PET Tau Brain Imaging and Blood-Based Molecular Biomarkers of Tauopathy

Funding opportunity

Application of PET Tau Brain Imaging and Blood-Based Molecular Biomarkers of Tauopathy in Canadian Armed Forces Members and Veterans with Occupational Exposure to Blast and Heavy Weapons

Anticipated timeline and budget

Background

This funding opportunity involves a prospective cohort study using positron emission tomography (PET) imaging to evaluate brain health and risk of tau-related neurodegeneration in military personnel and Veterans sustaining occupational exposure to blast overpressure.

Members of the Canadian Armed Forces (CAF), who are routinely exposed to low-intensity, repeated blast overpressure from explosive breaching and heavy weaponry during training and operations, face a heightened risk of cumulative neurological damage. This exposure heightens their vulnerability to long-term neurodegenerative disorders, including progressive tauopathies, which are marked by the accumulation of aggregated filaments of the microtubule-associated protein tau in the brain. Among these, chronic traumatic encephalopathy (CTE) is particularly associated with repeated head impacts. Traditionally confirmed post-mortem through the identification of distinct phosphorylated tau protein patterns around cerebral vessels, CTE and related disorders manifest as significant cognitive, behavioral, and psychiatric disturbances.

This research aims to advance our understanding and diagnostic capabilities of these conditions by employing both first-generation and innovative second-generation positron emission tomography (PET) tau radiotracers. Specifically, it will utilize [18F] flortaucipir (also known as [18F] AV-1451) alongside the novel, first-in-class 4R-tau tracer [18F]OXD-2115, which has been optimized for imaging non-Alzheimer’s tauopathies. These will target and visualize tau deposits within the living brain. This imaging should be supplemented by analysis of peripheral blood samples for tauopathy biomarkers, including several isoforms of hyperphosphorylated tau proteins (such as P-Tau-181, P-Tau-217, P-Tau-231, brain-derived Tau), using ultrasensitive immunoassays. This comprehensive approach allows for the concurrent assessment of molecular signatures in both brain and blood, providing an integrated view of the neurodegenerative processes affecting at-risk military members and Veterans.

The primary objective of this initiative is to enhance methods for early detection, differential diagnosis, and monitoring of disease progression in CAF personnel and Veterans exposed to blast overpressure. By integrating cutting-edge invivo brain imaging technologies with molecular biomarker analysis, this project seeks to strengthen early detection and intervention strategies, significantly improving the management of tau-related neurodegeneration. These advancements will have a lasting impact on long-term health outcomes, operational effectiveness, and the overall career longevity and well-being of military personnel.

Research objectives

This funding opportunity is seeking submissions to conduct a prospective cohort study that will provide the following:

1. Enhanced Diagnostic Imaging
   • To evaluate the effectiveness of first-generation and advanced second-generation high-affinity tau-positron emission tomography (PET) radiotracers ([18F]flortaucipir and [18F]OXD-2115) in detecting tau protein deposits in the brains of CAF members and Veterans with repetitive occupational blast/weapons exposure, and healthy non-blast exposed civilians. This objective aims to refine the use of these radiotracers to capture early signs of tauopathy in individuals with occupational exposure to blast overpressure.
2. Biomarker Identification and Validation
   • To identify and validate peripheral blood-based biomarkers related to tauopathy and neurodegeneration, including the measurement of multiple isoforms of hyperphosphorylated tau proteins (i.e., P-Tau-181, P-Tau-217, P-tau-231, brain-derived Tau) using single-molecule arrays ultrasensitive digital immunoassays. This will facilitate development of a blood test that can be used in conjunction with brain imaging to assess neurodegenerative changes.
3. Modeling of PET Imaging and Molecular Biomarker Data
   • To correlate PET imaging findings with blood biomarker levels to create a comprehensive molecular diagnostic profile. This involves integrating the data to understand the relationship between visible brain changes and peripheral biomarker manifestations, aiding in the differential diagnosis and progression monitoring of neurodegenerative conditions.
4. Early Detection and Monitoring
   • To develop protocols and less invasive methodologies for the early detection and ongoing monitoring of tauopathies among exposed military personnel. This aims to establish a routine screening and surveillance mechanism that can be integrated into the health monitoring systems of the armed forces.
5. Interventional Strategies
   • To assess the potential utility and feasibility of early interventions based on the diagnostic data gathered through imaging and blood biomarkers. This includes evaluating therapeutic approaches and lifestyle modifications to slow the progression of neurodegeneration and improve the quality of life for affected individuals.
6. Recommendations for Health Policy and Military Practices
   • To inform and potentially reform health policy and military practices based on the findings, aiming to enhance protective measures, adjust training protocols, and develop targeted support and rehabilitation services for personnel at risk or already showing signs of neurodegenerative impairments.

This comprehensive study seeks to leverage advanced in vivo medical imaging and biomolecular technologies to address the pressing brain health concerns related to the risk of neurodegenerative diseases among military personnel, ultimately enhancing operational readiness and extending the careers of those serving in the CAF.

Milestones/Phases of progress/Desired outputs

The project should consist of 3 main phases (See table below).

Preparatory Phase

1. Development of study protocols, including the preparation and submission of research ethics protocols to the participating institutional Research Ethics Boards for approval.
2. Budgeting and purchasing of research materials, equipment.
3. Recruitment and training of staff including clinicians, research coordinators, graduate students, technicians etc.
4. Pilot data collection, following established protocol for a sample of eligible participants, including clinical assessments, scanning and blood draws.

Application Phase

1. Active recruitment and screening of military/Veteran and civilian volunteers for enrolment and testing.
2. Collection of clinical test data, enhanced diagnostic imaging with PET-tau radiotracers and matched blood draws for measurement of peripheral Tau isoforms.
3. Testing of data quality and study compliance at key recruitment milestones (10%, 50% and 75% of data collected).

Evaluation Phase

1. Analysis of group differences in PET-tau imaging and molecular biomarkers.
2. Predictive modelling modeling of PET-tau imaging and molecular biomarker data
3. Final reporting with recommendations for health policy and military practices.

Desired outputs

• An ethics protocol that covers the data collection for the study should be prepared for endorsement by the DRDC sponsor and for submission to the awardee’s institution’s research ethics board as well as the DRDC Human Research Ethics Committee.
• Feasibility data supporting the use of PET-tau imaging as an in vivo intervention for early detection/monitoring of tauopathy/CTE in military members, in the form of summary reports.
• Comprehensive clinical and neurobehavioural assessments, PET-tau neuroimaging and blood biomarker data assessing the risk of neurodegeneration/tauopathy.
• Reports, in the form of coauthored external peer-reviewed scientific literature publications, supporting the research objectives noted above on relevant military populations of interest.
• Language of work is English

Applicant qualifications and requirements for selection

• Proposals must be led by a senior investigator with a PhD in in neuroscience and/or multi-modal neuroimaging, with demonstrated research expertise repetitive brain injury and/or neurodegenerative diseases, specifically as it relates to military brain health.
• Must have onsite institutional access to a research-grade PET scanner and the capacity for the in-house generation of both [18F]flortaucipir and [18F]OXD-2115 tau-PET radiopharmaceuticals for use in human research.
• A publication history in neuroimaging of brain and mental health disorders and (sub)concussive brain injuries, prioritizing in vivo positron emission tomography (PET) imaging of tauopathy in relation to military brain health.
• Have at least one of the following: publications, research grants, awards or projects, as a proven record of carrying out brain and mental health research in support of the CAF.
• Strong expertise in PET imaging experimental study design, as demonstrated by peer-reviewed publications.
• The applicant must have the capacity to collect and biobank peripheral blood biospecimens for fluid biomarker assessments, and be within reasonable distance to DRDC Toronto Research Centre, due to the requirement for frequent and timely exchange of biological samples and other research materials.

Application deadline

Please download and submit the Research Funding Application form.

Enquiries

Questions about this funding opportunity can be sent to the VAC Research office.