brain. The hippocampi had much more variability across participants, likely because of differences in segmentation protocol and less distinct boundaries. Most methods showed no indication of bias based on the short-term interval results, and direct measures provided good consistency in terms of symmetry and transitivity. The resulting annualized rates of change derived from the model ranged from, for whole brain: -1.4% to -2.2% (AD) and -0.35% to -0.67% (control), for ventricles: 4.6% to 10.2% (AD) and 1.2% to 3.4% (control), and for hippocampi: -1.5% to -7.0% (AD) and -0.4% to -1.4% (control). There were large and statistically significant differences in the sample size requirements between many of the techniques. The lowest sample sizes for each of these structures, for a trial with a 12month follow-up period, were 242 (95% CI: 154 to 422) for whole brain, 168 (95% CI: 112 to 282) for ventricles, 190 (95% CI: 146 to 268) for left hippocampi, and 158 (95% CI: 116 to 228) for right hippocampi. This analysis represents one of the most extensive statistical comparisons of a large number of different atrophy measurement techniques from around the globe. The challenge data will remain online and publicly available so that other groups can assess their methods.

Effect of high-dose simvastatin on brain atrophy and disability in secondary progressive multiple sclerosis (MS-STAT): a randomised, placebo-controlled, phase 2 trial.

BACKGROUND: Secondary progressive multiple sclerosis, for which no satisfactory treatment presently exists, accounts for most of the disability in patients with multiple sclerosis. Simvastatin, which is widely used for treatment of vascular disease, with its excellent safety profile, has immunomodulatory and neuroprotective properties that could make it an appealing candidate drug for patients with secondary progressive multiple sclerosis. METHODS: We undertook a double-blind, controlled trial between Jan 28, 2008, and Nov 4, 2011, at three neuroscience centres in the UK. Patients aged 18-65 years with secondary progressive multiple sclerosis were randomly assigned (1:1), by a centralised web-based service with a block size of eight, to receive either 80 mg of simvastatin or placebo. Patients, treating physicians, and outcome assessors were masked to treatment allocation. The primary outcome was the annualised rate of whole-brain atrophy measured from serial volumetric MRI. Analyses were by intention to treat and per protocol. This trial is registered with ClinicalTrials.gov, number NCT00647348. FINDINGS: 140 participants were randomly assigned to receive either simvastatin (n=70) or placebo (n=70). The mean annualised atrophy rate was significantly lower in patients in the simvastatin group (0·288% per year [SD 0·521]) than in those in the placebo group (0·584% per year [0·498]). The adjusted difference in atrophy rate between groups was -0·254% per year (95% CI -0·422 to -0·087; p=0·003); a 43% reduction in annualised rate. Simvastatin was well tolerated, with no differences between the placebo and simvastatin groups in proportions of participants who had serious adverse events (14 [20%] vs nine [13%]). INTERPRETATION: High-dose simvastatin reduced the annualised rate of whole-brain atrophy compared with placebo, and was well tolerated and safe. These results support the advancement of this treatment to phase 3 testing. FUNDING: The Moulton Foundation [charity number 1109891], Berkeley Foundation [268369], the Multiple Sclerosis Trials Collaboration [1113598], the Rosetrees Trust [298582] and a personal contribution from A Pidgley, UK National Institute of Health Research (NIHR) University College London Hospitals/UCL Biomedical Research Centres funding scheme.

Short-interval observational data to inform clinical trial design in Huntington's disease.

OBJECTIVES: To evaluate candidate outcomes for disease-modifying trials in Huntington's disease (HD) over 6-month, 9-month and 15-month intervals, across multiple domains. To present guidelines on rapid efficacy readouts for disease-modifying trials. METHODS: 40 controls and 61 patients with HD, recruited from four EU sites, underwent 3 T MRI and standard clinical and cognitive assessments at baseline, 6 and 15 months. Neuroimaging analysis included global and regional change in macrostructure (atrophy and cortical thinning), and microstructure (diffusion metrics). The main outcome was longitudinal effect size (ES) for each outcome. Such ESs can be used to calculate sample-size requirements for clinical trials for hypothesised treatment efficacies. RESULTS: Longitudinal changes in macrostructural neuroimaging measures such as caudate atrophy and ventricular expansion were significantly larger in HD than controls, giving rise to consistently large ES over the 6-month, 9-month and 15-month intervals. Analogous ESs for cortical metrics were smaller with wide CIs. Microstructural (diffusion) neuroimaging metrics ESs were also typically smaller over the shorter intervals, although caudate diffusivity metrics performed strongly over 9 and 15 months. Clinical and cognitive outcomes exhibited small longitudinal ESs, particularly over 6-month and 9-month intervals, with wide CIs, indicating a lack of precision. CONCLUSIONS: To exploit the potential power of specific neuroimaging measures such as caudate atrophy in disease-modifying trials, we propose their use as (1) initial short-term readouts in early phase/proof-of-concept studies over 6 or 9 months, and (2) secondary end points in efficacy studies over longer periods such as 15 months.

An exploratory double-blind, randomized clinical trial with selisistat, a SirT1 inhibitor, in patients with Huntington's disease.

AIMS: Selisistat, a selective SirT1 inhibitor is being developed as a potentially disease-modifying therapeutic for Huntington's disease (HD). This was the first study of selisistat in HD patients and was primarily aimed at development of pharmacodynamic biomarkers. METHODS: This was a randomized, double-blind, placebo-controlled, multicentre exploratory study. Fifty-five male and female patients in early stage HD were randomized to receive 10 mg or 100 mg of selisistat or placebo once daily for 14 days. Blood sampling, clinical and safety assessments were conducted throughout the study. Candidate pharmacodynamic markers included circulating soluble huntingtin and innate immune markers. RESULTS: Selisistat was found to be safe and well tolerated, and systemic exposure parameters showed that the average steady-state plasma concentration achieved at the 10 mg dose level (125 nm) was comparable with the IC50 for SirT1 inhibition. No adverse effects on motor, cognitive or functional readouts were recorded. While circulating levels of soluble huntingtin were not affected by selisistat in this study, the biological samples collected have allowed development of assay technology for use in future studies. No effects on innate immune markers were seen. CONCLUSIONS: Selisistat was found to be safe and well tolerated in early stage HD patients at plasma concentrations within the anticipated therapeutic concentration range.

Alzheimer's disease first symptoms are age dependent: Evidence from the NACC dataset.

INTRODUCTION: Determining the relationship between age and Alzheimer's disease (AD) presentation is important to improve understanding and provide better patient services. METHODS: We used AD patient data (N = 7815) from the National Alzheimer Coordinating Center database and multinomial logistic regression to investigate presentation age and first cognitive/behavioral symptoms. RESULTS: The odds of having a nonmemory first cognitive symptom (including impairment in judgment and problem solving, language, and visuospatial function) increased with younger age (P < .001, all tests). Compared with apathy/withdrawal, the odds of having depression and "other" behavioral symptoms increased with younger age (P < .02, both tests), whereas the odds of having psychosis and no behavioral symptom increased with older age (P < .001, both tests). DISCUSSION: There is considerable heterogeneity in the first cognitive/behavioral symptoms experienced by AD patients. Proportions of these symptoms change with age with patients experiencing increasing nonmemory cognitive symptoms and more behavioral symptoms at younger ages.