Biology subjects

Bussiere, T.

Publications and source records attributed to Bussiere, T..

4 recordsLinked to original sources

bioRxiv2026

An in vivo model of Amyloid-Related Imaging Abnormalities (ARIA) predicts ARIA incidence of anti-Aβ antibodies seen in clinical trials

Amyloid-related imaging abnormality (ARIA) is the most common adverse event associated with amyloid-beta (A{beta}) immunotherapy. The neuropathology underlying active ARIA lesions has been studied in only a few rare fatal cases. A faithful translational model of ARIA should allow a better understanding of pathogenic mechanisms and enable development of mitigation strategies. Since bapineuzumab induced the most frequent and severe forms of ARIA in humans, we assessed the ability of its murine precursor, 3D6, to induce ARIA-like lesions by applying clinically-validated MRI sequences in a mouse model with extensive amyloid deposition. Using this paradigm we documented ARIA-like changes based on their imaging features, location, and temporal evolution and established postmortem histopathologic correlates. We observed that ARIA-like lesions were ubiquitously induced with 3D6, including T2-hyperintense leptomeningeal effusions, T2-hyperintense parenchymal lesions and T2* hypointense parenchymal lesions. Histological assays demonstrated meningovascular inflammation as well as vascular mural permeation and microvascular lesions, including microhemorrhages and microinfarcts. Compared to 3D6-treated mice, animals treated with mouse analogues of aducanumab and gantenerumab showed less frequent radiologic and histopathologic ARIA-like lesions with delayed onset. Our results align well with the differential incidence of ARIA observed in humans treated with different anti-A{beta} antibodies. Collectively, our studies demonstrate that: i) anti-A{beta} antibodies chronically administered to 5xFAD mice can induce MRI lesions reminiscent of human ARIA; ii) this paradigm allows identification of transient lesions other than microhemorrhages, and (iii) the incidence and severity of ARIA-like lesions induced with three clinically tested antibodies faithfully recapitulates that seen in humans. One Sentence SummaryMRI and histological correlation in a preclinical ARIA mouse model treated with anti-A{beta} antibodies that recapitulates results seen in humans.

neuroscience↗

bioRxiv2024

Engineering anti-amyloid antibodies with transferrin receptor targeting improves safety and brain biodistribution

Although the first generation of immunotherapies for Alzheimers disease (AD) are now clinically approved, amyloid-related imaging abnormalities (ARIA) remain a major safety problem for this class of drugs. Here, we report an antibody transport vehicle (ATV) targeting the transferrin receptor (TfR) for brain delivery of amyloid beta (A{beta}) antibodies that significantly reduced ARIA-like lesions and improved plaque target engagement in a mouse model of amyloid deposition. Asymmetrical Fc mutations (ATVcisLALA) allowed the molecule to selectively retain effector function only when bound to A{beta} while mitigating TfR-related hematology liabilities. Mice treated with ATVcisLALA:A{beta} exhibited broad brain parenchymal antibody distribution; in contrast, anti-A{beta} IgG was highly enriched at arterial perivascular spaces where vascular A{beta} localizes and likely plays a role in induction of ARIA. Importantly, ATVcisLALA: A{beta} almost completely eliminated ARIA-like lesions and vascular inflammation associated with anti-A{beta} treatment. Taken together, ATVcisLALA has the potential to significantly improve both safety and efficacy of A{beta} immunotherapy through enhanced biodistribution mediated by transport across the blood-brain barrier.

neuroscience↗

bioRxiv2019

Kinetic fingerprint of antibody therapies predicts outcomes of Alzheimer clinical trials

The amyloid cascade hypothesis, according to which the self-assembly of amyloid-{beta} peptide (A{beta}) is a causative process in Alzheimers disease, has driven many therapeutic efforts for the past 20 years. Failures of clinical trials investigating A{beta}-targeted therapies have been interpreted as evidence against this hypothesis, irrespective of the characteristics and mechanisms of action of the therapeutic agents, which are highly challenging to assess. We bring together kinetic analysis with quantitative binding measurements to address the mechanisms of action of four clinical stage anti-A{beta} antibodies, aducanumab, gantenerumab, bapineuzumab and solanezumab. We reveal and quantify the striking differences of these antibodies on the aggregation kinetics and on the production of oligomeric aggregates, and link these effects to the affinity and stoichiometry of each antibody for monomeric and fibrillar forms of A{beta}. Our results uncover that, uniquely amongst these four antibodies, aducanumab dramatically reduces the flux of oligomeric forms of A{beta}.

biophysics↗

bioRxiv2019

An artistic approach to neurofeedback for emotion regulation

Neurofeedback has been shown to be a promising tool for learning to regulate ones own emotions in healthy populations and in neuropsychiatric disorders. While it has been suggested that neurofeedback performance improves when sensory feedback is related to the pathology under consideration, it is still difficult to represent in real time a proper feedback representative of our emotional state. Since emotion is a central part of peoples dealings with artworks, we have initiated a collaboration between neuroscientists and artists to develop a visual representation of emotions that can be used in neurofeedback experiences. As a result of this collaboration, emotions were represented as particles, moving in a white sphere according to valence and arousal levels. In this study, several possibilities for particle control were explored: direction of particles, their concentration in a specific place, or their gravity. 107 participants evaluated these performances, either in laboratory condition or at various scientific and artistic events. At the end of the experiment, questionnaires were distributed to participants who were asked to indicate on scales ranging from 0 to 5 how artistic the different representations were and could be used as a clinical activity, whether they thought they had successfully controlled the particles during the neurofeedback exercise, and whether they had appreciated the experience. We found that influing on the direction and concentration of particles was considered the most artistic with an average score around 3/5. 47% of the participants considered the concentration of particles as artistic. In addition, although this is not the purpose of this study, we found that participants could significantly control the direction of particles during this session. These encouraging results constitute a first step before evaluating the effectiveness of our emotional neurofeedback over several sessions in healthy, then pathological populations.

neuroscience↗