Drug Development.

The lack of an in-vivo pathology marker for synuclein pathology has been a long standing challenge for dementia for Lewy bodies (DLB) research. This issue is critically important for phase II trials, which are often small, requiring the precise measurement of the biological effects, whether disease modifying or symptomatic. Recent advances have enabled the determination of alpha-synuclein pathology status with CSF measurements, using aggregation assays [RT-QUIC].

Drug Development.

Background: CT1812 is an experimental therapeutic sigma-2 receptor modulator in development for Alzheimer's disease (AD) and dementia with Lewy bodies. CT1812 reduces the affinity of Aβ oligomers to bind to neurons and exert synaptotoxic effects. This phase 2, multi-center, international, randomized, double-blind, placebo-controlled trial assessed safety, tolerability and effects of CT1812 on cognitive function in individuals with AD.

Drug Development.

Background: Alzheimer's disease (AD) trials report a high screening failure rate (potentially eligible trial candidates who do not meet inclusion/exclusion criteria during screening) due to multiple factors including stringent eligibility criteria. Here, we report the main reasons for screening failure in the 12-week screening phase of the ongoing evoke (NCT04777396) and evoke+ (NCT04777409) trials of semaglutide in early AD.

Method: Key inclusion criteria were age 55-85 years; mild cognitive impairment due to AD (Clinical Dementia Rating [CDR] global score of 0.

Drug Development.

Background: Differences in patient characteristics across geographical regions may result in heterogeneity in clinical trial populations. evoke (NCT04777396) and evoke+ (NCT04777409) are two phase 3, multinational, randomised trials investigating semaglutide versus placebo in individuals with mild cognitive impairment or mild dementia due to Alzheimer's disease (AD) (early AD). We present baseline characteristics across the geographical regions in evoke/evoke+.

Drug Development.

Background: Mivelsiran (ALN-APP) is an investigational, intrathecally administered RNA interference therapeutic designed to lower levels of amyloid-β (Aβ) peptide, a key driver of Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA) pathogenesis, by reducing upstream production of amyloid precursor protein (APP). We report additional safety, pharmacodynamic, and biomarker data from the double-blind, placebo-controlled, single ascending dose part of the ongoing mivelsiran Phase 1 study (NCT05231785).

Method: Patients with early-onset AD (symptom onset <65 years of age, Clinical Dementia Rating global score 0.

Drug Development.

Background: The first disease-modifying treatments (DMTs) for Alzheimer's disease (AD) have been approved in the USA, marking profound changes in AD-diagnosis and treatment. This will bring new challenges in terms of clinician-patient communication. We aimed to collect the perspectives of memory clinic professionals regarding the most important topics to address and what (tools) would support professionals and their patients and care partners to engage in a meaningful conversation on whether (or not) to initiate treatment.

Drug Development.

Background: evoke and evoke+ are phase 3, randomized, placebo-controlled trials currently investigating the glucagon-like peptide-1 receptor agonist semaglutide as disease-modifying therapy (DMT) in persons with early Alzheimer's disease (AD). How the evoke and evoke+ trial populations compare with other phase 3 programs for DMTs in early AD has not been described.

Method: We compare the inclusion/exclusion criteria and baseline characteristics of the evoke/evoke+ trial populations with those of Clarity AD (lecanemab) and TRAILBLAZER-ALZ-2 (donanemab): two recent phase 3 trials assessing anti-amyloid monoclonal antibodies in persons with early AD.

Drug Development.

Background: Oral ALZ-801 (valiltramiprosate), a brain-penetrant agent that inhibits amyloid-oligomer formation is being evaluated in a fully enrolled APOLLOE4 Phase 3 trial in APOE4/4 homozygotes with Early Alzheimer's disease (AD). ALZ-801 effects on plasma AD biomarkers were evaluated in a 104-week Phase 2 study in APOE4-carriers with CSF+ AD biomarkers. APOE4 is a major risk factor for amyloid-related imaging abnormalities (ARIA) in AD patients.

Drug Development.

Background: In a 16-week, 91-patient placebo-controlled clinical study in DLB ("AscenD-LB";NCT04001517), neflamapimod improved outcomes on the CDR Sum-of-Boxes (p = 0.023 vs. placebo) and Timed Up and Go test (p = 0.

Drug Development.

Background: Lecanemab, a novel humanized immunoglobulin G1 monoclonal antibody targeting both neurotoxic Aβ protofibrils and Aβ plaques, has demonstrated the ability to substantially reduce markers of amyloid and significantly slow clinical decline on multiple measures of cognition and function in early AD in phase 2 (Study 201) and phase 3 (Clarity AD) studies. In these clinical studies, several plasma biomarkers assessments (Aβ42/40 ratio, p-tau181, GFAP, and p-tau217) showed improvements comparing lecanemab with placebo. Herein, we utilized modelling and simulations to evaluate the long-term effects of lecanemab on biomarkers of neurodegeneration in plasma.

Drug Development.

Background: ALZ-801 (valiltramiprosate), an oral brain-penetrant amyloid-oligomer inhibitor in Phase 3 testing in APOE4/4 homozygotes (APOLLOE4 trial). A 2-year Phase 2 biomarker study was completed evaluating ALZ-801 (265 mg BID) on plasma biomarkers, MRI, cognition, and clinical benefit in EAD APOE4 carriers. At trial end, subjects could enroll in a 1-year long-term extension with an ongoing biomarker and cognition analysis.

Drug Development.

Background: Irsenontrine (e2027) is a potent and selective PDE9 inhibitor that increases cellular cGMP which is important for glutamatergic synaptic function. Irsenontrine was investigated to improve cognition in Lewy Body Dementia (LBD; DLB and PDD), and recent phase 2 study data suggests that irsenontrine could be more effective in DLB patients without amyloid copathology. Here, we evaluated differential change from baseline levels in proteins associated with cGMP pathway in DLB participants without amyloid co-pathology (DLB A-) compared to DLB participants with amyloid co-pathology (DLB A+).

Dementia Care Research and Psychosocial Factors.

Background: To support informal caregivers of persons with dementia (PwD), it is fundamental to understand how objective and subjective indicators of care burden are interrelated. This study used psychometric network analyses to explore care burden indicators and extend current models of care in informal caregivers of PwDs.

Methods: Baseline data from an intervention study of 170 informal caregivers of community-dwelling PwDs was used.

Dementia Care Research and Psychosocial Factors.

Background: Facial emotion recognition testing in Alzheimer's disease (AD) patients has been identified as key for early detection and as a marker for disease progression. Emotion recognition remains one of the most difficult domains to assess in culturally diverse populations due to a lack of culturally adapted tools. This study assessed the feasibility of a cross-cultural test for emotion recognition, the TIE-93, in French and North African populations living in France.

Dementia Care Research and Psychosocial Factors.

Background: 'Intellectual assets' generated in traditional university settings, that may not fit the interests of the standard 'valuation criteria' (i.e. commercially profitable), such as non-pharmacological dementia care research, often remain siloed within their respective research disciplines and originating institutions.

Simultaneous Concentration and T Mapping of Brain Metabolites by Fast Multi-Echo Spectroscopic Imaging.

The purpose of this study was to produce metabolite-specific T and concentration maps in a clinically compatible time frame. A multi-TE 2D MR spectroscopic imaging (MRSI) experiment (multi-echo single-shot MRSI [MESS-MRSI]) deployed truncated and partially sampled multi-echo trains from single scans and was combined with simultaneous multiparametric model fitting. It was tested in vivo for the brain in five healthy subjects.

Technology and Dementia Preconference.

Background: Developing culture-fair tests that measure constructs equivalently across different ethno-lingual groups is challenging, given the diverse cultural variations that impact neurocognitive measurement. Multi-level measurement invariance must be established before interpreting scores similarly across groups, both within and between cultures for meaningful comparisons.

Method: We set out to test whether a neurocognitive tool (BENCI) behaves the same way across the males (n = 311) and the females group (n = 291) using measurement invariance testing with multigroup confirmatory factor analysis.

Dementia Care Practice.

Background: Data-driven criteria for DNA testing were implemented in routine care of Alzheimer Center Amsterdam. We aimed to explore patients' perspectives and considerations regarding their decision to (not) be tested for a monogenic cause of their disease.

Methods: In this mixed method study, 150 of 519 new patients visiting Alzheimer Center Amsterdam who fulfilled the criteria were offered DNA-diagnostics: 86(57%) accepted, 64(43%) did not.

Dementia Care Practice.

Background: Treatment with monoclonal antibodies against amyloid-β slowed cognitive decline in recent randomized clinical trials in patients with mild cognitive impairment (MCI) and early dementia due to Alzheimer's disease (AD). However, trial eligibility criteria may affect generalizability to clinical practice.

Methods: We extracted eligibility criteria for trials of aducanumab, lecanemab and donanemab from published reports, and applied these to participants with MCI and early clinical AD dementia from the population-based Rotterdam Study.

Technology and Dementia Preconference.

Background: Alzheimer's Disease (AD) is associated with sleep disturbances. Moreover, individuals with sleep disturbances have been reported to have a higher risk for developing AD. The measurement of sleep behavior therefore opens the opportunity for a potential digital biomarker of AD.

Cardiovascular, kidney and safety outcomes with canagliflozin in older adults: A combined analysis from the CANVAS Program and CREDENCE trial.

Aim: SGLT2 inhibitors may be underused in older adults with type 2 diabetes due to concerns about safety and tolerability. This pooled analysis of the CANVAS Program and CREDENCE trial examined the efficacy and safety of canagliflozin according to age.

Methods: Pooled individual participant data from the CANVAS Program (n = 10 142) and CREDENCE trial (n = 4401) were analysed by baseline age (<65 years, 65 to <75 years, and ≥75 years).

ProPr54 web server: predicting σ promoters and regulon with a hybrid convolutional and recurrent deep neural network.

σ serves as an unconventional sigma factor with a distinct mechanism of transcription initiation, which depends on the involvement of a transcription activator. This unique sigma factor σ is indispensable for orchestrating the transcription of genes crucial to nitrogen regulation, flagella biosynthesis, motility, chemotaxis and various other essential cellular processes. Currently, no comprehensive tools are available to determine σ promoters and regulon in bacterial genomes.

Toll-like receptor adaptor protein TIRAP has specialized roles in signaling, metabolic control and leukocyte migration upon wounding in zebrafish larvae.

The TIRAP protein is an adaptor protein in TLR signaling which links TLR2 and TLR4 to the adaptor protein Myd88. The transcriptomic profiles of zebrafish larvae from a , and mutant and the corresponding wild type controls under unchallenged developmental conditions revealed a specific involvement of in calcium homeostasis and myosin regulation. Metabolomic profiling showed that the mutation results in lower glucose levels, whereas a mutation leads to higher glucose levels.

Double-level osteotomy (DLO) for varus deformity results in over a decade of mean survival without compromising subsequent total knee arthroplasty function at a mean 26-year follow-up.

Purpose: Double-level osteotomies (DLOs) have shown promising results for knee joint preservation, however, most ultimately progress in terms of degenerative disease resulting in conversion to total knee arthroplasty (TKA). Therefore, the purpose of this study was to examine the time to TKA conversion, long-term clinical outcomes and revision rates of patients who have undergone TKA after prior ipsilateral DLO.

Methods: Patients who underwent simultaneous or staged DLO and subsequently underwent conversion to TKA at a single academic institution from 1997 to 2022 were evaluated.

Early intervention in psychosis programs in Africa, Asia and Latin America; challenges and recommendations.

Background: While early intervention in psychosis (EIP) programs have been increasingly implemented across the globe, many initiatives from Africa, Asia and Latin America are not widely known. The aims of the current review are (a) to describe population-based and small-scale, single-site EIP programs in Africa, Asia and Latin America, (b) to examine the variability between programs located in low-and-middle income (LMIC) and high-income countries in similar regions and (c) to outline some of the challenges and provide recommendations to overcome existing obstacles.

Methods: EIP programs in Africa, Asia and Latin America were identified through experts from the different target regions.