Thomas D. Parker

Following traumatic brain injury, the ability of conventional diffusion-weighted MRI analysis techniques to resolve tract-specific white matter damage, particularly in crossing fibre regions, is limited. Using fixel-based analysis, this study aimed to identify white matter abnormalities in chronic traumatic brain injury patients and to resolve the effects of traumatic brain injury on distinct white matter tracts, especially in crossing fibre regions. In this cross-sectional study, diffusion-weighted MRI were acquired from adults with chronic moderate-to-severe traumatic brain injury (N = 29; median time since injury 1.9 years) and matched healthy controls (N = 17). Whole-brain and tract-of-interest analyses compared differences in white matter connectivity represented by fixel-wise metrics (fibre density, fibre bundle cross-section and combined fibre density and bundle cross-section) between groups. Regions where crossing white matter fibres demonstrates differential damage were identified. Significant reductions were found in all corrected fixel-wise metrics in traumatic brain injury patients, with distinct spatial distributions between metrics. Combined fibre density and bundle cross-section demonstrated the highest sensitivity out of the fixel-wise metrics and fractional anisotropy, detecting abnormalities in 73.6% of examined tracts. Fixel-based analysis resolved the distinct effects of traumatic brain injuries on crossing fibres with 14% of tract pairings containing crossing fibres (131/927) demonstrating robust evidence of differential damage (i.e. significant difference between groups in the fixel-wise metric of one tract in the pair but not the other tract within the same voxel). Fixel-based analysis identified variabilities in white matter abnormalities in traumatic brain injury patients. Crucially, fixel-based analysis was able to resolve injury-related tract-specific alterations even in crossing fibre regions, supporting further exploration of fixel-wise metrics as more specific biomarkers of white matter alterations in traumatic brain injury.

Background: Determining whether MRI brain scans demonstrate atrophy that is beyond “normal for age” is challenging. Automated measurements of structural metrics in individual brain regions have shown promise as biomarkers of neurodegeneration, yet widely available reference standards that aid interpretation at the individual level are lacking. Normative modelling, enabling standardized “brain charts”, represents a significant step in addressing this challenge by generating individualized age- and sex- adjusted centile scores derived from large, aggregated datasets for MRI-derived quantitative metrics. Methods: Using normative data from 56,173 participants across the life course, we have developed regional cortical thickness and amygdala/hippocampal volume brain charts (adjusted for total intracranial volume) that can be applied at the individual level. At the group level, we investigate whether regional centile scores relate to cognitive performance (mini-mental state examination) and discriminate individuals with neuropathological evidence of Alzheimer’s disease ( n = 351) from propensity-matched controls from the National Alzheimer's Coordinating Center (NACC) dataset. In addition, we explored the relationships between disease stage, cognition, regional tau deposition and regional centile scores in amyloid-β-PET-positive individuals with Alzheimer’s disease dementia ( n = 39) and mild cognitive impairment ( n = 71) from the Alzheimer’s Disease Neuroimaging Initiative-3 (ADNI-3). We then extended this approach to phenotypes of frontotemporal lobar degeneration using the Neuroimaging in Frontotemporal Dementia dataset ( n = 113). Results: We demonstrate BrainChart’s application to illustrative individual cases. At the group level, we show that in Alzheimer’s disease, regional centile scores from brain charting predicted cognitive performance, temporal lobe tau PET tracer uptake and discriminated disease groups from propensity matched cognitively normal controls in independent cohorts. Distinct patterns of age-inappropriate cortical atrophy were also evident in different clinical phenotypes of frontotemporal lobar degeneration from the Neuroimaging in Frontotemporal Dementia dataset. Conclusions: Regional centile scores derived from an extensive normative dataset represent a generalizable method for objectively identifying atrophy in neurodegenerative diseases and can be applied to determine neurodegenerative atrophy at the individual level.

Background: Contact sports, including rugby union, are associated with higher rates of neurodegenerative dementia, due to various underlying pathologies such as Alzheimer’s disease (AD) and chronic traumatic encephalopathy (CTE). New ultrasensitive multiplexed immunoassays may clarify disease mechanisms after repetitive head impacts (RHI) and traumatic brain injury, potentially aiding risk-stratification, early diagnosis and dementia treatment. Methods: Midlife participants in the ABHC cohort underwent plasma biomarker quantification (NULISA - NUcleic acid Linked Immuno-Sandwich Assay; n=124 markers), 3T MRI, trauma exposure ascertainment and phenotyping. Regressions quantified exposure-specific protein expression, relationship to trauma (including position) and brain atrophy, using cluster analysis to test correlates of traumatic encephalopathy syndrome (TES). Results: 197 former elite rugby players and 33 controls were assessed. 24 (12.2%) met criteria for TES but none had dementia. Ex-players returned reduced plasma glial fibrillary acidic protein (GFAP), kallikrein-6 (KLK6) and synaptosomal-associated protein 25 (SNAP25). Ex-forwards specifically showed reduced plasma beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), amyloid beta-38 (Aβ38), and increased phospho-tau ₁₈₁ (p-tau ₁₈₁ ). KLK6 was lower in ex-backs than controls. No biomarkers related to career duration, concussion load or regional brain volume, nor did clustering relate to TES. Conclusions: Ex-players showed distinctive plasma biomarker changes, more prominently in ex-forwards, possibly reflecting greater RHI exposure. Plasma KLK6, an endothelial serine protease, was reduced across the ex-player group, with potential diagnostic or prognostic utility in future. Reduced GFAP and SNAP25 in ex-forwards has an uncertain basis, while elevated p-tau- ₁₈₁ more so than p-tau ₂₁₇ points towards non-AD tau pathology. Our findings motivate longitudinal characterisation, including comparison with other neurodegenerative diseases.

Epidemiological studies have shown that elite rugby players are at greater risk of neurodegenerative disease in later life, with post-mortem studies conducted in ex-players demonstrating the presence of neuropathologies related to repetitive head impacts, such as chronic traumatic encephalopathy. However, detailed prospective data establishing the clinical presentation of former rugby players with brain health concerns are lacking. In particular, the rates of traumatic encephalopathy syndrome, the clinical correlate of chronic traumatic encephalopathy, and the relationship between clinical outcomes and repetitive head impacts are unknown. Two hundred former elite rugby players with brain health concerns and 33 matched healthy control subjects were assessed. Self-reported concussion history, career duration, player position, self-rated scales of depression, anxiety, sleep quality, post-concussion symptoms and quality of life, self and informant ratings of neuropsychiatric symptoms and executive function behaviours, were obtained. Formal cognitive testing, traumatic encephalopathy syndrome classification and 3 T MRI were performed. Former players had a median age of 44 years (90.5% male, median career length = 10.5 years, median self-reported career concussions = 7); 63% were forwards and 37% were backs. Ex-players had elevated scores compared to controls on all symptom scales except sleep quality. Despite frequent subjective memory complaints, performance on cognitive testing did not significantly differ from controls. No players fulfilled criteria for dementia. Twenty-four former players fulfilled research criteria for traumatic encephalopathy syndrome (seven with cognitive impairment, 12 with neurobehavioral dysregulation, five with both). Provisional levels of certainty for chronic traumatic encephalopathy were relatively low (21 ‘suggestive’, three ‘possible’, zero ‘probable/definite’). Forwards and those with higher self-reported concussions were more likely to be classified as having traumatic encephalopathy syndrome based on neurobehavioral disturbance. Symptom burden (depressive and anxiety symptoms, post-concussion symptoms, behaviour rating of executive dysfunction, and neuropsychiatric symptom severity) was higher in those with higher self-reported concussions but was unrelated to years of play or position played. Cavum septum pellucidum was visible on structural imaging in 24% of players (12% in controls) and was more common in the high compared to low concussion group (32% versus 16%). In summary, former elite rugby players in mid-life had significant symptom burden, especially those self-reporting more concussions. In contrast, objective cognitive impairments and traumatic encephalopathy syndrome were relatively uncommon and there was no evidence of dementia. These results provide insights into the clinical presentations of former elite rugby players with brain health concerns during mid-life and highlight the complex relationship between symptoms, cognition and head impact exposure.

Repetitive head impacts and traumatic brain injuries in contact sports, such as rugby union, are associated with increased risk of neurodegenerative diseases such as Alzheimer's disease and chronic traumatic encephalopathy. Advances in fluid and imaging biomarkers are transforming dementia diagnosis but have not been systematically applied to individuals previously exposed to head impacts during rugby participation. We used biomarkers, including those with sensitivity and specificity for early Alzheimer's pathology to explore neurodegenerative risk in mid-life elite retired rugby players with significant repetitive head impact exposure. Plasma neurofilament light, glial fibrillary acid protein, amyloid-β (Aβ)42, Aβ40 and phospho-tau217 were quantified using ultrasensitive single molecule array digital enzyme-linked immunosorbent assay (SiMoA) in former elite rugby players as well as age/sex-matched unexposed controls. 3 T MRI and neuropsychology assessments were performed, with National Institute for Neurological Disorders and Stroke criteria used to ascertain the presence of traumatic encephalopathy syndrome. Regression models were used to relate plasma/imaging biomarkers to clinical phenotype. Individual-levels analyses were performed for fluid and imaging metrics, based on control biomarker distributions. Biomarker data from two aligned un-exposed Alzheimer's cohorts were included to contextualize our findings. Two hundred ex-rugby players (median age 44 years, 90% males) and 33 unexposed controls were assessed. Twenty-four (12%) ex-players fulfilled criteria for traumatic encephalopathy syndrome but none had dementia. Plasma phospho-tau217 concentrations were 17.6% higher in ex-rugby players than controls (95% confidence interval 3.7–33.3, P = 0.047). A total of 46 (23.1%) ex-players had elevated phospho-tau217 at the individual level; as did 18 (9.0%) players in relation to raised plasma neurofilament light. Ex-players’ concentrations were lower than in unexposed adults with late onset Alzheimer's disease (n = 69). Ex-players also showed significantly reduced volumes in the frontal/cingulate cortex on voxel-based morphometry at the group level; with reduced white matter and lower hippocampal volume associated with longer career durations within ex-players. Trauma-associated white matter changes measured with diffusion tensor imaging were uncommon in ex-players (4.6%). Traumatic encephalopathy syndrome was significantly more common in ex-players with elevated phospho-tau217, while those with raised plasma neurofilament light had significantly more anxiety and depressive symptoms. Frontal brain volumes correlated negatively with neurofilament light (r = −0.21, P = 0.010), and hippocampal volumes correlated negatively with phospho-tau217 (r = −0.19, P = 0.024). Elite rugby participation is associated with abnormal fluid and neuroimaging neurodegeneration biomarkers in mid-life. These include elevated phospho-tau217, which may indicate amyloid-dependent tau pathology. The results provide support for using state-of-the-art neurodegenerative biomarkers in the evaluation of long-term effects of sports head impact exposure.

Background: The hippocampus is a key site of atrophy in Alzheimer’s disease (AD) and MRI derived estimates of hippocampal volume have been shown to be a robust biomarker of AD‐related neurodegeneration. However, its application at the individual level is limited by the lack of reference standards from large normative datasets that can be applied across a wide range of settings. We aimed to investigate the utility of hippocampal volume centile scores adjusted for age, sex and total intracranial volume (TIV) derived from a normative data from 101,457 participants across the life course, as a biomarker of neurodegeneration in AD.Methods: BrainChart calculates age and sex adjusted centile scores for structural MRI metrics using a GAMLSS (Generalised Additive Models for Location Scale and Shape) approach and can be applied to individual datasets using an out‐of‐sample centile scoring approach that calculates study‐specific offsets (Bethlehem, Seidlitz, White et al. Nature 2022). Using this approach, we developed models for Freesurfer derived estimates of hippocampal volume additionally incorporating TIV as a co‐variate. This was then applied to 351 individuals with pathologically confirmed AD (median scan time prior to death 5.9 years) from the NACC dataset, as well as 110 amyloid‐PET positive patients from the ADNI‐3 cohort (MCI n=71, AD dementia n=39). Wilcoxon rank‐sum tests were used to assess differences between patient groups and cognitively normal controls from the relevant datasets. Spearman’s rank correlations were used to assess relationships with cognition (MMSE score).Results: Median centile scores were reduced in all patient groups (pathologically confirmed AD cases left = 0.13, right =0.13; amyloid‐PET positive MCI cases left=0.12, right=0.16; and amyloid‐PET positive AD dementia left=0.01, right=0.02). This was significantly different to cognitively normal controls from both the NACC dataset (n=1400, cases left=0.52, right=0.52) and ADNI‐3 dataset (n=247, cases left=0.50, right=0.50), all to a significance level of p<0.0001. Hippocampal centile scores strongly predicted MMSE score in both cohorts (Spearmans’ Rho range 0.37‐0.41, p<0.001).Conclusion: BrainChart age, sex and TIV adjusted hippocampal volume centile scores, derived from an extensive normative dataset, represent a method for objectively identifying neurodegeneration in AD that is interpretable at the individual level.

Background: In elite athletes, participation in sports associated with repetitive head injury exposure has been linked to an increased risk of neurodegeneration later in life. However, there has been limited study in more general populations. We aimed to investigate whether participation in such sports impacted outcomes relevant to brain health in a cohort of British‐born older adults.Methods: 441 participants from Insight 46 (a sub‐study of the 1946 British Birth Cohort) were asked whether they participated in rugby, soccer, or boxing, consistently for at least a year (yes/no) at various epochs of life (<20, 20‐49 and 50+ years). Individuals underwent baseline florbetapir‐PET, serial brain MRI and cognitive assessments (mean age at baseline assessment 70.6 years, mean interval between visits = 2.4 years). A range of life course data were included in analyses, including attitudes to sports, education, engagement in physical activity and self‐reported symptomatic head injury.Result: As only one female identified as participating in rugby, soccer, or boxing, only males were included in analyses: 101/232 males (43.5%) stated they participated in at least one of these sports, 46 of whom participated for more than one epoch. Univariate analyses revealed participation was associated with a range of demographic factors including: a preference “to play rough sports” aged 13 (p<0.001); a higher level of education (p = 0.007); engagement in physical activity aged 36 (p<0.001); and 43 (p = 0.017); and greater risk of self‐reported symptomatic head injury (35.3% vs 14.7%, p<0.001).There were no significant associations between participation in these sports and baseline cognitive function or decline, beta‐amyloid deposition, white matter hypertintensity volume, or baseline/longitudinal change in total brain or hippocampal volume (table 1).Longer duration of participation (≥ two epochs vs one) was associated with lower hippocampal volume at baseline (p = 0.006) but did not predict subsequent atrophy or any other outcome examined (table 2).Conclusion: Previous exposure to sports associated with repetitive head injuries is common amongst British‐born older adults and associated with a range of demographic factors relevant to brain health. Longer duration of exposure predicted lower hippocampal volume age 70 years, but there was no evidence of significantly accelerated atrophy or cognitive decline beyond this.

Pathophysiology and outcomes after Traumatic Brain Injury (TBI) are complex and heterogenous. Current classifications are uninformative about pathophysiology. Proteomic approaches with fluid-based biomarkers are ideal for exploring complex disease mechanisms, as they enable sensitive assessment of an expansive range of processes potentially relevant to TBI pathophysiology. We used novel high-dimensional, multiplex proteomic assays to assess altered plasma protein expression in acute TBI. We analysed samples from 88 participants from the BIO-AX-TBI cohort (n=38 moderate-severe TBI [Mayo Criteria], n=22 non-TBI trauma, n=28 non-injured controls) on two platforms: Alamar NULISA™ CNS Diseases and OLINK^® Target 96 Inflammation. Patient participants were enrolled after hospital admission, and samples taken at a single timepoint up to 10 days post-injury. Participants also had neurofilament light, GFAP, total tau, UCH-L1 (all Simoa^®) and S100B (Millipore) data. The Alamar panel assesses 120 proteins, most of which were previously unexplored in TBI, plus proteins with known TBI-specificity, such as GFAP. A subset (n=29 TBI, n=24 non-injured controls) also had subacute (10 days to 6 weeks post-injury) 3T MRI measures of lesion volume and white matter injury (fractional anisotropy). Differential Expression analysis identified 16 proteins with TBI-specific significantly different plasma expression. These were neuronal markers (calbindin2, UCH-L1, visinin-like protein1), astroglial markers (S100B, GFAP), neurodegenerative disease proteins (total tau, pTau231, PSEN1, amyloid-beta-42, 14-3-3γ), inflammatory cytokines (IL16, CCL2, ficolin2), cell signalling (SFRP1), cell metabolism (MDH1) and autophagy related (sequestome1) proteins. Acute plasma levels of UCH-L1, PSEN1, total tau and pTau231 correlated with subacute lesion volume. Sequestome1 was positively correlated, whilst CLL2 was inversely correlated, with white matter fractional anisotropy. Neuronal, astroglial, tau and neurodegenerative proteins correlated with each other, IL16, MDH1 and sequestome1. Exploratory clustering (k means) by acute protein expression identified 3 TBI subgroups that differed in injury patterns, but not age or outcome. One TBI cluster had significantly lower white matter fractional anisotropy than control-predominant clusters, but had significantly lower lesion subacute lesions volumes than another TBI cluster. Proteins that overlapped on two platforms had excellent (r>0.8) correlations between values. We identified TBI-specific changes in acute plasma levels of proteins involved in neurodegenerative disease, inflammatory and cellular processes. These changes were related to patterns of injury, thus demonstrating that processes previously only studied in animal models are also relevant in human TBI pathophysiology. Our study highlights how proteomic approaches might improve classification and understanding of TBI pathophysiology, with implications for prognostication and treatment development.

Introduction Although limited, recent research suggests that contact sport participation might have an adverse long-term effect on brain health. Further work is required to determine whether this includes an increased risk of neurodegenerative disease and/or subsequent changes in cognition and behaviour. The Advanced BiomaRker, Advanced Imaging and Neurocognitive Health Study will prospectively examine the neurological, psychiatric, psychological and general health of retired elite-level rugby union and association football/soccer players. Methods and analysis 400 retired athletes will be recruited (200 rugby union and 200 association football players, male and female). Athletes will undergo a detailed clinical assessment, advanced neuroimaging, blood testing for a range of brain health outcomes and neuropsychological assessment longitudinally. Follow-up assessments will be completed at 2 and 4 years after baseline visit. 60 healthy volunteers will be recruited and undergo an aligned assessment protocol including advanced neuroimaging, blood testing and neuropsychological assessment. We will describe the previous exposure to head injuries across the cohort and investigate relationships between biomarkers of brain injury and clinical outcomes including cognitive performance, clinical diagnoses and psychiatric symptom burden. Ethics and dissemination Relevant ethical approvals have been granted by the Camberwell St Giles Research Ethics Committee (Ref: 17/LO/2066). The study findings will be disseminated through manuscripts in clinical/academic journals, presentations at professional conferences and through participant and stakeholder communications.

Background Hearing loss has been proposed as a modifiable risk factor for dementia. However, the relationship between hearing, neurodegeneration, and cognitive change, and the extent to which pathological processes such as Alzheimer’s disease and cerebrovascular disease influence these relationships, is unclear. Methods Data from 287 adults born in the same week of 1946 who underwent baseline pure tone audiometry (mean age=70.6 years) and two time point cognitive assessment/multimodal brain imaging (mean interval 2.4 years) were analysed. Hearing impairment at baseline was defined as a pure tone average of greater than 25 decibels in the best hearing ear. Rates of change for whole brain, hippocampal and ventricle volume were estimated from structural MRI using the Boundary Shift Integral. Cognition was assessed using the Pre-clinical Alzheimer’s Cognitive Composite. Regression models were performed to evaluate how baseline hearing impairment associated with subsequent brain atrophy and cognitive decline after adjustment for a range of confounders including baseline β-amyloid deposition and white matter hyperintensity volume. Results 111 out of 287 participants had hearing impairment. Compared with those with preserved hearing, hearing impaired individuals had faster rates of whole brain atrophy, and worse hearing (higher pure tone average) predicted faster rates of hippocampal atrophy. In participants with hearing impairment, faster rates of whole brain atrophy predicted greater cognitive change. All observed relationships were independent of β-amyloid deposition and white matter hyperintensity volume. Conclusions Hearing loss may influence dementia risk via pathways distinct from those typically implicated in Alzheimer’s and cerebrovascular disease in cognitively unimpaired older adults.