Spotting and Managing Adult Repeated Traumas in the Brain

Older adults with a history of concussions have a 2x greater risk of developing dementia, however it is not clear why some individuals show resilience and are cognitively healthy, while others struggle and show more pronounced cognitive deficits. Concussions are a form of mild traumatic brain injury (mTBI) that are induced by the impact of biomechanical forces on the brain. In Canada, there are approximately 94,000 activity-limiting concussions per year in individuals aged 12 and over (Statistics Canada). Despite increasing awareness of concussion risks, the objective assessment of long-term consequences of concussion remains a notoriously difficult clinical problem; a multimodal approach is required to improve the understanding and treatment of individuals with a history of mTBI.

Advancement of Technology: NeuroTracker is a state-of-the-art technology which shows promise as a functional biomarker of brain-health, as well as cognitive training tool. NeuroTracker has the ability to serve as an accessible detection method and therapeutic for adults at risk of dementia due to a history of concussion.

Objectives \& Experimental Approach: The goal of this research project will be to examine aging older adult males and females with a history of concussion to determine if there are biomarkers that are indicative of cognitive trajectories.

Aim 1 will investigate cognitive-differences in individuals with a history of concussion. The investigators will examine the results of comprehensive neuropsychological and NeuroTracker assessments and task-based neurocognitive performance in older adults (60+ years) with and without histories of concussion.

Aim 2 will identify unique biomarkers from individuals with a history of concussion. The investigators will examine neuroimaging metrics, biomarkers obtained from blood samples, and NeuroTracker performance metrics from older males and females with and without a history of concussion. These results will be compared with those from Aim 1 to help identify positive and negative prognostic predictors for cognitive performance.

Aim 3 will examine how cognitive training with NeuroTracker affects trajectories of aging over time with two longitudinal follow up sessions. Participants will be assigned into a NeuroTracker training, or activities as a normal six-month intervention. The investigators will collect neuropsychological, blood, and neuroimaging biomarkers immediately post-intervention and six-month follow-up time points. Longitudinal follow-up will allow us to examine different trajectories of aging between groups of older adults with and without history of concussion.

Preliminary data: Our preliminary data suggest that adults with and without histories of concussion perform differently on NeuroTracker, and have different neuroimaging signatures. The investigators expect that combining these biomarkers with blood biomarkers will allow for the most comprehensive assessment of brain-health in adults with histories of concussion. NeuroTracker training is an effective cognitive training tool. The investigators expect that 6-months of NeuroTracker intervention will improve brain-health related outcomes in adults aged 60+.

Project Milestones: At the conclusion of year 1 of funding, The investigators expect to have completed participant recruitment and baseline assessments, allowing us to prepare manuscripts based on cross-sectional data from aims 1\&2. Year 2 will involve ongoing data analysis with participant follow-ups post-intervention \& 6-month follow up, and presentation of initial findings. Year 3 will comprise finishing data collection, presenting longitudinal data and preparing the final manuscript.

Development: Correlations between NeuroTracker baselines and blood biomarker and DTI imaging assessments of brain condition, and correlations between NeuroTracker learning rates with training over time and corresponding improvements in blood biomarker and DTI imaging assessments of brain condition will allow NeuroTracker to market itself as a competitive and accessible health tool.

Deliverables This project is expected to produce definitive correlational data between NeuroTracker, blood-based biomarkers and diffusion tension imaging assessments, establishing combined baselines with unprecedented sensitivity for diagnosing the neurological deficits in aging, caused by a history of concussion. This will establish the relevance of NeuroTracker baselines as a functional biomarker of these long-term effects on brain functioning and brain health, and determine the appropriate assessment protocol for such sensitivity. Additionally, the long-term effects of concussions will be revealed in terms of specific sex and gender differences. Finally, if NeuroTracker is effective at recovering associated neurological deficits, a 6-month bi-weekly training protocol will be validated as a therapeutic intervention, with measures of specifically rejuvenated cognitive functions via standardised neuropsychological assessments. Our team expects to prepare two-academic manuscripts \& multiple community presentations (in English and French) to disseminate the results of this study.

Problem Statement and Background Older adults with a history of concussions have a 2x greater risk of developing dementia however it is not clear why some individuals show resilience and are cognitively healthy, while others struggle and show more pronounced cognitive deficits. The sequelae can include physical complaints (e.g. headache, dizziness, nausea, sleep disturbance), cognitive signs (e.g. changes in memory and executive functions), and emotional symptoms (e.g. changes in mood). Although many individuals recover from these symptoms within 10 days, there is now considerable evidence that concussions are a risk factor for the development of neurodegenerative diseases.

Technology Inclusion \& Goals NeuroTracker has the potential to serve as a new functional biomarker of brain health and as a cognitive enhancer. It's a task that engages multiple brain networks all at once, demanding the utilization of working memory, complex motion comprehension, and wide-ranging attention management to keep track of numerous objects over time and space. The investigators anticipate that NeuroTracker will synergistically augment the exploratory assessments of long-term concussion effects that rely on blood-based biomarkers and neuroimaging. This unique enhancement could, for the first time, significantly boost the detection sensitivity. Such improvement could reach a level high enough to identify the subtle, yet impactful long-term effects of concussions which may extend into later life. Moreover, this project aims to determine the healing potential of NeuroTracker, specifically as a proactive training tool for cognitive function rehabilitation. This could be pivotal in fostering healthy active aging, allowing individuals to recover and reintegrate cognitive abilities necessary for a vibrant life in their later years.

Research Team: The investigators have assembled a cross-province, diverse multidisciplinary team of experts, allowing us to incorporate state-of-the-art cognitive performance software (i.e. NeuroTracker), neuropsychological assessment, neuroimaging (diffusion tensor imaging; DTI), and blood-based biomarkers, to provide a detailed multimodal framework for assessing the impact of previous concussions. The investigators have also built strong relationships with the Institute for Aging and Life Long Health, as well as the Victoria Brain Injury Society. Our team will have a focus on looking at brain imaging and blood biomarkers, with concurrent neuropsychological and NeuroTracker assessments, and work with graduate and medical school trainees recruited specifically for this project. The identification of biomarkers, including NeuroTracker performance, provides critical insight, as cognitive performance can remain within normal limits when biomarkers of neurodegeneration are present. This is also a critical time-point for interventions aimed at preventing cognitive decline to be instigated. The approaches developed here will be shared within the health care system, both nationally and internationally, given the composition of our team.

Preliminary Data in relation to specific aims: The investigators have recently published several papers that demonstrate our use of neuropsychological assessment and NeuroTracker in elderly and concussed populations; our ability to perform DTI in these populations. Most recently, the investigators have collected preliminary data with 16 participants with a history of concussion and 18 matched controls to examine the extent to which cognitive performance differs between adults with and without a history of concussion. This study examined NeuroTracker performance, as well as cognitive performance using a series of standardized neuropsychological assessments focused on memory, executive functioning, and symptoms of concussion. The results indicated that individuals with remote histories of multiple concussions continue to experience concussion-related symptoms, even years after their injuries (as measured by the Sport Concussion Assessment Tool) and that these individuals had poorer performance across neuropsychological measures of memory and executive functioning. Data from NeuroTracker suggested that individuals with a history of concussion have slower learning curves and worse performance over time than those without.

The investigators have also collected MRI data on older adults with and without a history of concussion, locally at West Coast Medical Imaging (analyses currently in progress), and have completed projects examining diffusion tensor imaging metrics in individuals with dementia compared to healthy controls. Interestingly, another study compared individuals from the Baltimore Longitudinal Study of Aging who reported a concussion an average of 23 years prior, to individuals with no history of concussion, and found that those with prior concussion had microstructural differences in the fornix, anterior corona radiata and superior longitudinal fasciculus using diffusion tensor imaging. They concluded that concussions can produce lasting structural changes in the brain. The proposed study would build on this work by expanding the methods used and investigating longitudinal trajectories.

Methods General Methods and Timelines: A total of 100 aged (60+) adults with a history of concussion and 100 aged adults without a history of concussion will be recruited to the study. Please note that recruitment will be rolling and is anticipated to be complete by year 1.5 of our 3-year timeframe.

The investigators will recruit participants through collaboration with the University of Victoria's Institute on Aging and Lifelong Health, the Victoria Brain Injury Society (VBIS), local media outlets, posters in community spaces, and by word of mouth. A power analysis (GPower Statistical Software) indicates the proposed sample size would be sufficient to determine, at minimum, a moderately weak effect size (f = 0.17). The investigators have chosen to recruit 100 participants per group to account for a maximum of 15% participant attrition over the study period. The sample size is also notably large for a neuroimaging study.

Inclusion criteria will be based on age (60+ years) and history of concussion (with the most recent concussion occurring at least one year prior to the study). Consistent with the literature, the history of concussion will be determined by interviewing participants about their experience with each experience of concussion (e.g. how was the injury sustained (sports injury, vehicle accident, etc.), how long has it been since the injury, did they experience a loss of consciousness during the event, how was their concussion diagnosed, what were their symptoms and when did the symptoms resolve).

The interview will also gather information on age,