Breton Michael Asken

The link between repetitive head impact (RHI) exposure, later-life cognitive decline, and neurobehavioral dysregulation (NBD) is not well understood. Recent work has implicated inflammation and limbic dysfunction as relevant RHI correlates. Our goal was to integrate plasma and CSF inflammatory biomarkers, structural brain imaging, and clinical measures in former elite American football players to better understand reasons for RHI-related cognitive and neurobehavioral changes. Participants were from the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy Research Project, which recruited male former college/professional football players with RHI and asymptomatic unexposed (UE) controls with no history of contact sports, military combat, or traumatic brain injury/concussion. Our study focused on plasma/CSF inflammatory biomarkers (interleukin [IL]-6, tumor necrosis factor [TNF]-α, glial fibrillary acidic protein), limbic white matter (WM) microstructure (diffusion tensor imaging: fractional anisotropy [FA], mean diffusivity [MD]), and clinical measures (memory, executive function, NBD). Hierarchical linear regressions assessed change in variance explained (ΔR²) among inflammation, WM, and clinical outcomes in former football players. Post hoc analyses tested whether associations differed by group (football vs UE; group interactions) or were stronger in football players considered at highest risk of CTE. Our sample included 223 men (n = 170 football players: age 57.2 ± 8.1 years, 33% non-Hispanic/Black; n = 53 UE participants: age 59.4 ± 8.6 years, 34% non-Hispanic/Black). In football players, higher inflammation was associated with lower limbic FA (plasma IL-6: ΔR² = 0.03 [0.001-0.09], p = 0.03; CSF IL-6: ΔR² = 0.03 [-0.01 to 0.11], p = 0.03; plasma TNF-α: ΔR² = 0.05 [0.01-0.11], p = 0.003) and higher limbic MD (CSF IL-6: ΔR² = 0.06 [0.007-0.15], p = 0.01). Inflammation was more strongly related to limbic WM microstructure in football players than in UE participants. Worse WM microstructure was associated with worse memory in football players (FA: ΔR² = 0.05 [0.003-0.14], p = 0.007; MD: ΔR² = 0.07, p = 0.003 [0.008-0.16]). Most of the observed associations were stronger in the CTE probable subgroup. There were no direct associations between plasma or CSF markers of inflammation and cognition. In former elite football players, elevated plasma and CSF inflammatory markers were associated with poorer limbic WM microstructure, which in turn related to worse cognition. Given the limbic system's role in cognition and behavior, inflammation may be a modifiable target for RHI-related neurodegeneration. Limitations include the cross-sectional design and limited generalizability to other contact sports, lower levels of play, female athletes, or other RHI sources.

Background: Repetitive head impact exposure (RHI) is the only known risk factor for chronic traumatic encephalopathy (CTE), a distinct neurodegenerative tauopathy. Most aging studies ask participants about prior traumatic brain injury (TBI), but not common sources of RHI. Understanding the public health footprint of RHI requires targeted questioning of lifetime exposure. To set the stage for our Featured Research Session on CTE, we report RHI prevalence using gold standard methods across independent aging and dementia cohorts. Method: The Boston University Repetitive Head Impact Exposure Assessment (BU‐RHIEA) was administered across three cohorts: BU Alzheimer's Disease Research Center (ADRC), UCSF ADRC, and 1Florida ADRC. Participants recruited explicitly with concerns about cognitive effects of prior head trauma were excluded. The BU‐RHIEA queries participation in contact/collision sports (e.g., American football, soccer, ice hockey, boxing) and military service as well as prior TBI. We report RHI and TBI prevalence estimates from the BU‐RHIEA relative to estimates from the National Alzheimer's Coordinating Center Uniform Data Set (NACC UDS). In a subset of participants with frontotemporal dementia, we evaluated the clinical relevance of prior RHI through associations with age of symptom onset and rate of disease progression. Result: Data come from 736 participants (age 70.4±9.6, 44.3% male, 43.1% cognitively impaired). Based on NACC UDS, 223 (30.2%) reported any prior TBI (Figure 1). When providing a formal TBI definition, frequency increased to 300 (40.8%). Sport and military history are not known through NACC UDS. Based on the BU‐RHIEA, 221 (30.0%) participants reported any prior contact/collision sport play. Among males, 92 (28.2%) previously played American football and 98 (30.1%) served in the military. In participants with frontotemporal dementia, prior RHI related to younger symptom onset and more rapid cognitive decline (Figure 2). Conclusion: There is a high risk of underestimating the scope of RHI influence on brain aging. Among older adults, history of TBI and RHI from popular contact/collision sports is exceedingly common but unrecognized. RHI may contribute to the wide variability observed in the onset and progression of neurodegenerative conditions. Studying head trauma exposure relevant for later‐life brain health, such as sport‐ and military‐related RHI, requires dedicated questioning.

Objective: There are diagnostic disparities in dementia across ethno-racial communities. The potential contribution of measurement bias in cognitive assessments was investigated by examining the factor structure and measurement invariance of the Uniform Data Set neuropsychological battery (UDS3-NB) across ethno-racial groups as well as Spanish and English speakers along a cognitive continuum. Methods: Data were from the National Alzheimer's Coordinating Center (NACC) and the 1Florida Alzheimer's Disease Research Center (1FLADRC). Confirmatory factor analyses were conducted in NACC (n = 29,462; M age = 71.0, SD = 10.4; 58.5% female, M education = 15.8, SD = 3.0; 68.6% non-Hispanic White, 5.3% -primary Spanish speaking) to determine the UDS3-NB factor structure. Measurement invariance was tested in NACC and separately within 1FLADRC (n = 829; M age = 69.9, SD = 8.5; 56.5% female; M education = 14.6, SD = 3.5 years; 33.3% non-Hispanic White, 33.8% primary Spanish speaking), across ethno-racial (non-Hispanic White, Hispanic White, Black/African American), primary language (English, Spanish), and cognitive status (cognitively normal, mild cognitive impairment, dementia). Invariance was assessed at configural, metric, scalar, and strict levels. Results: A 4-factor model (memory, processing speed/executive functioning, language, attention) demonstrated acceptable to good fit in NACC (CFI = 0.97, TLI = 0.96, RMSEA = 0.07, SRMR = 0.03) and 1FLADRC (CFI = 0.97, TLI = 0.96, RMSEA = 0.05, SRMR = 0.04). Standardized factor loadings ranged from 0.43-0.87. Metric invariance was supported across all contrasts in both cohorts. Higher levels of invariance were cohort-dependent: CN vs. MCI achieved strict invariance in both cohorts, whereas non-Hispanic White vs. Hispanic White and English vs. Spanish only achieved strict invariance in NACC. Conclusions: The UDS3-NB demonstrates structural validity and metric equivalence across ethno-racial, linguistic, and cognitive status groups.

INTRODUCTION: Glial fibrillary acidic protein (GFAP) may contribute to Alzheimer's pathology at early disease stages. GFAP moderation of Alzheimer's disease (AD)‐related neurodegeneration and cognition is unclear. METHODS: We examined plasma GFAP moderation of AD biomarkers (amyloid beta [Aβ]‐positron emission tomography [PET][A]; plasma phosphorylated tau‐181 [p‐tau181][T ₁ ]), neurodegeneration (plasma NfL[N _plasma ]; structural magnetic resonance imaging [MRI][N _MRI ]), and cognition (Cog _memory ; Cog _executive ) in two cohorts: University of California San Francisco (UCSF) ( N = 212, 91.0% non‐Hispanic/Latino White [NHLW], age = 74.7 [7.6] years, 75.9% cognitively unimpaired [CU]) and 1Florida Alzheimer's Disease Research Centers (1FLADRC; N = 582, 32.8% NHLW, age = 70.7 [8.5] years, 28.9% CU). RESULTS: Plasma GFAP consistently moderated A–T ₁ (UCSF: β = 0.46, p = 0.012; 1FLADRC: β = 0.12, p  = 0.029). The association between elevated Aβ‐PET and increased (p‐tau) was strengthened at higher GFAP concentrations. In 1FLADRC, GFAP moderated T ₁ –N _plasma/MRI. In UCSF, GFAP moderated T ₁ –Cog _{memory/executive} and N _MRI –Cog _{memory/executive} . Higher GFAP consistently related to worse neurodegeneration and cognition (main effects). DISCUSSION: Across demographically and clinically heterogeneous cohorts, plasma GFAP is a key moderator of AD and may help identify individuals at greatest risk of AD‐related neurodegeneration and cognitive decline. Highlights: AD biomarkers were measured in two demographically and clinically distinct cohorts. Plasma GFAP moderated Aβ‐PET to p‐tau associations in both UCSF and 1FLADRC. Cohort‐dependent, GFAP moderated p‐tau to neurodegeneration and cognition associations. All moderations revealed strengthened disease associations with higher plasma GFAP. Plasma GFAP may help identify individuals at greatest risk of AD‐related decline.

INTRODUCTION: Early‐onset Alzheimer's disease (EOAD) may have distinct biomarker and clinical features from late‐onset AD (LOAD). EOAD is understudied in ethnically heterogeneous populations.METHODS: We studied EOAD (N = 44, age 64.7 ± 5.5, 55% female, 52% Hispanic/Latino), LOAD (N = 113), early‐onset non‐AD (EOnonAD, N = 114), and clinically normal (CN, N = 93) individuals from the 1Florida Alzheimer's Disease Research Center. Group differences and demographic interactions were evaluated in plasma (phosphorylated tau217, glial fibrillary acidic protein, neurofilament light chain), neuroimaging (amyloid positron emission tomography, brain magnetic resonance imaging), and global function (Mini‐Mental State Examination, Clinical Dementia Rating Sum of Boxes).RESULTS: AD‐related biomarkers and global function were consistently worse in EOAD than EOnonAD and CN, and similar or worse than LOAD. Among EOAD, younger age related to greater amyloid burden among non‐Hispanic/Latino individuals only. AD‐related biomarker changes were more severe in females than males among non‐Hispanic/Latino EOAD, but more severe among males in Hispanic/Latino EOAD.DISCUSSION: The biological and clinical features of EOAD may differ by sex and ethnicity.Highlights: Alzheimer's disease (AD) biomarkers and global functional measures were measured in Hispanic and non‐Hispanic individuals with early‐onset AD (EOAD). Overall, AD‐related biomarkers and global function were consistently worse in EOAD than non‐AD cognitive decline and controls, and similar or worse than late‐onset AD. Younger age related to greater amyloid burden among non‐Hispanic EOAD, but not Hispanic EOAD. Hispanic EOAD males had more severe changes than females, contrasting findings in non‐Hispanic EOAD (females more severe than males).

Background: Exposure to repetitive head impacts (RHI) is associated with increased risk for chronic traumatic encephalopathy (CTE), a neurodegenerative tauopathy, and other neuropathological changes. Biological drivers of RHI-related neurodegeneration are not well understood. We interrogated the plasma proteome in aging adults with prior RHI compared to healthy controls (CTL) and individuals with Alzheimer’s disease (AD), including a subset characterized neuropathologically at autopsy. Methods: Proximity extension assay (Olink Explore®) quantified 2,779 plasma proteins in 22 RHI patients (all AD-biomarker negative), 39 biomarker-confirmed AD, and 44 CTL. A subset of participants went to autopsy (N = 16) allowing for comparisons of the antemortem plasma proteome between autopsy-confirmed CTE + (N = 7) and CTE- (N = 9). Differential abundance and co-expression network analyses identified plasma proteomic signatures of RHI, which were functionally annotated using gene ontology and cell type enrichment analysis. Nonparametric correlations examined plasma proteomic associations with orthogonally-measured plasma biomarkers, global cognitive function, and semi-quantitative ratings of neuropathology burden at autopsy. Results: Differential abundance analysis revealed 434 increased (vs. 6 decreased) proteins in RHI vs. CTL and 193 increased (vs. 14 decreased) in RHI vs. AD. Network analysis identified 9 protein co-expression modules (M1-M9), of which 7 were elevated in RHI compared to AD or CTL. Modules with increased abundance in RHI were enriched for mitochondrial/metabolic, cell division, and immunovascular (e.g., cell adhesion, TNF-signaling) processes. RHI-related modules exhibited strong and selective correlations with immunoassay-based plasma IL-6 in RHI cases, including the M2 TNF-signaling/cell adhesion module which harbored proteins that strongly tracked with cognitive function. RHI-related plasma protein signatures were similar in the subset of participants with autopsy-confirmed CTE, including immune and metabolic modules that positively correlated with medial temporal lobe tau and TDP-43 burden. Conclusions: Molecular pathways in plasma most consistently implicated in RHI were tied to immune response, mitochondrial function, and cell metabolism. RHI-related proteomic signatures tracked with antemortem cognitive severity and postmortem neuropathological burden, providing converging evidence for their role in disease progression. Differentially abundant proteins and co-expression modules in RHI may inform mechanisms linking RHI to increased dementia risk, thus guiding diagnostic biomarker and therapeutic development for at-risk populations.

The long-recognized association of brain injury with increased risk of dementia has undergone significant refinement and more detailed study in recent decades. Chronic traumatic encephalopathy (CTE) is a specific neurodegenerative tauopathy related to prior exposure to repetitive head impacts (RHI). We aim to contextualize CTE within a historical perspective and among emerging data which highlights the scientific and conceptual evolution of CTE-related research in parallel with the broader field of neurodegenerative disease and dementia. We provide a narrative state-of-the-science update on CTE neuropathology, clinical manifestations, biomarkers, different types and patterns of head impact exposure relevant for CTE, and the complicated influence of neurodegenerative co-pathology on symptoms. Now almost 20 years since the initial case report of CTE in a former American football player, the field of CTE continues evolving with increasing clarity but also several ongoing controversies. Our understanding of CTE neuropathology outpaces that of disease-specific clinical correlates or the development of in-vivo biomarkers. Diagnostic criteria for symptoms attributable to CTE are still being validated, but leveraging increasingly available biomarkers for other conditions like Alzheimer's disease may be helpful for informing the CTE differential diagnosis. As diagnostic refinement efforts advance, clinicians should provide care and/or referrals to providers best suited to treat an individual patient's clinical symptoms, many of which have evidence-based behavioral treatment options that are etiologically agnostic. Several ongoing research initiatives and the gradual accrual of gold standard clinico-pathological data will pay dividends for advancing the many existing gaps in the field of CTE.

Objective: The long-term health of former athletes with a history of multiple concussions and/or repetitive head impact (RHI) exposure has been of growing interest among the public. The true proportion of dementia cases attributable to neurotrauma and the neurobehavioral profile/sequelae of multiple concussion and RHI exposure among athletes has been difficult to determine. Methods: Across three exposure paradigms (i.e. group comparisons of athletes vs. controls, number of prior concussions, and level of RHI exposure), this review characterizes the prevalence of neurodegenerative/neurological disease, changes in cognitive and psychiatric function, and alterations on neuroimaging. We highlight sources of variability across studies and provide suggested directions for future investigations. Results: The most robust finding reported in the literature suggests a higher level of symptom endorsement (general, psychiatric, and cognitive) among those with a greater history of sport-related concussion from adolescence to older adulthood. Pathological processes (e.g. atrophy, tau deposition, and hypometabolism) may be more likely to occur within select regions (frontal and temporal cortices) and structures (thalamus and hippocampus). However, studies examining concussion(s) and RHI exposure with imaging outcomes have yet to identify consistent associations or evidence of a dose-response relationship or a threshold at which associations are observed. Discussion: Studies have not observed a simple dose-response relationship between multiple concussions and/or RHI exposure with cognitive, psychiatric, or in vivo neurobiological outcomes, particularly at lower levels of play. The relationship between prior concussion and RHI exposure with long-term outcomes in former athletes is complex and likely influenced by -several non-injury-related factors.

CSF biomarkers of Aβ42 and phosphorylated tau (p-tau181) are used clinically for the detection of Alzheimer disease (AD) pathology during life. CSF biomarker validation studies have largely used clinical diagnoses and/or amyloid PET imaging as the reference standard. The few existing CSF-to-autopsy studies have been restricted to late-stage AD. This CSF-to-autopsy study investigated associations between CSF biomarkers of AD and AD neuropathologic changes among brain donors who had normal cognition at the time of lumbar puncture (LP). This was a retrospective study of brain donors from the National Alzheimer's Coordinating Center who had normal cognition at the time of LP and who had measurements of CSF Aβ42 and p-tau181 performed with Lumipulse assays. All brain donors were from Washington University Knight ADRC. Staging of AD neuropathologic change (ADNC) was made based on National Institute on Aging-Alzheimer's Association criteria. For this study, participants were divided into 2 categories: "AD-" (no AD/low ADNC) and "AD+" (intermediate/high ADNC). Accuracy of each biomarker for discriminating AD status was evaluated using area under the curve (AUC) statistics generated using predicted probabilities from binary logistic regressions that controlled for age, sex, APOE ε4, and interval between LP and death. The average age at LP was 79.3 years (SD = 5.6), and the average age at death was 87.1 years (SD = 6.5). Of the 49 brain donors, 24 (49%) were male and 47 (95.9%) were White. 20 (40.8%) had autopsy-confirmed AD. The average interval from LP until death was 7.76 years (SD = 4.31). CSF p-tau181/Aβ42 was the optimal predictor of AD, having excellent discrimination accuracy (AUC = 0.97, 95% CI 0.94-1.00, p = 0.003). CSF p-tau181 alone had the second-best discrimination accuracy (AUC = 0.92, 95% CI 0.84-1.00, p = 0.001), followed by CSF Aβ42 alone (AUC = 0.92, 95% CI 0.85-1.00, p = 0.007), while CSF t-tau had the numerically lowest discrimination accuracy (AUC = 0.87, 95% CI 0.76-0.97, p = 0.005). Effects remained after controlling for prevalent comorbid neuropathologies. CSF p-tau181/Aβ42 was strongly associated with CERAD ratings of neuritic amyloid plaque scores and Braak staging of NFTs. This study supports Lumipulse-measured CSF Aβ42 and p-tau181 and, particularly, the ratio of p-tau181 to Aβ42, for the early detection of AD pathophysiologic processes. This study provides Class II evidence that Lumipulse measures of p-tau181/Aβ42 in the CSF accurately discriminated cognitively normal participants with and without Alzheimer disease neuropathologic change.