Profu (Sweden)

Comparative data on the bleeding risk in cancer-free patients aged ≥65 years treated with rivaroxaban or apixaban for venous thromboembolism is scarce. The aim was to compare major bleeding rates between rivaroxaban and apixaban during primary treatment (0 - 6 months) and secondary treatment (6 months - 5 years). Additionally, all-cause mortality and recurrent pulmonary embolism (PE) were assessed. A register-based cohort study of cancer-free patients in Sweden aged ≥65 years with a first-time PE or deep vein thrombosis and a filled prescription of rivaroxaban or apixaban between January 1, 2014, and July 1, 2023. Cox proportional hazard models were used to compare rates of bleeding, all-cause mortality, and recurrent PE. 19,090 patients were included; 7572 on rivaroxaban and 11,518 on apixaban. During primary treatment, rates of major bleeding were 4.4 (95 % confidence interval (CI) 3.7-5.2) per 100 patient-years on rivaroxaban and 3.3 (2.8-3.9) on apixaban, adjusted hazard ratio (aHR) 1.46 (1.15-1.85). During secondary treatment, major bleeding rates were 1.4 (1.2-1.7) per 100 patient-years on rivaroxaban and 1.2 (1.0-1.5) on apixaban, aHR 1.24 (0.94-1.63). No difference was seen in recurrent PE, however, a higher mortality was seen for patients on rivaroxaban. During primary treatment, apixaban was associated with a lower risk of major bleeding than rivaroxaban without a corresponding increase in recurrent PE risk. During secondary treatment, no difference in bleeding risk was observed. The Swedish Heart and Lung Foundation. The Swedish State under the agreement between the Swedish Government and the county councils.

BackgroundDown Syndrome (DS) individuals develop Alzheimer's Disease (AD) neuropathology by the age of 40 due to the triplication of Chromosome 21 and the amyloid precursor protein gene. This genetic alteration leads to an overproduction of Aß, resulting in amyloid accumulation. However, triplication of other Chr21 genes may be involved in AD pathogenesis in DS, and affect amyloid processing and alter subspecies production. This study compares plasma Aß subspecies using mass spectrometry (MS) in DS, sAD and PS1 mutations.MethodPlasma from adults with DS who were cognitively stable (CS‐DS; n = 46; mean age 33.5), cognitive stable older adults from the general population (CS; n = 42; mean age 71.7), DS deemed prodromal or with AD (DS pAD/AD; n = 25; mean age 53.5), early onset sporadic pAD/AD (n = 27; mean age 63.9) and with presenilin 1 mutations (n = 6; mean age 50.5) were analysed using IP‐MS for Aß 1‐37, 1‐38, 1‐40, and 1‐42. In those with DS, Simoa assays for Aß 40 and 42, neurofilament light (Nfl), glial fibrillary protein (GFAP, pTau181 and pTau231 were also obtained, and an Event‐Based Model (EBM) was used to determine the sequence of changes associated with AD.ResultDS individuals had consistently higher levels of Aß1‐37, 1‐38, 1‐40, and 1‐42 compared to CS general population adults, sporadic pAD/AD, and those with PS1 mutations. DS pAD/ AD had increased Aß ratios for 1‐ 40/1‐37 and 1‐37/ 1‐38 compared to sporadic pAD/AD, but similar ratios when compared to those with PS1 mutations. Age‐related patterns of changes in Aβ1‐37 and 1‐38 subspecies in DS pAD/AD differed compared to sporadic pAD/AD, but changes in Aβ 1‐40 and 1‐42 levels were similar. APOE ε4 was associated with Ab 1‐37 levels in DS. Changes Aβ1‐42/1‐38, 1‐42/1‐37, and 1‐42/1‐40 were early events followed by changes in NfL, GFAP, pTau 181 and pTau 231.ConclusionAll Aß subspecies are increased in DS compared to sAD, with higher 1‐40/1‐37 ratios and different age associated changes. Measurement of Aβ subspecies with IP‐MS may help to identify early AD in DS. Further work could determine the nature of differences in subspecies compared to sAD.

BackgroundWhite matter inflammation significantly contributes to the progression of Alzheimer’s disease (AD). Changes in the translocator protein (TSPO), an in‐vivo marker of brain inflammation, have been observed in white matter (WM) through in‐vitro binding assays, immunostaining, and TSPO PET‐based quantification. Our objective was to assess the effects of glial inflammation in WM via TSPO‐PET on AD biomarkers and cognitive decline, beyond grey matter (GM) inflammation, across the AD spectrum.MethodEighty‐eight elderly participants from the Translational Biomarkers in Aging and Dementia cohort (44% Aβ‐positive, 38% cognitively impaired) underwent diffusion‐weighted MRI, TSPO‐PET (11C‐PBR28), amyloid‐PET (18F‐AZD4694), tau‐PET (18F‐MK6240), and plasma Aβ42/40, ptau181, ptau231, GFAP, and NfL. Diffusion‐weighted modeling differentiated free water from fiber integrity indexed by fractional anisotropy. Inflammation was assessed via TSPO standardized uptake value ratios normalized to cerebellar grey. We investigated associations of the TSPO signal in the normal‐appearing WM (eroded by 2mm3) with each of the AD biomarkers, diffusion metrics, and cognition; adjusted for age, sex, (and education). GM and WM TSPO signals were tested in the same models.ResultWe observed a significant three‐way interaction between amyloid, GM TSPO, and WM TSPO on Tau (Braak‐3 tau: p = 0.013, Braak‐4: p = 0.029, Braak‐5: p = 0.018, Braak‐6: p = 0.005). Decomposing this interaction, individuals with greater amyloid in the presence of greater occipital WM TSPO displayed greater Tau (Figure 1A, left: Braak‐3 tau, right: Braak‐6 tau). No such effect was found with GM TSPO in the occipital lobe (Figure 1B) but there was a significant effect with GM TSPO in the cingulate cortex (Braak‐45 tau: p = 0.001‐0.004). Further, TSPO signal in the occipital WM was associated with greater concentrations of plasma GFAP (p = 0.039) and with lower fiber integrity (p = 0.029), but there was no association with plasma Aβ4240, ptau231, ptau181, or NfL. Last, TSPO signal in the occipital WM modulated the effect of amyloid‐related tau increases on several cognitive domains (including executive function and language; Figure 2).ConclusionInflammation in the posterior WM, as quantified through TSPO‐PET, modulated the relationship between amyloid and tau and between amyloid‐related tau effects on cognitive dysfunction. These effects were beyond GM TSPO. Our findings highlight the importance of WM inflammation in the pathogenesis of AD.

BackgroundPatients benefit from antiplatelet therapy after coronary-artery bypass grafting (CABG) for an acute coronary syndrome. Whether the addition of ticagrelor to aspirin, as compared with aspirin alone, further reduces the risk of adverse cardiovascular outcomes is unclear.MethodsIn this open-label, registry-based, clinical trial conducted at 22 Nordic cardiothoracic surgery centers, we randomly assigned patients in a 1:1 ratio to receive either ticagrelor plus aspirin or aspirin alone for 1 year after CABG for an acute coronary syndrome. The primary outcome was a composite of death, myocardial infarction, stroke, or repeat revascularization, evaluated at 1 year. A key secondary outcome was net adverse clinical events, defined as a primary-outcome event or major bleeding.ResultsA total of 2201 patients were randomly assigned to receive ticagrelor plus aspirin (1104 patients) or aspirin alone (1097 patients). The mean age of the patients was 66 years, and 14.4% were women. A primary-outcome event occurred in 53 patients (4.8%) in the ticagrelor-plus-aspirin group and 50 (4.6%) in the aspirin-alone group (hazard ratio, 1.06; 95% confidence interval [CI], 0.72 to 1.56; P=0.77). Net adverse clinical events occurred in 9.1% of patients in the ticagrelor-plus-aspirin group and 6.4% in the aspirin-alone group (hazard ratio, 1.45; 95% CI, 1.07 to 1.97). Major bleeding occurred in 4.9% of patients in the ticagrelor-plus-aspirin group and 2.0% in the aspirin-alone group (hazard ratio, 2.50; 95% CI, 1.52 to 4.11).ConclusionsAmong patients who underwent CABG for an acute coronary syndrome, ticagrelor plus aspirin did not result in a lower incidence of death, myocardial infarction, stroke, or repeat coronary revascularization than aspirin alone at 1 year. (Funded by the Swedish Research Council and others; TACSI ClinicalTrials.gov number, NCT03560310; EudraCT number, 2017-001499-43; EU Clinical Trials number, 2023-508551-40-00.)

Abstract BackgroundBlood‐based biomarkers offer a cost‐effective and simple alternative for clinical use in the context of Alzheimer’s disease (AD). It has already been shown that plasma phosphorylated tau at threonine 217 (p‐tau217) is associated with amyloid (Aß), neurofibrillary tau tangles, and cognitive decline. Longitudinal studies confirmed its ability to track AD progression. Therefore, the aim of this study is to evaluate the potential utility of changes in plasma p‐tau217 as secondary outcome in clinical trials across the AD spectrum.MethodWe included 189 individuals with available plasma p‐tau217 measurements at two time points (24 months follow‐up) across two cohorts:[MYHAT‐NI, population‐based(USA): 51 Cognitively Unimpaired(CU); BICWALZS, memory clinic(South Korea): 135 Cognitively Impaired(CI) individuals], all with baseline Aß‐PET. Plasma p‐tau217 was quantified using the ALZpath assay. We used linear regression to investigate p‐tau217 association with cognitive decline. Effect size was determined by biomarker mean change divided by the standard deviation. We also estimated the sample size required to detect a 25% drug effect on p‐tau217 reduction with 80% power at a significance level of 0.05.ResultBaseline and longitudinal changes in p‐tau217 were significantly associated with cognitive decline independently of Aß status in both CU and CI individuals (Table 1). Functionally, individuals classified with mild dementia(CDR‐SB>4.5) showed greater and pronounced annual changes in p‐tau217 compared to the other groups (Figure 1A). Notably, Aß+ individuals presented a higher effect size for p‐tau217 changes in both CU(0.79) and CI(0.74) groups, compared to the whole population (Figure 2B). The sample size required for a clinical trial including of Aß+ individuals were 1,276 for CU and 940 for the CI. Cost analysis revealed that in trials recruiting CU Aß+ individuals targeting tau pathology using p‐tau217 as a secondary outcome was 1.5, 3.7, and 3.9 times more cost‐effective than 18F‐MK‐6240 tau‐PET, 18F‐Flortaucipir tau‐PET, and p‐tau181, respectively (Figure 2). Similarly, in trials with CI Aß+ participants, p‐tau217 was 1.5 times less expensive than [18F]‐MK‐6240 tau‐PET, and 3.7 times less than [18F]‐Flortaucipir tau‐PET.ConclusionOur results demonstrated that changes in plasma p‐tau217 is associated with cognitive decline across the AD continuum. Furthermore, p‐tau217 shows promise as a secondary outcome in AD clinical trials.

Abstract BackgroundGiven the increasing usage of plasma biomarkers for Alzheimer’s disease (AD) studies, it is necessary to better understand relationships between plasma biomarker and PET and MR imaging outcomes, particularly within the AT(N) framework.MethodWe evaluated plasma samples from 233 subjects (age 74.05.9y) who underwent 3T MR and both [11C]PiB and [18F]flortaucipir (FTP) PET imaging. SUVR values were calculated for Global PiB, and Meta‐Temporal FTP. An AD signature cortical thickness (CT) composite was derived from MR images using FreeSurfer 5.3, Blood samples were processed and sampled to obtain measures of plasma Aβ42, Aβ40, p‐tau181, p‐tau217, p‐tau231 and neurofilament light (NfL), and glial fibrillary acidic protein (GFAP). Imaging outcomes were split into infra (‐) and supra (+) threshold groups using 1.35 SUVR for Global PiB, 1.18 SUVR for Meta‐Temporal FTP, and 2.7 mm for CT. Plasma Aβ was expressed as Aβ42/Aβ40 ratio while p‐tau181, p‐tau217, p‐tau231, NfL, and GFAP were natural‐log‐transformed to normally distribute the data. Simple regression models between continuous variables of each imaging‐derived measure and all plasma biomarkers were evaluated.ResultFull group regression model R2 and regional p‐values are shown in Table 1, suprathreshold regressions are shown in Table 2. Full Global PiB was significantly associated with all plasma biomarkers while CT was associated with NfL, p‐tau181, and p‐tau231. Meta‐Temporal FTP was associated with GFAP and p‐tau217. Additionally, A+Global PiB was significantly associated with Aβ42/Aβ40, GFAP, and p‐tau217; (N+) CT with NfL; and T+ Meta‐Temporal FTP with p‐tau181 and GFAP.ConclusionThe significant associations between suprathreshold imaging and plasma biomarkers suggests that, in A+, T+, or (N+) both capture abnormal AD pathophysiology. Further, the absence of an association in the infrathrehold cases supports that the suprathreshold associations are not artifactual. Future work will explore plasma thresholds and concordance between imaging and plasma AT(N).

Background: Recent research confirms insulin resistance (IR) not only as risk factor for type 2 diabetes mellitus (T2DM) but also for Alzheimer’s disease (AD). Diet restrictions in patients with T2DM or obesity alone may, thus, not only improve insulin sensitivity (IS) of the CNS but may beneficially affect AD-related biomarkers known to early recognize long-term AD risks. To prove this hypothesis, we investigated the effects of a controlled, potentially health-promoting dietary intervention on both glucose metabolism (IR) and AD biomarkers in cognitively healthy, obese adults. Methods: One-hundred-and-eleven adults (60±7y, BMI 31.1±3.5kg/m², 47 males) were randomized either to the intervention group consuming a plant-based diet or the control group maintaining their habitual Western diet. Both diets were isoenergetic to ensure a constant body weight. At baseline and after 6 weeks intervention, OGTT was performed and HOMA-IR and OGIS were calculated. Fasting plasma levels of AD biomarkers (neurofilament light chain, glial fibrillary acidic protein, amyloid-beta (Aβ) 42/40, and phosphorylated tau (p-tau) 181 and 231; Simoa assay), glucose, HbA1c and serum insulin were measured. Data were analyzed via linear mixed-effect models and regression analyses. Results: Fasting glucose and insulin levels were in borderline high physiological ranges; a possible IR was indicated. After 6 weeks, there were no diet-induced differences in fasting levels of glucose, insulin, AD biomarkers, and IR measures (all p>0.05). However, a positive association of fasting levels of p-tau181 and HOMA-IR (β=0.464, p=0.038) and p-tau231 and HbA1c (β=2.693, p=0.029) and a negative trend for Aβ40 and OGIS (β=−0.049; p=0.055) were found. Conclusion: Impaired insulin sensitivity is associated with unfavorable changes in AD-related biomarker levels in adults with diabetes risk, highlighting the relevance of glucose metabolism in cognitive health. Disclosure H.Huber: None. M.Simon: None. N.J.Ashton: None. L.Weinhold: None. M.Schmid: None. M.Coenen: None. B.Stoffel-wagner: None. K.Blennow: Other Relationship; Acumen, BioArctic, Eisai, Biogen, Eisai Co., Ltd., Lilly, Novartis, Ono Pharmaceutical Co., Ltd., Prothena, Roche Diagnostics, Siemens, Brain Biomarker Solutions, Julius Clinical, ALZPath. P.Stehle: None. H.Zetterberg: None. Funding German Federal Ministry of Education and Research (01EA1707, 01EA1809A); Swedish Research Council (2017-00915, 2022-00732, 2022-01018); Swedish Alzheimer Foundation (AF-930351, AF-939721, AF-968270); Hjärnfonden, Sweden (FO2017-0243, ALZ2022-0006, FO2022-0270); Swedish State (ALFGBG-715986, ALFGBG-965240, ALFGBG-71320); European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236, JPND2021-00694); Alzheimer’s Association (ZEN-21-848495, SG-23-1038904 QC); European Union’s Horizon Europe Research and Innovation Programme (101053962, 860197); Alzheimer Drug Discovery Foundation (201809-2016862); AD Strategic Fund/Alzheimer's Association (ADSF-21-831376-C, ADSF-21-831381-C, ADSF-21-831377-C); Bluefield Project; Olav Thon Foundation; Erling-Persson Family Foundation; Stiftelsen för Gamla Tjänarinnor; UK Dementia Research Institute (UKDRI-1003)

Background: Changes in fatty acid metabolism are an important component of the pathogenesis of type 2 diabetes mellitus (T2DM). Fatty acid uptake in tissues can be measured with positron emission tomography (PET) imaging, employing the fatty acid analogue 18F-FTHA radiotracer. We aimed to evaluate the repeatability of assessments of fatty acid uptake in tissues with a new whole-body PET/MRI (magnetic resonance) imaging method in people with obesity with or without T2DM. Methods: 17 completers underwent 4 repeated examinations under standardised conditions, twice under fasting and twice postprandially (PP). Tissue-specific fatty acid uptake (FAU) and uptake rate was measured using 18F-FTHA and dynamic whole-body PET/MRI in skeletal muscle, subcutaneous and visceral adipose tissues (SAT, VAT), myocardium and brain. Free fatty acid levels were measured over time. The repeatability of PET measurements under fasting, and under PP, was assessed by calculating the intraclass correlation coefficient (ICC 2,1) along with its 95 % confidence intervals; ICC ≥ 0.75 indicates excellent, 0.6 - 0.74 good, 0.4 - 0.59 fair and <0.4 poor reliability. Results: In the fasted state, repeatability of the net uptake rate in muscle tissue was found to be excellent, ICC 0.91 (0.78 - 0.96) and good in myocardium, ICC 0.64 (0.27-0.86). Repeatability of FAU in other tissues was at least fair (ICC SAT 0.80 (0.54-0.91), VAT 0.64 (0.27-0.85), brain 0.75 (0.46-0.90). In the PP experiments, variability increased especially for the FAU estimates, but the repeatability of the uptake rate was acceptable (ICC >0.4) for most investigated tissues, and good for muscle (ICC 0.73 (0.42-0.89). Conclusion: 18F-FTHA-PET/MRI provides information on tissue-specific fatty acid uptake with good reliability, and excellent repeatability for the muscle under fasting. The method has potential to provide insights in monitoring and evaluating treatment effects in interventional trials. Disclosure I.Laitinen: Employee; Antaros Medical. T.Coskun: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. Z.Milicevic: Employee; Eli Lilly and Company. L.Johansson: Employee; Antaros Medical, Stock/Shareholder; Antaros Medical. P.Nuutila: None. S.Ekström: Employee; Antaros Medical. H.Haraldsson: Employee; Antaros Medical. S.Pierrou: Stock/Shareholder; AstraZeneca. K.Kalliokoski: Consultant; Synektik S.A., Stock/Shareholder; Faron Pharmaceuticals Oy, CRST Oy. M.Kiugel: None. M.Scheinin: Consultant; Orion Pharma, Employee; Clinical Research Services Turku - CRST Oy, Other Relationship; Antaros Medical AB, Biogen, Boehringer Ingelheim International GmbH, Falk GmbH and Co Kg, Imbria, Novartis AG, Novo Nordisk A/S, Provention Bio, Inc., Stock/Shareholder; Clinical Research Services Turku - CRST Oy. S.Southekal: Employee; Eli Lilly and Company. M.Lu: None.

Abstract BackgroundIndividuals who have Down syndrome frequently develop early onset Alzheimer’s disease, a neurodegenerative condition caused by the build‐up of aggregated amyloid‐β and tau proteins in the brain. Amyloid‐β is produced by APP, a gene located on chromosome 21. People who have Down syndrome have three copies of chromosome 21 and thus also an additional copy of APP; this genetic change drives the early development of Alzheimer’s disease in these individuals.MethodsHere we use a combination of next‐generation mouse models of Down syndrome (Tc1, Dp3Tyb Dp(10)2Yey and Dp(17)3Yey) and a knockin mouse model of amyloid‐β accumulation (AppNL‐F) to determine how chromosome 21 genes other than APP modulate APP/amyloid‐β in the brain when in three copies.ResultsWe demonstrate that three copies of other chromosome 21 genes are sufficient to partially ameliorate amyloid‐β accumulation in the brain. We go on to identify a subregion of chromosome 21 that contains the gene/genes causing this decrease in amyloid‐β accumulation and investigate the role of two lead candidate genes Dyrk1a and Bace2.ConclusionThus an additional copy of chromosome 21 genes, other than APP, can modulate APP/amyloid‐β in the brain under physiological conditions. This work provides critical mechanistic insight into the development of disease and an explanation for the typically later age of onset of dementia in people who have AD‐DS compared to those who have familial AD caused by triplication of APP.