This review demonstrates the value of central pharmacodynamics (PD), including positron emission tomography (PET) and computerized cognitive testing, to supplement pharmacokinetic (PK) and peripheral PD for determining the target dose range for clinical efficacy testing of emestedastat, an 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) inhibitor. Combined data from 6 clinical trials in cognitively normal volunteers and patients with Alzheimer disease included a population PK model, endocrine PD, a human PET trial (11β-HSD1 brain imaging), and computerized cognitive testing. PK and PET findings were similar in volunteers and patients with Alzheimer disease. PK modeling suggested that 20 mg daily would be optimal to maintain cerebrospinal fluid concentrations above the brain half maximal inhibitory concentration. However, subsequent PET scanning suggested that emestedastat doses of 10 or even 5 mg daily may be sufficient to adequately inhibit 11β-HSD1. With once-daily doses of 5-20 mg in cognitively normal, older volunteers, a consistent pattern of pro-cognitive benefit, without dose-response, was seen as improvement in attention and working memory but not episodic memory. Thus, emestedastat therapeutic activity might be attained at doses lower than those predicted from cerebrospinal fluid drug levels. Doses as low as 5 mg daily may be efficacious and were studied in subsequent trials.

Liraglutide, a glucagon-like peptide 1 (GLP-1) agonist and antidiabetic drug, has shown neuroprotective effects in animal models. In this study, we aimed to evaluate the safety and efficacy of liraglutide in mild to moderate Alzheimer's disease syndrome. 'Evaluating liraglutide in Alzheimer's disease' (ELAD) is a multicenter, randomized, double-blind, placebo-controlled phase 2b trial in 204 participants with mild to moderate Alzheimer's disease syndrome with no diabetes. Participants received daily injections of liraglutide or placebo for 52 weeks. They underwent fluorodeoxyglucose positron emission tomography, magnetic resonance imaging and detailed neuropsychometric evaluations. The primary outcome was a change in cerebral glucose metabolic rate. Secondary outcomes were safety and tolerability and cognitive changes. The primary outcome showed no significant differences in cerebral glucose metabolism (difference = -0.17; 95% confidence interval: -0.39 to 0.06; P = 0.14) between the two groups. The secondary outcome-score on the Alzheimer's Disease Assessment Scale-Executive domain (ADAS-Exec)-performed better in liraglutide-treated patients compared to placebo (0.15; 95% confidence interval: 0.03-0.28; unadjusted P = 0.01). No significant differences were observed in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) (-0.58; 95% confidence interval: -3.13 to 1.97; unadjusted P = 0.65) or Clinical Dementia Rating-Sum of Boxes (CDR-SoB) (-0.06; 95% confidence interval: -0.57 to 0.44; unadjusted P = 0.81) scores. Liraglutide was generally safe and well tolerated in non-diabetic patients with Alzheimer's disease. ClinicalTrials.gov identifier: NCT01843075 .

Background:Blood biomarkers are proposed as a diagnostic alternative to amyloid PET or cerebrospinal fluid (CSF) analyses for the diagnosis of Alzheimer's disease (AD). Relatively little is known of the natural history of patients identified by different blood biomarkers. Objective:To identify patients with elevated plasma phosphorylated tau (pTau)181 from a prior Phase 2a trial, and explore the natural histories of their clinical progression, and potential efficacy of Xanamem, a selective inhibitor of 11beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in these patients. Methods:A prespecified, double-blind analysis was conducted in 72 participants with clinically diagnosed AD and available plasma samples from baseline and Week 12 of the "XanADu" Phase 2a trial of Xanamem versus placebo. The analysis prespecified plasma pTau181 > median to identify patients more likely to have AD ("H", > 6.74 pg/mL, n = 34). Cohen's d (d) of≥0.2 defined potential clinical significance. Results:In the placebo group, H patients showed greater clinical progression compared to L patients (pTau181≤median) on ADCOMS (d = 0.55, p < 0.001), CDR-SB (d = 0.63, p < 0.001), MMSE (d = 0.52, p = 0.12), and ADAS-Cog14 (d = 0.53, p = 0.19). In H patients, a potentially clinically meaningful Xanamem treatment effect compared to placebo was seen in the CDR-SB (LS mean difference 0.6 units, d = 0.41, p = 0.09) and Neuropsychological Test Battery (NTB; LS mean difference 1.8 units, d = 0.26, p = 0.48) but not ADCOMS or ADAS-Cog14. Conclusions:This trial demonstrates that elevated plasma pTau181 identifies participants more likely to have progressive AD and is a suitable method for enrichment in AD clinical trials. Xanamem treatment showed evidence of potential clinically meaningful benefits.

Abstract Background Cognitive impairment is common in haemodialysis patients with no known beneficial interventions. Cooler dialysate slows brain white-matter changes, but its effect on cognition is unknown. This feasibility trial was performed to inform a fully-powered, randomised trial to assess this. Methods We aimed to randomise (1:1) 90 haemodialysis patients to this double-blinded, randomised controlled feasibility trial to standard care (dialysate-temperature 36.5 °C) or intervention (35 °C). Eligible patients were adult chronic haemodialysis recipients with no established diagnosis of dementia or psychiatric disease. The primary outcome was change in Montreal Cognitive Assessment (MoCA) score at 12-months. Secondary outcomes included recruitment and attrition rates, reasons for non-recruitment, intradialytic hypotension, depression, patient burden, computerised cognition test battery, and quality of life. Findings Of 334 patients screened, 160 were eligible. 99 declined mainly for the extra non-dialysis day study visits. Sixty-one patients consented, 43 randomised – 20 in standard care, 23 in intervention arms; 13 withdrew for non-dialysis day visits and 5 without reason before randomisation. 27 patients (12 standard care, 15 intervention) completed the trial – 5 died, 1 transplanted, 4 withdrew consent, and 6 could not attend due to the pandemic. Low temperature dialysis was well tolerated. There was no difference in change in MoCA from baseline to 12 months between the standard and intervention arms; 1.0 (-2.8–3.0, p = 0.755) and − 2.0 (-1.0 - -4.0, p = 0.047) respectively. There were no differences between groups on any secondary measures. There were no significant adverse events reported. Discussion The trial was significantly affected by the COVID-19 pandemic contributing to an attrition rate of 27%. The non-dialysis day research visits were mainly responsible for low recruitment and consent withdrawal. There are several learning points, described in the article, which will inform design of definitive trials in this area in the future. Trial registration ClinicalTrials.gov Identifier NCT03645733. Registration date 24/08/2018.

BACKGROUND:Cognitive impairment is common in haemodialysis patients with no known beneficial interventions. Cooler dialysate slows brain white-matter changes, but its effect on cognition is unknown. This feasibility trial was performed to inform a fully-powered, randomised trial to assess this. METHODS:We aimed to randomise (1:1) 90 haemodialysis patients to this double-blinded, randomised controlled feasibility trial to standard care (dialysate-temperature 36.5 °C) or intervention (35 °C). Eligible patients were adult chronic haemodialysis recipients with no established diagnosis of dementia or psychiatric disease. The primary outcome was change in Montreal Cognitive Assessment (MoCA) score at 12-months. Secondary outcomes included recruitment and attrition rates, reasons for non-recruitment, intradialytic hypotension, depression, patient burden, computerised cognition test battery, and quality of life. FINDINGS:Of 334 patients screened, 160 were eligible. 99 declined mainly for the extra non-dialysis day study visits. Sixty-one patients consented, 43 randomised - 20 in standard care, 23 in intervention arms; 13 withdrew for non-dialysis day visits and 5 without reason before randomisation. 27 patients (12 standard care, 15 intervention) completed the trial - 5 died, 1 transplanted, 4 withdrew consent, and 6 could not attend due to the pandemic. Low temperature dialysis was well tolerated. There was no difference in change in MoCA from baseline to 12 months between the standard and intervention arms; 1.0 (-2.8-3.0, p = 0.755) and - 2.0 (-1.0 - -4.0, p = 0.047) respectively. There were no differences between groups on any secondary measures. There were no significant adverse events reported. DISCUSSION:The trial was significantly affected by the COVID-19 pandemic contributing to an attrition rate of 27%. The non-dialysis day research visits were mainly responsible for low recruitment and consent withdrawal. There are several learning points, described in the article, which will inform design of definitive trials in this area in the future. TRIAL REGISTRATION:ClinicalTrials.gov Identifier NCT03645733. Registration date 24/08/2018.

Introduction Digital cognitive assessments are gathering importance for the decentralized remote clinical trials of the future. Before including such assessments in clinical trials, they must be tested to confirm feasibility and acceptability with the intended participant group. This study presents usability and acceptability data from the Speech on the Phone Assessment (SPeAk) study. Methods Participants ( N = 68, mean age 70.43 years, 52.9% male) provided demographic data and completed baseline and 3-month follow-up phone based assessments. The baseline visit was administered by a trained researcher and included a spontaneous speech assessment and a brief cognitive battery (immediate and delayed recall, digit span, and verbal fluency). The follow-up visit repeated the cognitive battery which was administered by an automatic phone bot. Participants were randomized to receive their cognitive test results acer the final or acer each study visit. Participants completed acceptability questionnaires electronically acer each study visit. Results There was excellent retention (98.5%), few technical issues ( n = 5), and good interrater reliability. Participants rated the assessment as acceptable, confirming the ease of use of the technology and their comfort in completing cognitive tasks on the phone. Participants generally reported feeling happy to receive the results of their cognitive tests, and this disclosure did not cause participants to feel worried. Discussion The results from this usability and acceptability analysis suggest that completing this brief battery of cognitive tests via a telephone call is both acceptable and feasible in a midlife-to-older adult population in the United Kingdom, living at risk for Alzheimer's disease.

Major depressive disorder (MDD) and other mental health issues pose a substantial burden on the workforce. Approximately half a million Canadians will not be at work in any week because of a mental health disorder, and more than twice that number will work at a reduced level of productivity (presenteeism). Although it is important to determine whether work plays a role in a mental health condition, at initial presentation, patients should be diagnosed and treated per appropriate clinical guidelines. However, it is also important for patient care to determine the various causes or triggers including work-related factors. Clearly identifying the stressors associated with the mental health disorder can help clinicians to assess functional limitations, develop an appropriate care plan, and interact more effectively with worker’s compensation and disability programs, as well as employers. There is currently no widely accepted tool to definitively identify MDD as work-related, but the presence of certain patient and work characteristics may help. This paper seeks to review the evidence specific to depression in the workplace, and provide practical tips to help clinicians to identify and treat work-related MDD, as well as navigate disability issues.

Clinical assessment remains the gold standard for diagnosing dementia, monitoring progression, and conducting clinical research. Biomarkers hold promise for targeted therapeutic approaches, selection of participants in clinical trials, and direct physiological efficacy readouts. However, the anchoring of biomarker research to clinical symptomatology is often based on short and insensitive cognitive screening. This gives the impression that cognitive symptoms occur relatively late and that their progression in the early stages of the disease is slow. A thorough cognitive assessment is a powerful tool and has a key role in the accurate and early diagnosis of dementia. It is very different from the cognitive testing usually seen in biomarker research and drug development. Yet the distinction between these approaches is unclear to many. This paper highlights the misconceptions around cognitive research in dementia and suggests a way forward to facilitate biomarker and drug development through the improved utility of cognitive assessment tools.

Background: Psilocybin, a psychoactive serotonin receptor partial agonist, has been reported to acutely reduce clinical symptoms of depressive disorders. Psilocybin's effects on cognitive function have not been widely or systematically studied. Aim: The aim of this study was to explore the safety of simultaneous administration of psilocybin to healthy participants in the largest randomised controlled trial of psilocybin to date. Primary and secondary endpoints assessed the short- and longer-term change in cognitive functioning, as assessed by a Cambridge Neuropsychological Test Automated Battery (CANTAB) Panel, and emotional processing scales. Safety was assessed via endpoints which included cognitive function, assessed by CANTAB global composite score, and treatment-emergent adverse event (TEAE) monitoring. Methods: In this phase 1, randomised, double-blind, placebo-controlled study, healthy participants (n=89; mean age 36.1 years; 41 females, 48 males) were randomised to receive a single oral dose of 10 or 25 mg psilocybin, or placebo, administered simultaneously to up to six participants, with one-to-one psychological support - each participant having an assigned, dedicated therapist available throughout the session. Results: In total, 511 TEAEs were reported, with a median duration of 1.0 day; 67% of all TEAEs started and resolved on the day of administration. There were no serious TEAEs, and none led to study withdrawal. There were no clinically relevant between-group differences in CANTAB global composite score, CANTAB cognitive domain scores, or emotional processing scale scores. Conclusions: These results indicate that 10 mg and 25 mg doses of psilocybin were generally well tolerated when given to up to six participants simultaneously and did not have any detrimental short- or long-term effects on cognitive functioning or emotional processing.

INTRODUCTION:There is good evidence to support that major trauma networks significantly reduce morbidity and mortality in severely injured patients. However, following the introduction of major trauma centres (MTCs) in England in 2012, early concerns were raised regarding the effect on hip fracture patients. The aim of our study was to review data from the National Hip Fracture Database for fractured neck of femur (FNOF) patients, comparing patient outcomes between MTCs and trauma units (TUs), and the national regions of the UK. METHODS:NHFD data from 2018 for all hospitals in England, Wales and NI was collected using the charts and dashboards available online. We recorded data for the following outcomes: time to surgery, acute hospital length of stay, overall hospital length of stay, discharge to original residence within 120 days, crude 30-day mortality and adjusted 30-day mortality. We conducted a one-way ANOVA test to calculate statistical differences for each outcome measure by MTC vs TU and then separately for the regions of the UK divided into England, Wales and Northern Ireland (NI). RESULTS:Data for 175 hospitals are included in this study; 22 of which were MTCs. The total number of operative cases were 65,848. 9668 of these occurred in MTC compared to 56,180 in TUs. This equates to an annual average of 439 per MTC and 367 per TU. Despite this, there was no statistically significant difference observed in all outcomes for MTC vs TU. Patients in NI waited longer for their surgery (60.3 h, p < 0.001), whilst patients in Wales had the longest overall hospital length of stay (31.6 days, p < 0.001). However, there was no difference in patients' crude 30-day mortality (p = 0.480) or adjusted 30-day mortality (p = 0.191). CONCLUSION:These findings are reassuring for MTCs in England. We found no evidence to suggest that FNOF patients are treated inferiorly, or have worse outcomes, at MTCs vs TUs. FNOF patients in NI waited longer for their surgery but this did not have any significant difference on 30-day mortality rates. The care of FNOF patients in NI may warrant further study.

Introduction Identifying cost-effective, non-invasive biomarkers of Alzheimer’s disease (AD) is a clinical and research priority. Speech data are easy to collect, and studies suggest it can identify those with AD. We do not know if speech features can predict AD biomarkers in a preclinical population. Methods and analysis The Speech on the Phone Assessment (SPeAk) study is a prospective observational study. SPeAk recruits participants aged 50 years and over who have previously completed studies with AD biomarker collection. Participants complete a baseline telephone assessment, including spontaneous speech and cognitive tests. A 3-month visit will repeat the cognitive tests with a conversational artificial intelligence bot. Participants complete acceptability questionnaires after each visit. Participants are randomised to receive their cognitive test results either after each visit or only after they have completed the study. We will combine SPeAK data with AD biomarker data collected in a previous study and analyse for correlations between extracted speech features and AD biomarkers. The outcome of this analysis will inform the development of an algorithm for prediction of AD risk based on speech features. Ethics and dissemination This study has been approved by the Edinburgh Medical School Research Ethics Committee (REC reference 20-EMREC-007). All participants will provide informed consent before completing any study-related procedures, participants must have capacity to consent to participate in this study. Participants may find the tests, or receiving their scores, causes anxiety or stress. Previous exposure to similar tests may make this more familiar and reduce this anxiety. The study information will include signposting in case of distress. Study results will be disseminated to study participants, presented at conferences and published in a peer reviewed journal. No study participants will be identifiable in the study results.

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.

The global fight against Alzheimer's disease (AD) poses unique challenges for the field of neuropsychology. Along with the increased focus on early detection of AD pathophysiology, characterizing the earliest clinical stage of the disease has become a priority. We believe this is an important time for neuropsychology to consider how our approach to the characterization of cognitive impairment can be improved to detect subtle cognitive changes during early-stage AD. The present article aims to provide a critical examination of how we define and measure cognitive status in the context of aging and AD. First, we discuss pitfalls of current methods for defining cognitive impairment within the context of research shifting to earlier (pre)symptomatic disease stages. Next, we introduce a shift towards a more continuous approach for identifying early markers of cognitive decline and characterizing progression and discuss how this may be facilitated by novel assessment approaches. Finally, we summarize potential implications and challenges of characterizing cognitive status using a continuous approach.

Alzheimer’s disease (AD) pathology is partly characterized by accumulation of aberrant forms of tau protein. Here we report the results of ADAMANT, a 24-month double-blinded, parallel-arm, randomized phase 2 multicenter placebo-controlled trial of AADvac1, an active peptide vaccine designed to target pathological tau in AD (EudraCT 2015-000630-30). Eleven doses of AADvac1 were administered to patients with mild AD dementia at 40 μg per dose over the course of the trial. The primary objective was to evaluate the safety and tolerability of long-term AADvac1 treatment. The secondary objectives were to evaluate immunogenicity and efficacy of AADvac1 treatment in slowing cognitive and functional decline. A total of 196 patients were randomized 3:2 between AADvac1 and placebo. AADvac1 was safe and well tolerated (AADvac1 n = 117, placebo n = 79; serious adverse events observed in 17.1% of AADvac1-treated individuals and 24.1% of placebo-treated individuals; adverse events observed in 84.6% of AADvac1-treated individuals and 81.0% of placebo-treated individuals). The vaccine induced high levels of IgG antibodies. No significant effects were found in cognitive and functional tests on the whole study sample (Clinical Dementia Rating-Sum of the Boxes scale adjusted mean point difference −0.360 (95% CI −1.306, 0.589)), custom cognitive battery adjusted mean z-score difference of 0.0008 (95% CI −0.169, 0.172). We also present results from exploratory and post hoc analyses looking at relevant biomarkers and clinical outcomes in specific subgroups. Our results show that AADvac1 is safe and immunogenic, but larger stratified studies are needed to better evaluate its potential clinical efficacy and impact on disease biomarkers. The authors present the results of a 24-month phase 2 study of AADvac1, a tau vaccine against Alzheimer’s disease. AADvac1 was safe and induced high levels of antibodies. In the whole study sample, there were no significant changes on clinical outcomes.

The endosome-associated protein Rab5 is a central player in the molecular mechanisms leading to degeneration of basal forebrain cholinergic neurons (BFCN), a long-standing target for drug development. As p38α kinase is a Rab-5 activator, we hypothesized that inhibition of this kinase held potential as an approach to treat diseases associated with BFCN loss. Herein we report that treatment with an oral small molecule p38α kinase inhibitor reversed pathological disease progression in the basal forebrain in a mouse model that develops BFCN degeneration. Further, the preclinical results were successfully translated to the clinic, with improvement of clinical outcomes associated with cholinergic function in a clinical study in dementia with Lewy bodies (DLB), a disease in which BFCN dysfunction and degeneration is the primary driver of disease expression. The findings both advances a novel approach to treating DLB and validates the translational platform that provided the mechanistic rationale for advancing that approach.

BACKGROUND:Type 2 diabetes is a risk factor for Alzheimer's disease (AD), and AD brain shows impaired insulin signalling. The role of peripheral insulin resistance on AD aetiopathogenesis in non-diabetic patients is still debated. Here we evaluated the influence of insulin resistance on brain glucose metabolism, grey matter volume and white matter lesions (WMLs) in non-diabetic AD subjects.METHODS:In total, 130 non-diabetic AD subjects underwent MRI and [18F]FDG PET scans with arterial cannula insertion for radioactivity measurement. T1 Volumetric and FLAIR sequences were acquired on a 3-T MRI scanner. These subjects also had measurement of glucose and insulin levels after a 4-h fast on the same day of the scan. Insulin resistance was calculated by the updated homeostatic model assessment (HOMA2). For [18F]FDG analysis, cerebral glucose metabolic rate (rCMRGlc) parametric images were generated using spectral analysis with arterial plasma input function.RESULTS:In this non-diabetic AD population, HOMA2 was negatively associated with hippocampal rCMRGlc, along with total grey matter volumes. No significant correlation was observed between HOMA2, hippocampal volume and WMLs.CONCLUSIONS:In non-diabetic AD, peripheral insulin resistance is independently associated with reduced hippocampal glucose metabolism and with lower grey matter volume, suggesting that peripheral insulin resistance might influence AD pathology by its action on cerebral glucose metabolism and on neurodegeneration.

Go/No-Go decision making in early phase clinical trials is challenging for drug developers working in Alzheimer's disease. Recent negative trial results have been attributed to a lack of efficacy and important safety concerns. Furthermore, demonstrated target engagement has rarely translated into demonstrable clinical efficacy. Cognitive data might provide valuable insights at various points during drug development, and a thoughtful and robust set of decision-making criteria, specified a priori, can and should be applied under many circumstances. This review provides insights into how to utilize cognitive data for Go/No-Go decisions, with an emphasis on how these cognitive criteria differ depending on the context (e.g., stage of development, mechanism of action and trial design).