Perampanel, an antagonist of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, for the treatment of epilepsy: studies in human epileptic brain and nonepileptic brain and in rodent models.

Perampanel [Fycompa, 2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl)benzonitrile hydrate 4:3; Eisai Inc., Woodcliff Lake, NJ] is an AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor antagonist used as an adjunctive treatment of partial-onset seizures. We asked whether perampanel has AMPA receptor antagonist activity in both the cerebral cortex and hippocampus associated with antiepileptic efficacy and also in the cerebellum associated with motor side effects in rodent and human brains. We also asked whether epileptic or nonepileptic human cortex is similarly responsive to AMPA receptor antagonism by perampanel. In rodent models, perampanel decreased epileptic-like activity in multiple seizure models. However, doses of perampanel that had anticonvulsant effects were within the same range as those engendering motor side effects. Perampanel inhibited native rat and human AMPA receptors from the hippocampus as well as the cerebellum that were reconstituted into Xenopus oocytes. In addition, with the same technique, we found that perampanel inhibited AMPA receptors from hippocampal tissue that had been removed from a patient who underwent surgical resection for refractory epilepsy. Perampanel inhibited AMPA receptor-mediated ion currents from all the tissues investigated with similar potency (IC50 values ranging from 2.6 to 7.0 µM). Cortical slices from the left temporal lobe derived from the same patient were studied in a 60-microelectrode array. Large field potentials were evoked on at least 45 channels of the array, and 10 µM perampanel decreased their amplitude and firing rate. Perampanel also produced a 33% reduction in the branching parameter, demonstrating the effects of perampanel at the network level. These data suggest that perampanel blocks AMPA receptors globally across the brain to account for both its antiepileptic and side-effect profile in rodents and epileptic patients.

Safety Profile of a Cognitively Unimpaired Older Population with Elevated Cerebral Amyloid in a 4.5-Year Clinical Trial.

BACKGROUND: Preclinical Alzheimer's disease is increasingly studied in clinical trials. Although safety signals are routinely monitored in clinical trial populations with Alzheimer's disease, it can be challenging to identify new safety signals against background rates of age-related medical comorbidities. OBJECTIVES: To report detailed safety data from a cognitively unimpaired older population with evidence of elevated cerebral amyloid levels on amyloid positron emission tomography in the placebo arm of a Phase 3 clinical trial. DESIGN: Phase 3, 4.5-year, multicenter, placebo-controlled trial. SETTING: Placebo data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study. PARTICIPANTS: Enrolled participants were aged 65-85 years with a global Clinical Dementia Rating score of 0, a Mini-Mental State Examination score of 25-30, a Wechsler Memory Scale Logical Memory IIa (delayed recall) score of 6-18, and elevated brain amyloid levels on 18F-florbetapir positron emission tomography. MEASUREMENTS: Study participants who received placebo were followed up with post-baseline safety measures. Assessments included review of concomitant medication and adverse events, the Columbia Suicide Severity Rating Scale, electrocardiograms, and neuroimaging (brain magnetic resonance imaging). RESULTS: In total, 591 study participants (mean age [standard deviation] 71.9 [5.0] years) were assigned to and received placebo in the A4 study, and were followed up to 240 weeks. Participants were primarily White (93.9%) and from the United States (86.8%); 60.4% were women. The most common serious adverse events (incidence rate per 100 person-years) were pneumonia (incidence rate=0.4; 95% confidence interval=0.2-0.7) and atrial fibrillation (incidence rate=0.4; 95% confidence interval=0.2-0.7). The most common treatment-emergent adverse events were upper respiratory tract infection (incidence rate=10.9; 95% confidence interval=9.4-12.5), fall (incidence rate=7.7; 95% confidence interval=6.6-9.0), and nasopharyngitis (incidence rate=5.8; 95% confidence interval=4.8-6.9). The most common ischemia-related findings on magnetic resonance imaging were subcortical infarction (incidence rate=1.4; 95% confidence interval=1.0-2.0) and acute ischemia (incidence rate=0.6; 95% confidence interval=0.3-1.0). Emergent amyloid-related imaging abnormalities with hemosiderin deposition occurred in 32.8% of participants who received placebo; the primary factor associated with these events during the post-baseline period was the number of microhemorrhages at baseline (odds ratio=349.9; 95% confidence interval=247.6-494.4; adjusted p<0.001). CONCLUSION: Safety findings in the placebo-treated group from the A4 study provide a robust characterization of expected safety in a clinical trial population with preclinical Alzheimer's disease. These results may provide context in planning future studies and safety evaluations during ongoing blinded studies in preclinical Alzheimer's disease.

Longitudinal Phospho-tau217 Predicts Amyloid Positron Emission Tomography in Asymptomatic Alzheimer's Disease.

BACKGROUND: Blood-based AD biomarkers such as plasma P-tau217 are increasingly used in clinical trials as a screening tool. OBJECTIVES: To assess the utility of an electrochemiluminescence (ECL) immunoassay in predicting brain amyloid PET status in cognitively unimpaired individuals. SETTING: Plasma samples collected at baseline, week 12, and week 240 or endpoint originated from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial and the companion Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study. PARTICIPANTS: Both A4 and LEARN enrolled eligible cognitively unimpaired persons 65 to 85 years. Individuals with elevated brain amyloid PET levels were eligible for the A4 Study, while those without elevated brain amyloid PET levels were eligible for the LEARN Study. INTERVENTION: Participants in the A4 Study received intravenous solanezumab (up to 1600 mg) or placebo every 4 weeks. The LEARN Study is an observational study without intervention. MEASUREMENTS: Plasma P-tau217 concentration levels from A4 Study participants were measured using an ECL immunoassay. Receiver Operating Characteristic (ROC) curve analysis was performed for each biomarker against amyloid positivity, defined by ≥22 CL and ≥ 33 CL. RESULTS: Receiver operating characteristic curve (ROC) analysis indicates high diagnostic value of P-tau217 in individuals with amyloid PET ≥ 20 (Area under the ROC (AUROC): 0.87) and ≥ 33 CL (AUROC: 0.89). Repeated testing with the placebo group taken 12 weeks apart (range: 68 to 143 days) and the LEARN participants taken between 1.4 and 1.75 years resulted in a strong positive correlation (Corr. 0.91 (0.90 to 0.92)). CONCLUSION: An ECL immunoassay testing plasma P-tau217 accurately predicts amyloid PET positivity in cognitively unimpaired individuals. Our future analyses aim to determine if use of this assay may reduce the screening burden of preclinical individuals into anti-amyloid clinical trials.

Pre-Randomization Predictors of Study Discontinuation in a Preclinical Alzheimer's Disease Randomized Controlled Trial.

BACKGROUND: Participant discontinuation from study treatment in a clinical trial can leave a trial underpowered, produce bias in statistical analysis, and limit interpretability of study results. Retaining participants in clinical trials for the full study duration is therefore as important as participant recruitment. OBJECTIVE: This analysis aims to identify associations of pre-randomization characteristics of participants with premature discontinuation during the blinded phase of the Anti-Amyloid treatment in Asymptomatic AD (A4) Study. DESIGN: All A4 trial randomized participants were classified as having prematurely discontinued study during the blinded period of the study for any reason (dropouts) or completed the blinded phase of the study on treatment (completers). SETTING: The trial was conducted across 67 study sites in the United States, Canada, Japan and Australia through the global COVID-19 pandemic. PARTICIPANTS: The sample consisted of all 1169 A4 trial randomized participants. MEASUREMENTS: Pre-randomization demographic, clinical, amyloid PET and genetic predictors of study discontinuation were evaluated using a univariate generalized linear mixed model (GLMM), with discontinuation status as the binary outcome, each predictor as a fixed effect, and site as a random effect to account for differences among study sites in the trial. Characteristics significant at p<0.10 were then included in a multivariable GLMM. RESULTS: Among randomized participants, 339 (29%) discontinued the study during the blinded period (median follow-up time in trial: 759 days). From the multivariable analysis, the two main predictors of study discontinuation were screening State-Trait Anxiety Inventory (STAI) scores (OR = 1.07 [95%CI = 1.02; 1.12]; p=0.002) and age (OR = 1.06 [95%CI = 1.03; 1.09]; p<0.001). Participants with a family history of dementia (OR = 0.75 [95%CI = 0.55; 1.01]; p=0.063) and APOE ε4 carriers (OR = 0.79 [95%CI = 0.6; 1.04]; p=0.094) were less likely to discontinue from the study, with the association being marginally significant. In these analyses, sex, race and ethnicity, cognitive scores and amyloid/tau PET scores were not associated with study dropout. CONCLUSIONS: In the A4 trial, older participants and those with higher levels of anxiety at baseline as measured by the STAI were more likely to discontinue while those who had a family history of dementia or were APOE ε4 carriers were less likely to drop out. These findings have direct implications for future preclinical trial design and selection processes to identify those individuals at greatest risk of dropout and provide information to the study team to develop effective selection and retention strategies in AD prevention studies.

Amyloid and Tau Prediction of Cognitive and Functional Decline in Unimpaired Older Individuals: Longitudinal Data from the A4 and LEARN Studies.

BACKGROUND: Converging evidence suggests that markers of Alzheimer's disease (AD) pathology in cognitively unimpaired older individuals are associated with high risk of cognitive decline and progression to functional impairment. The Anti-Amyloid Treatment in Asymptomatic Alzheimer's disease (A4) and Longitudinal Evaluation of Amyloid and Neurodegeneration Risk (LEARN) Studies enrolled a large cohort of cognitively normal older individuals across a range of baseline amyloid PET levels. Recent advances in AD blood-based biomarkers further enable the comparison of baseline markers in the prediction of longitudinal clinical outcomes. OBJECTIVES: We sought to evaluate whether biomarker indicators of higher levels of AD pathology at baseline predicted greater cognitive and functional decline, and to compare the relative predictive power of amyloid PET imaging, tau PET imaging, and a plasma P-tau217 assay. DESIGN: All participants underwent baseline amyloid PET scan, plasma P-tau217; longitudinal cognitive testing with the Primary Alzheimer Cognitive Composite (PACC) every 6 months; and annual functional assessments with the clinical dementia rating (CDR), cognitive functional index (CFI), and activities of daily living (ADL) scales. Baseline tau PET scans were obtained in a subset of participants. Participants with elevated amyloid (Aß+) on screening PET who met inclusion/exclusion criteria were randomized to receive placebo or solanezumab in a double-blind phase of the A4 Study over 240+ weeks. Participants who did not have elevated amyloid (Aß-) but were otherwise eligible for the A4 Study were referred to the companion observational LEARN Study with the same outcome assessments over 240+ weeks. SETTING: The A4 and LEARN Studies were conducted at 67 clinical trial sites in the United States, Canada, Japan and Australia. PARTICIPANTS: Older participants (ages 65-85) who were cognitively unimpaired at baseline (CDR-GS=0, MMSE 25-30 with educational adjustment, and Logical Memory scores within the normal range LMIIa 6-18) were eligible to continue in screening. Aß+ participants were randomized to either placebo (n=583) or solanezumab (n=564) in the A4 Study. A subset of Aß+ underwent tau PET imaging in A4 (n=350). Aß- were enrolled into the LEARN Study (n=553). MEASUREMENTS: Baseline 18-F Florbetapir amyloid PET, 18-F Flortaucipir tau PET in a subset and plasma P-tau217 with an electrochemiluminescence (ECL) immunoassay were evaluated as predictors of cognitive (PACC), and functional (CDR, CFI and ADL) change. Models were evaluated to explore the impact of baseline tertiles of amyloid PET and tertiles of plasma P-tau217 on cognitive and functional outcomes in the A4 Study compared to LEARN. Multivariable models were used to evaluate the unique and common variance explained in longitudinal outcomes based on baseline predictors, including effects for age, gender, education, race/ethnic group, APOEε4 carrier status, baseline PACC performance and treatment assignment in A4 participants (solanezumab vs placebo). RESULTS: Higher baseline amyloid PET CL and P-tau217 levels were associated with faster rates of PACC decline, and increased likelihood of progression to functional impairment (CDR 0.5 or higher on two consecutive measurements), both across LEARN Aß- and A4 Aß+ (solanezumab and placebo arms). In analyses considering all baseline predictor variables, P-tau217 was the strongest predictor of PACC decline. Among participants in the highest tertiles of amyloid PET or P-tau217, >50% progressed to CDR 0.5 or greater. In the tau PET substudy, neocortical tau was the strongest predictor of PACC decline, but plasma P-tau217 contributed additional independent predictive variance in commonality variance models. CONCLUSIONS: In a large cohort of cognitively unimpaired individuals enrolled in a Phase 3 clinical trial and companion observational study, these findings confirm that higher baseline levels of amyloid and tau markers are associated with increased rates of cognitive decline and progression to functional impairment. Interestingly, plasma P-tau217 was the best predictor of decline in the overall sample, superior to baseline amyloid PET. Neocortical tau was the strongest predictor of cognitive decline in the subgroup with tau PET, suggesting that tau deposition is most closely linked to clinical decline. These findings indicate that biomarkers of AD pathology are useful to predict decline in an older asymptomatic population and may prove valuable in the selection of individuals for disease-modifying treatments.

Can We Use Blood Biomarkers as Entry Criteria and for Monitoring Drug Treatment Effects in Clinical Trials? A Report from the EU/US CTAD Task Force.

In randomized clinical trials (RCTs) for Alzheimer's Disease (AD), cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers are currently used for the detection and monitoring of AD pathological features. The use of less resource-intensive plasma biomarkers could decrease the burden to study volunteers and limit costs and time for study enrollment. Blood-based markers (BBMs) could thus play an important role in improving the design and the conduct of RCTs on AD. It remains to be determined if the data available on BBMs are strong enough to replace CSF and PET biomarkers as entry criteria and monitoring tools in RCTs.

Amyloid-Related Imaging Abnormalities and Other MRI Findings in a Cognitively Unimpaired Population With and Without Cerebral Amyloid.

BACKGROUND: Screening data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies provide a unique opportunity to compare magnetic resonance imaging (MRI) findings such as amyloid-related imaging abnormalities (ARIA) in cognitively unimpaired elderly with and without elevated cerebral amyloid. OBJECTIVES: To compare screening MRI findings, such as ARIA, in the cognitively unimpaired potential participants of a clinical trial with and without elevated cerebral amyloid. DESIGN: Cross-sectional analysis of structural MRI findings in screening data from the A4 and LEARN studies. SETTING: The A4 Study is a multi-center international clinical trial. The LEARN Study is a multi center observational study in the United States. PARTICIPANTS: Clinically normal older adults (65-85 years) with elevated cerebral amyloid (Aß+; n = 1250, A4) and without elevated cerebral amyloid (Aß-; n = 538, LEARN). MEASUREMENTS: Participants underwent florbetapir positron emission tomography for Aß+/- classification. A centrally read 3T MRI to assess for study eligibility was conducted on study qualified MRI scanners. RESULTS: No ARIA-effusions (ARIA-E) was detected on screening MRI in the Aß+ or Aß- cohorts. At least one ARIA-H (microhemorrhages [MCH] or superficial siderosis [SS]) was present in 18% of the Aß+ cohort compared with 8% in Aß- (P < 0.001). In the Aß+ cohort, approximately 2% of screening MRIs demonstrated MCH ≥4 compared with 0% in Aß-. The presence of two apolipoprotein E ε4 (APOEε4) alleles (vs no ε4 alleles) in the Aß+ cohort increased the odds for presence of MCH (odds ratio [OR] = 2.03; 95% CI, 1.23 to 3.27, P = 0.004). Cortical infarctions (4% vs 0%) and subcortical infarctions (10% vs 1%) were observed at statistically significantly higher prevalence in the Aß+ cohort compared with Aß- (P < 0.001). Females showed reduced odds of MCH in the Aß+ cohort by a factor of 0.63 (95% CI, 0.47 to 0.84, P = 0.002). CONCLUSIONS: ARIA-E is rare in cognitively unimpaired Aß+ and Aß- populations prior to anti-amyloid drug intervention. ARIA-H in Aß+ was greater than in Aß- populations.

Blood Biomarkers from Research Use to Clinical Practice: What Must Be Done? A Report from the EU/US CTAD Task Force.

Timely and accurate diagnosis of Alzheimer's disease (AD) in clinical practice remains challenging. PET and CSF biomarkers are the most widely used biomarkers to aid diagnosis in clinical research but present limitations for clinical practice (i.e., cost, accessibility). Emerging blood-based markers have the potential to be accurate, cost-effective, and easily accessible for widespread clinical use, and could facilitate timely diagnosis. The EU/US CTAD Task Force met in May 2022 in a virtual meeting to discuss pathways to implementation of blood-based markers in clinical practice. Specifically, the CTAD Task Force assessed: the state-of-art for blood-based markers, the current use of blood-based markers in clinical trials, the potential use of blood-based markers in clinical practice, the current challenges with blood-based markers, and the next steps needed for broader adoption in clinical practice.

Platform Trials to Expedite Drug Development in Alzheimer's Disease: A Report from the EU/US CTAD Task Force.

A diverse range of platforms has been established to increase the efficiency and speed of clinical trials for Alzheimer's disease (AD). These platforms enable parallel assessment of multiple therapeutics, treatment regimens, or participant groups; use uniform protocols and outcome measures; and may allow treatment arms to be added or dropped based on interim analyses of outcomes. The EU/US CTAD Task Force discussed the lessons learned from the Dominantly Inherited Alzheimer's Network Trials Unit (DIAN-TU) platform trial and the challenges addressed by other platform trials that have launched or are in the planning stages. The landscape of clinical trial platforms in the AD space includes those testing experimental therapies such as DIAN-TU, platforms designed to test multidomain interventions, and those designed to streamline trial recruitment by building trial-ready cohorts. The heterogeneity of the AD patient population, AD drugs, treatment regimens, and analytical methods complicates the design and execution of platform trials, yet Task Force members concluded that platform trials are essential to advance the search for effective AD treatments, including combination therapies.

Donanemab (LY3002813) Phase 1b Study in Alzheimer's Disease: Rapid and Sustained Reduction of Brain Amyloid Measured by Florbetapir F18 Imaging.

BACKGROUND: Donanemab (LY3002813) is an IgG1 antibody directed at an N­terminal pyroglutamate of amyloid beta epitope that is present only in brain amyloid plaques. OBJECTIVES: To assess effects of donanemab on brain amyloid plaque load after single and multiple intravenous doses, as well as pharmacokinetics, safety/tolerability, and immunogenicity. DESIGN: Phase 1b, investigator- and patient-blind, randomized, placebo-controlled study. SETTING: Patients recruited at clinical research sites in the United States and Japan. PARTICIPANTS: 61 amyloid plaque-positive patients with mild cognitive impairment due to Alzheimer's disease and mild-to-moderate Alzheimer's disease dementia. INTERVENTION: Six cohorts were dosed with donanemab: single dose 10-, 20- or 40- mg/kg (N = 18), multiple doses of 10-mg/kg every 2 weeks for 24 weeks (N = 10), and 10- or 20-mg/kg every 4 weeks for 72 weeks (N=18) or placebo (N = 15). MEASUREMENTS: Brain amyloid plaque load, using florbetapir positron emission tomography, was assessed up to 72 weeks. Safety was evaluated by occurrence of adverse events, magnetic resonance imaging, electrocardiogram, vital signs, laboratory testing, neurological monitoring, and immunogenicity. RESULTS: Treatment with donanemab resulted in rapid reduction of amyloid, even after a single dose. By 24 weeks, amyloid positron emission tomography mean changes from baseline for single donanemab doses in Centiloids were: -16.5 (standard error 11.22) 10-mg/kg intravenous; 40.0 (standard error 11.23) 20 mg/kg intravenous; and -49.6 (standard error 15.10) 40-mg/kg intravenous. Mean reduction of amyloid plaque in multiple dose cohorts by 24 weeks in Centiloids were: 55.8 (standard error 9.51) 10-mg/kg every 2 weeks; -50.2 (standard error 10.54) 10-mg/kg every 4 weeks; and -58.4 (standard error 9.66) 20-mg/kg every 4 weeks. Amyloid on average remained below baseline levels up to 72 weeks after a single dose of donanemab. Repeated dosing resulted in continued florbetapir positron emission tomography reductions over time compared to single dosing with 6 out of 28 patients attaining complete amyloid clearance within 24 weeks. Within these, 5 out of 10 patients in the 20 mg/kg every 4 weeks cohort attained complete amyloid clearance within 36 weeks. When dosing with donanemab was stopped after 24 weeks of repeat dosing in the 10 mg every 2 weeks cohort, florbetapir positron emission tomography reductions were sustained up to 72 weeks. For the single dose cohorts on day 1, dose proportional increases in donanemab pharmacokinetics were observed from 10 to 40 mg/kg. Dose proportional increases in pharmacokinetics were also observed at steady state with the multiple dose cohorts. Donanemab clearance was comparable across the dose levels. Mean donanemab elimination-half-life following 20 mg/kg single dose was 9.3 days with range of 5.6 to 16.2 days. Greater than 90% of patients had positive treatment-emergent antidrug antibodies with donanemab. However, overall, the treatment-emergent antidrug antibodies did not have a significant impact on pharmacokinetics. Donanemab was generally well tolerated. Amongst the 46 participants treated with donanemab, the following amyloid-related imaging abnormalities, common to the drug class, were observed: 12 vasogenic cerebral edema events (12 [19.7%] patients), 10 cerebral microhemorrhage events (6 [13.0%] patients), and 2 superficial siderosis events (2 [4.3%] patients). CONCLUSIONS: Single and multiple doses of donanemab demonstrated a rapid, robust, and sustained reduction up to 72 weeks in brain amyloid plaque despite treatment-emergent antidrug antibodies detected in most patients. Amyloid-related imaging abnormalities were the most common treatment-emergent event.

Item-Level Investigation of Participant and Study Partner Report on the Cognitive Function Index from the A4 Study Screening Data.

BACKGROUND: Greater subjective cognitive changes on the Cognitive Function Index (CFI) was previously found to be associated with elevated amyloid (Aß) status in participants screening for the A4 Study, reported by study partners and the participants themselves. While the total score on the CFI related to amyloid for both sources respectively, potential differences in the specific types of cognitive changes reported by either participants or their study partners was not investigated. OBJECTIVES: To determine the specific types of subjective cognitive changes endorsed by participants and their study partners that are associated with amyloid status in individuals screening for an AD prevention trial. DESIGN, SETTING, PARTICIPANTS: Four thousand four hundred and eighty-six cognitively unimpaired (CDR=0; MMSE 25-30) participants (ages 65-85) screening for the A4 Study completed florbetapir (Aß) Positron Emission Tomography (PET) imaging. Participants were classified as elevated amyloid (Aß+; n=1323) or non-elevated amyloid (Aß-; n=3163). MEASUREMENTS: Prior to amyloid PET imaging, subjective report of changes in cognitive functioning were measured using the CFI (15 item questionnaire; Yes/Maybe/No response options) and administered separately to both participants and their study partners (i.e., a family member or friend in regular contact with the participant). The impact of demographic factors on CFI report was investigated. For each item of the CFI, the relationship between Aß and CFI response was investigated using an ordinal mixed effects model for participant and study partner report. RESULTS: Independent of Aß status, participants were more likely to report 'Yes' or 'Maybe' compared to the study partners for nearly all CFI items. Older age (r= 0.06, p<0.001) and lower education (r=-0.08, p<0.001) of the participant were associated with higher CFI. Highest coincident odds ratios related to Aß+ for both respondents included items assessing whether 'a substantial decline in memory' had occurred in the last year (ORsp= 1.35 [95% CI 1.11, 1.63]; ORp= 1.55 [95% CI 1.34, 1.79]) and whether the participant had 'seen a doctor about memory' (ORsp= 1.56 [95% CI 1.25, 1.95]; ORp =1.71 [95% CI 1.37, 2.12]). For two items, associations were significant for only study partner report; whether the participant 'Repeats questions' (ORsp = 1.30 [95% CI 1.07, 1.57]) and has 'trouble following the news' (ORsp= 1.46[95% CI 1.12, 1.91]). One question was significant only for participant report; 'trouble driving' (ORp= 1.25 [95% CI 1.04, 1.49]). CONCLUSIONS: Elevated Aß is associated with greater reporting of subjective cognitive changes as measured by the CFI in this cognitively unimpaired population. While participants were more likely than study partners to endorse change on most CFI items, unique CFI items were associated with elevated Aß for participants and their study partners, supporting the value of both sources of information in clinical trials.

Combination Therapy for Alzheimer's Disease: Perspectives of the EU/US CTAD Task Force.

Combination therapy is expected to play an important role for the treatment of Alzheimer's disease (AD). In October 2018, the European Union-North American Clinical Trials in Alzheimer's Disease Task Force (EU/US CTAD Task Force) met to discuss scientific, regulatory, and logistical challenges to the development of combination therapy for AD and current efforts to address these challenges. Task Force members unanimously agreed that successful treatment of AD will likely require combination therapy approaches that target multiple mechanisms and pathways. They further agreed on the need for global collaboration and sharing of data and resources to accelerate development of such approaches.

Detecting Treatment Group Differences in Alzheimer's Disease Clinical Trials: A Comparison of Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) and the Clinical Dementia Rating - Sum of Boxes (CDR-SB).

The Alzheimer's Disease Assessment Scale's cognitive subscale (ADAS-Cog) has been widely used as an outcome measure in Alzheimer's Disease (AD) clinical trials. In its original form (ADAS-Cog11), the scale has been used successfully in mild-to-moderate AD dementia populations, but its use is more limited in the study of earlier disease (mild cognitive impairment [MCI] or mild dementia due to AD) owing to lack of appropriate sensitivity of some items. With recent focus on earlier treatment, efforts have focused on the development of more sensitive tools, including the Clinical Dementia Rating-Sum of Boxes (CDR-SB), a global assessment tool to evaluate both cognition and function. The ability of the ADAS-Cog and CDR-SB to detect treatment group differences in the clinical trial environment has not been systematically studied. The aim of this analysis was to compare the utility of these tools in detecting treatment group differences, by reviewing study findings identified through advanced searches of clinicaltrials.gov and Ovid, and press releases and scientific presentations. Findings from placebo-controlled studies of ≥ 6m duration and enrolling >100 participants were included; reporting of both the ADAS-Cog and CDR-SB at endpoint was also a requirement. Of the >300 records identified, 34 studies fulfilled the criteria. There were significant placebo versus active drug group differences based on findings from at least one measure for 14 studies. The ADAS-Cog detected treatment differences more frequently than the CDR-SB. Based on these and previously published findings, the ADAS-Cog appears more useful than the CDR-SB in detecting treatment group differences.

Fermi surface of CeIn3 above the Néel critical field.

We report measurements of the de Haas-van Alphen effect in CeIn(3) in magnetic fields extending to approximately 90 T, well above the Néel critical field of mu(0)H(c) approximately 61 T. The unreconstructed Fermi surface a sheet is observed in the high magnetic field polarized paramagnetic limit, but with its effective mass and Fermi surface volume strongly reduced in size compared to that observed in the low magnetic field paramagnetic regime under pressure. The spheroidal topology of this sheet provides an ideal realization of the transformation from a "large Fermi surface" accommodating f electrons to a "small Fermi surface" when the f-electron moments become polarized.

Development Review of the BACE1 Inhibitor Lanabecestat (AZD3293/LY3314814).

Several ongoing clinical development programs are investigating potential disease-modifying treatments for Alzheimer's disease (AD), including lanabecestat (AZD3293/LY3314814). Lanabecestat is a brain-permeable oral inhibitor of human beta-site amyloid (Aß) precursor protein-cleaving enzyme 1 (BACE1) that reduces Aß production. As a potent BACE1 inhibitor, lanabecestat significantly reduced soluble Aß species and soluble amyloid precursor proteins (sAPPß) in mouse, guinea pig, and dog in a time- and dose-dependent manner. Significant reductions in plasma and cerebrospinal fluid (CSF) Aß1-40 and Aß1-42 were observed in Phase 1 studies of healthy subjects and AD patients treated with lanabecestat. Three lanabecestat trials are ongoing and intended to support registration in Early AD: (1) Phase 2/3 study in patients with mild cognitive impairment (MCI) due to AD and mild AD dementia (AMARANTH, NCT02245737); (2) Delayed-start extension study (AMARANTH-EXTENSION, NCT02972658) for patients who have completed treatment in the AMARANTH Study; and (3) Phase 3 study in mild AD dementia (DAYBREAK-ALZ, NCT02783573). This review will discuss the development of lanabecestat, results from the completed nonclinical and clinical studies, as well as describe the ongoing Phase 3 clinical trials.

A Combined Measure of Cognition and Function for Clinical Trials: The Integrated Alzheimer's Disease Rating Scale (iADRS).

It is generally recognized that more sensitive instruments for the earliest stages of Alzheimer's disease (AD) are needed. The integrated Alzheimer's Disease Rating Scale (iADRS) combines scores from 2 widely accepted measures, the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and the Alzheimer's Disease Cooperative Study - instrumental Activities of Daily Living (ADCS-iADL). Disease progression and treatment differences as measured by the iADRS were analyzed using data from solanezumab EXPEDITION, EXPEDITION2, and EXPEDITION-EXT Studies; semagacestat IDENTITY Study; and donepezil ADCS - mild cognitive impairment (ADCS-MCI) Study. Psychometric properties of the iADRS were established through principal component analysis (PCA) and estimation of contributions of subscores and individual item scores to the iADRS total score. The iADRS performed better than most composites and scales in detecting disease progression and comparably or better than individual scales in detecting treatment differences. PCA demonstrated the iADRS can be divided into two principal components primarily representing cognitive items and instrumental ADLs. Dynamic ranges of the subscales were similar across all studies, reflecting approximately equal contributions from both subscales to the iADRS total score. In item analyses, every item contributed to the total score, with varying strength of contributions by item and across data sets. The iADRS demonstrated acceptable psychometric properties and was effective in capturing disease progression from MCI through moderate AD and treatment effects across the early disease spectrum. These findings suggest the iADRS can be used in studies of mixed populations, ensuring sensitivity to treatment effects as subjects progress during studies of putative disease-modifying agents.

A descriptive analysis of asthma in the U.S. Navy Submarine Force.

BACKGROUND: The U.S. Navy Submarine Force offers a unique opportunity to study asthma because of the relative socioeconomic and physical homogeneity of the population and the closed environment occupational exposure. Currently, asthma is disqualifying from submarine service, which results in a significant loss of experienced personnel. METHODS: We performed a retrospective analysis of 119 U.S. Navy submariner disqualification packages for asthma between 1989-1993. RESULTS: We found a 0.16% annual period prevalence of asthma in the active duty enlisted Atlantic Fleet Submarine Force. Two groups of asthma disqualifications were identified with a significant increase above their proportional representation in the fleet: enlisted personnel (p < 0.01) and submarine recruits (p < 0.0001). The proportion of African-American personnel also had a tendency toward increased asthma disqualification (p < 0.08). There were no differences in prevalence of asthma between crews of ballistic missile submarines or fast attack submarines. Asthma risk factors reported in the civilian literature (childhood history of asthma, family history of asthma and non-drug allergies) were highly represented in our study (41%, 46% and 68% of submariners, respectively). Most disqualified submariners had "mild" asthma based on the diagnostic work-up. The methacholine challenge test appeared to carry a disproportionate diagnostic weight despite its low specificity. CONCLUSION: Although the period prevalence of asthma is low in the U.S. Navy Submarine Force, submariners disqualified for asthma have similar historical and ethnic risk factors as the civilian population.

Recreational scuba divers' aversion to low-frequency underwater sound.

Increasing use of active low-frequency sonar by submarines and ships raises the risk of accidental exposure of recreational divers to low-frequency underwater sound (LFS). This study aimed to characterize the subjective responses of recreational scuba divers to LFS to ascertain the extent to which LFS may impact their enjoyment, comfort, or time spent underwater. Seventeen male and nine female recreational scuba divers participated. Diving was conducted in an acoustically transparent tank located within a larger anechoic pool. Subjects wore scuba gear and were positioned I m below the surface in a prone position. The sound transducer was located 4 m directly below the diver's head. Sound exposures consisted of three signal types (pure tone, 30 Hz hyperbolic sweep up, and 30 Hz hyperbolic sweep down) each presented at six center frequencies from 100 to 500 Hz and six sound pressure levels(SPL) ranging from 130 to 157 dB re 1 microPa. The duration of each sound exposure was 7 s. Subjects responded via an underwater console to rate aversion to LFS on a category-ratio scale, and to indicate the presence or absence of vibration of any body part. Aversion to LFS and the percent incidence of vibration increased as the SPL increased. The percent incidence of vibration decreased linearly with increasing frequency. At the highest SPL the probability that an aversion rating would exceed Very Severe (7 on the category-ratio scale) was predicted to be 19%. There was no significant difference in aversion among signal types. The 100 Hz frequency was the most aversive frequency (P < 0.05). A plot of aversion vs. frequency showed a U-shaped function with minimum aversion at 250 Hz. In conclusion, diver aversion to LFS is dependent upon SPL and center frequency. The highest aversion rating was given for 100 Hz, this frequency corresponded with the greatest probability of detecting vibration. Factors other than vibration seem to account for aversion to the highest frequencies. Our data suggest that LFS exposures up to 145 dB re 1 microPa at frequencies between 100 and 500 Hz will have minimal impact on the recreational diver.

Gamma-to-electron magnetic spectrometer (GEMS): an energy-resolved γ-ray diagnostic for the National Ignition Facility.

The gamma-to-electron magnetic spectrometer, having better than 5% energy resolution, is proposed to resolve γ-rays in the range of E(o) ± 20% in single shot, where E(o) is the central energy and is tunable from 2 to 25 MeV. Gamma-rays from inertial confinement fusion implosions interact with a thin Compton converter (e.g., beryllium) located at approximately 300 cm from the target chamber center (TCC). Scattered electrons out of the Compton converter enter an electromagnet placed outside the NIF chamber (approximately 600 cm from TCC) where energy selection takes place. The electromagnet provides tunable E(o) over a broad range in a compact manner. Energy resolved electrons are measured by an array of quartz Cherenkov converters coupled to photomultipliers. Given 100 detectable electrons in the energy bins of interest, 3 × 10(14) minimum deuterium/tritium (DT) neutrons will be required to measure the 4.44 MeV (12)C γ-rays assuming 200 mg/cm(2) plastic ablator areal density and 3 × 10(15) minimum DT neutrons to measure the 16.75 MeV DT γ-ray line.

A transgenic mouse model of neuroepithelial cell specific inducible overexpression of dopamine D1-receptor.

Dopamine and its receptors appear in the brain during early embryonic period suggesting a role for dopamine in brain development. In fact, dopamine receptor imbalance resulting from impaired physiological balance between D1- and D2-receptor activities can perturb brain development and lead to persisting changes in brain structure and function. Dopamine receptor imbalance can be produced experimentally using pharmacological or genetic methods. Pharmacological methods tend to activate or antagonize the receptors in all cell types. In the traditional gene knockout models the receptor imbalance occurs during development and also at maturity. Therefore, assaying the effects of dopamine imbalance on specific cell types (e.g. precursor versus postmitotic cells) or at specific periods of brain development (e.g. pre- or postnatal periods) is not feasible in these models. We describe a novel transgenic mouse model based on the tetracycline dependent inducible gene expression system in which dopamine D1-receptor transgene expression is induced selectively in neuroepithelial cells of the embryonic brain at experimenter-chosen intervals of brain development. In this model, doxycycline-induced expression of the transgene causes significant overexpression of the D1-receptor and significant reductions in the incorporation of the S-phase marker bromodeoxyuridine into neuroepithelial cells of the basal and dorsal telencephalon indicating marked effects on telencephalic neurogenesis. The D1-receptor overexpression occurs at higher levels in the medial ganglionic eminence (MGE) than the lateral ganglionic eminence (LGE) or cerebral wall (CW). Moreover, although the transgene is induced selectively in the neuroepithelium, D1-receptor protein overexpression appears to persist in postmitotic cells. The mouse model can be modified for neuroepithelial cell-specific inducible expression of other transgenes or induction of the D1-receptor transgene in other cells in specific brain regions by crossbreeding the mice with transgenic mouse lines available already.