Drug Development.

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 clinical pharmacology, including the approach to dose selection and proof-of-concept studies.

Drug Development.

Background: Iron is vital for metabolism but can act as a catalyst for oxidative damage. Elevated brain iron, determined from biomarkers of iron (CSF ferritin and quantitative susceptibility mapping MRI) and from post-mortem measurement of brain iron, has been associated with accelerated cognitive decline in multiple Alzheimer's disease (AD) clinical, cohorts. These findings supported the hypothesis that treatment with the brain-permeable iron chelator deferiprone may be associated clinical benefit in AD.

Drug Development.

Real-world data on the uptake, effectiveness and safety of new diagnostics and disease-modifying (DMT) treatments for Alzheimer's Disease (AD) are imperative. This can be achieved through patient registries. A major challenge is how to embed registry data capture into routine clinical practice.

Technology and Dementia Preconference.

Background: Alzheimer's disease (AD) is a progressive neurodegenerative condition, with considerable variation in disease progression from the mild cognitive impairment (MCI) stage. Predicting disease progression will support prognostic decisions and patient management. Here we designed a machine learning (ML) stack model, where a classifier was used to differentiate MCI progressors from non-progressors (i.

Technology and Dementia Preconference.

Background: The success of therapeutic options for treatment of Alzheimer's disease (AD) and the growing emphasis for such treatment to commence in the pre-clinical phase makes it necessary to have robust empirical models of clinical disease progression to understand findings from clinical trials, allow clinicians to evaluate effects of new drugs, and to select individuals for future trials. Such models have been developed from relatively small samples, with incomplete data/substantial loss to follow-up. The ADOPIC consortium provides the largest complete AD natural history sample to date.

Development and Validation of a Tool to Predict Onset of Mild Cognitive Impairment and Alzheimer Dementia.

Importance: The ability to predict the onset of mild cognitive impairment (MCI) and Alzheimer dementia (AD) could allow older adults and clinicians to make informed decisions about dementia care.

Objective: To assess whether the age at onset of MCI and AD can be predicted using a statistical modeling approach.

Design, Setting, And Participants: This prognostic study used data from 2 aging and dementia cohort studies-the Australian Imaging, Biomarker and Lifestyle (AIBL) study and the Alzheimer's Disease Neuroimaging Initiative (ADNI)-for model development and validation of the Florey Dementia Index (FDI), a tool used to predict the age at onset of MCI and AD in older adults.

COCHLEA: Longitudinal Cognitive Performance of Older Adults with Hearing Loss and Cochlear Implants at 4.5-Year Follow-Up.

Objectives: Hearing loss is highly prevalent in older adults and is independently associated with accelerated cognitive decline. Cochlear implants are usually the only effective treatment for people with severe-profound hearing loss, who have the highest risk of cognitive decline and dementia, however, very few receive them. Current evidence of the effects of cochlear implant use on cognitive decline/dementia outcomes is limited and unclear.

Effect of ketamine on anxiety: findings from the Ketamine for Adult Depression Study.

Background: Anxiety disorders and treatment-resistant major depressive disorder (TRD) are often comorbid. Studies suggest ketamine has anxiolytic and antidepressant properties.

Aims: To investigate if subcutaneous racemic ketamine, delivered twice weekly for 4 weeks, reduces anxiety in people with TRD.

Clinical Pharmacology and Approach to Dose Selection of Emestedastat, a Novel Tissue Cortisol Synthesis Inhibitor for the Treatment of Central Nervous System Disease.

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.

In defence of ferroptosis.

Rampant phospholipid peroxidation initiated by iron causes ferroptosis unless this is restrained by cellular defences. Ferroptosis is increasingly implicated in a host of diseases, and unlike other cell death programs the physiological initiation of ferroptosis is conceived to occur not by an endogenous executioner, but by the withdrawal of cellular guardians that otherwise constantly oppose ferroptosis induction. Here, we profile key ferroptotic defence strategies including iron regulation, phospholipid modulation and enzymes and metabolite systems: glutathione reductase (GR), Ferroptosis suppressor protein 1 (FSP1), NAD(P)H Quinone Dehydrogenase 1 (NQO1), Dihydrofolate reductase (DHFR), retinal reductases and retinal dehydrogenases (RDH) and thioredoxin reductases (TR).

Sex-Based Differences in Endovascular Thrombectomy Outcomes for Large Ischemic Stroke: A SELECT2 Subanalysis.

Background: Several social and biological factors are shown to differentially affect stroke outcomes between men and women. We evaluated whether clinical outcomes and endovascular thrombectomy (EVT) treatment effects differed between the sexes in patients presenting with large ischemic stroke.

Methods: The SELECT2 trial (A Randomized Controlled Trial to Optimize Patient's Selection for Endovascular Treatment in Acute Ischemic Stroke) was a randomized controlled trial assessing the efficacy and safety of EVT in patients with large strokes across the United States, Canada, Europe, Australia, and New Zealand between October 2019 and September 2022.

The association between cytokines and cognitive function in patients with major depressive disorder and controls.

Background: Cognitive dysfunction is a symptom of depression (MDD). While the involvement of the immune system has long been suggested to contribute to the biological underpinnings of depression, less is known about the underpinnings of cognitive dysfunction. A recent genome-wide association study pointed to genes related to immune function to be relevant for cognitive processes in depression.

Magnetic Resonance Imaging of Gastric Motility in Conscious Rats.

Introduction: Gastrointestinal (GI) magnetic resonance imaging (MRI) enables simultaneous assessment of gastric peristalsis, emptying, and intestinal filling and transit. However, GI MRI in animals typically requires anesthesia, which complicates physiology and confounds interpretation and translation to humans. This study aimed to establish GI MRI in conscious rats, and for the first time, characterize GI motor functions in awake versus anesthetized conditions.

Developmental dysfunction in a preclinical model of Kcnq2 developmental and epileptic encephalopathy.

Background: Developmental and epileptic encephalopathies (DEE) are rare but severe neurodevelopmental disorders characterised by early-onset seizures often combined with developmental delay, behavioural and cognitive deficits. Treatment for DEEs is currently limited to seizure control and provides no benefits to the patients' developmental and cognitive outcomes. Genetic variants are the most common cause of DEE with KCNQ2 being one of the most frequently identified disease-causing genes.

A stratified treatment algorithm in psychiatry: a program on stratified pharmacogenomics in severe mental illness (Psych-STRATA): concept, objectives and methodologies of a multidisciplinary project funded by Horizon Europe.

Schizophrenia (SCZ), bipolar (BD) and major depression disorder (MDD) are severe psychiatric disorders that are challenging to treat, often leading to treatment resistance (TR). It is crucial to develop effective methods to identify and treat patients at risk of TR at an early stage in a personalized manner, considering their biological basis, their clinical and psychosocial characteristics. Effective translation of theoretical knowledge into clinical practice is essential for achieving this goal.

Lost and found: dynamics of relationship and employment status over time in people with affective and psychotic spectrum disorders.

Background: Employment and relationship are crucial for social integration. However, individuals with major psychiatric disorders often face challenges in these domains.

Aims: We investigated employment and relationship status changes among patients across the affective and psychotic spectrum - in comparison with healthy controls, examining whether diagnostic groups or functional levels influence these transitions.

The effect of ovariectomy, 17β-estradiol treatment, and progesterone treatment on dopaminergic regulation of prepulse inhibition in adult and adolescent female mice.

The aim of the present study was to investigate the role of ovarian hormones on dopaminergic regulation of prepulse inhibition (PPI), a measure of sensorimotor gating deficient in schizophrenia and other psychiatric illnesses. Either in adulthood (11 weeks of age) or adolescence (5 weeks of age), female mice underwent ovariectomy (OVX) and were implanted with 17β-estradiol, progesterone, or a combination of these hormones. All mice were tested in adulthood for the acute effect of the dopamine receptor agonist, apomorphine, on PPI.

A pathway-based genetic score for inflammation: An indicator of vulnerability to phthalate-induced adverse neurodevelopment outcomes.

Introduction: Phthalates, chemical additives used to enhance plastic products' flexibility, are easily released into the environment, and can harm the brain development through various mechanisms including inflammation. Genetic variation influencing an individual's susceptibility to inflammation may play a role in the effects of phthalate exposure on neurodevelopment however there is no summary measure developed for genetic susceptibility to inflammation.

Methods: We developed a genetic pathway function score for inflammation (gPFS), based on the transcriptional activity of the inflammatory response pathway in the brain and other tissues.

Short term GABA antagonist treatment improves long term sleep quality, memory, and decision-making in a Down syndrome mouse model.

Down syndrome (DS) is a common genetic condition affecting people worldwide. It involves cognitive disabilities for which there are no drug therapies. The Ts65Dn mouse model of DS shows cognitive impairment due to a reduction in neuron number and connectivity as well as excessive neuronal activity, as GABA antagonist treatment restores memory in these mice.

Contrasting genetic burden for bipolar disorder: Early onset versus late onset in an older adult bipolar disorder sample.

Older Adults with Bipolar Disorder (OABD) represent a heterogeneous group, including those with early and late onset of the disorder. Recent evidence shows both groups have distinct clinical, cognitive, and medical features, tied to different neurobiological profiles. This study explored the link between polygenic risk scores (PRS) for bipolar disorder (PRS-BD), schizophrenia (PRS-SCZ), and major depressive disorder (PRS-MDD) with age of onset in OABD.

Gross anatomical features of the insular cortex in affective disorders.

Introduction: The number of insular gyri is elevated in patients with schizophrenia. Thus, it has potential as a marker of early neurodevelopmental abnormalities. However, currently it remains unclear whether patients with other neuropsychiatric disorders, such as affective disorders, also have this gross brain anatomical feature.