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Abstract The Alzheimer's disease (AD) research community continues to make great strides in expanding approaches for early detection and treatment of the disease, including recent advances in our understanding of fundamental AD pathophysiology beyond the classical targets: beta‐amyloid and tau. Recent clinical trial readouts implicate a variety of non‐amyloid/non‐tau (NANT) approaches that show promise in slowing cognitive decline for people with AD. The Alzheimer's Association Research Roundtable (AARR) meeting held on December 13–14, 2022, reviewed the current state of NANT targets on underlying AD pathophysiology and their contribution to cognitive decline, the current data on a diverse range of NANT biomarkers and therapeutic targets, and the integration of NANT concepts in clinical trial designs. Participants also discussed the current definition of therapies that target underlying AD pathophysiology, what endpoints best define what is considered a meaningful change beyond the current approved definition for clinical efficacy, and how the recent NANT findings should inform the development of future guidelines for AD classification and personalized treatment strategies. Highlights The Alzheimer's Association Research Roundtable (AARR) convened leaders from industry, academia, and government to review the current state of non‐beta amyloid and non‐tau (NANT) targets on underlying Alzheimer's disease (AD) pathophysiology. The totality of scientific and clinical evidence supports the hypothesis that emerging NANT targets play a role in cognitive decline and neurodegeneration in AD. New biomarkers based on NANT targets must be globally developed and implemented with specific consideration of fluid biomarkers as a cost‐effective clinical option, to ensure better, more equitable treatment options for AD.

Abstract INTRODUCTION The aggregation and spread of hyperphosphorylated, pathological tau in the human brain is hypothesized to play a key role in Alzheimer's disease (AD) as well as other neurogenerative tauopathies. O‐GlcNAcylation, an important post‐translational modification of tau and many other proteins, is significantly decreased in brain tissue of AD patients relative to healthy controls. Increased tau O‐GlcNAcylation has been shown to reduce tau pathology in mouse in vivo tauopathy models. O‐GlcNAcase (OGA) catalyzes the removal of O‐GlcNAc from tau thereby driving interest in OGA inhibition as a potential therapeutic approach to reduce tau pathology and slow the progression of AD. METHODS A multidisciplinary approach was used to identify ceperognastat (LY3372689) as a potent OGA inhibitor, including an extensive discovery effort with synthetic chemistry, structure‐based drug design, and in vivo OGA enzyme occupancy studies. Preclinical studies assessed the target engagement, inhibition of OGA enzyme activity, OGA enzyme occupancy, and changes in tau O‐GlcNAc. Four clinical Phase 1 studies of ceperognastat in healthy participants were performed to assess clinical safety and tolerability, pharmacokinetics (PK), and enzyme occupancy. RESULTS Ceperognastat is a potent, central nervous system (CNS)‐penetrant, low‐dose inhibitor of OGA, which can achieve > 95% OGA enzyme occupancy in animal and human brain. Overall, ceperognastat had an acceptable safety profile in Phase 1 clinical studies with no serious adverse events reported following single and multiple dosing. The PK, enzyme occupancy, and safety profile supported Phase 2 development of ceperognastat. DISCUSSION Ceperognastat is an orally available, highly potent, CNS‐penetrant OGA inhibitor that achieved high (> 80%) OGA enzyme occupancy and increased brain O‐GlcNAc‐tau preclinically. Ceperognastat demonstrated > 95% OGA enzyme occupancy in Phase 1 trials. These occupancy data informed the dose selection for the Phase 2 clinical program. Highlights Ceperognastat is a highly potent, CNS‐penetrant OGA inhibitor. Ceperognastat is both orally available and CNS‐penetrant even when given at low doses. Ceperognastat can achieve > 95% OGA enzyme occupancy in the animal and human brain. Ceperognastat had an acceptable safety profile in Phase 1 clinical studies.

Abstract INTRODUCTION Alzheimer's disease (AD) is characterized by the presence of both amyloid and tau pathology. In vivo diagnosis can be made with amyloid and tau positron emission tomography (PET) imaging. Emergent evidence supports that amyloid and tau accumulation are associated and that amyloid accumulation may precede that of tau. This report further investigates the relationship between amyloid and tau to assess whether elevated cortical tau can predict elevated amyloid in participants with early symptomatic AD. METHODS Florbetapir F18 and flortaucipir F18 uptake were evaluated from baseline PET scans collected in three multi‐center studies with cognitively impaired participants, including A05 (N = 306; NCT02016560), TB (N = 310; TRAILBLAZER‐ALZ; NCT03367403), and TB2 (N = 1165; TRAILBLAZER‐ALZ 2; NCT04437511). Images were assessed using visual and quantitative approaches to establish amyloid (A+) and tau (T+) positivity, as well as a combination method (tauVQ) to establish T+. Associations between global amyloid and tau were evaluated with positive and negative predictive values (PPV, NPV) and likelihood ratios (LR+, LR–). Predictive values within subgroups according to ethnicity, race, cognitive score, age, and sex were also evaluated. The relationship between regional tau (four target and two reference regions were tested) and global amyloid was investigated in A05 participant scans using receiver‐operating characteristic (ROC) curves. RESULTS PPV for amyloid positivity was ≥93% for all three trials using various A+ and T+ definitions, including visual, quantitative, and combination methods. Population characteristics did not have an impact on A+ predictability. Regional analyses (early tau (Eτ) volume of interest (VOI), temporal, parietal, frontal) revealed significant area under the ROC curve in Eτ VOI compared to frontal region, regardless of reference region and consistent among visual and quantitative A+ definitions (p < 0.001). DISCUSSION These findings suggest that a positive tau PET scan is associated (≥93%) with amyloid positivity in individuals with early symptomatic AD, with the potential benefits of reducing clinical trial and health care expenses, radiation exposure, and participant time. Highlights Positron emission tomography (PET) evaluates candidates for Alzheimer's disease (AD) research. A positive tau PET scan is associated (≥93%) with amyloid positivity. A positive amyloid PET is not necessarily associated with tau positivity. Tau PET could be the sole diagnostic tool to confirm candidates for AD trials.

Robotic technologies for rehabilitating motor impairments from neurological injuries have been the focus of intensive research and capital investment for more than 30 years. However, these devices have failed to convincingly demonstrate greater restoration of patient function compared to conventional therapy. Nevertheless, robots have value in reducing the manual effort required for physical therapists to provide high-intensity, high-dose interventions. In most robotic systems, therapists remain outside the control loop to act as high-level supervisors, selecting and initiating robot control algorithms to achieve a therapeutic goal. The low-level physical interactions between the robot and the patient are handled by adaptive algorithms that can provide progressive therapy. In this perspective, we examine the physical therapist's role in the control of rehabilitation robotics and whether embedding therapists in lower-level robot control loops could enhance rehabilitation outcomes. We discuss how the features of many automated robotic systems, which can provide repeatable patterns of physical interaction, may work against the goal of driving neuroplastic changes that promote retention and generalization of sensorimotor learning in patients. We highlight the benefits and limitations of letting therapists physically interact with patients through online control of robotic rehabilitation systems, and explore the concept of trust in human-robot interaction as it applies to patient-robot-therapist relationships. We conclude by highlighting several open questions to guide the future of therapist-in-the-loop rehabilitation robotics, including how much control to give therapists and possible approaches for having the robotic system learn from therapist-patient interactions.

Abstract Background Previous studies found that [18F]LSN3316612 was a promising positron emission tomography (PET) radioligand for imaging O-GlcNAcase in nonhuman primates and human volunteers. This study sought to further evaluate the suitability of [18F]LSN3316612 for human clinical research. Methods Kinetic evaluation of [18F]LSN3316612 was conducted in a combined set of baseline brain scans from 17 healthy human volunteers and test-retest imaging was conducted in 10 of these volunteers; another 6 volunteers had whole-body scans to measure radiation exposure to body organs. Total distribution volume (V T) estimates were compared for the one- and two-tissue compartment models with the arterial input function. Test-retest variability and reliability were evaluated via mean difference and intraclass correlation coefficient (ICC). The time stability of V T was assessed down to a 30-min scan time. An alternative quantification method for [18F]LSN3316612 binding without blood was also investigated to assess the possibility of eliminating arterial sampling. Results Brain uptake was generally high and could be quantified as V T with excellent identifiability using the two-tissue compartment model. [18F]LSN3316612 exhibited good absolute test-retest variability (12.5%), but the arithmetic test-retest variability was far from 0 (11.3%), reflecting a near-uniform increase of V T on the retest scan in nine of 10 volunteers. V T values were stable after 110 min in all brain regions, suggesting that no radiometabolites accumulated in the brain. Measurements obtained using only brain activity (i.e., area under the curve (AUC) from 150–180 min) correlated strongly with regional V T values during test-retest conditions (R 2 = 0.84), exhibiting similar reliability to V T (ICC = 0.68 vs. 0.64). Estimated radiation exposure for [18F]LSN3316612 PET was 20.5 ± 2.1 μSv/MBq, comparable to other 18F-labeled radioligands for brain imaging. Conclusions [18F]LSN3316612 is an excellent PET radioligand for imaging O-GlcNAcase in the human brain. Alternative quantification without blood is possible, at least for within-subject repeat studies. However, the unexplained increase of V T under retest conditions requires further investigation.

The advent of sophisticated robotics and AI technology makes sending humans into hazardous and distant environments to carry out inspections increasingly avoidable. Being able to send a robot, rather than a human, into a nuclear facility or deep space is very appealing. However, building these robotic systems is just the start and we still need to carry out a range of verification and validation tasks to ensure that the systems to be deployed are as safe and reliable as possible. Based on our experience across three research and innovation hubs within the UK’s “Robots for a Safer World” programme, we present an overview of the relevant techniques and challenges in this area. As the hubs are active across nuclear, offshore, and space environments, this gives a breadth of issues common to many inspection robots.

Brain volume measurements extracted from structural MRI data sets are a widely accepted neuroimaging biomarker to study mouse models of neurodegeneration. Whether to acquire and analyze data in vivo or ex vivo is a crucial decision during the phase of experimental designs, as well as data analysis. In this work, we extracted the brain structures for both longitudinal in vivo and single-time-point ex vivo MRI acquired from the same animals using accurate automatic multi-atlas structural parcellation, and compared the corresponding statistical and classification analysis. We found that most gray matter structures volumes decrease from in vivo to ex vivo, while most white matter structures volume increase. The level of structural volume change also varies between different genetic strains and treatment. In addition, we showed superior statistical and classification power of ex vivo data compared to the in vivo data, even after resampled to the same level of resolution. We further demonstrated that the classification power of the in vivo data can be improved by incorporating longitudinal information, which is not possible for ex vivo data. In conclusion, this paper demonstrates the tissue-specific changes, as well as the difference in statistical and classification power, between the volumetric analysis based on the in vivo and ex vivo structural MRI data. Our results emphasize the importance of longitudinal analysis for in vivo data analysis.

Background: Non-invasive characterization of the pathological features of Alzheimer's disease (AD) could enhance patient management and the development of therapeutic strategies. Magnetic resonance imaging texture analysis (MRTA) has been used previously to extract texture descriptors from structural clinical scans in AD to determine cerebral tissue heterogeneity. In this study, we examined the potential of MRTA to specifically identify tau pathology in an AD mouse model and compared the MRTA metrics to histological measures of tau burden.Methods: MRTA was applied to T2 weighted high-resolution MR images of nine 8.5-month-old rTg4510 tau pathology (TG) mice and 16 litter matched wild-type (WT) mice. MRTA comprised of the filtration-histogram technique, where the filtration step extracted and enhanced features of different sizes (fine, medium, and coarse texture scales), followed by quantification of texture using histogram analysis (mean gray level intensity, mean intensity, entropy, uniformity, skewness, standard-deviation, and kurtosis). MRTA was applied to manually segmented regions of interest (ROI) drawn within the cortex, hippocampus, and thalamus regions and the level of tau burden was assessed in equivalent regions using histology.Results: Texture parameters were markedly different between WT and TG in the cortex (E, p < 0.01, K, p < 0.01), the hippocampus (K, p < 0.05) and in the thalamus (K, p < 0.01). In addition, we observed significant correlations between histological measurements of tau burden and kurtosis in the cortex, hippocampus and thalamus.Conclusions: MRTA successfully differentiated WT and TG in brain regions with varying degrees of tau pathology (cortex, hippocampus, and thalamus) based on T2 weighted MR images. Furthermore, the kurtosis measurement correlated with histological measures of tau burden. This initial study indicates that MRTA may have a role in the early diagnosis of AD and the assessment of tau pathology using routinely acquired structural MR images.

Background: Calcitonin gene-related peptide (CGRP) is pivotal in the pathophysiology of migraine headaches and represents a promising target for migraine treatment. The humanized monoclonal antibody galcanezumab (LY2951742) binds to CGRP and may be effective in migraine prophylaxis.Objectives: The primary objective was to evaluate the safety and tolerability of single and multiple doses of galcanezumab in humans. Secondary objectives included assessing the pharmacokinetics and evaluating target engagement.Methods: A double-blind, randomized, placebo-controlled study (NCT 01337596) with single escalating and multiple subcutaneous (SC) doses of galcanezumab was performed in healthy male volunteers. Single doses of 1, 5, 25, 75, 200, and 600 mg of galcanezumab (n = 7/dose) or placebo (n = 2/dose) were injected SC in six consecutive cohorts of nine subjects each. One cohort of nine subjects received multiple (4) 150 mg doses of galcanezumab or placebo every other week. Target engagement was evaluated by measuring inhibition of capsaicin-induced increase in dermal blood flow (DBF).Findings: Sixty-three subjects were randomized and included in the safety analyses. Galcanezumab was well tolerated in single doses (1–600 mg SC) and consecutive doses (150 mg SC). There was no dose-dependent difference in type or frequency of treatment-emergent adverse events, and no clinically meaningful difference when compared with placebo. Pharmacokinetics were linear. Galcanezumab induced a robust, dose-dependent, and durable inhibition of capsaicin-induced increase in DBF, supporting the continued clinical development of galcanezumab for prophylaxis in migraine patients.