Blarcamesine for the treatment of Early Alzheimer's Disease: Results from the ANAVEX2-73-AD-004 Phase IIB/III trial.

Background: There are no approved oral disease-modifying treatments for Alzheimer's disease (AD).

Objectives: The objective of this study was to assess efficacy and safety of blarcamesine (ANAVEX®2-73), an orally available small-molecule activator of the sigma-1 receptor (SIGMAR1) in early AD through restoration of cellular homeostasis including autophagy enhancement.

Design: ANAVEX2-73-AD-004 was a randomized, double-blind, placebo-controlled, 48-week Phase IIb/III trial.

The role of bacterial size, shape and surface in macrophage engulfment of uropathogenic E. coli cells.

Uropathogenic Escherichia coli (UPEC) can undergo extensive filamentation in the host during acute urinary tract infections (UTIs). It has been hypothesised that this morphological plasticity allows bacteria to avoid host immune responses such as macrophage engulfment. However, it is still unclear what properties of filaments are important in macrophage-bacteria interactions.

Pooling Alzheimer's disease clinical trial data to develop personalized medicine approaches is easier said than done: A proof-of-principle study and call to action.

Unlabelled: With the advent of the first generation of disease-modifying treatments for Alzheimer's disease, it is clearer now more than ever that the field needs to move toward personalized medicine. Pooling data from past trials may help identify subgroups most likely to benefit from specific treatments and thus inform future trial design. In this perspective, we report on our effort to pool data from past Alzheimer's disease trials to identify patients most likely to respond to different treatments.

Effects of Oral ALZ-801/Valiltramiprosate on Plasma Biomarkers, Brain Hippocampal Volume, and Cognition: Results of 2-Year Single-Arm, Open-Label, Phase 2 Trial in APOE4 Carriers with Early Alzheimer's Disease.

Introduction: ALZ-801/valiltramiprosate is a small-molecule oral inhibitor of beta amyloid (Aβ) aggregation and oligomer formation being studied in a phase 2 trial in APOE4 carriers with early Alzheimer's disease (AD) to evaluate treatment effects on fluid and imaging biomarkers and cognitive assessments.

Methods: The single-arm, open-label phase 2 trial was designed to evaluate the effects of the ALZ-801 265 mg tablet taken twice daily (after 2 weeks once daily) on plasma fluid AD biomarkers, hippocampal volume (HV), and cognition over 104 weeks in APOE4 carriers. The study enrolled subjects aged 50-80 years, with early AD [Mini-Mental State Examination (MMSE) ≥ 22, Clinical Dementia Rating-Global (CDR-G) 0.

Phase 2A Learnings Incorporated into RewinD-LB, a Phase 2B Clinical Trial of Neflamapimod in Dementia with Lewy Bodies.

Background: In an exploratory 91-participant phase 2a clinical trial (AscenD-LB, NCT04001517) in dementia with Lewy bodies (DLB), neflamapimod showed improvement over placebo on multiple clinical endpoints. To confirm those results, a phase 2b clinical study (RewinD-LB, NCT05869669 ) that is similar to AscenD-LB has been initiated.

Objectives: To optimize the choice of patient population, primary endpoint, and biomarker evaluations in RewinD-LB.

Phase 1/2a Intravenous and Subcutaneous Oligomer-Specific Antibody KHK6640 in Mild to Moderate Alzheimer's Disease.

Background: KHK6640 is a novel humanized anti-amyloid beta oligomer-specific antibody. Both KHK6640 and the mouse parent antibody E64 have demonstrated high potency and efficacy for cognitive improvement in several rodent Alzheimer's disease models, including an anti-amyloid beta injection mouse model and in age-matched double transgenic littermates. The favorable safety and pharmacokinetic profiles of KHK6640 reported in preclinical studies warrant clinical trials in Alzheimer's disease patients.

Cognitive and Functional Change Over Time in Cognitively Healthy Individuals According to Alzheimer Disease Biomarker-Defined Subgroups.

Background And Objectives: It is unclear to what extent cognitive outcome measures are sensitive to capture decline in Alzheimer disease (AD) prevention trials. We aimed to analyze the sensitivity to changes over time of a range of neuropsychological tests in several cognitively unimpaired, biomarker-defined patient groups.

Methods: Cognitively unimpaired individuals from the Amsterdam Dementia Cohort and the SCIENCe project with available AD biomarkers, obtained from CSF, PET scans, and plasma at baseline, were followed over time (4.

Experiences of and recommendations on clinical trial design in Alzheimer's disease from the participant's point of view: a mixed-methods study in two clinical trial centers in the Netherlands.

Introduction: In the context of the development of pharmaceutical interventions, expectations and experiences of participants are essential. Their insights may be particularly helpful to address the challenges of recruiting and retaining participants for Alzheimer's disease (AD) clinical trials. We examined clinical trial participants' experiences to optimize trial design in Alzheimer's disease (AD).

Brain-Computer interface control of stepping from invasive electrocorticography upper-limb motor imagery in a patient with quadriplegia.

Most spinal cord injuries (SCI) result in lower extremities paralysis, thus diminishing ambulation. Using brain-computer interfaces (BCI), patients may regain leg control using neural signals that actuate assistive devices. Here, we present a case of a subject with cervical SCI with an implanted electrocorticography (ECoG) device and determined whether the system is capable of motor-imagery-initiated walking in an assistive ambulator.

Easy, bias-free Bayesian hierarchical modeling of the psychometric function using the Palamedes Toolbox.

A hierarchical Bayesian method is proposed that can be used to fit multiple psychometric functions (PFs) simultaneously across conditions and subjects. The method incorporates the generalized linear model and allows easy reparameterization of the parameters of the PFs, for example, to constrain parameter values across conditions or to code for experimental effects (e.g.

Decreased integrity of the monoaminergic tract is associated with a positive response to MPH in patients with vascular cognitive impairment - proof of principle study STREAM-VCI.

Background: Patients with vascular cognitive impairment (VCI) are very heterogeneous in both symptoms and type of cerebrovascular pathology. This might be an important reason why there is no symptomatic treatment available for VCI patients. In this study, we investigated in patients with VCI, whether there was an association between a positive response to methylphenidate and galantamine and the type of cerebrovascular disease, structural damage to specific neurotransmitter systems, cerebral perfusion, and presence of co-morbid Alzheimer (AD) pathology.

Vascular Cognitive Impairment and cognitive decline; a longitudinal study comparing different types of vascular brain injury - The TRACE-VCI study.

Background: Little is known about the trajectories of cognitive decline in relation to different types of vascular brain injury in patients presenting at a memory clinic with Vascular Cognitive Impairment (VCI).

Methods: We included 472 memory clinic patients (age 68 (±8.2) years, 44% female, MMSE 25.

Preclinical and randomized clinical evaluation of the p38α kinase inhibitor neflamapimod for basal forebrain cholinergic degeneration.

The endosome-associated GTPase 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 is a Rab5 activator, we hypothesized that inhibition of this kinase holds potential as an approach to treat diseases associated with BFCN loss. Herein, we report that neflamapimod (oral small molecule p38α inhibitor) reduces Rab5 activity, reverses endosomal pathology, and restores the numbers and morphology of BFCNs in a mouse model that develops BFCN degeneration.

Cerebral blood flow, amyloid burden, and cognition in cognitively normal individuals.

Purpose: The role of cerebral blood flow (CBF) in the early stages of Alzheimer's disease is complex and largely unknown. We investigated cross-sectional and longitudinal associations between CBF, amyloid burden, and cognition, in cognitively normal individuals with subjective cognitive decline (SCD).

Methods: We included 187 cognitively normal individuals with SCD from the SCIENCe project (65 ± 8 years, 39% F, MMSE 29 ± 1).

Design-development of an at-home modular brain-computer interface (BCI) platform in a case study of cervical spinal cord injury.

Objective: The objective of this study was to develop a portable and modular brain-computer interface (BCI) software platform independent of input and output devices. We implemented this platform in a case study of a subject with cervical spinal cord injury (C5 ASIA A).

Background: BCIs can restore independence for individuals with paralysis by using brain signals to control prosthetics or trigger functional electrical stimulation.

Association of CSF, Plasma, and Imaging Markers of Neurodegeneration With Clinical Progression in People With Subjective Cognitive Decline.

Background And Objectives: Multiple biomarkers have been suggested to measure neurodegeneration (N) in the AT(N) framework, leading to inconsistencies between studies. We investigated the association of 5 N biomarkers with clinical progression and cognitive decline in individuals with subjective cognitive decline (SCD).

Methods: We included individuals with SCD from the Amsterdam Dementia Cohort and SCIENCe project, a longitudinal cohort study (follow-up 4±3 years).

Neuropsychiatric Symptoms as Predictor of Poor Clinical Outcome in Patients With Vascular Cognitive Impairment.

Objective: Examine the association between neuropsychiatric symptoms (NPS) and clinical outcome in memory clinic patients with vascular brain injury.

Design/setting: TRACE-VCI prospective memory clinic cohort with follow-up (2.1 ± 0.

Workload Management System for Cricketers.

Cricketers are dynamic players in the field and hence more vulnerable to injuries. The injury rate of Sri Lankan cricketers is very high, resulting in their careers being shortened. Therefore, we established a workload management system for cricketers to resolve this issue with wearable Inertial Measurement Unit (IMU) sensors mounted on their bodies.

Implantable brain-computer interface for neuroprosthetic-enabled volitional hand grasp restoration in spinal cord injury.

Loss of hand function after cervical spinal cord injury severely impairs functional independence. We describe a method for restoring volitional control of hand grasp in one 21-year-old male subject with complete cervical quadriplegia (C5 American Spinal Injury Association Impairment Scale A) using a portable fully implanted brain-computer interface within the home environment. The brain-computer interface consists of subdural surface electrodes placed over the dominant-hand motor cortex and connects to a transmitter implanted subcutaneously below the clavicle, which allows continuous reading of the electrocorticographic activity.

BDNF-Met polymorphism and amyloid-beta in relation to cognitive decline in cognitively normal elderly: the SCIENCe project.

Brain-derived neurotrophic factor (BNDF) plays a role in synapse integrity. We investigated in 398 cognitively normal adults (60±8years, 41% female, MMSE=28±1) the joint association of the Val66Met polymorphism of the BDNF gene (Met+/-) and plasma BDNF levels and abnormal cerebrospinal fluid (CSF) amyloid-beta status (A+/-) with cognitive decline and dementia risk. Age-, sex- and education-adjusted linear mixed models showed that compared to Met-A-, Met+A+ showed steeper decline on tests of global cognition, memory, language, attention and executive functioning, while Met-A+ showed steeper decline on a smaller number of tests.

Diversity in Alzheimer's disease drug trials: The importance of eligibility criteria.

Introduction: To generalize safety and efficacy findings, it is essential that diverse populations are well represented in Alzheimer's disease (AD) drug trials. In this review, we aimed to investigate participant diversity in disease-modifying AD trials over time, and the frequencies of participant eligibility criteria.

Methods: A systematic review was performed using Medline, Embase, the Cochrane Library, and Clinicaltrials.