Association of β-Amyloid Accumulation With Executive Function in Adults With Unimpaired Cognition

Background and Objectives:The neuropathological changes underlying Alzheimer´s disease (AD) start before overt cognitive symptoms arise, but it is not well-known how they relate to the first subtle cognitive changes. The objective for this study was to examine the independent associations of the AD hallmarks β-amyloid (Aβ), tau, and neurodegeneration with different cognitive domains in cognitively unimpaired (CU) individuals.Methods:In this cross-sectional study, CU participants from the prospective BioFINDER-2 study were included. All had CSF biomarkers (Aβ42 and P-tau181), MRI (cortical thickness of AD-susceptible regions), Aβ-PET (neocortical uptake), tau-PET (entorhinal uptake), and cognitive test data for i) memory, ii) executive function, iii) verbal function, iv), and visuospatial function. Multivariable linear regression models were performed, using either CSF Aβ42, P-tau181 and cortical thickness or Aβ-PET, tau-PET, and cortical thickness, as predictors of cognitive function. The results were validated in an independent cohort (ADNI).Results:316 CU participants were included from the BioFINDER-2 study. Abnormal Aβ-status was independently associated with the executive measure, regardless of modality (CSF Aβ42 β=0.128, p=0.024; Aβ-PET β=0.124, p=0.049), while tau was independently associated with memory (CSF P-tau181 β=0.132, p=0.018; tau-PET β=0.189, p=0.002). Cortical thickness was independently associated with the executive measure and verbal fluency in both models (p=0.005-0.018). To examine the relationships in the earliest stage of preclinical AD, only participants with normal biomarkers of tau and neurodegeneration were included (n=217 CSF-based; n=246 PET-based). Again, Aβ-status was associated with executive function (CSF Aβ42, β=0.189, p=0.005; Aβ-PET, β=0.146, p=0.023), but not with other cognitive domains. The results were overall replicated in the ADNI cohort (n=361).Discussion:These findings suggest that Aβ is independently associated with worse performance on an executive measure but not with memory performance, which instead is associated with tau pathology. This may have implications for early preclinical AD screening and outcome measures in AD trials targeting Aβ pathology.

Performing Cost-Effectiveness Analyses to Support Policy Making: Key Lessons From the Assessment of Aducanumab

The purpose of this paper is to describe the process and the methods of cost-effectiveness analysis for clinicians interested in joining or leading aspects of this branch of evidence-based research. Cost-effectiveness is a useful tool for policymakers and is considered a starting point for discussions of fair pricing. Clinicians are important members of teams conducting cost-effectiveness analyses, particularly as it relates to integrating their clinical expertise into the decisions around the design and conduct of the analysis. Their input is essential in assuring that models adequately reflect clinical practice and are informed by expert judgments of how existing data can best be interpreted to build a comprehensive analysis of the clinical and economic outcomes of different treatment options. We illustrate specific contributions that clinicians are well positioned to make in these teams using a recent cost-effectiveness analysis of aducanumab that was conducted to support fair drug pricing. While discussing these contributions, we explain key components of a cost-effectiveness analysis, such as time horizon, health states, and perspective, to support the understanding of the methods of cost-effectiveness by the clinical researchers and to promote a common dialogue among these multidisciplinary teams.

Long-term Effect of Regular Physical Activity and Exercise Habits in Patients With Early Parkinson Disease

Objective:Owing to the lack of long-term observations and/or comprehensive adjustment for confounding factors, reliable conclusions regarding long-term effects of exercise and regular physical activity in Parkinson’s disease (PD) have yet to be drawn. Here, using data from the Parkinson’s Progression Markers Initiative study that includes longitudinal and comprehensive evaluations of many clinical parameters, we examined the long-term effects of regular physical activity and exercise habits on the course of PD.Methods:In this observational cohort study, we primarily used the multivariate linear mixed-effects models to analyze the interaction effects of their regular physical activity and moderate-to-vigorous exercise levels, measured through the Physical Activity Scale for the Elderly questionnaire, on the progression of clinical parameters, after adjusting for age, sex, levodopa-equivalent dose, and disease duration. We also calculated bootstrapping 95% confidence intervals (CIs), and conducted sensitivity analyses using the multiple imputation method and subgroup analyses using the propensity score matching to match for all baseline background factors.Results:237 early PD patients [median (interquartile range); age, 63.0 (56.0–70.0) years; Male, 69.2%; follow-up duration, 5.0 (4.0–6.0) years] were included. Regular physical activity and moderate-to-vigorous exercise levels at the baseline did not significantly affect the subsequent clinical progression of PD. However, average regular overall physical activity levels over time were significantly associated with slower deterioration of postural and gait stability [standardized fixed-effects coefficients of the interaction term (βinteraction) = -0.10 (95% CI, -0.14 to -0.06)], activities of daily living [βinteraction = 0.08 (95% CI, 0.04 to 0.12)], and processing speed [βinteraction = 0.05 (95% CI, 0.03 to 0.08)] in PD patients. Moderate-to-vigorous exercise levels were preferentially associated with slower decline of postural and gait stability [βinteraction = -0.09 (95% CI, -0.13 to -0.05)] and work-related activity levels were primarily associated with slower deterioration of processing speed [βinteraction = 0.07 (95% CI, 0.04 to 0.09)]. Multiple imputation and propensity score matching confirmed the robustness of our results.Conclusions:In the long-term, the maintenance of high regular physical activity levels and exercise habits was robustly associated with better clinical course of PD, with each type of physical activity having different effects.Trial Registration Information:Clinicaltrials.gov (NCT01176565). A link to trial registry page is https://clinicaltrials.gov/ct2/show/NCT01141023.Classification of Evidence:This study provides Class II evidence that sustained increase in overall regular physical activity levels in patients with early Parkinson disease was associated with slower decline of several clinical parameters.

Cost-Effectiveness and Value-Based Pricing of Aducanumab for Patients With Early Alzheimer Disease

Introduction:Aducanumab was granted accelerated approval with a conflicting evidence base, near-unanimous FDA Advisory Committee vote to reject approval, and a widely criticized launch price of $56,000 per year. The objective of this analysis was to estimate its cost-effectiveness.Methods:We developed a Markov model to compare aducanumab in addition to supportive care to supportive care alone over a lifetime horizon. Results were presented from both the health system and modified societal perspective. The model tracked the severity of disease and the care setting. Incremental cost-effectiveness ratios were calculated, and a threshold analysis was conducted to estimate at what price aducanumab would meet commonly used cost-effectiveness thresholds.Results:Using estimates of effectiveness based on pooling of data from both pivotal trials, patients treated with aducanumab spent four more months in earlier stages of AD. Over the lifetime time horizon, treating a patient with aducanumab results in 0.154 more QALYs gained per patient and 0.201 evLYGs per patient from the health care system perspective, with additional costs of approximately $204,000 per patient. The incremental outcomes were similar for the modified societal perspective. At the list price of $56,000 per year, the cost-effectiveness ranged from $1.02 million per evLYG to $1.33 million per QALY gained from the health care system perspective; and from $938,000 per evLYG to $1.27 million per QALY gained in the modified societal perspective. The annual price to meet commonly used cost-effectiveness thresholds ranged from $2,950 to $8,360, which represents a discount of 85-95% off from the annual launch price set by the manufacturer. Using estimates of effectiveness based only on the trial that suggested a benefit, the mean incremental cost was greater than $400,000 per QALY gained.Discussion:Patients treated with aducanumab received minimal improvements in health outcomes at considerable cost. This resulted in incremental cost-effectiveness ratios that far exceeded commonly used value thresholds, even under optimistic treatment effectiveness assumptions. These findings are subject to the substantial uncertainty regarding whether aducanumab provides any true net health benefit, but evidence available currently suggests that an annual price of aducanumab of $56,000 is not in reasonable alignment with its clinical benefits.

Clinical Outcome After Endovascular Treatment in Patients With Active Cancer and Ischemic Stroke: A MR CLEAN Registry Substudy

Objective:To explore clinical and safety outcomes of patients with acute ischemic stroke (AIS) and active cancer after endovascular treatment (EVT).Methods:Using data from the MR CLEAN Registry, we compared patients with active cancer (defined as cancer diagnosed within 12 months prior to stroke, metastatic disease, or current cancer treatment) to patients without cancer. Outcomes were 90-day modified Rankin Scale (mRS) score, mortality, successful reperfusion (eTICI scores≥2b), symptomatic intracranial hemorrhage (sICH), and recurrent stroke. Subgroup analyses were performed in patients with a pre-stroke mRS score of 0 or 1 and according to treatment setting (curative or palliative). Analyses were adjusted for prognostic variables.Results:Of 2583 patients who underwent EVT, 124 (4.8%) had active cancer. They more often had pre-stroke disability (mRS≥2: 34.1% vs. 16.6%). The treatment setting was palliative in 25.3% of the patients. There was a shift towards worse functional outcome at 90 days in patients with active cancer (adjusted common OR 2.2, 95% CI 1.5-3.2). At 90 days, patients with active cancer were less often independent (mRS 0-2: 22.6% vs. 42.0%, aOR 0.5, 95% CI 0.3-0.8), and more often dead (52.2% vs. 26.5%, aOR 3.2, 95% CI 2.1-4.9). Successful reperfusion (67.8% vs. 60.5%, aOR 1.4, 95% CI 1.0-2.1) and sICH rates (6.5% vs. 5.9%, aOR 1.1, 95 %CI 0.5-2.3) did not differ. Recurrent stroke within 90 days was more common in patients with active cancer (4.0% vs. 1.3%, aOR 3.1, 95% CI 1.2-8.1). The sensitivity analysis of patients with a pre-stroke mRS of 0 or 1 showed that patients with active cancer still had a worse outcome at 90 days (acOR 1.9, 95% CI 1.2-3.0). Patients with active cancer in a palliative treatment setting regained functional independence less often compared to patients in a curative setting (18.2% vs. 32.1%) and mortality was also higher (81.8% vs. 39.3%).Conclusions:Despite similar technical success, patients with active cancer had significantly worse outcomes after EVT for AIS. Moreover, they had an increased risk of recurrent stroke. Nevertheless, about a quarter of the patients regained functional independence and the risk of other complications, most notably sICH, was not increased.Classification of Evidence:This study provides Class I evidence that patients with active cancer undergoing EVT for AIS have worse functional outcomes at 90 days compared to those without active cancer.

Efficacy and Safety of Selumetinib in Pediatric Patients With Neurofibromatosis Type 1: A Systematic Review and Meta-analysis

Background and Objectives:Although the recent approval of selumetinib is expected to transform the management of children with Neurofibromatosis type 1 (NF1), particularly those with symptomatic and inoperable PN, no systematic review has summarized their efficacy and safety based on the latest studies. This study was conducted to systematically evaluate the efficacy and safety of selumetinib in children with NF1Methods:Original articles reporting the efficacy and safety of selumetinib in patients with NF1 were identified in PubMed and EMBASE up to January 28, 2021. The pooled objective response rates (ORRs) and disease control rates (DCRs) were calculated using the DerSimonian–Laird method based on random-effects modeling. The pooled proportion of adverse events (AEs) was also calculated. The quality of the evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation system.Results:Five studies involving 126 patients were included in our analysis. The studies had a very low to moderate quality of the evidence. The pooled ORR was 73.8% (95% CI: 57.3–85.5%), and the DCR was 92.5% (95% CI: 66.5–98.7%). The two most common AEs were diarrhea, which had a pooled rate of 63.8% (95% CI, 52.9–73.4%) and an increase in creatine kinase levels, which had a pooled rate of 63.3% (95% CI, 35.6–84.3%).Discussion:Our results indicate that selumetinib is an effective and safe treatment for pediatric patients with symptomatic, inoperable plexiform neurofibromas. Further larger-scale randomized controlled studies are needed to confirm the long-term outcome of patients treated with this drug.

Magnetic Resonance Spectroscopy of Hypoxic-Ischemic Encephalopathy After Cardiac Arrest

Objective:To correlate brain metabolites to clinical outcome using magnetic resonance spectroscopy (MRS) in patients undergoing targeted temperature management (TTM) after cardiac arrest, and assess their relationships to MRI and EEG variables.Methods:A prospective cohort of 50 patients was studied. The primary outcome was coma recovery to follow commands. Comparison of MRS measures in the posterior cingulate gyrus, parietal white matter, basal ganglia, and brainstem were also made to 25 normative control subjects.Results:Fourteen of 50 achieved coma recovery before hospital discharge. There was a significant decrease in total N-acetyl-aspartate (NAA/Cr) and an increase in lactate (Lac/Cr) in patients who did not recover, with changes most prominent in the posterior cingulate gyrus. Patients who recovered had decrease in NAA/Cr as compared to control subjects. NAA/Cr had a strong monotonic relationship with MRI cortical apparent diffusion coefficient (ADC); lactate level exponentially increased with decreasing ADC. EEG suppression/burst suppression was universally associated with lactate elevation.Conclusions:NAA and lactate changes are associated with clinical/MRI/EEG changes consistent with hypoxic-ischemic encephalopathy (HIE) and are most prominent in the posterior cingulate gyrus. NAA/Cr decrease observed in patients with good outcomes suggests mild HIE in patients asymptomatic at hospital discharge. The appearance of cortical lactate represents a deterioration of aerobic energy metabolism and is associated with EEG background suppression, synaptic transmission failure, and severe, potentially irreversible HIE.Classification of Evidence:This study provides Class IV evidence that in patients undergoing TTM after cardiac arrest, brain MRS-determined decrease in total NAA/Cr and an increase in Lac/Cr are associated with an increased risk of not recovering.