Immediate Reactions to Alzheimer Biomarker Disclosure in Cognitively Unimpaired Individuals in a Global Truncated Randomized Trial.

Background and Objectives: Preclinical Alzheimer disease (AD) trials simultaneously test candidate treatments and the implications of disclosing biomarker information to cognitively unimpaired individuals. Methods: The EARLY trial was a randomized, double-blind, placebo-controlled, phase 2b/3 study conducted in 143 centers across 14 countries from November 2015 to December 2018 after being stopped prematurely because of treatment-related hepatotoxicity. Participants age 60-85 years deemed cognitively unimpaired were disclosed an elevated or not elevated brain amyloid result by a certified clinician. Among 3,686 participants, 2,066 underwent amyloid imaging, 1,394 underwent CSF biomarker assessment, and 226 underwent both. Among biomarker-tested participants with at least one change score on an outcome of interest, 680 with elevated and 2,698 with not elevated amyloid were included in this analysis. We compared the Geriatric Depression Scale (GDS), the State-Trait Anxiety Scale (STAI), and the Columbia Suicide Severity Rating Scale (CSSRS) before disclosure between amyloid groups. After disclosure, we assessed for differences in the Impact of Events Scale (IES, collected 24-72 hours after disclosure), a measure of intrusive thoughts. Additional scales included the Concerns for AD scale. Results: Among 3378 included participants, the mean (SD) age was 69.0 (5.3); most were female (60%) and White race (84%). No differences were observed before disclosure between participants with elevated and not elevated amyloid for the GDS, STAI, or CSSRS. Participants with elevated amyloid demonstrated higher Concerns for AD scores compared with participants with not elevated amyloid before disclosure. Participants with elevated amyloid demonstrated higher IES scores (9.6 [10.8] vs 5.1 [8.0]) after disclosure and increased Concerns about AD. Patterns of reactions (elevated vs not elevated) were similar for biomarker modalities, although scores were lower among those undergoing CSF compared with PET testing. Although score differences were apparent comparing geographical regions, patterns of group differences were similar. Discussion: Although sample bias must be considered, these results suggest that amyloid disclosure resulted in increased perceived risk and mild distress in those learning an elevated result. Although this study did not assess psychological safety, observed associations intrusive thoughts and distress could be important considerations in the future clinical practice.

Ascertainment and Statistical Issues for Randomized Trials of Cardiovascular Interventions for Cognitive Impairment and Dementia.

There has been considerable progress in the prevention and treatment of cardiovascular disease, reducing the population burden of cardiovascular morbidity and mortality. Recently, some randomized trials, including the SPRINT (Systolic Blood Pressure Intervention Trial), have suggested that improvements in cardiovascular risk factors may also slow cognitive decline and reduce the eventual development of dementia. Unfortunately, the randomized trial template that has been used repeatedly to successfully demonstrate reductions in major adverse cardiac events faces several design and analytic obstacles when applied in the context of cognitive decline and dementia. Here, we review these obstacles, motivated by SPRINT and the context of selecting an appropriate cognitive end point for future preventive randomized trials. A few options are available, spanning neuropsychological test scores or composites reflecting specific domains of cognitive function, adjudicated cognitive impairment, or potentially physiological biomarkers. This choice entails considerations around statistical power, modes of ascertainment, the clinical relevance of treatment effects, a myriad of statistical issues (interval censoring, missing data, the competing risk of death, practice effects, etc), as well as ethical considerations around equipoise. Collectively, these considerations indicate that trials aiming to mitigate the cardiovascular contribution to cognitive decline and dementia will generally need to be large, inclusive of a wide age range of older adults, and with multiple years of follow-up.

Plasma Aß42/Aß40 and phospho-tau217 concentration ratios increase the accuracy of amyloid PET classification in preclinical Alzheimer's disease.

INTRODUCTION: Incorporating blood-based Alzheimer's disease biomarkers such as tau and amyloid beta (Aß) into screening algorithms may improve screening efficiency. METHODS: Plasma Aß, phosphorylated tau (p-tau)181, and p-tau217 concentration levels from AHEAD 3-45 study participants were measured using mass spectrometry. Tau concentration ratios for each proteoform were calculated to normalize for inter-individual differences. Receiver operating characteristic (ROC) curve analysis was performed for each biomarker against amyloid positivity, defined by > 20 Centiloids. Mixture of experts analysis assessed the value of including tau concentration ratios into the existing predictive algorithm for amyloid positron emission tomography status. RESULTS: The area under the receiver operating curve (AUC) was 0.87 for Aß42/Aß40, 0.74 for phosphorylated variant p-tau181 ratio (p-tau181/np-tau181), and 0.92 for phosphorylated variant p-tau217 ratio (p-tau217/np-tau217). The Plasma Predicted Centiloid (PPC), a predictive model including p-tau217/np-tau217, Aß42/Aß40, age, and apolipoprotein E improved AUC to 0.95. DISCUSSION: Including plasma p-tau217/np-tau217 along with Aß42/Aß40 in predictive algorithms may streamline screening preclinical individuals into anti-amyloid clinical trials. CLINICALTRIALS: gov Identifier: NCT04468659 HIGHLIGHTS: The addition of plasma phosphorylated variant p-tau217 ratio (p-tau217/np-tau217) significantly improved plasma biomarker algorithms for identifying preclinical amyloid positron emission tomography positivity. Prediction performance at higher NAV Centiloid levels was improved with p-tau217/np-tau217. All models generated for this study are incorporated into the Plasma Predicted Centiloid (PPC) app for public use.

Two Phase 3 Trials of Gantenerumab in Early Alzheimer's Disease.

BACKGROUND: Monoclonal antibodies that target amyloid-beta (Aß) have the potential to slow cognitive and functional decline in persons with early Alzheimer's disease. Gantenerumab is a subcutaneously administered, fully human, anti-Aß IgG1 monoclonal antibody with highest affinity for aggregated Aß that has been tested for the treatment of Alzheimer's disease. METHODS: We conducted two phase 3 trials (GRADUATE I and II) involving participants 50 to 90 years of age with mild cognitive impairment or mild dementia due to Alzheimer's disease and evidence of amyloid plaques on positron-emission tomography (PET) or cerebrospinal fluid (CSF) testing. Participants were randomly assigned to receive gantenerumab or placebo every 2 weeks. The primary outcome was the change from baseline in the score on the Clinical Dementia Rating scale-Sum of Boxes (CDR-SB; range, 0 to 18, with higher scores indicating greater cognitive impairment) at week 116. RESULTS: A total of 985 and 980 participants were enrolled in the GRADUATE I and II trials, respectively. The baseline CDR-SB score was 3.7 in the GRADUATE I trial and 3.6 in the GRADUATE II trial. The change from baseline in the CDR-SB score at week 116 was 3.35 with gantenerumab and 3.65 with placebo in the GRADUATE I trial (difference, -0.31; 95% confidence interval [CI], -0.66 to 0.05; P = 0.10) and was 2.82 with gantenerumab and 3.01 with placebo in the GRADUATE II trial (difference, -0.19; 95% CI, -0.55 to 0.17; P = 0.30). At week 116, the difference in the amyloid level on PET between the gantenerumab group and the placebo group was -66.44 and -56.46 centiloids in the GRADUATE I and II trials, respectively, and amyloid-negative status was attained in 28.0% and 26.8% of the participants receiving gantenerumab in the two trials. Across both trials, participants receiving gantenerumab had lower CSF levels of phosphorylated tau 181 and higher levels of Aß42 than those receiving placebo; the accumulation of aggregated tau on PET was similar in the two groups. Amyloid-related imaging abnormalities with edema (ARIA-E) occurred in 24.9% of the participants receiving gantenerumab, and symptomatic ARIA-E occurred in 5.0%. CONCLUSIONS: Among persons with early Alzheimer's disease, the use of gantenerumab led to a lower amyloid plaque burden than placebo at 116 weeks but was not associated with slower clinical decline. (Funded by F. Hoffmann-La Roche; GRADUATE I and II ClinicalTrials.gov numbers, NCT03444870 and NCT03443973, respectively.).

Beach-Chair Versus Lateral Decubitus Positioning for Primary Arthroscopic Anterior Shoulder Stabilization: A Consecutive Series of 641 Shoulders.

BACKGROUND: There are limited data comparing the beach-chair (BC) versus lateral decubitus (LD) position for arthroscopic anterior shoulder stabilization. PURPOSE: To identify predictors of instability recurrence and revision after anterior shoulder stabilization and evaluate surgical position and glenoid bone loss as independent predictors of recurrence and revision at short- and midterm follow-ups. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A consecutive series of 641 arthroscopic anterior stabilization procedures were performed from 2005 to 2019. All shoulders were evaluated for glenohumeral bone loss on magnetic resonance imaging. The primary outcomes of interest were recurrence and revision. Multivariable logistic regression models were used to assess the relationships of outcomes with age, position, glenoid bone loss group, and track. RESULTS: A total of 641 shoulders with a mean age of 22.3 years (SD, 4.45 years) underwent stabilization and were followed for a mean of 6 years. The overall 1-year recurrent instability rate was 3.3% (21/641) and the revision rate was 2.8% (18/641). At 1 year, recurrence was observed in 2.3% (11/487) and 6.5% (10/154) of BC and LD shoulders, respectively. The 5-year recurrence and revision rates were 15.7% (60/383) and 12.8% (49/383), respectively. At 5 years, recurrence was observed in 16.4% (48/293) and 13.3% (12/90) of BC and LD shoulders, respectively. Multivariable modeling demonstrated that surgical position was not associated with a risk of recurrence after 1 year (odds ratio [OR] for LD vs BC, 1.39; P = .56) and 5 years (OR for LD vs BC, 1.32; P = .43), although younger age at index surgery was associated with a higher risk of instability recurrence (OR, 1.73 per SD [4.1 years] decrease in age; P < .03). After 1 and 5 years, surgical position results were similar in a separate multivariable logistic regression model of revision surgery as the dependent variable, when adjusted for age, surgical position, bone loss group, and track. At 5 years, younger age was an independent risk factor for revision: OR 1.68 per SD (4.1 years) decrease in age (P < .05). CONCLUSION: Among fellowship-trained orthopaedic surgeons, there was no difference in rates of recurrence and revision surgery after performing arthroscopic anterior stabilization in either the BC or the LD position at 1- and 5-year follow-ups. In multivariable analysis, younger age, but not surgical position, was an independent risk factor for recurrence.

Trial of Solanezumab in Preclinical Alzheimer's Disease.

BACKGROUND: Trials of monoclonal antibodies that target various forms of amyloid at different stages of Alzheimer's disease have had mixed results. METHODS: We tested solanezumab, which targets monomeric amyloid, in a phase 3 trial involving persons with preclinical Alzheimer's disease. Persons 65 to 85 years of age with a global Clinical Dementia Rating score of 0 (range, 0 to 3, with 0 indicating no cognitive impairment and 3 severe dementia), a score on the Mini-Mental State Examination of 25 or more (range, 0 to 30, with lower scores indicating poorer cognition), and elevated brain amyloid levels on 18F-florbetapir positron-emission tomography (PET) were enrolled. Participants were randomly assigned in a 1:1 ratio to receive solanezumab at a dose of up to 1600 mg intravenously every 4 weeks or placebo. The primary end point was the change in the Preclinical Alzheimer Cognitive Composite (PACC) score (calculated as the sum of four z scores, with higher scores indicating better cognitive performance) over a period of 240 weeks. RESULTS: A total of 1169 persons underwent randomization: 578 were assigned to the solanezumab group and 591 to the placebo group. The mean age of the participants was 72 years, approximately 60% were women, and 75% had a family history of dementia. At 240 weeks, the mean change in PACC score was -1.43 in the solanezumab group and -1.13 in the placebo group (difference, -0.30; 95% confidence interval, -0.82 to 0.22; P = 0.26). Amyloid levels on brain PET increased by a mean of 11.6 centiloids in the solanezumab group and 19.3 centiloids in the placebo group. Amyloid-related imaging abnormalities (ARIA) with edema occurred in less than 1% of the participants in each group. ARIA with microhemorrhage or hemosiderosis occurred in 29.2% of the participants in the solanezumab group and 32.8% of those in the placebo group. CONCLUSIONS: Solanezumab, which targets monomeric amyloid in persons with elevated brain amyloid levels, did not slow cognitive decline as compared with placebo over a period of 240 weeks in persons with preclinical Alzheimer's disease. (Funded by the National Institute on Aging and others; A4 ClinicalTrials.gov number, NCT02008357.).

Autograft-Only and Allograft-Augmented Hamstring Autograft Have Similar Failure Rates After Anterior Cruciate Ligament Reconstruction.

Purpose: To compare failure rates and clinical outcomes after hamstring autograft anterior cruciate ligament (ACL) reconstruction with and without allograft augmentation by a single surgeon otherwise using the same surgical technique. Methods: This was a retrospective analysis with prospectively collected patient-reported outcomes of primary hamstring autograft ACL reconstruction with and without allograft augmentation performed in a military population by a single surgeon. The primary outcome measure was graft failure, defined as graft rupture confirmed by use of magnetic resonance imaging scans and/or revision ACL reconstruction. The secondary outcome measure was the postoperative Knee Injury and Osteoarthritis Outcome Score. Results: This study included 112 patients with a mean follow-up period of 65.3 months. In patients with a graft diameter of 8 mm or greater, there was no difference in failure rates (9.4% for autograft only vs 6.3% for hybrid, P = .59). There was a higher failure rate in patients in the autograft-only group with a graft diameter of less than 8 mm (29.4%) when compared with the hybrid graft group (6.3%, P = .008). There were no hybrid grafts less than 8 mm in diameter. There were no differences in the Knee Injury and Osteoarthritis Outcome Score between groups as long as the graft diameter was 8 mm or greater. Conclusions: In patients undergoing hamstring ACL reconstruction, there was no significant difference in graft failure rates or outcome scores between autograft only and autograft with allograft augmentation as long as grafts were 8 mm or greater. High failure rates were seen when the graft diameter was less than 8 mm. Level of Evidence: Level III, retrospective cohort study.

Safety and tolerability of lumbar puncture for the evaluation of Alzheimer's disease.

Introduction: Lumbar puncture (LP) to collect and examine cerebrospinal fluid (CSF) is an important option for the evaluation of Alzheimer's disease (AD) biomarkers but it is not routinely performed due to its invasiveness and link to adverse effects (AE). Methods: We include all participants who received at least one LP in the Alzheimer's Disease Neuroimaging Initiative (ADNI) Study. For comparison between groups, two-sample t-tests for continuous, and Pearson's chi-square test for categorical variables were performed. Results: Two hundred twenty-seven LP-related AEs were reported by 172 participants after 1702 LPs (13.3%). The mean age of participants who reported at least one AE was 69.79 (standard deviation (SD) 6.3) versus none 72.44 (7.17) years (p < 0.001) with female predominance (115/172 = 67.4% vs 435/913 = 48%), and had greater entorhinal cortical thickness and hippocampal volume (3.903 (0.782) vs 3.684 (0.775) mm, p = 0.002; 7.38 (1.06) vs 7.05 (1.15) mm3, p < 0.001), respectively. Discussion: We found that younger age, female sex, and greater thickness of the entorhinal cortex were associated with a higher rate of LP-related AE reports.

Heterogeneity in Preclinical Alzheimer's Disease Trial Cohort Identified by Image-based Data-Driven Disease Progression Modelling.

Importance: Undetected biological heterogeneity adversely impacts trials in Alzheimer's disease because rate of cognitive decline - and perhaps response to treatment - differs in subgroups. Recent results show that data-driven approaches can unravel the heterogeneity of Alzheimer's disease progression. The resulting stratification is yet to be leveraged in clinical trials. Objective: Investigate whether image-based data-driven disease progression modelling could identify baseline biological heterogeneity in a clinical trial, and whether these subgroups have prognostic or predictive value. Design: Screening data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer Disease (A4) Study collected between April 2014 and December 2017, and longitudinal data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) observational study downloaded in February 2022 were used. Setting: The A4 Study is an interventional trial involving 67 sites in the US, Canada, Australia, and Japan. ADNI is a multi-center observational study in North America. Participants: Cognitively unimpaired amyloid-positive participants with a 3-Tesla T1-weighted MRI scan. Amyloid positivity was determined using florbetapir PET imaging (in A4) and CSF Aß(1-42) (in ADNI). Main Outcomes and Measures: Regional volumes estimated from MRI scans were used as input to the Subtype and Stage Inference (SuStaIn) algorithm. Outcomes included cognitive test scores and SUVr values from florbetapir and flortaucipir PET. Results: We included 1,240 Aß+ participants (and 407 Aß- controls) from the A4 Study, and 731 A4-eligible ADNI participants. SuStaIn identified three neurodegeneration subtypes - Typical, Cortical, Subcortical - comprising 523 (42%) individuals. The remainder are designated subtype zero (insufficient atrophy). Baseline PACC scores (A4 primary outcome) were significantly worse in the Cortical subtype (median = -1.27, IQR=[-3.34,0.83]) relative to both subtype zero (median=-0.013, IQR=[-1.85,1.67], P<.0001) and the Subcortical subtype (median=0.03, IQR=[-1.78,1.61], P=.0006). In ADNI, over a four-year period (comparable to A4), greater cognitive decline in the mPACC was observed in both the Typical (-0.23/yr; 95% CI, [-0.41,-0.05]; P=.01) and Cortical (-0.24/yr; [-0.42,-0.06]; P=.009) subtypes, as well as the CDR-SB (Typical: +0.09/yr, [0.06,0.12], P<.0001; and Cortical: +0.07/yr, [0.04,0.10], P<.0001). Conclusions and Relevance: In a large secondary prevention trial, our image-based model detected neurodegenerative heterogeneity predictive of cognitive heterogeneity. We argue that such a model is a valuable tool to be considered in future trial design to control for previously undetected variance.

Natural cubic splines for the analysis of Alzheimer's clinical trials.

Mixed model repeated measures (MMRM) is the most common analysis approach used in clinical trials for Alzheimer's disease and other progressive diseases measured with continuous outcomes over time. The model treats time as a categorical variable, which allows an unconstrained estimate of the mean for each study visit in each randomized group. Categorizing time in this way can be problematic when assessments occur off-schedule, as including off-schedule visits can induce bias, and excluding them ignores valuable information and violates the intention to treat principle. This problem has been exacerbated by clinical trial visits which have been delayed due to the COVID19 pandemic. As an alternative to MMRM, we propose a constrained longitudinal data analysis with natural cubic splines that treats time as continuous and uses test version effects to model the mean over time. Compared to categorical-time models like MMRM and models that assume a proportional treatment effect, the spline model is shown to be more parsimonious and precise in real clinical trial datasets, and has better power and Type I error in a variety of simulation scenarios.

Evaluation of Blood-Based Plasma Biomarkers as Potential Markers of Amyloid Burden in Preclinical Alzheimer's Disease.

BACKGROUND: Participant eligibility for the A4 Study was determined by amyloid PET imaging. Given the disadvantages of amyloid PET imaging in accessibility and cost, blood-based biomarkers may serve as a sufficient biomarker and more cost-effective screening tool for patient enrollment into preclinical AD trials. OBJECTIVE: To determine if a blood-based screening test can adequately identify amyloid burden in participants screened into a preclinical AD trial. METHODS: In this cross-sectional study, 224 participants from the A4 Study received an amyloid PET scan (18Florbetapir) within 90 days of blood sample collection. Blood samples from all study participants were processed within 2 h after phlebotomy. Plasma amyloid measures were quantified by Shimazdu and C2 N Diagnostics using mass spectrometry-based platforms. A corresponding subset of blood samples (n = 100) was processed within 24 h after phlebotomy and analyzed by C2 N. RESULTS: Plasma Aß42/Aß40 demonstrated the highest association for Aß accumulation in the brain with an AUC 0.76 (95%CI = 0.69, 0.82) at C2 N and 0.80 (95%CI = 0.75, 0.86) at Shimadzu. Blood samples processed to plasma within 2 h after phlebotomy provided a better prediction of amyloid PET status than blood samples processed within 24 h (AUC 0.80 versus 0.64; p < 0.001). Age, sex, and APOE ɛ4 carrier status did not the diagnostic performance of plasma Aß42/Aß40 to predict amyloid PET positivity in A4 Study participants. CONCLUSION: Plasma Aß42/Aß40 may serve as a potential biomarker for predicting elevated amyloid in the brain. Utilizing blood testing over PET imaging may improve screening efficiency into clinical trials.

Improving generalizability and study design of Alzheimer's disease cohort studies in the United States by including under-represented populations.

The poor generalizability of clinical research data due to the enrollment of highly educated, non-Latinx White participants hampers the development of therapies for Alzheimer's disease (AD). Black and Latinx older adults have a greater risk for dementia, yet it is unclear how health-care disparities and sociocultural factors influence potential AD therapies and prognosis. Low enrollment of under-represented populations may be attributable to several factors including greater exclusion due to higher rates of comorbidities, lower access to AD clinics, and the legacy of unethical treatment in medical research. This perspective outlines solutions tested in the Brain Health Registry (BHR) and the Alzheimer's Disease Neuroimaging Initiative (ADNI), including culturally-informed digital research methods, community-engaged research strategies, leadership from under-represented communities, and the reduction of exclusion criteria based on comorbidities. Our successes demonstrate that it is possible to increase the inclusion and engagement of under-represented populations into US-based clinical studies, thereby increasing the generalizability of their results.

Revision Arthroscopic Bankart Repair Results in High Failure Rates and a Low Return to Duty Rate Without Recurrent Instability.

PURPOSE: The purpose of this study was to determine, in a military population without critical bone loss, the rate of recurrent instability after revision arthroscopic stabilization for failed primary arthroscopic Bankart repair. METHODS: Forty-one revision arthroscopic stabilizations were performed at a single military institution between 2005 to 2016 for recurrent anterior shoulder instability after primary arthroscopic Bankart repair. Minimum follow-up was 2 years, and shoulders with glenoid bone loss >20% were excluded. The primary outcome of interest was the incidence of failure, defined by recurrent instability. RESULTS: Age at revision surgery averaged 22.9 ± 4.3 years, and 88% were either service academy cadets or active duty combat arms soldiers. Mean follow-up was 7.8 years. Twenty-three patients (56%) returned to duty without recurrent instability after revision arthroscopic stabilization. Eighteen patients (44%) experienced recurrent instability after return to duty. Glenoid bone loss averaged 6.2% (95% confidence interval [CI], 3.2%-9.2%) in the successful group and 5.7% (95% CI, 3.1%-8.3%) in the failure group (P = .808). CONCLUSIONS: Revision arthroscopic stabilization of failed primary arthroscopic Bankart repair has a failure rate of 44% in a young military population. The similar amounts of bone loss between groups indicates that bone loss is not the primary determinant of failure in revision arthroscopic stabilization. LEVEL OF EVIDENCE: IV, Case Series.

Why a clinical trial is as good as its outcome measure: A framework for the selection and use of cognitive outcome measures for clinical trials of Alzheimer's disease.

A crucial aspect of any clinical trial is using the right outcome measure to assess treatment efficacy. Compared to the rapidly evolved understanding and measurement of pathophysiology in preclinical and early symptomatic stages of Alzheimer's disease (AD), relatively less progress has been made in the evolution of clinical outcome assessments (COAs) for those stages. The current paper aims to provide a benchmark for the design and evaluation of COAs for use in early AD trials. We discuss lessons learned on capturing cognitive changes in predementia stages of AD, including challenges when validating novel COAs for those early stages and necessary evidence for their implementation in clinical trials. Moving forward, we propose a multi-step framework to advance the use of more effective COAs to assess clinically meaningful changes in early AD, which will hopefully contribute to the much-needed consensus around more appropriate outcome measures to assess clinical efficacy of putative treatments. HIGHLIGHTS: We discuss lessons learned on capturing cognitive changes in predementia stages of AD. We propose a framework for the design and evaluation of performance based cognitive tests for use in early AD trials. We provide recommendations to facilitate the implementation of more effective cognitive outcome measures in AD trials.

Tau positron emission tomography in preclinical Alzheimer's disease.

Rates of tau accumulation in cognitively unimpaired older adults are subtle, with magnitude and spatial patterns varying in recent reports. Regional accumulation also likely varies in the degree to which accumulation is amyloid-ß-dependent. Thus, there is a need to evaluate the pattern and consistency of tau accumulation across multiple cognitively unimpaired cohorts and how these patterns relate to amyloid burden, in order to design optimal tau end points for clinical trials. Using three large cohorts of cognitively unimpaired older adults, the Anti-Amyloid Treatment in Asymptomatic Alzheimer's and companion study, Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (n = 447), the Alzheimer's Disease Neuroimaging Initiative (n = 420) and the Harvard Aging Brain Study (n = 190), we attempted to identify regions with high rates of tau accumulation and estimate how these rates evolve over a continuous spectrum of baseline amyloid deposition. Optimal combinations of regions, tailored to multiple ranges of baseline amyloid burden as hypothetical clinical trial inclusion criteria, were tested and validated. The inferior temporal cortex, fusiform gyrus and middle temporal cortex had the largest effect sizes of accumulation in both longitudinal cohorts when considered individually. When tau regions of interest were combined to find composite weights to maximize the effect size of tau change over time, both longitudinal studies exhibited a similar pattern-inferior temporal cortex, almost exclusively, was optimal for participants with mildly elevated amyloid ß levels. For participants with highly elevated baseline amyloid ß levels, combined optimal composite weights were 53% inferior temporal cortex, 31% amygdala and 16% fusiform. At mildly elevated levels of baseline amyloid ß, a sample size of 200/group required a treatment effect of 0.40-0.45 (40-45% slowing of tau accumulation) to power an 18-month trial using the optimized composite. Neither a temporal lobe composite nor a global composite reached 80% power with 200/group with an effect size under 0.5. The focus of early tau accumulation on the medial temporal lobe has resulted from the observation that the entorhinal cortex is the initial site to show abnormal levels of tau with age. However, these abnormal levels do not appear to be the result of a high rate of accumulation in the short term, but possibly a more moderate rate occurring early with respect to age. While the entorhinal cortex plays a central role in the early appearance of tau, it may be the inferior temporal cortex that is the critical region for rapid tau accumulation in preclinical Alzheimer's disease.

The AHEAD 3-45 Study: Design of a prevention trial for Alzheimer's disease.

INTRODUCTION: The Alzheimer's disease (AD) continuum begins with a long asymptomatic or preclinical stage, during which amyloid beta (Aß) is accumulating for more than a decade prior to widespread cortical tauopathy, neurodegeneration, and manifestation of clinical symptoms. The AHEAD 3-45 Study (BAN2401-G000-303) is testing whether intervention with lecanemab (BAN2401), a humanized immunoglobulin 1 (IgG1) monoclonal antibody that preferentially targets soluble aggregated Aß, initiated during this asymptomatic stage can slow biomarker changes and/or cognitive decline. The AHEAD 3-45 Study is conducted as a Public-Private Partnership of the Alzheimer's Clinical Trial Consortium (ACTC), funded by the National Institute on Aging, National Institutes of Health (NIH), and Eisai Inc. METHODS: The AHEAD 3-45 Study was launched on July 14, 2020, and consists of two sister trials (A3 and A45) in cognitively unimpaired (CU) individuals ages 55 to 80 with specific dosing regimens tailored to baseline brain amyloid levels on screening positron emission tomography (PET) scans: intermediate amyloid (≈20 to 40 Centiloids) for A3 and elevated amyloid (>40 Centiloids) for A45. Both trials are being conducted under a single protocol, with a shared screening process and common schedule of assessments. A3 is a Phase 2 trial with PET-imaging end points, whereas A45 is a Phase 3 trial with a cognitive composite primary end point. The treatment period is 4 years. The study utilizes innovative approaches to enriching the sample with individuals who have elevated brain amyloid. These include recruiting from the Trial-Ready Cohort for Preclinical and Prodromal Alzheimer's disease (TRC-PAD), the Australian Dementia Network (ADNeT) Registry, and the Japanese Trial Ready Cohort (J-TRC), as well as incorporation of plasma screening with the C2N mass spectrometry platform to quantitate the Aß 42/40 ratio (Aß 42/40), which has been shown previously to reliably identify cognitively normal participants not likely to have elevated brain amyloid levels. A blood sample collected at a brief first visit is utilized to "screen out" individuals who are less likely to have elevated brain amyloid, and to determine the participant's eligibility to proceed to PET imaging. Eligibility to randomize into the A3 Trial or A45 Trial is based on the screening PET imaging results. RESULT: The focus of this article is on the innovative design of the study. DISCUSSION: The AHEAD 3-45 Study will test whether with lecanemab (BAN2401) can slow the accumulation of tau and prevent the cognitive decline associated with AD during its preclinical stage. It is specifically targeting both the preclinical and the early preclinical (intermediate amyloid) stages of AD and is the first secondary prevention trial to employ plasma-based biomarkers to accelerate the screening process and potentially substantially reduce the number of screening PET scans.

Applications of artificial intelligence in dementia research.

More than 50 million older people worldwide are suffering from dementia, and this number is estimated to increase to 150 million by 2050. Greater caregiver burdens and financial impacts on the healthcare system are expected as we wait for an effective treatment for dementia. Researchers are constantly exploring new therapies and screening approaches for the early detection of dementia. Artificial intelligence (AI) is widely applied in dementia research, including machine learning and deep learning methods for dementia diagnosis and progression detection. Computerized apps are also convenient tools for patients and caregivers to monitor cognitive function changes. Furthermore, social robots can potentially provide daily life support or guidance for the elderly who live alone. This review aims to provide an overview of AI applications in dementia research. We divided the applications into three categories according to different stages of cognitive impairment: (1) cognitive screening and training, (2) diagnosis and prognosis for dementia, and (3) dementia care and interventions. There are numerous studies on AI applications for dementia research. However, one challenge that remains is comparing the effectiveness of different AI methods in real clinical settings.

Arthroscopic Anatomic Knotless Coracoclavicular Ligament Repair Without Coracoid Drilling.

Acromioclavicular joint injuries are common in young active patients. A wide variety of surgical techniques exist to address specific complications associated with surgery. Complications after surgery include loss of reduction, fracture of the clavicle or coracoid, failure of fixation, and prominent and symptomatic hardware. This technique aims to reduce these complications with an arthroscopic anatomic coracoclavicular ligament repair using knotless adjustable loop buttons with fifth-generation suture tape and no drilling of the coracoid.

TurboID functions as an efficient biotin ligase for BioID applications in Xenopus embryos.

BioID is a proximity labeling strategy whose goal is to identify in vivo protein-protein interactions. The central components of this strategy are modified biotin ligase enzymes that promiscuously add biotin groups to proteins in close proximity. The transferred biotin group provides a powerful tag for purification and thus identification of interacting proteins. While a variety of modified biotin ligases were created for BioID, the original enzymes were inefficient, required long incubation times, and high intracellular biotin concentrations for protein labeling. These limitations hinder the application of BioID in contexts such as developing embryos where processes such as cell division and cell fate decisions occur rapidly. Recently, a new biotin ligase called TurboID was developed that addressed many of the deficiencies of previous enzymes. In this paper we compare TurboID to the BioID2 biotin ligase in developing Xenopus embryos. We find that the TurboID enzyme has several advantages over the BioID2 enzyme. TurboID labels proteins efficiently without the addition of additional biotin and occurs at a range of temperatures compatible with the culturing of Xenopus embryos. Biotinylation events occurred rapidly and were limited by TurboID expression and not its activity. Thus, TurboID is an efficient tool for BioID applications in Xenopus embryos and its use should facilitate the identification of interacting proteins in specific networks and complexes during Xenopus development.

Prospective Evaluation of Posterior Glenoid Bone Loss After First-time and Recurrent Posterior Glenohumeral Instability Events.

BACKGROUND: Although posterior glenohumeral instability is becoming an increasingly recognized cause of shoulder pain, the role of posterior glenoid bone loss on outcomes remains incompletely understood. PURPOSES: To prospectively determine the amount of bone loss associated with posterior instability events and to determine predisposing factors based on preinstability imaging. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: A total of 1428 shoulders were evaluated prospectively for ≥4 years. At baseline, a subjective history of shoulder instability was ascertained for each patient, and bilateral noncontrast magnetic resonance imaging (MRI) scans of the shoulders were obtained regardless of any reported history of shoulder instability. The cohort was prospectively followed during the study period, and those who were diagnosed with posterior glenohumeral instability were identified. Postinjury MRI scans were obtained and compared with the screening MRI scans. Glenoid version, perfect-circle-based bone loss was measured for each patient's pre- and postinjury MRI scans using previously described methods. RESULTS: Of the 1428 shoulders that were prospectively followed, 10 shoulders sustained a first-time posterior instability event and 3 shoulders sustained a recurrent posterior instability event. At baseline, 11 of 13 shoulders had some amount of glenoid dysplasia and/or bone loss. The change in glenoid bone loss was 5.4% along the axis of greatest loss (95% CI, 3.8%-7.0%; P = .009), 4.4% at the glenoid equator (95% CI, 2.7%-6.2%; P = .016), and 4.2% of total glenoid area (95% CI, 2.9%-5.3%; P = .002). Recurrent glenoid instability was associated with a greater amount of absolute bone loss along the axis of greatest loss compared with first-time instability (recurrent: 16.8% ± 1.1%; 95% CI, 14.6%-18.9%; first-time: 10.0% ± 1.5%; 95% CI, 7.0%-13.0%; P = .005). Baseline glenoid retroversion ≥10° was associated with a significantly greater percentage of bone loss along the axis of greatest loss (≥10° of retroversion: 13.5% ± 2.0%; 95% CI, 9.6%-17.4%; <10° of retroversion: 8.5% ± 0.8%; 95% CI, 7.0%-10.0%; P = .045). CONCLUSIONS: Posterior glenohumeral instability events were associated with glenoid bone loss of 5%. The amount of glenoid bone loss after a recurrent posterior glenohumeral instability event was greater than that after first-time instability. Glenoid retroversion ≥10° was associated with a greater amount of posterior glenoid bone loss after a posterior instability event.