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Background: The spread of tau pathology closely correlates with the disease course and cognitive decline in Alzheimer's disease (AD). Tau-targeting immunotherapies are being developed to stop the spread of tau pathology and thus halt disease progression. In this post hoc analysis of the ADAMANT clinical trial, we examined the performance of AADvac1, an active immunotherapy targeting the microtubule-binding region (MTBR) of tau, in a subgroup of participants with elevated plasma p-tau217, indicating AD-related neuropathological changes., Methods: ADAMANT was a 24-month, randomized, placebo-controlled, parallel-group, double-blinded, multicenter, phase 2 clinical trial in subjects with mild AD. The trial participants were randomized 3:2 to receive six doses of AADvac1 or placebo at 4-week intervals, followed by five booster doses at 14-week intervals. The primary outcome was safety. The secondary outcomes were the Clinical Dementia Rating-Sum of Boxes (CDR-SB), the Alzheimer's Disease Cooperative Study - Activities of Daily Living score for Mild Cognitive Impairment 18-item version (ADCS-ADL-MCI-18), and immunogenicity. Volumetric MRI, plasma neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) were exploratory outcomes. The inclusion criterion for this post-hoc analysis was a baseline plasma p-tau217 level above the cutoff for AD., Results: Among 196 ADAMANT participants, 137 were positive for plasma p-tau217 (mean age 71.4 years, 59% women). AADvac1 was safe and well tolerated in this subgroup. AADvac1 reduced the rate of accumulation of log-plasma NfL by 56% and that of GFAP by 73%. The treatment differences in the CDR-SB and ADCS-ADL-MCI-18 scores favored AADvac1 but were not statistically significant. AADvac1 had no effect on whole-brain volume but nonsignificantly reduced the loss of brain cortical tissue in several regions. Importantly, the impact on the study outcomes was more pronounced in participants with higher anti-tau antibody levels., Conclusions: These results suggest that AADvac1 tau immunotherapy can reduce plasma biomarkers of neurodegeneration and neuroinflammation. These findings and possible observations on brain atrophy and cognition are hypothesis-generating and warrant further evaluation in a larger clinical trial., Trial Registration: EudraCT 2015-000630-30 (primary) and NCT02579252., Competing Interests: Declarations. Ethics approval and consent to participate: The ADAMANT study protocol (provided with the Statistical Analysis Plan in Clinical Trial Material Supplement) was approved by the appropriate ethics committees and competent authorities [8]. All patients and their caregivers provided written informed consent before the study procedures. Consent for publication: Not applicable. Competing interests: All authors affiliated with AXON Neuroscience SE or AXON Neuroscience R&D Services SE received salaries from their respective companies. Petr Novak received payments from F. Hoffmann-La Roche AG. The investigators’ institutions received reimbursement on a per-patient per-visit basis. Bengt Winblad received personal fees from Axon Neuroscience for participating in SAB and DSMB. Howard H Feldman reports serving as a consultant to AXON Neuroscience through a service agreement with UC San Diego. No funds have been personally received, and no funding for this manuscript has been received. All the authors affiliated with ADx NeuroSciences received a salary. Eugeen Vanmechelen is a cofounder of the company., (© 2024. The Author(s).)

Introduction: Alzheimer's disease (AD) is marked by the accumulation of fibrillary aggregates composed of pathological tau protein. Although neuroinflammation is frequently observed in conjunction with tau pathology, current preclinical evidence does not sufficiently establish a direct causal role in tau tangle formation. This study aimed to evaluate whether chronic Toll-like receptor 4 (TLR4) stimulation, induced by a high dose of lipopolysaccharide (LPS, 5 mg/kg), exacerbates neurofibrillary tangle (NFT) pathology in a transgenic mouse model of tauopathy that expresses human truncated 151-391/3R tau, an early feature of sporadic AD., Methods: We utilized a transgenic mouse model of tauopathy subjected to chronic TLR4 stimulation via weekly intraperitoneal injections of LPS over nine consecutive weeks. Neurofibrillary tangle formation, microglial activation, and tau hyperphosphorylation in the brainstem and hippocampus were assessed through immunohistochemistry, immunofluorescence, and detailed morphometric analysis of microglia., Results: Chronic LPS treatment led to a significant increase in the number of Iba-1 + microglia in the LPS-treated group compared to the sham group ( p  < 0.0001). Notably, there was a 1.5- to 1.7-fold increase in microglia per tangle-bearing neuron in the LPS-treated group. These microglia exhibited a reactive yet exhausted phenotype, characterized by a significant reduction in cell area ( p  < 0.0001) without significant changes in other morphometric parameters, such as perimeter, circumference, solidity, aspect ratio, or arborization degree. Despite extensive microglial activation, there was no observed reduction in tau hyperphosphorylation or a decrease in tangle formation in the brainstem, where pathology predominantly develops in this model., Discussion: These findings suggest that chronic TLR4 stimulation in tau-transgenic mice results in significant microglial activation but does not influence tau tangle formation. This underscores the complexity of the relationship between neuroinflammation and tau pathology, indicating that additional mechanisms may be required for neuroinflammation to directly contribute to tau tangle formation., Competing Interests: The 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 © 2024 Basheer, Muhammadi, Freites, Avila, Momand, Hryntsova, Smolek, Katina and Zilka.)

The cerebral biomarkers, neurofilament light chain (NfL), amyloid-β, tau, and neuron specific enolase (NSE) reflect a wide spectrum of neurological damage in the brain and spinal cord. With this study, we aimed to assess whether these biomarkers hold any potential diagnostic value for the three most common canine neurological diseases. Canines suffering from meningoencephalitis of unknown origin (MUO), brain tumors, and selected non-infectious myelopathies were included. For each diagnosis, we analyzed these biomarkers in the cerebrospinal fluid collected via cranial puncture from the cisterna magna. Elevated levels of CSF tau, NfL, and NSE were observed in MUO, with all three biomarkers being intercorrelated. Tau and NSE were increased while amyloid-β was decreased in dogs suffering from tumors. In contrast, no biomarker changes were observed in dogs with myelopathies. Covariates such as age, sex, or castration had minimal impact. CSF biomarkers may reflect molecular changes related to MUO and tumors, but not to non-infectious myelopathies. The combination of NfL, tau, and NSE may represent useful biomarkers for MUO as they reflect the same pathology and are not influenced by age., (© 2024. The Author(s).)

Miyoshi myopathy/dysferlinopathy (MMD) is a rare muscle disease caused by DYSF gene mutations. Apart from skeletal muscles, DYSF is also expressed in the brain. However, the impact of MMD-causing DYSF variants on brain structure and function remains unexplored. To investigate this, we utilized magnetic resonance (MR) modalities (MR volumetry and 31 P MR spectroscopy) in a family with seven children, four of whom have the illness. The MMD siblings showed distinct differences from healthy controls: (1) a significant (p < 0.001) right-sided volume asymmetry (+ 232 mm 3 ) of the inferior lateral ventricles; and (2) a significant (p < 0.001) decrease in [Mg 2+ ], along with a modified energy metabolism profile and altered membrane turnover in the hippocampus and motor and premotor cortices. The patients' [Mg 2+ ], energy metabolism, and membrane turnover measures returned to those of healthy relatives after a month of 400 mg/day magnesium supplementation. This work is the first to describe anatomical and functional abnormalities characteristic of neurodegeneration in the MMD brain. Therefore, we call for further examination of brain functions in larger cohorts of MMD patients and testing of magnesium supplementation, which has proven to be an effective corrective approach in our study., (© 2024. The Author(s).)

The transcellular propagation of the aberrantly modified protein tau along the functional brain network is a key hallmark of Alzheimer's disease and related tauopathies. Inoculation-based tau propagation models can recapitulate the stereotypical spread of tau and reproduce various types of tau inclusions linked to specific tauopathy, albeit with varying degrees of fidelity. With this systematic review, we underscore the significance of judicious selection and meticulous functional, biochemical, and biophysical characterization of various tau inocula. Furthermore, we highlight the necessity of choosing suitable animal models and inoculation sites, along with the critical need for validation of fibrillary pathology using confirmatory staining, to accurately recapitulate disease-specific inclusions. As a practical guide, we put forth a framework for establishing a benchmark of inoculation-based tau propagation models that holds promise for use in preclinical testing of disease-modifying drugs., (© 2024. The Author(s).)

Background: Tau pathology correlates with and predicts clinical decline in Alzheimer's disease. Approved tau-targeted therapies are not available., Methods: ADAMANT, a 24-month randomised, placebo-controlled, parallel-group, double-blinded, multicenter, Phase 2 clinical trial (EudraCT2015-000630-30, NCT02579252) enrolled 196 participants with Alzheimer's disease; 119 are included in this post-hoc subgroup analysis. AADvac1, active immunotherapy against pathological tau protein. A machine learning model predicted likely Amyloid+Tau+ participants from baseline MRI., Statistical Methods: MMRM for change from baseline in cognition, function, and neurodegeneration; linear regression for associations between antibody response and endpoints., Results: The prediction model achieved PPV of 97.7% for amyloid, 96.2% for tau. 119 participants in the full analysis set (70 treatment and 49 placebo) were classified as A+T+. A trend for CDR-SB 104-week change (estimated marginal means [emm] = -0.99 points, 95% CI [-2.13, 0.13], p = 0.0825]) and ADCS-MCI-ADL (emm = 3.82 points, CI [-0.29, 7.92], p = 0.0679) in favour of the treatment group was seen. Reduction was seen in plasma NF-L (emm = -0.15 log pg/mL, CI [-0.27, -0.03], p = 0.0139). Higher antibody response to AADvac1 was related to slowing of decline on CDR-SB (rho = -0.10, CI [-0.21, 0.01], p = 0.0376) and ADL (rho = 0.15, CI [0.03, 0.27], p = 0.0201), and related to slower brain atrophy (rho = 0.18-0.35, p < 0.05 for temporal volume, whole cortex, and right and left hippocampus)., Conclusions: In the subgroup of ML imputed or CSF identified A+T+, AADvac1 slowed AD-related decline in an antibody-dependent manner. Larger anti-tau trials are warranted., Funding: AXON Neuroscience SE., Competing Interests: Declaration of interests Nick Cullen received personal fees from AXON Neuroscience SE. All authors affiliated with AXON NEUROSCIENCE SE or one of its subsidiaries received salary from their respective companies. Jozef Hanes, Eva Kontsekova, and Branislav Kovacech report patents with AXON Neuroscience R&D Services SE. Petr Novak received payments from F. Hoffmann-La Roche AG. The investigators’ institutions received reimbursement on a per-patient per-visit basis. Duygu Tosun’s institution received payments from AXON Neuroscience for image processing, and payments to the institution from Siemens Medical Solutions USA, Inc., Takeda Pharmaceutical Company Ltd., DOD WW81XWH-19-1-0669, NIH/NIA U19AG024904, NIH/NIA U01AG068057, NIH/NIA U24AG074855, NIH/NIA R01AG058676. Reinhold Schmidt has received personal fees and honoraria for image analyses from AXON NEUROSCIENCE. Stefan Ropele reports no conflict of interest. Bengt Winblad reports personal fees for taking part in Scientific Advisory Board meetings and Data Safety Management Board meetings from AXON NEUROSCIENCE, and from Alzinova DSMB and Artery TX SAB. Dr. Feldman reports a service agreement between Axon Neuroscience and UCSD for consulting and travel with all payments to UCSD and no personal funds received. Other activities to report include: grant funding from Annovis (QR Pharma), Vivoryon (Probiodrug), AC Immune, and LuMind; service agreements for consulting activities with LuMind, Genentech (DSMB), Roche/Banner (DMC), Tau Consortium (SAB), Samus Therapeutics, Biosplice Therapeutics, Novo Nordisk Inc., Janssen Research & Development LLC, and Arrowhead Pharmaceuticals with no personal funds received and all payments to UCSD. He also reports a philanthropic donation to UCSD from the Epstein Family Alzheimer's Disease Collaboration for therapeutic research in AD., (Copyright © 2023 AXON NEUROSCIENCE SE. Published by Elsevier B.V. All rights reserved.)

Protein kinases (PKs) have emerged as one of the most intensively investigated drug targets in current pharmacological research, with indications ranging from oncology to neurodegeneration. Tau protein hyperphosphorylation was the first pathological post-translational modification of tau protein described in Alzheimer's disease (AD), highlighting the role of PKs in neurodegeneration. The therapeutic potential of protein kinase inhibitors (PKIs)) and protein phosphatase 2 A (PP2A) activators in AD has recently been explored in several preclinical and clinical studies with variable outcomes. Where a number of preclinical studies demonstrate a visible reduction in the levels of phospho-tau in transgenic tauopathy models, no reduction in neurofibrillary lesions is observed. Amongst the few PKIs and PP2A activators that progressed to clinical trials, most failed on the efficacy front, with only a few still unconfirmed and potential positive trends. This suggests that robust preclinical and clinical data is needed to unequivocally evaluate their efficacy. To this end, we take a systematic look at the results of preclinical and clinical studies of PKIs and PP2A activators, and the evidence they provide regarding the utility of this approach to evaluate the potential of targeting tau hyperphosphorylation as a disease modifying therapy., (© 2023. The Author(s).)

Background: The neutrophil to lymphocyte ratio (NLR) has demonstrated prognostic value in various malignant conditions, including gastric adenocarcinoma. However, chemotherapy may affect NLR., Objectives: To evaluate the prognostic value of NLR as an accessory decision-making tool in terms of operating patients after neoadjuvant chemotherapy in patients with resectable gastric cancer., Methods: We collected oncologic, perioperative, and survival data of patients with gastric adenocarcinoma who underwent curative intent gastrectomy and D2 lymphadenectomy between 2009 and 2016. The NLR was calculated from preoperative laboratory tests and classified as high (> 4) and low (≤ 4). The t-test, chi-square, Kaplan-Meier analysis, and Cox multivariate regression models were used to assess associations of clinical, histologic, and hematological variables with survival., Results: For 124 patients the median follow-up was 23 months (range 1-88). High NLR was associated with greater rate of local complication (r=0.268, P < 0.01). The rate of major complications (Clavien-Dindo ≥ 3) was higher in the high NLR group (28% vs. 9%, P = 0.022). Among the 53 patients who received neoadjuvant chemotherapy, those with low NLR had significantly improved disease-free survival (DFS) (49.7 vs. 27.7 months, P = 0.025). Low NLR was not significantly associated with overall survival (mean survival, 51.2 vs. 42.3 months, P = 0.19). Multivariate regression identified NLR group (P = 0.013), male gender (P = 0.04), and body mass index (P = 0.026) as independently associated with DFS., Conclusions: Among gastric cancer patients planned for curative intent surgery who underwent neoadjuvant chemotherapy, NLR may have prognostic value, particularly regarding DFS and postoperative complications.

Alzheimer's disease (AD) is an incurable neurodegenerative disease and the most frequently diagnosed type of dementia, characterized by (1) perturbed cerebral perfusion, vasculature, and cortical metabolism; (2) induced proinflammatory processes; and (3) the aggregation of amyloid beta and hyperphosphorylated Tau proteins. Subclinical AD changes are commonly detectable by using radiological and nuclear neuroimaging methods such as magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET), and single-photon emission computed tomography (SPECT). Furthermore, other valuable modalities exist (in particular, structural volumetric, diffusion, perfusion, functional, and metabolic magnetic resonance methods) that can advance the diagnostic algorithm of AD and our understanding of its pathogenesis. Recently, new insights into AD pathoetiology revealed that deranged insulin homeostasis in the brain may play a role in the onset and progression of the disease. AD-related brain insulin resistance is closely linked to systemic insulin homeostasis disorders caused by pancreas and/or liver dysfunction. Indeed, in recent studies, linkages between the development and onset of AD and the liver and/or pancreas have been established. Aside from standard radiological and nuclear neuroimaging methods and clinically fewer common methods of magnetic resonance, this article also discusses the use of new suggestive non-neuronal imaging modalities to assess AD-associated structural changes in the liver and pancreas. Studying these changes might be of great clinical importance because of their possible involvement in AD pathogenesis during the prodromal phase of the disease.

Purpose: Intraoperative ultrasonography (IOUS) of the liver is a crucial adjunct in every liver resection and may significantly impact intraoperative surgical decisions. However, IOUS is highly operator dependent and has a steep learning curve. We describe the design and assessment of an artificial intelligence (AI) system to identify focal liver lesions in IOUS., Methods: IOUS images were collected during liver resections performed between November 2020 and November 2021. The images were labeled by radiologists and surgeons as normal liver tissue versus images that contain liver lesions. A convolutional neural network (CNN) was trained and tested to classify images based on the labeling. Algorithm performance was tested in terms of area under the curves (AUCs), accuracy, sensitivity, specificity, F1 score, positive predictive value, and negative predictive value., Results: Overall, the dataset included 5043 IOUS images from 16 patients. Of these, 2576 were labeled as normal liver tissue and 2467 as containing focal liver lesions. Training and testing image sets were taken from different patients. Network performance area under the curve (AUC) was 80.2 ± 2.9%, and the overall classification accuracy was 74.6% ± 3.1%. For maximal sensitivity of 99%, the classification specificity is 36.4 ± 9.4%., Conclusions: This study provides for the first time a proof of concept for the use of AI in IOUS and show that high accuracy can be achieved. Further studies using high volume data are warranted to increase accuracy and differentiate between lesion types., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: The typical symptoms of Alzheimer's disease (AD) are cognitive impairment, disrupted spatial orientation, behavioral and psychiatric abnormalities, and later motor deficits. Neuropathologically, AD is characterized by deposits of pathological forms of endogenous proteins - amyloid-β, and neurofibrillary tau protein pathology. The latter closely correlates with brain atrophy and clinical impairment. Pharmacological therapies for these pathologies are largely absent, raising the question whether non-pharmacological interventions could be efficacious. Environmental factors can play a role in the manifestation of AD. It is unknown whether enriched environment (EE) can ameliorate the propagation of protein aggregates or their toxic components., Methods: We injected insoluble tau extracts from human brains with AD (600 or 900 ng per animal) into hippocampi of SHR72 transgenic rats that express non-mutated truncated human tau 151-391/4R, but usually do not develop hippocampal tangles. The rats had either standard housing, or could access an EE 5×/week for 3 months. Behavioral analysis included the Morris Water Maze (MWM). Histological analysis was used to assess the propagation of tau pathology., Results: Animals exposed to EE performed better in the MWM (spatial acquisition duration and total distance, probe test); unexposed animals improved over the course of acquisition trials, but their mean performance remained below that of the EE group. Enriched environment abrogated tau propagation and hippocampal tangle formation in the 600 ng group; in the 900 ng group, tangle formation was ∼10-fold of the 600 ng group, and unaffected by EE., Conclusion: Even a small difference in the amount of injected human AD tau can cause a pronounced difference in the number of resulting tangles. EE leads to a noticeably better spatial navigation performance of tau-injected animals. Furthermore, EE seems to be able to slow down tau pathology progression, indicating the possible utility of similar interventions in early stages of AD where tangle loads are still low., Competing Interests: VM, TS, ZK, SJ, BJ, IU, NZ, SK, and PN have received salary from AXON Neuroscience SE or one of its subsidiaries. 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 © 2022 Mate, Smolek, Kazmerova, Jadhav, Brezovakova, Jurkanin, Uhrinova, Basheer, Zilka, Katina and Novak.)

Objective: The purpose of this study was to examine the feasibility of using augmented reality during lead placement for sacral nerve stimulation (SNS)., Methods: The study was a prospective case series performed in a single tertiary center. Patients with fecal incontinence or urinary retention eligible for SNS according to the American society of colon and rectal surgeon's guidelines were included. Each patient underwent a computerized tomography scan of the sacrum and pelvic floor before surgery; and a segmentation of the sacral bone, the skin, and three fiducial markers on the lower back was produced. Surgical planning included the design of an ideal virtual transmission tract leading to the S3 foramen using the most suitable location and needle trajectory for introducing the lead. During the surgical intervention, a needle was inserted into the S3 foramen using the aligned tract as visualized using the Microsoft HoloLens first generation head mounted unit., Results: Overall, 11 patients were included. Mean operative time was 43.8 minutes (range 25-81 minutes). All patients reported a significant reduction from the preoperative level of the mean postoperative Cleveland Clinic Incontinence Score (CCIS) assessed 2 weeks after the temporary SNS implant (CCIS preoperative 13.3, postoperative 8.5; CI -7.35 to -2.25; P < 0.01). The surgeons reported the imaging useful, allowing accurate and easier approach., Conclusions: Intraoperative augmented reality imaging for needle application during SNS appears to be feasible, practical, and may be useful in additional procedures., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The emergence of new SARS-CoV-2 variants of concern B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma) and B.1.617.2 (Delta) that harbor mutations in the viral S protein raised concern about activity of current vaccines and therapeutic antibodies. Independent studies have shown that mutant variants are partially or completely resistant against some of the therapeutic antibodies authorized for emergency use., Methods: We employed hybridoma technology, ELISA-based and cell-based S-ACE2 interaction assays combined with authentic virus neutralization assays to develop second-generation antibodies, which were specifically selected for their ability to neutralize the new variants of SARS-CoV-2., Findings: AX290 and AX677, two monoclonal antibodies with non-overlapping epitopes, exhibit subnanomolar or nanomolar affinities to the receptor binding domain of the viral Spike protein carrying amino acid substitutions N501Y, N439K, E484K, K417N, and a combination N501Y/E484K/K417N found in the circulating virus variants. The antibodies showed excellent neutralization of an authentic SARS-CoV-2 virus representing strains circulating in Europe in spring 2020 and also the variants of concern B.1.1.7 (Alpha), B.1.351 (Beta) and B.1.617.2 (Delta). In addition, AX677 is able to bind Omicron Spike protein just like the wild type Spike. The combination of the two antibodies prevented the appearance of escape mutations of the authentic SARS-CoV-2 virus. Prophylactic administration of AX290 and AX677, either individually or in combination, effectively reduced viral burden and inflammation in the lungs, and prevented disease in a mouse model of SARS-CoV-2 infection., Interpretation: The virus-neutralizing properties were fully reproduced in chimeric mouse-human versions of the antibodies, which may represent a promising tool for COVID-19 therapy., Funding: The study was funded by AXON Neuroscience SE and AXON COVIDAX a.s., Competing Interests: Declaration of interests All authors affiliated with AXON COVIDAX a.s., AXON Neuroscience SE, AXON Neuroscience R&D Services SE (BKo, LF, PF, RSk, MZ, NP-I, AK, DP, GPR, KT, NTC, KM, PM, VP, KS, NB, JH, MPr, OC, MC, JP, MF, MN, NZ, EK) receive a salary from or were employed by the respective companies. Biomedical Research Center, the employer of MS and BKl, received reimbursement from AXON Neuroscience SE for neutralization assays performed according to the research contract. KB, VC, BB, TVi, JN, LE, VH, MPa, DR, TVy, PS, BM, DZ, GK, VN, JP and RSe have no conflict of interest., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)