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In Alzheimer's disease (AD), amyloid-β (Aβ) triggers the aggregation and spreading of tau pathology, which drives neurodegeneration and cognitive decline. However, the pathophysiological link between Aβ and tau remains unclear, which hinders therapeutic efforts to attenuate Aβ-related tau accumulation. Aβ has been found to trigger neuronal hyperactivity and hyperconnectivity, and preclinical research has shown that tau spreads across connected neurons in an activity-dependent manner. Here, we hypothesized that neuronal hyperactivity and hypersynchronicity, resulting in functional connectivity increases, constitute a crucial mechanism by which Aβ facilitates the spreading of tau pathology. By combining Aβ positron emission tomography (PET), resting-state functional magnetic resonance imaging, and longitudinal tau-PET in 69 cognitively normal amyloid-negative controls and 140 amyloid-positive patients covering the AD spectrum, we confirmed that Aβ induces hyperconnectivity of temporal lobe tau epicenters to posterior brain regions that are vulnerable to tau accumulation in AD. This was replicated in an independent sample of 55 controls and 345 individuals with preclinical AD and low cortical tau-PET uptake, suggesting that the emergence of Aβ-related hyperconnectivity precedes neocortical tau spreading . Last, using longitudinal tau-PET and mediation analysis, we confirmed that these Aβ-related connectivity increases in tau epicenters to typical tau-vulnerable brain regions in AD mediated the effect of Aβ on faster tau accumulation, unveiling increased connectivity as a potential causal link between the two AD hallmark pathologies. Together, these findings suggest that Aβ promotes tau spreading by eliciting neuronal hyperconnectivity and that targeting Aβ-related neuronal hyperconnectivity may attenuate tau spreading in AD.

Background: "Patient Voices" is a software developed to promote the systematic collection of electronic patient-reported outcome measures (ePROMs) in routine oncology clinical practice., Objective: This study aimed to assess compliance with and feasibility of the Patient Voices ePROM system and analyze patient-related barriers in an Italian comprehensive cancer center., Methods: Consecutive patients with cancer attending 3 outpatient clinics and 3 inpatient wards were screened for eligibility (adults, native speakers, and being able to fill in the ePROMs) and enrolled in a quantitative and qualitative multimethod study. Compliance, reasons for not administering the ePROMs, patients' interaction needs, and patient-perceived System Usability Scale (range 0-100) were collected; semistructured interviews were carried out in a subsample of patients., Results: From June 2020 to September 2021, a total of 435 patients were screened, 421 (96.7%) were eligible, and 309 completed the ePROMs (309/421, 73.4%; 95% CI 69.8%-77.5%; mean age 63.3, SD 13.7 years). Organization problems and patient refusal were the main reasons for not administering the ePROMs (outpatients: 40/234, 17.1% and inpatients: 44/201, 21.9%). Help for tablet use was needed by 27.8% (47/169) of outpatients and 10.7% (15/140) of inpatients, while the support received for item interpretation was similar in the 2 groups (outpatients: 36/169, 21.3% and inpatients: 26/140, 18.6%). Average System Usability Scale scores indicated high usability in both groups (outpatients: mean 86.8, SD 15.8 and inpatients: mean 83.9, SD 18.8). Overall, repeated measurement compliance was 76.9% (173/225; outpatients only). Interviewed patients showed positive attitudes toward ePROMs. However, there are barriers to implementation related to the time and cognitive effort required to complete the questionnaires. There is also skepticism about the usefulness of ePROMs in interactions with health care professionals., Conclusions: This study provides useful information for future ePROM implementation strategies, aimed at effectively supporting the routine clinical management and care of patients with cancer. In addition, these findings may be relevant to other organizations willing to systematically collect PROMs or ePROMs in their clinical routines., Trial Registration: ClinicalTrials.gov NCT03968718; https://clinicaltrials.gov/study/NCT03968718., (©Cinzia Brunelli, Sara Alfieri, Emanuela Zito, Marco Spelta, Laura Arba, Linda Lombi, Luana Caselli, Augusto Caraceni, Claudia Borreani, Anna Roli, Rosalba Miceli, Gabriele Tine', Ernesto Zecca, Marco Platania, Giuseppe Procopio, Nicola Nicolai, Luigi Battaglia, Laura Lozza, Morena Shkodra, Giacomo Massa, Daniele Loiacono, Giovanni Apolone. Originally published in JMIR Cancer (https://cancer.jmir.org), 22.01.2025.)

Single-cell proteomics (SCP) promises to revolutionize biomedicine by providing an unparalleled view of the proteome in individual cells. Here, we present a high-sensitivity SCP workflow named Chip-Tip, identifying >5,000 proteins in individual HeLa cells. It also facilitated direct detection of post-translational modifications in single cells, making the need for specific post-translational modification-enrichment unnecessary. Our study demonstrates the feasibility of processing up to 120 label-free SCP samples per day. An optimized tissue dissociation buffer enabled effective single-cell disaggregation of drug-treated cancer cell spheroids, refining overall SCP analysis. Analyzing nondirected human-induced pluripotent stem cell differentiation, we consistently quantified stem cell markers OCT4 and SOX2 in human-induced pluripotent stem cells and lineage markers such as GATA4 (endoderm), HAND1 (mesoderm) and MAP2 (ectoderm) in different embryoid body cells. Our workflow sets a benchmark in SCP for sensitivity and throughput, with broad applications in basic biology and biomedicine for identification of cell type-specific markers and therapeutic targets., Competing Interests: Competing interests: D.B.B.-J. and N.B. are employees of Evosep Biosystems. D.H., F.I. and A.S. are employees of Cellenion SASU. H.H., M.H. and X.L. are employees of Thermo Fisher Scientific. The other authors declare no competing interests., (© 2025. The Author(s).)

Aging affects the 12-lead electrocardiogram (ECG) and correlates with cardiovascular disease (CVD). AI-ECG models estimate aging effects as a novel biomarker but have only been evaluated on single ECGs-without utilizing longitudinal data. We validated an AI-ECG model, originally trained on Brazilian data, using a German cohort with over 20 years of follow-up, demonstrating similar performance (r 2 = 0.70) to the original study (0.71). Incorporating longitudinal ECGs revealed a stronger association with cardiovascular risk, increasing the hazard ratio for mortality from 1.43 to 1.65. Moreover, aging effects were associated with higher odds ratios for atrial fibrillation, heart failure, and mortality. Using explainable AI methods revealed that the model aligns with clinical knowledge by focusing on ECG features known to reflect aging. Our study suggests that aging effects in longitudinal ECGs can be applied on population level as a novel biomarker to identify patients at risk early., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Traumatic brain injury is widely viewed as a risk factor for dementia, but the biological mechanisms underlying this association are still unclear. In previous studies, traumatic brain injury has been associated with the hallmark pathologies of Alzheimer's disease, i.e. amyloid-β plaques and neurofibrillary tangles comprised of hyperphosphorylated tau. Depending on the type and location of trauma, traumatic brain injury can induce spatially heterogeneous brain lesions that may pre-dispose for the development of Alzheimer's disease pathology in aging. Therefore, we hypothesized that a history of traumatic brain injury may be related to spatially heterogeneous amyloid-β and tau pathology patterns that deviate from the stereotypical temporo-parietal patterns in Alzheimer's disease. To test this, we included 103 Vietnam War veterans of whom 65 had experienced traumatic brain injury ( n = 40, 38.8% mild; n = 25, 24.3% moderate/severe). Most individuals had a history of 1 ( n = 35, 53.8%) or 2 ( n = 15, 23.1%) traumatic brain injury events. We included the group without a history of traumatic brain injury ( n = 38, 36.9%) as controls. The majority was cognitively normal ( n = 80, 77.7%), while a subset had mild cognitive impairment ( n = 23, 22.3%). All participants underwent [ 18 F]florbetapir/Amyvid amyloid-β PET and [ 18 F]flortaucipir/Tauvid tau-PET 39.63 ± 18.39 years after their last traumatic brain injury event. We found no differences in global amyloid-β and tau-PET levels between groups, suggesting that a history of traumatic brain injury does not pre-dispose to accumulate amyloid-β or tau pathology in general. However, we found that traumatic brain injury was associated with altered spatial patterns of amyloid-β and tau, with relatively greater deposition in fronto-parietal brain regions. These regions are prone to damage in traumatic brain injury, while they are typically only affected in later stages of Alzheimer's disease. Moreover, in our traumatic brain injury groups, the association between amyloid-β and tau was reduced in Alzheimer-typical temporal regions but increased in frontal regions that are commonly associated with traumatic brain injury. Altogether, while acknowledging the relatively small sample size and generally low levels of Alzheimer's disease pathology in this sample, our findings suggest that traumatic brain injury induces spatial patterns of amyloid-β and tau that differ from patterns observed in typical Alzheimer's disease. Furthermore, traumatic brain injury may be associated with a de-coupling of amyloid-β and tau in regions vulnerable in Alzheimer's disease. These findings indicate that focal brain damage in early/mid-life may change neurodegenerative trajectories in late-life., Competing Interests: C.G. is supported by a Dementia Fellowship grant from ZonMW (10510022110010). E.G.B.V. is PI for DIAN trials, WashU, ACI, Alnylam, CogRX therapeutics, New Amsterdam Pharma, Janssen, Roche, Vivoryon, ImmunoBrain, Alector, Biogen, BMS, Prothena, GSK, Aviadobio, Treeway. E.G.B.V. is consulent for New Amsterdam Pharma, Treeway, Vivoryon, Biogen, Vigil Neuroscience, ImmunoBrain Checkpoint, Roche, Eli Lilly en Esai. Y.A.L.P. has received funding from the Dutch Brain Foundation, ZonMW, NWO and the Mooiste Contact Fonds (both paid to her institution). Projects of R.O. received support of the European Research Council, ZonMw, NWO, National Institute of Health, Alzheimer Association, Alzheimer Nederland, Stichting Dioraphte, Cure Alzheimer’s fund, Health Holland, ERA PerMed, Alzheimerfonden, Hjarnfonden, Avid Radiopharmaceuticals, Janssen Research & Development, Roche, Quanterix and Optina Diagnostics. R.O. was speaker at symposia organized by GE healthcare. R.O. is an advisory board member for Asceneuron, Bristol Myers Squibb and Biogen. All the aforementioned has been paid to the institutions. R.O. is part of the editorial board of Alzheimer’s Research & Therapy and the European Journal of Nuclear Medicine and Molecular Imaging. N.F. received research support from the Alzheimer Forschung Initiative, the Hertie Network of Excellence in Neuroscience, the German Parkinson Foundation (DPG), the Legerlotz Foundation, the Gerhard and Ilse Schick Foundation, the Alzheimer’s Association, the Bright Focus Foundation, LMU excellence and the DFG excellence initiative, as well as speaker honoraria from Eisai, GE Healthcare, Life Molecular Imaging and Consulting Honoraria from MSD., (© The Author(s) 2025. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Purpose of the Report: Adults with Down Syndrome (DS) have a substantially increased risk for Alzheimer's disease (AD) due to the triplicated amyloid-precursor-protein gene on chromosome 21, resulting in amyloid and tau accumulation. However, tau PET assessments are not sufficiently implemented in DS-AD research or clinical work-up, and second-generation tau tracers such as [ 18 F]PI-2620 have not been thoroughly characterized in adults with DS. We aim at illustrating feasibility and potential diagnostic value of tau PET imaging with [ 18 F]PI-2620 for the diagnosis of DS-AD., Materials and Methods: Five adults with DS (40% female, aged 43-62) and cognitive decline underwent clinical assessments, neuropsychological testing, lumbar puncture and multimodal neuroimaging. All underwent [ 18 F]PI-2620 tau PET. Visual read of tau PET scans was performed by three blinded raters, assessing increased tracer uptake in brain areas corresponding to the six Braak stage regions and basal ganglia., Results: Visual read of tau burden revealed three tau-positive individuals which corresponded to their clinical decline while two cognitively stable individuals were rated as negative. Rating showed high inter-rater reliability for all Braak stages., Conclusion: Tau PET imaging is a feasible and important biomarker assessment in the differential diagnosis of cognitive decline in adults with DS at risk of developing AD., Competing Interests: MB is a member of the Neuroimaging Committee of the EANM, received speaker honoraria from Roche, GE healthcare and Life Molecular Imaging and served as an advisor of MIAC and Life Molecular Imaging. NF received speaker and travel honoraria from Life Molecular Imaging, speaker honoraria from GE Healthcare and Eli Lilly and consulting honoraria from MSD. JL reported personal/ speaker/consulting fees from Bayer Vital, Biogen, Eisai, Teva, Zambon, Merck, Roche, Axon Neuroscience, Thieme medical publishers, W. Kohlhammer GmbH, and Modag GmbH, and having a patent for Oral Phenylbutyrate for Treatment of Human 4-Repeat Tauopathies pending. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2025 Wagemann, Brendel, Franzmeier, Nübling, Gnörich, Zaganjori, Prix, Stockbauer, Wlasich, Loosli, Sandkühler, Frontzkowski, Höglinger and Levin.)

Ovarian cancer remains the most lethal gynecological malignancy. Despite the approval of promising targeted therapy such as bevacizumab and PARP inhibitors, 5-year survival has not improved significantly. Thus, there is an urgent need for new therapeutics. New advancements in therapeutic strategies target the pivotal hallmarks of cancer. This review is giving an updated overview of innovative and upcoming therapies for the treatment of ovarian cancer that focuses specific on the hallmarks of cancer. The hallmarks of cancer constitute a broad concept to reenact complexity of malignancies and furthermore identify possible targets for new treatment strategies. For this purpose, we analyzed approvals and current clinical phase III studies (registered at ClinicalTrials.gov (National Library of Medicine, National Institutes of Health; U.S. Department of Health and Human Services, 2024)) for new drugs on the basis of their mechanisms of action and identified new target approaches. A broad spectrum of new promising drugs is currently under investigation in clinical phase III studies targeting mainly the hallmarks "self-sufficiency in growth signals," "genomic instability," and "angiogenesis." The benefit of immune checkpoint inhibitors in ovarian cancer has been demonstrated for the first time. Besides, targeting the tumor microenvironment is of growing interest. Replicative immortality, energy metabolism, tumor promoting inflammation, and the microbiome of ovarian cancer are still barely targeted by drugs. Nevertheless, precision medicine, which focuses on specific disease characteristics, is becoming increasingly important in cancer treatment., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

177 Lu-vipivotide tetraxetan prostate-specific membrane antigen ( 177 Lu-PSMA) therapy is under current scientific investigation and aims to become established in the treatment of metastatic castration-resistant prostate cancer (mCRPC). However, real-world evidence in treatment comparison is scant. Methods: We relied on the FRAMCAP database and compared cabazitaxel versus 177 Lu-PSMA therapy in mCRPC patients regarding progression-free survival (PFS) and overall survival (OS). Sensitivity analyses addressed second- to fourth-line mCRPC treatment to approximate current phase III patient selection criteria. Results: Of 373 patients, 14% received cabazitaxel, 65% received 177 Lu-PSMA, and 21% received both. Patients undergoing 177 Lu-PSMA therapy were significantly older than cabazitaxel patients (median, 72 y vs. 66 y; P < 0.01), and a higher proportion had an Eastern Cooperative Oncology Group score of 2 or more (12% vs. 5.0%, P = 0.1). Rates of a prostate-specific antigen decline of at least 50% were 32% versus 0% for 177 Lu-PSMA versus cabazitaxel. In outcome analyses, significant superior median PFS was observed for 177 Lu-PSMA versus cabazitaxel (13.4 mo vs. 7.1 mo, P < 0.001), even after multivariable adjustment (hazard ratio, 0.38; P < 0.001). Regarding OS, rates also significantly differed, with median OS of 14.7 mo versus 16.5 mo versus 29.6 mo for cabazitaxel versus 177 Lu-PSMA versus both treatments ( P < 0.01). In sensitivity analyses of second- to fourth-line mCRPC treatment, PFS rates and median OS rates for cabazitaxel versus 177 Lu-PSMA versus both therapies qualitatively remained the same as for the entire cohort. Conclusion: In a real-world setting, 177 Lu-PSMA provides significantly better PFS and qualitatively better OS rates than does cabazitaxel chemotherapy and should therefore be considered a valuable treatment option for advanced mCRPC patients according to the European Medicines Agency approval., (© 2025 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: Healthcare systems around the world are increasingly facing severe challenges due to problems such as staff shortage, changing demographics and the reliance on an often strongly human-dependent environment. One approach aiming to address these issues is the development of new telemedicine applications. The currently researched network standard 6G promises to deliver many new features which could be beneficial to leverage the full potential of emerging telemedical solutions and overcome the limitations of current network standards., Methods: We developed a telerobotic examination system with a distributed robot control infrastructure to investigate the benefits and challenges of distributed computing scenarios, such as fog computing, in medical applications. We investigate different software configurations for which we characterize the network traffic and computational loads and subsequently establish network allocation strategies for different types of modular application functions (MAFs)., Results: The results indicate a high variability in the usage profiles of these MAFs, both in terms of computational load and networking behavior, which in turn allows the development of allocation strategies for different types of MAFs according to their requirements. Furthermore, the results provide a strong basis for further exploration of distributed computing scenarios in medical robotics., Conclusion: This work lays the foundation for the development of medical robotic applications using 6G network architectures and distributed computing scenarios, such as fog computing. In the future, we plan to investigate the capability to dynamically shift MAFs within the network based on current situational demand, which could help to further optimize the performance of network-based medical applications and play a role in addressing the increasingly critical challenges in healthcare., Competing Interests: Declarations. Conflict of interest: The authors (Sven Kolb, Andrew Madden, Nicolai Kröger, Fidan Mehmeti, Franziska Jurosch, Lukas Bernhard, Wolfgang Kellerer, Dirk Wilhelm) have no Conflict of interest to declare that are relevant to the content of this article. Informed consent: This article does not contain patient data., (© 2024. The Author(s).)