John Harrison
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View article: Validating the cortisol hypothesis: Xanamem demonstrates positive clinical effects by lowering CNS cortisol
Validating the cortisol hypothesis: Xanamem demonstrates positive clinical effects by lowering CNS cortisol Open
Background Xanamem TM (Emestedastat) is an oral, selective 11β‐HSD1 inhibitor designed to reduce cortisol production in the brain under development for the treatment of AD. Clinical trials have demonstrated adequate target engagement by PE…
View article: The ongoing evolution of EVTOLs: urban transport potential and the security dimension
The ongoing evolution of EVTOLs: urban transport potential and the security dimension Open
This review article explores the evolution, potential applications and security applications of electric vertical take-off and landing (EVTOL) technology, highlighting its commercial, emergency, security and military uses in urban environm…
View article: Randomized phase 2a trial assessing a novel septin molecular glue in Alzheimer's disease
Randomized phase 2a trial assessing a novel septin molecular glue in Alzheimer's disease Open
INTRODUCTION Pharmacological restoration of septin filament integrity has the potential to provide symptomatic benefit and disease modification in Alzheimer's disease (AD). METHODS REM127, a septin modulator, was assessed in mild‐to‐modera…
View article: Exploring the potential of digital biomarkers as a measure of brain health ‘capital’
Exploring the potential of digital biomarkers as a measure of brain health ‘capital’ Open
Neurological conditions, including dementia, pose a major public health challenge, contributing to a significant and growing clinical, economic, and societal burden. Traditionally, research and clinical practice have focused on diseases li…
View article: Evaluation of cognitive, functional, and behavioral effects observed in EMERGE, a phase 3 trial of aducanumab in people with early Alzheimer's disease
Evaluation of cognitive, functional, and behavioral effects observed in EMERGE, a phase 3 trial of aducanumab in people with early Alzheimer's disease Open
INTRODUCTION In EMERGE (NCT02484547), participants receiving aducanumab had significantly less progression versus placebo on all prespecified clinical endpoints at week 78. Here, we explicate the clinical meaningfulness of these treatment …
View article: Smartphone- and Tablet-Based Tools to Assess Cognition in Individuals With Preclinical Alzheimer Disease and Mild Cognitive Impairment: Scoping Review
Smartphone- and Tablet-Based Tools to Assess Cognition in Individuals With Preclinical Alzheimer Disease and Mild Cognitive Impairment: Scoping Review Open
Background Assessment of cognitive decline in the earliest stages of Alzheimer disease (AD) is important but challenging. AD is a neurodegenerative disease characterized by gradual cognitive decline. Disease stages range from preclinical A…
View article: Clinical Pharmacology and Approach to Dose Selection of Emestedastat, a Novel Tissue Cortisol Synthesis Inhibitor for the Treatment of Central Nervous System Disease
Clinical Pharmacology and Approach to Dose Selection of Emestedastat, a Novel Tissue Cortisol Synthesis Inhibitor for the Treatment of Central Nervous System Disease Open
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 rang…
View article: Evaluation of effect of cooled haemodialysis on cognition in patients with end-stage kidney disease (ECHECKED) feasibility randomised controlled trial results
Evaluation of effect of cooled haemodialysis on cognition in patients with end-stage kidney disease (ECHECKED) feasibility randomised controlled trial results Open
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 …
View article: Do glial‐reactivity and cerebral blood flow modulate cerebral glucose metabolism in Alzheimer’s disease?
Do glial‐reactivity and cerebral blood flow modulate cerebral glucose metabolism in Alzheimer’s disease? Open
Background Alzheimer’s disease is a devastating neurodegenerative disorder with a complex pathogenesis. One main pathological feature utilised in diagnosis is neurodegeneration or neuronal injury, which is reflected in reductions in cerebr…
View article: Methods and Initial Data for A Massive Real‐World Deeply Phenotyped Cohort Study
Methods and Initial Data for A Massive Real‐World Deeply Phenotyped Cohort Study Open
Background Recent therapeutic successes in the treatment of Alzheimer’s disease (AD), and diagnostic tools such as blood‐based biomarkers, have energised the field to develop more specific diagnostics and therapies following the best princ…
View article: Development of Xanamem, an isoform 1 specific inhibitor of 11‐βHSD, as a procognitive and disease modifying treatment for mild/moderate Alzheimer’s disease. A pharmacodynamic and biomarker driven approach
Development of Xanamem, an isoform 1 specific inhibitor of 11‐βHSD, as a procognitive and disease modifying treatment for mild/moderate Alzheimer’s disease. A pharmacodynamic and biomarker driven approach Open
Background Selecting the optimal dose for clinical development is especially problematic for drugs directed at CNS‐specific targets. For drugs with a novel mechanism of action, these problems are often greater. We describe Xanamem’s clinic…
View article: Digital remote assessment of speech acoustics in cognitively unimpaired adults: feasibility, reliability and associations with amyloid pathology
Digital remote assessment of speech acoustics in cognitively unimpaired adults: feasibility, reliability and associations with amyloid pathology Open
Background Digital speech assessment has potential relevance in the earliest, preclinical stages of Alzheimer’s disease (AD). We evaluated the feasibility, test-retest reliability, and association with AD-related amyloid-beta (Aβ) patholog…
View article: Plasma pTau181 Predicts Clinical Progression in a Phase 2 Randomized Controlled Trial of the 11β-HSD1 Inhibitor Xanamem® for Mild Alzheimer’s Disease
Plasma pTau181 Predicts Clinical Progression in a Phase 2 Randomized Controlled Trial of the 11β-HSD1 Inhibitor Xanamem® for Mild Alzheimer’s Disease Open
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 identif…
View article: Methods for Neuroscience Drug Development: Guidance on Standardization of the Process for Defining Clinical Outcome Strategies in Clinical Trials
Methods for Neuroscience Drug Development: Guidance on Standardization of the Process for Defining Clinical Outcome Strategies in Clinical Trials Open
Neurosciences clinical trials continue to have notoriously high failure rates. Appropriate outcomes selection in early clinical trials is key to maximizing the likelihood of identifying new treatments in psychiatry and neurology. The field…
View article: Cognitive and Functional Change Over Time in Cognitively Healthy Individuals According to Alzheimer Disease Biomarker-Defined Subgroups
Cognitive and Functional Change Over Time in Cognitively Healthy Individuals According to Alzheimer Disease Biomarker-Defined Subgroups Open
In conclusion, functional, composite, and neuropsychological outcome measures across all cognitive domains detect changes over time in various biomarker-defined groups, with changes being most evident among individuals with more AD patholo…
View article: MRI CHANGES FOLLOWING TREATMENT OF GLP‐1 ANALOGUE, LIRAGLUTIDE IN ALZHEIMER’S DISEASE
MRI CHANGES FOLLOWING TREATMENT OF GLP‐1 ANALOGUE, LIRAGLUTIDE IN ALZHEIMER’S DISEASE Open
Background Preclinical evidence in transgenic models of Alzheimer’s disease (AD) suggests that liraglutide, a GLP1 analogue, exerts neuroprotective effects by reducing amyloid oligomers, normalising synaptic plasticity and reducing insulin…
View article: Feasibility and acceptability of automated cognitive assessment over the telephone in the SpeAK study
Feasibility and acceptability of automated cognitive assessment over the telephone in the SpeAK study Open
Background There is growing interest in the development of speech markers as novel, non‐invasive biomarkers of early Alzheimer’s disease (AD). Before including such speech assessments in clinical trials, the technology must be tested to co…
View article: Magnetic Resonance Spectroscopy metabolites as biomarkers of Alzheimer’s Disease
Magnetic Resonance Spectroscopy metabolites as biomarkers of Alzheimer’s Disease Open
Background Magnetic resonance spectroscopy (MRS) is a non‐invasive method of evaluating metabolite levels in the cerebral cortex. Measurable metabolites can provide markers of neuronal damage, glial activation and, neurotransmission, patho…
View article: Xanamem shows pro‐cognitive activity with clinically meaningful effect sizes across 3 independent, placebo‐controlled clinical trials
Xanamem shows pro‐cognitive activity with clinically meaningful effect sizes across 3 independent, placebo‐controlled clinical trials Open
Background Xanamem ® is a brain‐penetrant inhibitor of 11‐beta hydroxysteroid dehydrogenase type 1, which converts intracellular cortisone to cortisol and is highly expressed in brain regions such as the hippocampus. Elevated plasma and CS…
View article: Dysfunctional cerebral glucose transport in Alzheimer’s Disease
Dysfunctional cerebral glucose transport in Alzheimer’s Disease Open
Background Glucose is the primary energy source required for the homeostatic function of the brain. Glucose transporter 1 (GLUT1) present at the blood‐brain barrier is a key regulator of glucose transport into the brain. Reduced GLUT1 expr…
View article: Natural speech as a digital biomarker in preclinical Alzheimer’s disease: Usability of a remote burst speech assessment
Natural speech as a digital biomarker in preclinical Alzheimer’s disease: Usability of a remote burst speech assessment Open
Background Speech is a complex process, relying on multiple interacting cognitive functions. Fine‐grained speech analysis offers the potential for measuring subtle cognitive deficits in early‐stage Alzheimer’s disease (AD). As such, digita…
View article: VIVIAD, A Phase 2b Study Investigating Varoglutamstat in Patients with MCI or Mild AD: Analysis of Baseline Cognition Data
VIVIAD, A Phase 2b Study Investigating Varoglutamstat in Patients with MCI or Mild AD: Analysis of Baseline Cognition Data Open
Background Varoglutamstat (PQ912) is an oral, small molecule inhibitor of glutaminyl cyclase, preventing the formation of neurotoxic N3pE amyloid. A Phase 2a study (NCT02389413, Scheltens et al., 2018) reported encouraging first evidence o…
View article: Remote data collection speech analysis in people at risk for Alzheimer's disease dementia: usability and acceptability results
Remote data collection speech analysis in people at risk for Alzheimer's disease dementia: usability and acceptability results Open
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 acceptabil…
View article: What’s in a score: A longitudinal investigation of scores based on item response theory and classical test theory for the Amsterdam Instrumental Activities of Daily Living Questionnaire in cognitively normal and impaired older adults.
What’s in a score: A longitudinal investigation of scores based on item response theory and classical test theory for the Amsterdam Instrumental Activities of Daily Living Questionnaire in cognitively normal and impaired older adults. Open
IRT-based scores were less affected by scale attenuation than CTT-based scores. With regard to responsiveness, IRT-based scores showed more signal than CTT-based scores in early disease stages, highlighting the IRT-based scores' superior s…
View article: Practical pathway for the management of depression in the workplace: a Canadian perspective
Practical pathway for the management of depression in the workplace: a Canadian perspective Open
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…
View article: 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
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 Open
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 Alzheim…
View article: Further validation of the THINC‐it tool and extension of the normative data set in a study of<i>n</i> = 10.019 typical controls
Further validation of the THINC‐it tool and extension of the normative data set in a study of<i>n</i> = 10.019 typical controls Open
Introduction We report further validation and normative data for the THINC‐Integrated Tool (THINC‐it), a measure of cognitive function designed for use with individuals living with Major Depressive Disorder, but which is finding use in fur…