Guoqiao Wang

The DIAN-TU Next Generation Alzheimer's prevention trial: Adaptive design and disease progression model

The Dominantly Inherited Alzheimer Network Trials Unit (DIAN‐TU) trial is an adaptive platform trial testing multiple drugs to slow or prevent the progression of Alzheimers disease in autosomal dominant Alzheimers disease (ADAD) families. With completion of enrollment of the first two drug arms, the DIAN‐TU now plans to add new drugs to the platform, designated as the Next Generation (NexGen) prevention trial.

Differences in Alzheimer disease clinical trial outcomes based on age of the participants

Objective: We tested the a priori hypothesis that older participants differ in rates of decline on cognitive outcomes compared with younger participants, and examined the potential effect of age distributions on individual clinical trial outcomes. Methods: From a meta-database of 18 studies from the Alzheimers Disease Cooperative Study and the Alzheimers Disease Neuroimaging Initiative, we included a cohort of 2,793 participants for whom there were baseline demographic data and at least one postbaseline cognitive assessment on the Alzheimers Disease Assessment Scale–cognitive subscale (ADAS-cog), Clinical Dementia Rating–Sum of Boxes (CDR-SB), or Mini-Mental State Examination (MMSE). We used mixed-effects models (random coefficient models) to estimate change on the outcomes across 7 age groups ranging from younger than 61 years to older than 85 years after adjusting for education. Results: Significant worsening occurred in all age groups on all outcomes over time. The 4 older groups, aged 71 years and older, showed slower rates of decline on the ADAS-cog than the younger groups (p = 0.001). The older groups scored 2–3, 2–5, and 4–6 points better than the younger groups at 12, 18, and 24 months, respectively. There were similar differences across age groups for the MMSE, but not for the CDR-SB. Conclusions: The differences in change on the ADAS-cog between older and younger participants are substantially greater than differences expected between experimental drugs and placebo in current trials or differences between marketed cholinesterase inhibitors and placebo. The clinical interpretation of change on the ADAS-cog or MMSE differs depending on age. Until predictors of decline are better understood, considering effects of age on rates of change is particularly important regarding clinical practice and outcomes of trials.

Spatial patterns of neuroimaging biomarker change in individuals from families with autosomal dominant Alzheimer's disease: a longitudinal study

Background Models of Alzheimer disease propose a sequence of amyloid-β (Aβ) accumulation, hypometabolism, and structural declines that precede the onset of clinical dementia. These pathological features evolve both temporally and spatially in the brain. This study aimed to characterize where in the brain and when in the course of the disease neuroimaging biomarkers become abnormal. Methods We analyzed data from mutation non-carriers, asymptomatic carriers, and symptomatic carriers collected between January 1st 2009 and December 31st 2015 from families carrying PSEN1, PSEN2, or APP mutations enrolled in the Dominantly Inherited Alzheimer’s Network. We analyzed [11C]Pittsburgh Compound B positron emission tomography (PiB PET), [18F]Fluorodeoxyglucose (FDG PET), and structural magnetic resonance imaging (MRI) data using regions of interest to assess change throughout the brain. We estimated rates of biomarker change as a function of estimated years from symptom onset at baseline using linear mixed-effects models and determined the earliest point at which biomarker trajectories differed between mutation carriers and non-carriers. Findings PiB PET was available for 346 individuals, with 162 having longitudinal imaging; FDG PET was available for 352 (175 longitudinal); and MRI data was available for 377 (201 longitudinal). We found a sequence to pathological changes, with rates of Aβ deposition in mutation carriers being significantly different from non-carriers first (on average across regions that showed a significant difference at −18·9 (sd 3·3) years before expected onset), followed by hypometabolism (−14·1 years, sd 5·1) and lastly structural declines (−4·7 years, sd 4·2). This biomarker ordering was preserved in most, but not all, regions. The temporal emergence within a biomarker varied across the brain, with the precuneus being the first cortical region in each modality to show divergence between groups (−22·2 years before expected onset for Aβ accumulation, −18·8 years for hypometabolism, and −13·0 years for cortical thinning). Interpretation Mutation carriers had elevations in Aβ deposition, reduced glucose metabolism, and cortical thinning which preceded the expected onset of dementia. Accrual of these pathologies varied throughout the brain, suggesting differential regional and temporal vulnerabilities to Aβ, metabolic decline, and structural atrophy, which should be taken into account when using biomarkers in a clinical setting as well as designing and evaluating clinical trials.

Health insurance affects the use of disease-modifying therapy in multiple sclerosis

Objective: To evaluate the association between health insurance coverage and disease-modifying therapy (DMT) use for multiple sclerosis (MS). Methods: In 2014, we surveyed participants in the North American Research Committee on MS registry regarding health insurance coverage. We investigated associations between negative insurance change and (1) the type of insurance, (2) DMT use, (3) use of free/discounted drug programs, and (4) insurance challenges using multivariable logistic regressions. Results: Of 6,662 respondents included in the analysis, 6,562 (98.5%) had health insurance, but 1,472 (22.1%) reported negative insurance change compared with 12 months earlier. Respondents with private insurance were more likely to report negative insurance change than any other insurance. Among respondents not taking DMTs, 6.1% cited insurance/financial concerns as the sole reason. Of respondents taking DMTs, 24.7% partially or completely relied on support from free/discounted drug programs. Of respondents obtaining DMTs through insurance, 3.3% experienced initial insurance denial of DMT use, 2.3% encountered insurance denial of DMT switches, and 1.6% skipped or split doses because of increased copay. For respondents with relapsing-remitting MS, negative insurance change increased their odds of not taking DMTs (odds ratio [OR] 1.50; 1.16–1.93), using free/discounted drug programs for DMTs (OR 1.89; 1.40–2.57), and encountering insurance challenges (OR 2.48; 1.64–3.76). Conclusions: Insurance coverage affects DMT use for persons with MS, and use of free/discounted drug programs is substantial and makes economic analysis that ignores these supplements potentially inaccurate. The rising costs of drugs and changing insurance coverage adversely affect access to treatment for persons with MS.

Examining the joint effect of disability, health behaviors, and comorbidity on mortality in MS

Background:In multiple sclerosis (MS), comorbidities have been associated with disability progression and an increased risk of mortality. We investigated the association between comorbidities and mortality in MS after accounting for disability and health behaviors. Methods:We followed North American Research Committee on Multiple Sclerosis (NARCOMS) Registry participants who completed the Fall 2006 survey on comorbidities until death (reported or matched in the National Death Index) or date of last follow-up in 2014. We used proportional hazards regression to investigate the association between comorbidities and mortality, controlling for demographic, clinical, health behavior, and disability factors. Results:Of 9,496 participants meeting the inclusion criteria, 502 (5.3%) were deceased. Most participants reported having ⩽3 comorbid conditions (70.9% survivors, 76.9% decedents). In individual regression models, vascular, visual, and mental comorbidities were associated with increased mortality risk after adjustment for factors associated with survival. When combined into a single model, vascular (hazard ratio 1.269; 1.041–1.547), visual (1.490; 1.199–1.852), and mental comorbidities (excluding anxiety, 1.239; 1.024–1.499) remained independently associated with an increased risk of mortality. Conclusions:Presence of comorbidities was independently associated with an increased risk of mortality as compared to absence of comorbidities after adjusting for factors associated with survival. Specifically, vascular, visual, and mental comorbidities increased the risk of mortality. This highlights the need for clinicians to attend to these comorbidities, which can be modified by treatments or other interventions, and potentially reduce the risk of mortality in persons with MS who have these conditions.

Using baseline cognitive severity for enriching Alzheimer's disease clinical trials: How does Mini-Mental State Examination predict rate of change?

Post hoc analyses from clinical trials in Alzheimers disease (AD) suggest that more cognitively impaired participants respond differently from less impaired on cognitive outcomes. We examined pooled clinical trials data to assess the utility of enriching trials using baseline cognition.

National variation of technical factors in computed tomography of the head.

Objective The objectives of this study were to describe head computed tomography (CT) technical factors used in the United States; assess guideline compliance and variability by sex, geographic region, institution, and manufacturer; and compare with NEXT (Nationwide Evaluation of X-ray Trends) survey. Methods Two thousand thirty-five head CT studies from 895 sites were analyzed. Peak kilovoltage, exposure, slice and image number, slice thickness, field of view, interslice gap, reformations, examination inclusiveness, use of contrast, and reconstruction filter were compared by sex, geographic region, institution type, and manufacturer. Results One hundred twenty to 140 kVp (peak kilovoltage) was used by 99.8% of the sites. There was no correlation between mAs and kVp. There was a 30-fold increase in number of images and nearly 9-fold increase in number of slices from least to most. Nearly 4% use slice thickness and interslice gap greater than guidelines. There were significant regional differences in field of view, image number, and slice thickness. Some variation related to manufacturers was found. Minor difference was also found between academic and nonacademic institutions. There were significant differences in kVp and mAs compared with NEXT. Conclusions Significant variations in head CT technique exist in the United States.

Continuous Electroencephalography (cEEG) Monitoring and Outcomes of Critically Ill Patients

Background It is not clear whether performing continuous EEG (cEEG) in critically ill patients during intensive care unit (ICU) treatment affects outcomes at discharge. Material/Methods We prospectively matched 234 patients who received cEEG (cases) by admission diagnosis and sex to 234 patients who did not receive cEEG (controls) and followed them until discharge. Patients admitted due to seizures were excluded. The primary measures of outcome were Glasgow Coma Scale at Discharge (GCSD) and disposition at discharge, and the secondary measures of outcome were AED modifications, Glasgow Outcomes Scale, and Modified-Rankin Scale. These outcomes were compared between the cases and controls. Results Some differences in primary outcome measures between the groups emerged on univariate analyses, but these differences were small and not significant after controlling for covariates. Cases had longer ICU stays (p=0.002) and lower admission GCS (p=0.01) but similar GCSD (p=0.10). Of the secondary outcome measures, the mean (SD) number of AED modifications for cases was 2.2±3.1 compared to 0.4±0.8 for controls (p<0.0001); 170 (72.6%) cases had at least 1 AED modification compared to only 56 (24.1%) of the controls (p<0.0001). Conclusions Performing cEEG did not improve discharge outcome but it significantly influenced AED prescription patterns. Further studies assessing long-term outcomes are needed to better define the role of cEEG in this patient population.

Post Hoc Analyses of ApoE Genotype-Defined Subgroups in Clinical Trials.

BACKGROUND Many post hoc analyses of clinical trials in Alzheimers disease (AD) and mild cognitive impairment (MCI) are in small Phase 2 trials. Subject heterogeneity may lead to statistically significant post hoc results that cannot be replicated in larger follow-up studies. OBJECTIVE We investigated the extent of this problem using simulation studies mimicking current trial methods with post hoc analyses based on ApoE4 carrier status. METHODS We used a meta-database of 24 studies, including 3,574 subjects with mild AD and 1,171 subjects with MCI/prodromal AD, to simulate clinical trial scenarios. Post hoc analyses examined if rates of progression on the Alzheimers Disease Assessment Scale-cognitive (ADAS-cog) differed between ApoE4 carriers and non-carriers. RESULTS Across studies, ApoE4 carriers were younger and had lower baseline scores, greater rates of progression, and greater variability on the ADAS-cog. Up to 18% of post hoc analyses for 18-month trials in AD showed greater rates of progression for ApoE4 non-carriers that were statistically significant but unlikely to be confirmed in follow-up studies. The frequency of erroneous conclusions dropped below 3% with trials of 100 subjects per arm. In MCI, rates of statistically significant differences with greater progression in ApoE4 non-carriers remained below 3% unless sample sizes were below 25 subjects per arm. CONCLUSIONS Statistically significant differences for ApoE4 in post hoc analyses often reflect heterogeneity among small samples rather than true differential effect among ApoE4 subtypes. Such analyses must be viewed cautiously. ApoE genotype should be incorporated into the design stage to minimize erroneous conclusions.

Baseline EDSS proportions in MS clinical trials affect the overall outcome and power: A cautionary note.

Background: In randomized clinical trials, when treatments do not work equally effectively across stratifications of participants, observed event rates may differ from those hypothesized leading to deviations in estimated power. Objectives: To investigate the effect of distributions of baseline Expanded Disability Status Scale (EDSS) proportions in relapsing-remitting multiple sclerosis (RRMS) on the trial outcome, confirmed disability progression rate (CDPR), and power. Methods: We reported CDPRs in the CombiRx trial by baseline EDSS and by groups (1st (0, 1), 2nd (1.5, 2), 3rd (2.5, 3), and 4th (⩾3.5)) and investigated the effect of different combinations of baseline EDSS proportions on the trial outcome and power. Results: There were 244 (25.4%) participants in the 1st group, 368 (38.4%) in the 2nd group, 223 (23.3%) in the 3rd group, and 124 (12.9%) in the 4th group with CDPRs of 40.1%, 13.9%, 11.2%, and 16.9%, respectively. Both CDPR and power increased when the proportion of the 1st group increased in hypothetical trials with equal sample sizes in each arm, and a 10% increase in the 1st group led to a 5% increase in power. Conclusion: Various baseline EDSS proportions yielded different CDPRs and power, suggesting caution in interpretation of treatment effects across trials that enrolled participants with different proportions of baseline EDSS.