Universitair Ziekenhuis Leuven

Purpose This analysis of the CIRSE Registry for SIR-Spheres Therapy in France, CIRT-FR, reports on real-world outcomes of transarterial radioembolisation (TARE) with Y90 resin microspheres for hepatocellular carcinoma (HCC) and colorectal cancer liver metastases (CRLM) patients in France, focusing on safety, effectiveness and health-related quality of life (HRQoL). Results on patients treated based on national reimbursement criteria are discussed here. Methods Prospective, multicentre, observational study of HCC and CRLM patients treated between August 2017 and July 2020 with TARE Y90 resin microspheres. Patients were assigned to different analysis groups based on reimbursement recommendations. Follow-up period was at least 24 months with patient data collected every 3 months. Results In total, 252 (193 HCC, 59 CRLM) patients of CIRT-FR were included in the analysis. No differences in effectiveness, safety and HRQoL were found between analysis groups based on reimbursement recommendations. Median overall survival for HCC and CRLM was 19.0 (95% CI, 16.1–22.4) and 10.8 (95% CI, 8.0–13.5) months, respectively. Serious procedure-related adverse events occurred in 13% of the patients. HRQoL generally remained stable, with some fluctuations in function scores and symptoms. Conclusion In our cohorts, patients performed similarly regarding clinical outcomes irrespective of their analysis group based on reimbursement recommendations. Our results suggest that instead of restrictive reimbursement criteria, more decision-making power in selecting suitable patient groups could be given to multidisciplinary tumour boards. Results confirm that TARE with Y90 resin microspheres is an effective and safe treatment for liver cancer, with maintained HRQoL in most patients. Graphical abstract

Background Type 1 regulatory T (Tr1) cells are critical players in maintaining peripheral tolerance, by producing high IL‐10 levels in association with inducible T‐cell co‐stimulator (ICOS) expression. Whether these cells play a role in naturally acquired baked egg tolerance is unknown. Objectives Evaluate frequencies of egg‐responsive Tr1 and Th2 cells in egg‐allergic children that naturally acquired baked egg tolerance (BET) versus non‐egg‐allergic (NEA) children. Methods Peripheral blood mononuclear cells from 70 natural BET and 15 NEA children were stimulated for 7 days with ovalbumin and ovomucoid. By flowcytometry, egg‐responsive Tr1 cells were identified by co‐expression of CD49b and LAG3, and Th2 cells by expression of CD49b but absence of LAG3. Seven‐day cultured supernatant was analyzed for Th1, Th2, Tr1, and Th17 cytokines by MSD. Results Natural BET children had a higher percentage of egg‐responsive Th2 cells vs. NEA children (6.75% vs. 10.35%, p = .006). No significant difference was found in frequencies of egg‐responsive Tr1 cells between NEA and natural BET children (11.40% vs. 12.55%, p = .42), although Tr1‐related IL‐10 and IL‐21 production was higher in BET children. Interestingly, egg‐responsive Tr1 cells from NEA children expressed higher ICOS levels vs. natural BET children (97.90 vs. 88.20, p < .0001). Supernatant from natural BET children showed elevated levels of Th2 cytokines IL‐5, IL‐9 and IL‐13 and Th17 cytokine IL‐17A. Conclusion Natural BET children maintain increased egg‐specific Th2 responses, along with comparable proportions of egg‐responsive Tr1 cells exhibiting higher IL‐10 but lower ICOS expression in comparison with NEA children.

Background and Aims Treating ulcerative colitis (UC) in patients with prior advanced therapy (AT) exposure may be challenging. We report the efficacy and safety of risankizumab, a monoclonal interleukin 23p19 antibody, in patients with UC and prior inadequate response or intolerance to AT (AT-IR). Methods In the 12-week phase 3 INSPIRE induction study, patients were randomized to intravenous risankizumab 1200 mg or placebo. Clinical responders were randomized to subcutaneous risankizumab 180 mg, risankizumab 360 mg, or placebo (risankizumab withdrawal) in the 52-week phase 3 COMMAND maintenance study. This post hoc analysis assessed outcomes by AT-IR status, number, and mechanism of action. AT included biologics, Janus kinase inhibitors, and sphingosine-1-phosphate receptor modulators. Results Efficacy analyses included 472 Non-AT-IR and 503 AT-IR patients (induction), and 137 Non-AT-IR and 411 AT-IR patients (maintenance). More patients achieved clinical remission per Adapted Mayo score with risankizumab 1200 mg versus placebo at induction week 12 (Non-AT-IR, 29.7% versus 8.4%, nominal P < .0001; AT-IR, 11.4% versus 4.3%, nominal P = .0083); consistent with risankizumab 180 mg or risankizumab 360 mg versus placebo (withdrawal) at maintenance week 52 (NonAT-IR, 50.9% or 61.7% versus 31.1%, nominal P = .057 or P = .0033, respectively; AT-IR, 36.6% or 29.5% versus 23.2%, nominal P = .0159 or P = .2334, respectively). Risankizumab had increased efficacy over placebo, regardless of AT-IR number or mechanism of action, with higher efficacy rates for NonAT-IR compared to AT-IR. Safety results in Non-AT-IR and AT-IR patients were generally comparable in both induction and maintenance. Conclusion Risankizumab was effective and well tolerated, regardless of prior AT-IR status.

Self-regulation and executive functioning are known key predictors of future cognitive development and mental health. We examined the effect of early life neonatal stress, maternal perinatal stress, kangaroo care, maternal parenting behavior and secure child attachment on executive function at 2 years corrected age (CA) in children born preterm (i.e. < 34 weeks of gestation and/or < 1500 g birth weight). Neonatal child characteristics were recorded at the Neonatal Intensive Care Unit (NICU). We examined self-reported perinatal maternal stress during NICU stay, maternal emotional availability at 4 months CA, and child attachment security at 14 months CA. The executive function battery at 2 years CA was completed by 97 children. Low birth weight, a high number of skin breaking procedures and high level of maternal stress predicted lower executive function scores. Kangaroo care, non-intrusive maternal parenting behavior and secure attachment were associated with higher executive function scores. Even after controlling for background factors, modifiable factors such as neonatal child and mother stress, kangaroo care, parenting style, and child attachment style uniquely predict later executive functioning development, indicating that preventive interventions need to integrate multiple aspects of neuroprotective care, including supporting the child-parent bond, both at the NICU and beyond.

Background A subset of developmental disorders (DD) is characterized by disease-specific genome-wide methylation changes. These episignatures inform on the underlying pathogenic mechanisms and can be used to assess the pathogenicity of genomic variants as well as confirm clinical diagnoses. Currently, the detection of these episignature requires the use of indirect methylation profiling methodologies. We hypothesized that long-read whole genome sequencing would not only enable the detection of single nucleotide variants and structural variants but also episignatures. Methods Genome-wide nanopore sequencing was performed in 40 controls and 20 patients with confirmed or suspected episignature-associated DD, representing 13 distinct diseases. Following genomic variant and methylome calling, hierarchical clustering and dimensional reduction were used to determine the compatibility with microarray-based episignatures. Subsequently, we developed a support vector machine (SVM) for the detection of each DD. Results Nanopore sequencing-based methylome patterns were concordant with microarray-based episignatures. Our SVM-based classifier identified the episignatures in 17/19 patients with a (likely) pathogenic variant and none of the controls. The remaining patients in which no episignature was identified were also classified as controls by a commercial microarray assay. In addition, we identified all underlying pathogenic single nucleotide and structural variants and showed haplotype-aware skewed X-inactivation evaluation directs clinical interpretation. Conclusion This proof-of-concept study demonstrates nanopore sequencing enables episignature detection. In addition, concurrent haplotyped genomic and epigenomic analyses leverage simultaneous detection of single nucleotide/structural variants, X-inactivation, and imprinting, consolidating a multi-step sequential process into a single diagnostic assay.

Importance Preventive efforts in pregnancy-related alloimmunization have considerably decreased the prevalence of hemolytic disease of the fetus and newborn (HDFN). International studies are therefore essential to obtain a deeper understanding of the postnatal management and outcomes of HDFN. Taken together with numerous treatment options, large practice variations among centers may exist. Objectives To assess variations in postnatal management and outcomes of HDFN among international centers and to identify opportunities to improve care. Design, Setting, and Participants In this international, retrospective, cohort study, 31 expert centers from 22 countries retrieved data on neonates with HDFN managed between January 1, 2006, and July 1, 2021. Statistical analysis was performed from July 19, 2023, to October 28, 2024. Main Outcomes and Measures Main outcomes included the frequency of exchange transfusions, administration of intravenous immunoglobulin, administration of erythropoiesis-stimulating agents, and red blood cell transfusions, as well as the association of gestational age at birth with exchange transfusion frequency and risk factors for adverse neonatal outcomes. Results The study included 1855 neonates (median gestational age at birth, 36.4 weeks [IQR, 35.0-37.3 weeks]; 1034 boys [55.7%]), of whom 1017 (54.8%) received any form of antenatal treatment. Most neonates (1447 [78.0%]) had anti-D antibodies. Exchange transfusions were performed in 436 neonates (23.5%), with proportions in exchange transfusion frequency varying from 0% to 78% among centers. Intravenous immunoglobulin was administered to 429 of 1743 neonates (24.6%), with proportions varying from 0% to 100% among centers. A higher gestational age at birth was associated with a reduction in exchange transfusion frequency in neonates with intrauterine transfusion, decreasing from approximately 38.2% (13 of 34) at 34 weeks to 16.8% (18 of 107) after 37 weeks and 0 days. A weekly increase in gestational age at birth was associated with a 43.3% decrease (95% CI, 36.1%-49.7%) in the likelihood of adverse neonatal outcomes, and neonates who received an exchange transfusion were 1.55 (95% CI, 1.10-2.18) times more likely to experience unfavorable outcomes. Conclusions and Relevance In this cohort study of neonates with HDFN managed at 31 centers in 22 countries, significant practice variations in the postnatal management of HDFN were identified, highlighting the lack of, and need for, consensus. The study suggests that there is a potential beneficial clinical association of waiting for delivery until after 37 weeks and 0 days with frequency of exchange transfusions among neonates with HDFN. The framework to implement international guidelines is provided.

Human recombination-activating gene (RAG) deficiency can manifest with distinct clinical and immunological phenotypes. By applying a multiomics approach to a large group of RAG -mutated patients, we aimed at characterizing the immunopathology associated with each phenotype. Although defective T and B cell development is common to all phenotypes, patients with hypomorphic RAG variants can generate T and B cells with signatures of immune dysregulation and produce autoantibodies to a broad range of self-antigens, including type I interferons. T helper 2 (T H 2) cell skewing and a prominent inflammatory signature characterize Omenn syndrome, whereas more hypomorphic forms of RAG deficiency are associated with a type 1 immune profile both in blood and tissues. We used cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) analysis to define the cell lineage–specific contribution to the immunopathology of the distinct RAG phenotypes. These insights may help improve the diagnosis and clinical management of the various forms of the disease.

Background Conventional tests for inherited thrombophilia focus on the five most-established inherited thrombophilias; i.e. deficiencies in antithrombin, protein C, and protein S, and the factor V Leiden and prothrombin G20210A variants. These tests identify thrombophilia in approximately 40% of tested patients with venous thromboembolism (VTE). Next-generation sequencing allows to detect variants in multiple coagulation-related genes, yet its clinical value for VTE remains unknown. Objectives This study aims to report the findings from a multi-gene coagulation panel for VTE and assess its complementarity to conventional thrombophilia testing in clinical practice. Methodology We conducted a single-center retrospective analysis of VTE patients tested with the Thrombosis-Hemostasis multi-gene (THG) panel, comprising 31 diagnostic-grade genes involved in thrombosis and hemostasis, from January 2019 to December 2023. We compared the results of the THG panel with conventional tests and analyzed characteristics associated with positive gene panel results. Results The THG panel identified genetic variants in 63% of 194 VTE patients. Half of the variants were classified as (likely) pathogenic variants ((L)PV). Thirty-six (19%) cases carried variants in multiple genes. Among the 185 patients with available conventional test results, the THG panel detected non-compatible variants ((L)PV or variants of unknown significance (VUS)) in 76 patients (41%), which would remain undetected by performing conventional tests. Strictly concordant genetic findings were observed in 92 cases (50%). Conclusion The use of the THG panel provides more insights into the underlying thrombophilia of patients with VTE; however, its implications for patient management require further investigation.

Background Pathological tau accumulation is the primary constituent of neurofibrillary tangles and other tau aggregates seen in various neurodegenerative diseases collectively known as tauopathies. Recently, immunotherapeutic strategies focused on tau have shown promise in reducing tauopathy in both cellular and animal models. Method We previously used humanized yeast models to purify recombinant hyper‐phosphorylated human Tau for mouse immunizations and the isolation of a high‐affinity anti‐Tau monoclonal antibody (mAb) with enhanced diagnostic and prognostic capacities. Although conventional immunotherapeutic approaches targeting tau can influence tau pathogenesis, the majority of pathological tau remains in the cytosol of cells, not typically accessible to an extracellular antibody. Therefore, based on the in‐house mAb we designed a single‐chain fragment variable (ScFv), named 16B12, that is abundantly expressed in cellulo. Result Our results demonstrate that the expression of 16B12 significantly diminishes the presence of Tau aggregates in cells exposed to brain‐derived seeds obtained from Tau PS19 mice at different ages, as well as from individuals with Alzheimer’s disease at varying stages and patients with different Tauopathies (CBD, PSP, PiD). This reduction is higher compared to a known tau fibrillar core‐targeting nanobody or an off‐target ScFv. Conclusion Our conformational specific intrabody eliminates tauopathy in cellulo and our goal is to further explore the therapeutic capacities of the AAV‐delivered ScFv in delaying or eliminating tauopathy in human Tau transgenic mice.

Background The Amyloid Imaging to Prevent Alzheimer’s Disease (AMYPAD) Prognostic & Natural History Study (PNHS) is a prospective longitudinal PET cohort of over 1,500 non‐demented individuals from 10 parent cohorts across Europe. We provide an overview of ongoing efforts to curate and integrate magnetic resonance imaging (MRI) multimodal images across sites and to extract biologically meaningful information (i.e., image‐derived phenotypes; IDPs) in this early AD population. Data will be made available on the ADDI platform (fair.addi.ad‐datainitiative.org). Method Imaging protocols included core (T1w, T2w, T2*, FLAIR) and advanced (rs‐fMRI, SWI, DWI, and ASL) MRI sequences. Figure 1 provides an overview of the different acquisitions, their corresponding pipelines, and the obtained IDPs. For T1w images, we computed regional volumes and thickness values using FreeSurfer v7.1.1 (surfer.nmr.mgh.harvard.edu/). Morphometric similarity networks were computed using MIND (github.com/isebenius/MIND). White matter hyperintensity volumes were obtained from FLAIR images using Bayesian Model Selection (BaMoS). With rs‐fMRI, mean functional connectivity of canonical networks were extracted using FSL MELODIC and dual‐regression analyses after preprocessing with fMRIPrep v23.0.1 (fmriprep.org). Diffusion MRI scans were processed with QSIprep v0.16 (qsiprep.readthedocs.io) to compute tract‐based spatial statistics and tractograms to build structural connectivity matrices. Finally, cerebral blood flow and the spatial coefficient of variation were computed from ASL images using ExploreASL (github.com/ExploreASL). Statistical harmonization was performed using RELIEF (github.com/junjypark/RELIEF). Result Baseline and follow‐up characteristics of the 1537 subjects with available T1w are described in Table 1. Raw and statistically harmonized variants of 380 core and 298 advanced IDPs were calculated. Figure 2 shows the distribution of hippocampal volumes per site before and after statistical harmonization, and their relation with participants' age (R2raw=0.179, R2harmonized=0.422). Considering recent developments in the field, the AMYPAD PNHS aims to include additional IDPs associated with vascular health, such as perivascular spaces and other glymphatic system‐related markers. Conclusion We present the pipeline built for MRI harmonization and feature extraction of the AMYPAD PNHS dataset. The extracted IDPs can help identify novel imaging outcomes, support the development of disease progression models for the preclinical stages of AD, and provide a reference point for future studies to promote replicability and robustness of findings.

Background Tau‐PET imaging allows in‐vivo detection of neurofibrillary tangles. One tau‐PET tracer (i.e., [18F]flortaucipir) has received FDA‐approval for clinical use, and multiple other tau‐PET tracers have been implemented into clinical trials for participant selection and/or as a primary or secondary outcome measure. To optimize future use of tau‐PET, it is essential to understand how demographic, clinical and genetic factors affect tau‐PET‐positivity rates. Method This large‐scale multi‐center study includes 9713 participants from 35 cohorts worldwide who underwent tau‐PET with [18F]flortaucipir (n = 6420), [18F]RO948 (n = 1999), [18F]MK6240 (n = 878) or [18F]PI2620 (n = 416) (Table‐1). We analyzed individual‐level tau‐PET SUVR data using a cerebellar reference region that were processed either centrally (n = 3855) or by each cohort (n = 5858). We computed cohort‐specific SUVR thresholds based on the mean + 2 standard deviations in a temporal meta‐region of amyloid‐negative cognitively normal (CN) individuals aged >50. Logistic generalized estimating equations were used to estimate tau‐PET‐positivity probabilities, using an exchangeable correlation structure to account for within‐cohort correlations. Analyses were performed with (interactions between) age, amyloid‐status, and APOE‐e4 carriership as independent variables, stratified for syndrome diagnosis. Result The study included 5962 CN participants (7.5% tau‐PET‐positive), 1683 participants with mild cognitive impairment (MCI, 33.8% tau‐PET‐positive) and 2068 participants with a clinical diagnosis of dementia (62.1% tau‐PET‐positive) (Figure‐1). From age 60 to 80 years, the estimated prevalence of tau‐PET‐positivity increased from 1.2% [95% CI: 0.9%‐1.5%] to 3.7% [2.3%‐5.1%] among CN amyloid‐negative participants; and from 16.4% [10.8%‐22.1%] to 20.5% [18.8%‐22.2%] among CN amyloid‐positive participants. Among amyloid‐negative participants with MCI and dementia, from age 60 to 80 years, the estimated prevalence of tau‐PET‐positivity increased from 3.5% [1.6%‐5.3%] to 11.8% [7.1%‐16.5%] and from 12.6% [4.5%‐20.7%] to 15.9% [6.7%‐25.1%] respectively. In contrast, among amyloid‐positive participants with MCI and dementia, from age 60 to 80 years, the estimated prevalence of tau‐PET‐positivity decreased from 66.5% [57.0%‐76.0%] to 48.3% [42.9%‐53.8%] and from 92.3% [88.7%‐95.9%] to 73.4% [67.5%‐79.3%] respectively. APOE‐e4 status primarily modulated the association of age with tau‐PET‐positivity estimates among CN and MCI amyloid‐positive participants (Figure‐2). Conclusion This large‐scale multi‐cohort study provides robust prevalence estimates of tau‐PET‐positivity, which can aid the interpretation of tau‐PET in the clinic and inform clinical trial designs.

Background Dementia with Lewy bodies (DLB) is a an a‐synucleinopathy characterized by dementia and a combination of parkinsonism, visual hallucinations, fluctuating cognition or REM sleep behaviour disorder. Specific biomarkers for DLB are lacking. DLB‐related pattern (DLBRP) is a metabolic network imaging biomarker which expression can be quantified on a single patient basis. DLBRP has been identified in few different cohorts but lacks a multicentric validation. Methods FDG PET scans from 259 DLB patients and 176 normal controls (NC) were obtained from eight centres from European DLB Consortium (EDLB, 180 patients), Alzheimer’s disease Neuroimaging Initiative (ADNI, 135 NC) and local dataset from Ljubljana (LJU, 79 patients and 41 NC). FDG PET scans were pre‐processed and we used topographic profile rating to calculate the DLBRP expression (i.e. subject scores). Subject scores were compared between groups using t tests and ANOVA and correlated with clinical parameters using Pearson’s correlation coefficient. Results Patients from different centres differed in MMSE (p < 0.001), proportion of patients with parkinsonism (p < 0.001) and visual hallucinations (p < 0.001), but not in age (p = 0.15) or sex distribution (p = 0.13). DLB patients from all centres had significantly higher DLBRP expression than NCs (all p < 0.001). We could accurately distinguish between DLB and NC (AUC = 0.983) based on DLBRP expression. We observed a negative correlation between DLBRP expression and MMSE (r = –0.30, p < 0.001). The expression of DLBRP differed among centres, post hoc analysis showed that only patients from Barcelona had significantly lower DLBRP subject scores in comparison to other groups but they were also less cognitively impaired. Patients with visual hallucinations (p < 0.001) had significantly higher DLBRP expression than those without hallucinations and patients with abnormal Datscan™ (p = 0.02) had higher DLBRP expression than those with normal Datscan™. Other core features, levodopa or antidementives did not affect the DLBRP expression. Conclusions We showed that DLBRP can accurately distinguish between DLB and NC from multiple centres and different scanners. The DLBRP expression correlated with measurements of cognitive impairment. This validation study confirms that the DLBRP is a robust metabolic imaging biomarker of DLB.

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 The Amyloid Imaging to Prevent Alzheimer’s Disease (AMYPAD) Prognostic & Natural History Study (PNHS) is a prospective longitudinal PET cohort of over 1,500 non‐demented individuals from 10 parent cohorts across Europe. We provide an overview of ongoing efforts to curate and integrate magnetic resonance imaging (MRI) multimodal images across sites and to extract biologically meaningful information (i.e., image‐derived phenotypes; IDPs) in this early AD population. Data will be made available on the ADDI platform (fair.addi.ad‐datainitiative.org). Method Imaging protocols included core (T1w, T2w, T2*, FLAIR) and advanced (rs‐fMRI, SWI, DWI, and ASL) MRI sequences. Figure 1 provides an overview of the different acquisitions, their corresponding pipelines, and the obtained IDPs. For T1w images, we computed regional volumes and thickness values using FreeSurfer v7.1.1 (surfer.nmr.mgh.harvard.edu/). Morphometric similarity networks were computed using MIND (github.com/isebenius/MIND). White matter hyperintensity volumes were obtained from FLAIR images using Bayesian Model Selection (BaMoS). With rs‐fMRI, mean functional connectivity of canonical networks were extracted using FSL MELODIC and dual‐regression analyses after preprocessing with fMRIPrep v23.0.1 (fmriprep.org). Diffusion MRI scans were processed with QSIprep v0.16 (qsiprep.readthedocs.io) to compute tract‐based spatial statistics and tractograms to build structural connectivity matrices. Finally, cerebral blood flow and the spatial coefficient of variation were computed from ASL images using ExploreASL (github.com/ExploreASL). Statistical harmonization was performed using RELIEF (github.com/junjypark/RELIEF). Result Baseline and follow‐up characteristics of the 1537 subjects with available T1w are described in Table 1. Raw and statistically harmonized variants of 380 core and 298 advanced IDPs were calculated. Figure 2 shows the distribution of hippocampal volumes per site before and after statistical harmonization, and their relation with participants' age (R² raw=0.179, R² harmonized=0.422). Considering recent developments in the field, the AMYPAD PNHS aims to include additional IDPs associated with vascular health, such as perivascular spaces and other glymphatic system‐related markers. Conclusion We present the pipeline built for MRI harmonization and feature extraction of the AMYPAD PNHS dataset. The extracted IDPs can help identify novel imaging outcomes, support the development of disease progression models for the preclinical stages of AD, and provide a reference point for future studies to promote replicability and robustness of findings.

Background Synaptic loss is a critical early pathological hallmark of neurodegeneration, in particular in Alzheimer’s disease (AD), as evidenced by in vitro as well as in vivo PET studies. To date, it is not clear how blood‐based synaptic and AD biomarkers relate to synaptic density in the brains of non‐demented elderly, including those diagnosed with depression. Method This cross‐sectional study included 61 older adults with no history of dementia (age [mean±SD] = 71±6 years, MMSE (median[IQR] = 28[3], 64% female, 38% late‐life depression) from the Leuven late‐life depression (L3D) study. Plasma as well as [¹¹C]UCB‐J PET (synaptic vesicle protein 2A [SV2A]) were acquired from all participants. Subgroups underwent [¹⁸F]MK6240 (tau load, n = 51) and [¹⁸F]flutemetamol (amyloid‐β [Aβ] load, n = 48) PET. Plasma SNAP25, VAMP2 and pTau181 were quantified using Homebrew Simoa assays developed by ADx Neurosciences. Plasma GFAP, Aβ1‐42 and Aβ1‐40 were quantified using the Quanterix N4PE Simoa kit. Associations between biomarkers and SV2A density were evaluated using voxelwise regression models adjusted for age, sex and depression diagnosis at peak‐level Puncorrected <.05 and cluster‐level PFWE <.05. If significant clusters were detected, Spearman correlations were calculated across the identified clusters for each biomarker. Global brain Aβ and tau load were assessed in Aβ‐ and tau‐vulnerable regions and also correlated with plasma biomarkers. Result High GFAP levels associated with low synaptic density within temporal regions (GFAP cluster 1) as well as the precuneus and cingulate gyrus (GFAP cluster 2) with ρGFAP = ‐0.39 (P =.002, Figure 1A). High VAMP2 levels were associated with lower synaptic density within temporal and frontal and – to a lesser extent – occipital regions (ρVAMP2 = ‐0.55, P <.001, Figure 1B). For the Aβ1‐42/Aβ1‐40 ratio as well as pTau181 and SNAP25 levels, no associations with synaptic density were observed. Of note, study participants overall demonstrated low global Aβ and tau pathology (Figure 2) and no correlations were found with global Aβ nor tau load for any of the plasma biomarkers. Conclusion Plasma levels of GFAP and VAMP2 reflect synaptic density independently of pathological AD hallmarks in nondemented elderly with low evidence of AD pathology.

Background In Alzheimer disease (AD) changes in the small world network have been described, which can be considered as the balance between local connectivity, exhibited with the “clustering coefficient”, and global integration, investigated by “characteristic path length”. With high‐density EEG, we examined the effect of early spread of tau aggregates on these global graph measures. Method This study includes 47 participants who underwent a 100‐minute dynamic ¹⁸F‐MK6240 PET‐scan and a five‐minutes eyes closed 128‐channel resting‐state EEG. The total group consisted of 24 cognitively normal amyloid‐negative individuals (CN_N), 10 cognitively normal amyloid‐positive individuals (asymptomatic AD) (CN_P) and 13 patients with prodromal AD (Table 1). We calculated in the alpha frequency band the average undirected weighted Phase‐Lag‐Index and used this as weights for the graph and analyzed the global graph measures characteristic path length and clustering coefficient in sensor‐space. For both the whole group as for the constituent subgroups, we examined the Spearman correlation between these global graph measures and tau‐PET load in an a priori defined early‐metaVOI, comprised of the entorhinal and perirhinal cortex, hippocampus, parahippocampus and fusiform cortex. To investigate the difference between tau‐PET load, clustering coefficient and path length in the 3 subgroups, we applied a Kruskal‐Wallis test. Result There was a significant correlation of tau‐PET load with the characteristic path length (r=0.33; p=0.03) and also with the global clustering coefficient (r=‐0.39; p=0.007) in the whole group analysis. When considering the asymptomatic AD group separately, there was also a significant correlation of tau‐PET load with the characteristic path length (r=0.77; p=0.01) and with the global clustering coefficient (r=‐0.82; p=0.007). There was no significant correlation within the CN_N subgroup (path length r=‐0.03; p=0.91; clustering coefficient (r=‐0.06; p=0.80)), neither in the prodromal AD subgroup (path length r=‐0.13; p=0.67; clustering coefficient (r=‐0.03; p=0.92)) (Figure 1). There was a significant difference in tau‐PET load between the subgroups CN_N and prodromal AD (p<0.025) and in clustering coefficient and path length between the CN_N and the CN_P group versus the prodromal AD subgroup (p<0.025). Conclusion In the asymptomatic stage of AD, focal tau‐PET load in medial temporal cortex is associated with global electrophysiological measures of network disintegration.