Energy Research Centre of the Netherlands

Objective This randomised controlled trial evaluated the efficacy of the Tailored Injury Prevention in Adapted Sports (TIPAS) intervention on sports-related health problems in athletes participating in adaptive sports with physical impairments. Methods We randomly assigned 60 athletes participating in adaptive sports with physical impairments to an intervention group and 47 to a control group. The intervention group received direct, automated, predetermined preventive and management measures tailored to their weekly reported health problems, physical impairments and sports. The primary outcome was injury and illness prevalence over 40 weeks. Secondary outcomes were incidence, weekly cumulative severity score, weekly time loss, and total burden. A multinomial mixed methods analysis was performed to identify an intervention effect over time. Results The athletes (53 women, 54 men; age±45 years) reported 449 health problems (162 illnesses, 287 injuries) during the study period. The overall prevalence of health problems was 44% in the intervention group and 46% in the control group. Over time, no significant main intervention effect was found (illnesses OR: 1.02; 95% CI: 0.52 to 1.99; and injuries OR: 1.01; 95% CI: 0.55 to 1.86). However, a significant positive time×group interaction effect (p<0.001) indicated a reduction in injury prevalence in the intervention group over time, though not for illnesses. The rates versus severity analysis showed a significantly lower illness severity in the intervention group relative to the control group. Conclusion The TIPAS intervention provides a non-significant decrease in the overall prevalence of sport-related injuries and illnesses and may reduce the severity of sport-related illnesses throughout a Dutch sports season. This tailored online preventive strategy provides an accessible programme to consider in adapted sports suited to athletes’ physical impairments, sports participation and current health status. Trial registration number : ICTRP register: NL-OMON24078

Objectives. This study aims to determine recent lower extremity amputation (LEA) rates in individuals with and without diabetes mellitus (DM) in the Netherlands. Design. This is a retrospective, observational study of LEAs based on all-payer claims database (APCD) data from 2016 to 2021. Methods. This study analyzes LEAs using an APCD covering over 99% of the Dutch population. It assesses LEA rates in individuals with and without diabetes (types 1 and 2), focusing on 2016, when preventive diabetic foot care was fully implemented. All individuals aged ≥18 years detected with an LEA through reimbursement claims were included in the analysis. Results. The total number of individuals with reimbursed LEAs per year ranged from 5030 (35.7 per 100,000 individuals) to 5260 (38.1 per 100,000). In individuals with DM, this ranged from 2907 to 3081 (290.9 to 312.6 per 100,000). The highest LEA prevalence was found in individuals with type 1 DM (T1DM) (606.1-732.4 per 100,000). In individuals without DM, the yearly LEA rates ranged between 16.3 and 17.8 per 100,000. Approximately two thirds of all individuals with LEA were male (ratios 1.9-2.3). Conclusion. Compared to earlier Dutch studies, major LEA incidence appears to be slightly fluctuating over time, without an increase in minor amputations. This contrasts with other countries, where increased minor amputation rates are observed. These data provide valuable insights into LEA rates and emphasize that individuals most at risk are those with T1DM. More detailed studies, including longitudinal and clinical data, are needed to further specify groups and individuals at risk. Levels of Evidence: Level III: Retrospective cohort study

To evaluate and update about previous regression equations to derive standardized and individualized resistance settings for wheelchair‐specific anaerobic and aerobic capacity tests in wheelchair athletes. An isometric strength test, a sprint test, a Wingate anaerobic test (WAnT), and an aerobic graded exercise test (GXT) were performed by 43 wheelchair athletes on a computerized roller ergometer. Using previously developed regression equations, measured strength predicted anaerobic power and determined the individual's WAnT resistance. Subsequently, measured anaerobic power predicted aerobic power and determined the individual's GXT resistances. The WAnT was considered valid when peak rim velocity stayed below 3 m·s⁻¹ and the GXT when the test duration was between 8 and 12 min. After testing, individual test results were used to construct new regression equations to improve predictions for anaerobic and aerobic power. The strength test turned out to be nonstatic for the five strongest athletes. Consequently, their WAnT resistance was underestimated, resulting in the highest peak rim velocities. The GXT had durations below 8 min for seven athletes. The sprint test was feasible for every athlete and showed a better prediction for anaerobic power (R² = 0.84). The updated regression equation to predict aerobic power from anaerobic power resulted in an R² of 0.78. For future testing in wheelchair athletes, it is advised to use the newly developed athlete‐specific regression equations to predict (an) aerobic power and to set adequate WAnT and GXT resistances. These standardized and individualized settings will lead to interathlete and intra‐athlete comparable measures, used for athlete monitoring or to set training guidelines.

The FAIR principles provide guidance on improving the Findability, Accessibility, Interoperability, and Reusability of digital resources. Since the publication of the principles, several workflows have been proposed to support the process of making data FAIR (FAIRification). However, to respect the uniqueness of different communities, both the principles and the available workflows have been deliberately designed to remain agnostic in terms of standards, tools, and implementation choices. Consequently, FAIRification needs to be properly planned, and implementation details must be discussed with stakeholders and aligned with FAIRification objectives. To support this need, this paper describes GO-Plan, a method for identifying and refining FAIRification objectives. Leveraging on best practices from requirements and ontology engineering, the method aims at incrementally elaborating the most obvious aspects of the domain (e.g. the initial set of elements to be collected) into complex and comprehensive objectives. The definition of clear objectives enables stakeholders to communicate effectively and make informed implementation decisions, such as defining achievement criteria for distinct principles and identifying relevant metadata to be collected. GO-Plan has been validated in multiple discussion sessions with experts on FAIR, in an application to a real use case and in two hands-on tutorials with end-users.

Objective To compare growth, tolerance and safety parameters in very preterm infants receiving human milk (HM) fortified with a multicomponent cow’s milk-based HM fortifier (HMF; control) versus a novel HMF-containing lipids (including docosahexaenoic acid and arachidonic acid), higher protein and lower carbohydrate levels (test). Our hypothesis was that weight growth velocity in the test group would be non-inferior to that in the control group. Design Double-blind, randomised controlled trial. Setting Nine European neonatal intensive care units. Patients HM-fed infants born at <32-week gestational age. Interventions Fortification of HM with Test or Control HMF for a minimum of 21 days. Primary outcome Weight growth velocity between baseline and intervention day 21. Results From March 2018 to July 2020, 102 and 103 infants were enrolled in the test and control groups, respectively. Weight growth velocity during the first 21 days in the test group (mean 18.4 g/kg/day) was non-inferior to that of controls (mean 18.5 g/kg/day), with a difference in estimated means of –0.175 g/kg/day (90% CI –1.34 to +0.99 g/kg/day; per-protocol population). No significant differences between groups were observed for gain in length, head circumference or anthropometric Z-scores. Rates of digestive intolerance, stool frequency and consistency were comparable. No significant differences were reported in common neonatal morbidities including necrotising enterocolitis (test: 2.9%, control: 6.9%, mean difference –4.0% (95% CI –11.1% to 2.2%); all subjects treated population). Conclusions Use of the novel HMF containing lipids, higher protein and lower carbohydrate levels supports adequate postnatal growth and appears safe and well tolerated in very preterm infants. Trial registration number NCT03315221

The study investigated the effect of dietary inclusion of high amylose cornstarch (HA-starch) on cecal microbiota composition and volatile fatty acid (VFA) concentrations in weanling pigs fed high levels of cold-pressed canola cake (CPCC). Weaned pigs (240 mixed sex; 7.1 ± 1.2 kg) were housed in 40 pens (6 pigs/pen) and fed a common commercial diet for 7 days, followed by the experimental diets for 28-d, which contained either 0% or 40% CPCC with either 0% or 40% HA-starch. At the end of the study, one pig from each pen (n=8) was selected and euthanized to collect cecal digesta for microbial and VFA composition analyses. The HA-starch increased (p < 0.001) acetate, propionate, and butyrate concentrations, thereby increasing total VFA concentration (p < 0.001). There was a tendency for cecal butyrate and total VFA concentrations to decrease when pigs were fed the 40% CPCC diet without HA-starch but increase when fed the 40% CPCC diet containing 40% HA-starch (CPCC × HA-starch effect; p = 0.09), indicating HA-starch can increase cecal butyrate and total VFA concentrations in pigs fed a diet with high CPCC level. The proportions of Lactobacillus and Terrisporobacter were high, whereas low proportions of Streptococcus genus were observed in the cecal microbiota of pigs fed diets containing 40% HA-starch. Also, pathways consistent with carbohydrate digestion, absorption, and phosphate metabolism were enriched in pigs when the diet included 40% HA-starch. In summary, incorporating high amounts of HA-starch in a weanling pig diet containing high levels of CPCC may benefit intestinal health and digestive performance by enhancing the abundance of probiotic commensal bacteria, contributing to increased enzymatic activity and carbohydrate metabolism.

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. Method Consenting participants with confirmed brain amyloid and baseline MMSE scores of 18 to 26 were randomized equally to receive oral placebo, 100 or 300mg of CT1812 daily for 6 months. Exploratory efficacy outcomes included ADAS‐Cog11 and 13, Neurophysiological Test Battery, ADCS‐Clinical Global Impression of Change and ADCS‐Activities of Daily Living. The primary statistical analysis is treated (combined 100 and 300mg CT1812) versus placebo change from baseline in ADAS‐Cog11. Canonical AD biomarkers were assessed in CSF and plasma. Result One hundred fifty‐three participants were randomized. An interim analysis of the first 24 participants was performed where baseline demographics included mean age of 71.7 years, 15 females and a mean MMSE of 21.1. In the interim analysis there were twenty‐two TEAEs (7, 8, 7 in the 100, 300mg CT1812 and placebo groups, respectively) reported and in the CT1812 groups, all TEAEs were mild or moderate and there were no treatment related SAEs. There was a trend within these 24 participants for slower progression at six months in the CT1812 treated group with ADAS‐Cog11 improved 3.1 points relative to placebo according to the prespecified statistical model. Complete data from all participants including AEs, cognitive performance and canonical biomarkers will be presented with the ADAS‐Cog11 change from baseline relative to placebo for the pooled CT1812 treated group prespecified as the first cognitive assessment with ApoE4 status as a covariate. Conclusion CT1812 is an oral sigma‐2 modulator that displaces Aβ oligomers from neurons. Encouraging trends have been observed in previous studies (NCT03493282, NCT03522129, NCT04735536) and in an interim analysis of this phase 2 trial (NCT03507790). This trial will provide proof of concept data indicating if CT1812 can slow progression in people with mild to moderate AD. This study was supported by a grant from the NIH (AG058660).

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. Incidence of ARIA‐H (microhemorrhages, MH; superficial siderosis, SS) and of ARIA‐E (edema/effusion) was analyzed. Method This study enrolled 84 subjects (31 APOE4/4, 53 APOE3/4) MMSE ≥22 and CDR‐G 0.5 or 1.0, with positive amyloid and CSF p‐tau181 ≥60 pg/ml. Subjects received ALZ‐801 at 265 mg BID over 104 weeks, with MRI at baseline, 52 and 104 weeks following a standardized protocol including 2D FLAIR and T2* Gradient Echo. Study allowed subjects with any number of MH, but ARIA‐E and SS lesions >1cm were exclusionary. Data were evaluated centrally by Clario neuroradiologists for eligibility assessment and ARIA safety monitoring. The study’s primary outcome was plasma p‐tau181 reduction at 104 weeks. Result At baseline, mean age and MMSE were 69 years and 26 respectively, with 52% female and 70% MCI subjects. Of 84 enrolled, 83, 75 and 69 subjects had baseline, 52‐week and 104‐week MRI. Baseline MRIs showed >1 MH in 7/83 (8%), and 6/75 subjects (8%) with post‐treatment MRI developed new MH, all asymptomatic. At baseline, 5 subjects had 1‐4 MH, of whom 2 developed new MH (3‐4); 1 subject had >10 MH and developed 29 new MH. 3 subjects developed de novo MH (1‐3). There was no SS or ARIA‐E. Study primary outcome was achieved with significant p‐tau181 reduction (31%, p = 0.045) and 4% Aβ42 reduction (p = 0.042), with memory stabilization over 2 years (Hey, ADPD 2024). Conclusion The Phase 2 APOE4‐carrier population with positive CSF biomarkers showed low incidence of microhemorrhage (8%) over 2 years, all asymptomatic, with no siderosis or ARIA‐E. This 265 mg BID ALZ‐801 dose showed significant target engagement and promising cognitive effects in this study. These data suggest a low risk of ARIA with ALZ‐801 in APOE4 carriers with Early AD.

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. Method This 104‐week, open‐label study enrolled 84 subjects (MMSE 22‐30, CDR‐G 0.5‐1, positive amyloid‐PET or CSF biomarkers). Plasma and clinical testing occurred every 13 weeks; MRI every 52 weeks. Primary outcome was plasma p‐tau181; cognitive tests were Rey Auditory‐Verbal‐Learning Test (RAVLT) and Digit‐Symbol‐Substitution Test (DSST). Dr. Blennow’s Laboratory (Sweden) conducted plasma biomarker analyses (Simoa, Euroimmun assays). Hippocampal volume and cognitive tests were compared to matched group from ADNI‐1 observational study using simple matching (age, APOE4 genotype, disease stage) and propensity scores as covariates in the MMRM analysis. Clinical and HV benefit was determined by Cohen’s d score. For plasma biomarkers, observed data changes‐from‐baseline were analyzed with 2‐sided simple t‐tests. Result 84 subjects were enrolled; 51% female, 69 years, MMSE 26.0, 70%/30% had MCI/Mild AD; 70 completed 104‐weeks. Plasma p‐tau181 showed significant reductions at all timepoints reaching 31%‐43% over 52‐104 weeks (p = 0.045); Aβ42 decreased ∼4% over 104 weeks (p = 0.042). Hippocampal atrophy (3.6%) was ∼28% lower than matched external control (ADNI‐1). RAVLT‐total memory and DSST remained above/at baseline through 104 weeks; Cohen’s d clinical benefit effect in RAVLT and hippocampal volume ranged from 0.5 to 0.7. Cognitive stabilization correlated with decreased hippocampal atrophy (Spearman’s r = 0.38‐0.43, p≤0.002); and cortical thinning (r = 0.35‐0.58, p≤0.004). Most common TEAE was mild nausea, and no ARIA‐E was observed. Conclusion Over 2 years, oral ALZ‐801 reduced plasma p‐tau181. Cognitive stabilization correlated with reduced brain atrophy, showing treatment benefit compared to external controls. Cohen’s d values for hippocampal volume and cognition suggest strong clinical benefit. No ARIA‐E/vasogenic edema was detected. These biomarker results support the disease‐modifying effects of ALZ‐801 in Early AD with promising clinical efficacy and favorable safety in APOE4 carriers. A Phase 3 78‐week trial in APOE4/4 homozygotes Early AD (EAD) is ongoing with results expected in 2024.

Background Different patterns of atrophy exist in the dementia stage of AD. However, little is known about the heterogeneity of atrophy patterns and the mechanisms that drive subsequent propagation of the disease in the preclinical stages. Method From the AMYPAD‐PNHS cohort, we included a total of 1323 non‐demented individuals, including 1094 amyloid‐negative, and 229 amyloid‐positive participants (Table 1). Gray matter thickness in 100 regions of interest was measured using FreeSurfer. Global cortical amyloid burden was derived from amyloid PET scans in Centiloids (CL). Individuals were assigned to atrophy subtypes based on cortical thickness measures using Non‐Negative Matrix Factorization (Figure 1). Multinomial regression models were used to study differences between subtypes in age, sex, global CL and APOE E4 carriership. Linear regression models were used to investigate the effect of time on atrophy within each subtype. Coordinated deformation models (Figure 1, Shafiei et al. 2023) were used to estimate network‐based thickness changes in each region, by multiplying the effect of time in connected regions by the strengths of their connections. Connectivity strength was based on templates of functional, structural and morphometric similarity networks, and allowed us to evaluate differential mechanisms. Significance was tested using a permutation approach. Results Three significant subtypes of regional GM atrophy were identified:‘limbic predominant’, ‘typical AD’, and ‘diffuse cortical’ (Figure 2). Individuals assigned to the limbic predominant subtype were significantly older, while the typical AD subtype had more APOE E4 carriers compared to the others (all p<0.001). Both limbic predominant and typical AD subtypes had higher CL compared to the diffuse cortical atrophy subtype (all p<0.001). Significant longitudinal thickness changes per subtype are shown in Figure 2. In the typical AD subtype, all network architectures constrained longitudinal GM changes (p<0.001), while in the diffuse atrophy subtype, propagation was mostly determined by morphometric similarity (p<0.005). No significant prediction model was found for the limbic predominant subtype. Conclusion We show that atrophy subtypes can already be detected in non‐demented individuals. Progression of atrophy within subtypes is determined by network‐based mechanisms.

Background ALZ‐801 (valiltramiprosate) is an oral inhibitor of amyloid oligomer formation in development as a disease‐modifying AD treatment, including a fully enrolled APOLLOE4 Phase 3 trial in 325 APOE4/4 homozygotes. A Phase 2 study is evaluating ALZ‐801 effects on plasma biomarkers, brain volumes and cognitive outcomes in APOE4 carriers. Plasma p‐tau181 reduction over 104 weeks is primary endpoint. A study extension includes active treatment over additional 104 weeks for a total of 208 weeks (4 years). Long term analyses include plasma p‐tau181, Aβ42/40, p‐tau217, GFAP and other emerging biomarkers. Hippocampal volume and cognition are additional outcomes. Method This active study enrolled 84 APOE4 carriers (MMSE ≥22; positive CSF+ biomarkers) who receive ALZ‐801 265 mg BID. CSF/plasma biomarkers were conducted at Dr. Blennow’s laboratory (Simoa, EuroImmun assays). MRIs analyzed by Clario at baseline, 52, 104, and in the long‐term extension (LTE); cognitive and biomarker tests are every 26 weeks. Biomarkers are analyzed on observed cases, hippocampal volume (HV) and cognitive tests are analyzed by MMRM with two‐sided p‐values; with Spearman’s correlations of biomarker‐clinical outcomes. Result Baseline mean age was 69 years, MMSE 26, 51% females, and 70% MCI; and 83 subjects had any post‐treatment efficacy assessment. Total of 75 and 70 subjects completed 52 and 104 weeks. At 104 weeks, plasma p‐tau181 reduction was 31% (p=0.045), Aβ42 reduction was 4% (p=0.042). Hippocampal volume (HV) versus untreated matched subjects from ADNI showed ∼20% less atrophy (p<0.002). Immediate and delayed memory scores (Rey test) remained at baseline levels versus 21% decline in matched ADNI subjects (p<0.0001). Memory stabilization correlated with reduced HV atrophy (r= 0.44, p=0.0002). In the 66 ongoing LTE subjects, cognitive and HV ADNI comparisons and biomarker‐cognitive correlations at 130 weeks will be reported. Most common TEAE was mild nausea, with no ARIA‐E. Conclusion Biomarker positive APOE4 carriers showed significant plasma p‐tau181 and Aβ42 effects, with promising HV effects that correlated with cognitive benefit. Sustained long term benefits on these outcomes over 2.5 years could support disease modification with a continued favorable safety profile of ALZ‐801. Correlations of plasma biomarkers to long‐term clinical and imaging outcomes provides valuable insights into ALZ‐801 effects in AD.

Background The emergence of disease‐modifying drug therapies is expected to revolutionize the field of Alzheimer's disease (AD). Recent results from anti‐amyloid clinical trials highlight the importance of early identification and accurate risk‐stratification of individuals in early stages of the disease. In this context, the Amyloid Imaging to Prevent Alzheimer’s Disease (AMYPAD) Prognostic and Natural History Study (PNHS) was established, leveraging existing cohorts to alleviate the burden of recruiting de novo participants. Here, we describe the harmonization and integration efforts of brain imaging, clinical, cognitive, and fluid biomarker data. Access to the data is available through the Alzheimer’s Disease Data Initiative, with additional details provided at https://amypad.eu/data/ Method The AMYPAD PNHS integrates prospective and historical data from 32 European sites across 10 countries. These sites contribute data from 10 Parent Cohorts (PC), predominantly comprising non‐demented at‐risk subjects, including EPAD LCS, EMIF‐AD (60++ and 90+), ALFA+, FACEHBI, FPACK, UCL‐2010‐412, Microbiota, DELCODE, and the AMYPAD Diagnostic and Patient Management Study. A meticulous data curation process was implemented, harmonizing metrics and questionnaires through strategies such as recoding into categories, Percentage of Maximum Possible Scores, and z‐scores. Expert reviewers at each site conducted PET visual reads. Centralized quantification of static PET images, employing site‐specific Gaussian smoothing, yielded harmonized Centiloid values. Parametric modelling of dynamic PET scans was also performed providing metrics such as the distribution volume ratio. Result The initial data set includes 3366 participants (55% females, 67±8 years), with 2629 having at least one follow‐up visit (2.6±1.9 years). Of those, 1618 underwent baseline amyloid PET, 888 with follow‐up. The dataset incorporates clinical outcomes, biomarkers, risk factors, and other relevant variables (Figure 1). Distribution of participants based on amyloid PET status at baseline yielded 60% negative (<12CL), 24% grey‐zone (12‐50CL), and 16% positive (>50CL) cases. Conclusion The AMYPAD PNHS represents the largest European longitudinal dataset phenotyping individuals at risk of AD‐related progression. The consortium is currently evolving into its new phase, namely the Euro‐PAD collaborative framework, and the dataset will be expanded in terms of variables (e.g., currently integrating GWAS and advanced MRI data) and number of cohorts. Interested to join, please contact us at https://amypad.eu/

Background Different patterns of atrophy exist in the dementia stage of AD. However, little is known about the heterogeneity of atrophy patterns and the mechanisms that drive subsequent propagation of the disease in the preclinical stages. Method From the AMYPAD‐PNHS cohort, we included a total of 1323 non‐demented individuals, including 1094 amyloid‐negative, and 229 amyloid‐positive participants (Table 1). Gray matter thickness in 100 regions of interest was measured using FreeSurfer. Global cortical amyloid burden was derived from amyloid PET scans in Centiloids (CL). Individuals were assigned to atrophy subtypes based on cortical thickness measures using Non‐Negative Matrix Factorization (Figure 1). Multinomial regression models were used to study differences between subtypes in age, sex, global CL and APOE E4 carriership. Linear regression models were used to investigate the effect of time on atrophy within each subtype. Coordinated deformation models (Figure 1, Shafiei et al. 2023) were used to estimate network‐based thickness changes in each region, by multiplying the effect of time in connected regions by the strengths of their connections. Connectivity strength was based on templates of functional, structural and morphometric similarity networks, and allowed us to evaluate differential mechanisms. Significance was tested using a permutation approach. Results Three significant subtypes of regional GM atrophy were identified:‘limbic predominant’, ‘typical AD’, and ‘diffuse cortical’ (Figure 2). Individuals assigned to the limbic predominant subtype were significantly older, while the typical AD subtype had more APOE E4 carriers compared to the others (all p<0.001). Both limbic predominant and typical AD subtypes had higher CL compared to the diffuse cortical atrophy subtype (all p<0.001). Significant longitudinal thickness changes per subtype are shown in Figure 2. In the typical AD subtype, all network architectures constrained longitudinal GM changes (p<0.001), while in the diffuse atrophy subtype, propagation was mostly determined by morphometric similarity (p<0.005). No significant prediction model was found for the limbic predominant subtype. Conclusion We show that atrophy subtypes can already be detected in non‐demented individuals. Progression of atrophy within subtypes is determined by network‐based mechanisms.

Introduction: Cardiovascular disease is the commonest cause of death in Turner syndrome (TS) for which, arterial hypertension has a direct influence and is a key modifiable risk factor. Objective: To investigate the prevalence and patterns of hypertension diagnosis and management in adult patients with TS who are registered in a large international multicentre database (TS-HTN study). Methods: Retrospective multi-centre observational study of patients aged ≥18 years, included in the I-TS (International-TS) registry (2020-2022) utilising registry and participating centre collected data. Results: Twelve international centres participated, including 182 patients with the median age of 28 years (IQR 23,37.2). Arterial hypertension was recorded in 13.2% (n=24). The median age at hypertension diagnosis was 27 years (range 10,56), with 92% aged less than 50 years at the diagnosis. The majority (75%) were classified as primary hypertension (n=18). In binomial regression analysis, higher body-mass-index (BMI) was the only parameter significantly associated with the occurrence of hypertension (B=1.487, p=0.004). Among patients with aortic disease (n=9), 50% had Systolic BP ≥130 mmHg, and 66.6% had Diastolic BP ≥ 80 mmHg during the last clinic review. Angiotensin converting enzyme inhibitors (ACEi) were the commonest (n=16) medication prescribed, followed by Angiotensin receptor blockers (n=6), beta blockers (n=6), and calcium channel blockers (n=6). Conclusions: Arterial hypertension is common in TS and occurs form a young age. Overweight/obesity was a notable risk factors for hypertension. The frequency of sub-optimal BP control among high-risk patients highlights the importance of increased awareness and TS-specific consensus guidance on management.

Background Published data have highlighted associations between Alzheimer’s disease (AD) susceptibility loci and AD‐related brain changes. The amyloid imaging to prevent AD (AMYPAD) consortium is a European collaboration consisting of several parent cohorts, four of which had raw genotype array data available. We sought to integrate and harmonise the genetic data, calculate AD polygenic risk scores (PRS), and investigate their association with global amyloid deposition. Method Raw genetic data (GRCh37) was available for 753 non‐demented participants, which underwent standard pre‐imputation quality control (QC) using PLINK. Imputation was performed using the Michigan Imputation server and HRC reference panel, and standard post‐imputation QC was done prior to the final merging of cohorts. PRSice was used for PRS calculations with Stage 1 summary statistics from Kunkle et al. (2019) as base file and European individuals from 1000 Genomes as reference for clumping. We calculated several builds of PRS at three p‐value thresholds for SNP inclusion: 5 × 10‐8, 1 × 10‐5, and 0.1. These included PRSall, PRSAPOEonly (Chr19:45‐48.8Mb), APOEε2+ ε4 (the weighted sum of the two major APOE SNPs rs429358 and rs7412), PRSnoAPOE (all SNPs excluding Chr19:45‐48.8Mb), and a composite PRSnoAPOE+APOEε2+ ε4. All were corrected for genetic principal components 1‐5 and standardised against 1000 Genomes. Cross‐sectional global amyloid burden (expressed in Centiloids) was available for everyone. Linear regression models determined if PRS were associated with amyloid deposition (age, sex, and education as covariates). Significance was based on an uncorrected p<0.05 divided by the number of SNP inclusion thresholds (N = 3). Result Participants were 66.9±7.6 years, 58.6% female, and 207 (27%) considered amyloid positive (CL>21). In this preliminary analysis, we found that most PRS builds were significantly associated with amyloid at all SNP inclusion thresholds assessed (Table 1, representative plots Fig. 1A,1B), except for PRSnoAPOE (Table 1, representative plot Fig. 1C). Conclusion We highlight the significant influence of APOE in determining AD genetic predisposition, and that AD PRS are associated with amyloid deposition. Our results show that AMYPAD is a suitable cohort for studying genetic factors driving amyloid deposition before clinical onset, which we aim to extend with the inclusion of more parent cohorts, and regional and longitudinal amyloid data.

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. Setting: Multicenter - 52 medical research centers/hospitals in 5 countries. Intervention: 508 participants with early AD (Stage 3) were randomized to receive either blarcamesine (n = 338) in medium dose group 30 mg or in high dose group 50 mg or placebo (n = 170) oral capsules once daily for 48 weeks. Participants in these groups were offered to enroll into the open-label-extension study ATTENTION-AD, which completed June 2024, ClinicalTrials.gov Identifier NCT04314934. Measurements: The co-primary cognitive and functional outcomes were assessed as change in ADAS-Cog13 and ADCS-ADL from baseline to 48 weeks. The outcomes include the secondary outcome CDR-SB and biomarkers from the A/T/N spectrum, plasma Aβ42/40-ratio and global brain volume changes measured by MRI. All clinical endpoints were analyzed using mixed model for repeated measures (MMRM), plasma biomarker measurements were analyzed by Welch's t-test, and volumetric MRI scans were analyzed by general linear model. Results: Among 462 randomized participants in the intent-to-treat population (mean age, 73.7 years; 225 [48.7%] women), 338 (73.2%) completed the trial. The co-primary outcome was met under the multiplicity control rule, since the differences in the least-squares mean (LSM) change from baseline to 48 weeks between the prespecified blarcamesine and placebo groups for ADAS-Cog13 was significant at a level of P < 0.025 and for CDR-SB was significant at a level of P < 0.025, while ADCS-ADL did not reach significance at Week 48 (ADAS-Cog13 difference of -2.027 [95% CI -3.522 to -0.533]; P = 0.008; CDR-SB difference of -0.483 [95% CI -0.853 to -0.114]; P = 0.010; ADCS-ADL difference of 0.775 [95%CI -0.874 to 2.423]; P = 0.357). Plasma Aβ42/40-ratio increased significantly with blarcamesine group vs. placebo, (P = 0.048) and whole brain volume loss was significantly decreased (P = 0.002). Participants in the full safety population with ≥1 serious treatment-emergent adverse events (TEAEs) occurred in 56 participants (16.7%) in the blarcamesine and 17 (10.1%) in the placebo group. Common TEAEs included dizziness, which was transient and mostly mild to moderate in severity. One death in the blarcamesine group and 1 in the placebo group were both not considered treatment related. Conclusions: Blarcamesine, demonstrating a safety profile with no associated neuroimaging adverse events, significantly slowed clinical progression by 36.3% at 48 weeks with blarcamesine group as well as the individual 30 mg (by 34.6%) and 50 mg (by 38.5%) blarcamesine groups vs. placebo on the prespecified primary cognitive endpoint ADAS-Cog13. The prespecified secondary endpoint CDR-SB, which is used as the sole primary endpoint in recent successful AD drug submissions, is significantly improved at Week 48 with blarcamesine relative to placebo. The findings are supported by biomarkers from the A/T/N spectrum, including plasma Aβ42/40-ratio and reduction of whole brain atrophy. Additionally, the prespecified SIGMAR1 gene variant subgroup analysis confirmed beneficial clinical effect of blarcamesine group through upstream SIGMAR1 activation - subjects with the common SIGMAR1 wild-type gene (excluding carriers of the mutated SIGMAR1 rs1800866 variant) experienced an even greater significant clinical benefit with slowed clinical progression by 49.8% at 48 weeks on the prespecified primary cognitive endpoint ADAS-Cog13. Oral once daily blarcamesine could represent a novel treatment in early AD and be complementary or alternative to anti-beta amyloid drugs.

Purpose: The main aim of this study was to compare sitting pressure (peak pressure index (PPI) and peak pressure gradient (PPG)) between a daily wheelchair and fixed-frame handcycle, thereby assessing the effect of handcycle backrest angle, movement intensity and cushion type. Materials and methods: Twenty able-bodied participants performed static and dynamic (two intensities) tests in a wheelchair and handcycle. A honeycomb wheelchair cushion and standard foam handcycle cushion were used. Handcycle backrest angles were 45° and 60°. The PPI and PPG at the sacro-coccygeal (SC) and ischial tuberosity (IT) regions were determined with a pressure mat. Results: PPI at the IT-region was higher in the 60° handcycle condition than in the wheelchair (p = 0.04), while PPG at the IT-region did not differ significantly between the wheelchair and handcycle conditions (p > 0.05). PPI and PPG were higher at the 45° handcycle SC-region compared to the wheelchair IT-region (p < 0.03). PPI and PPG at the IT-region were higher with the 60° than with the 45° backrest angle (p < 0.01), while at the SC-region PPI was higher with the 45° backrest angle (p = 0.047). No clear influence of movement intensity was found. PPI and PPG at the IT-region and PPI of the SC-region in the handcycle were significantly lower with the wheelchair cushion than with the handcycle cushion (p < 0.01). Conclusion: Overall, sitting pressure was higher in the handcycle compared to the daily wheelchair. For handcyclists using an upright position, it is recommended to use a cushion designed to redistribute pressure, thereby reducing internal tissue pressure and shear.