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Background and Scope of Review Varying severities and frequencies of head trauma may result in dynamic acute and chronic pathophysiologic responses in the brain. Heightened attention to long-term effects of head trauma, particularly repetitive head trauma, has sparked recent efforts to identify neuroimaging biomarkers of underlying disease processes. Imaging modalities like structural magnetic resonance imaging (MRI) and positron emission tomography (PET) are the most clinically applicable given their use in neurodegenerative disease diagnosis and differentiation. In recent years, researchers have targeted repetitive head trauma cohorts in hopes of identifying in vivo biomarkers for underlying biologic changes that might ultimately improve diagnosis of chronic traumatic encephalopathy (CTE) in living persons. These populations most often include collision sport athletes (e.g., American football, boxing) and military veterans with repetitive low-level blast exposure. We provide a clinically-oriented review of neuroimaging data from repetitive head trauma cohorts based on structural MRI, FDG-PET, Aβ-PET, and tau-PET. We supplement the review with two patient reports of neuropathology-confirmed, clinically impaired adults with prior repetitive head trauma who underwent structural MRI, FDG-PET, Aβ-PET, and tau-PET in addition to comprehensive clinical examinations before death. Review Conclusions Group-level comparisons to controls without known head trauma have revealed inconsistent regional volume differences, with possible propensity for medial temporal, limbic, and subcortical (thalamus, corpus callosum) structures. Greater frequency and severity (i.e., length) of cavum septum pellucidum (CSP) is observed in repetitive head trauma cohorts compared to unexposed controls. It remains unclear whether CSP predicts a particular neurodegenerative process, but CSP presence should increase suspicion that clinical impairment is at least partly attributable to the individual’s head trauma exposure (regardless of underlying disease). PET imaging similarly has not revealed a prototypical metabolic or molecular pattern associated with repetitive head trauma or predictive of CTE based on the most widely studied radiotracers. Given the range of clinical syndromes and neurodegenerative pathologies observed in a subset of adults with prior repetitive head trauma, structural MRI and PET imaging may still be useful for differential diagnosis (e.g., assessing suspected Alzheimer’s disease).

Cognitive post‐acute sequelae of SARS‐CoV‐2 (PASC) can occur after mild COVID‐19. Detailed clinical characterizations may inform pathogenesis. We evaluated 22 adults reporting cognitive PASC and 10 not reporting cognitive symptoms after mild SARS‐CoV‐2 infection through structured interviews, neuropsychological testing, and optional cerebrospinal fluid (CSF) evaluations (53%). Delayed onset of cognitive PASC occurred in 43% and associated with younger age. Cognitive PASC participants had a higher number of pre‐existing cognitive risk factors (2.5 vs. 0; p = 0.03) and higher proportion with abnormal CSF findings (77% vs. 0%; p = 0.01) versus controls. Cognitive risk factors and immunologic mechanisms may contribute to cognitive PASC pathogenesis.

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.

Background Traumatic encephalopathy syndrome (TES) is a clinical phenotype sensitive but non-specific to underlying chronic traumatic encephalopathy (CTE) neuropathology. However, cognitive symptoms of TES overlap with Alzheimer’s disease (AD), and features of AD pathology like beta-amyloid (Aβ) plaques often co-occur with CTE, making clinical-to-pathological conclusions of TES diagnoses challenging. We investigated how Alzheimer’s neuropathological changes associated with cognition, brain volume, and plasma biomarkers in patients with repetitive head impacts (RHI)/TES, clinical AD, or typically aging controls. Methods We studied 154 participants including 33 with RHI/TES (age 61.5 ± 11.5, 100% male, 11/33 Aβ[ +]), 62 with AD and no known prior RHI (age 67.1 ± 10.2, 48% male, 62/62 Aβ[ +]), and 59 healthy controls without RHI (HC; age 73.0 ± 6.2, 40% male, 0/59 Aβ[ +]). Patients completed neuropsychological testing (memory, executive functioning, language, visuospatial) and structural MRI (voxel-based morphometry analysis), and provided plasma samples analyzed for GFAP, NfL, IL-6, IFN-γ, and YKL-40. For cognition and plasma biomarkers, patients with RHI/TES were stratified as Aβ[ +] or Aβ[ −] and compared to each other plus the AD and HC groups (ANCOVA adjusting for age and sex). Differences with at least a medium effect size (Cohen’s d  > 0.50) were interpreted as potentially meaningful. Results Cognitively, within the TES group, Aβ[ +] RHI/TES performed worse than Aβ[-] RHI/TES on visuospatial ( p  = .04, d  = 0.86) and memory testing ( p  = .07, d  = 0.74). Comparing voxel-wise brain volume, both Aβ[ +] and Aβ[ −] RHI/TES had lower medial and anterior temporal lobe volume than HC and did not significantly differ from AD. Comparing plasma biomarkers, Aβ[ +] RHI/TES had higher plasma GFAP than HC ( p  = .01, d  = 0.88) and did not significantly differ from AD. Conversely, Aβ[ −] RHI/TES had higher NfL than HC ( p  = .004, d  = 0.93) and higher IL-6 than all other groups ( p ’s ≤ .004, d ’s > 1.0). Conclusions Presence of Alzheimer’s pathology in patients with RHI/TES is associated with altered cognitive and biomarker profiles. Patients with RHI/TES and positive Aβ-PET have cognitive and plasma biomarker changes that are more like patients with AD than patients with Aβ[ −] RHI/TES. Measuring well-validated Alzheimer’s biomarkers in patients with RHI/TES could improve interpretation of research findings and heighten precision in clinical management.

We investigated whether clinically normal older adults with remote, mild traumatic brain injury (mTBI) show evidence of higher cortical Aβ burden. Our study included 134 clinically normal older adults (age 74.1 ± 6.8 years, 59.7% female, 85.8% white) who underwent Aβ positron emission tomography (Aβ-PET) and who completed the Ohio State University Traumatic Brain Injury Identification questionnaire. We limited participants to those reporting injuries classified as mTBI. A subset (N = 30) underwent a second Aβ-PET scan (mean 2.7 years later). We examined the effect of remote mTBI on Aβ-PET burden, interactions between remote mTBI and age, sex, and APOE status, longitudinal Aβ accumulation, and the interaction between remote mTBI and Aβ burden on memory and executive functioning. Of 134 participants, 48 (36%) reported remote mTBI (0, N = 86; 1, N = 31, 2+, N = 17; mean 37 ± 23 years since last mTBI). Effect size estimates were small to negligible for the association of remote mTBI with Aβ burden (p = .94, η 2  < 0.01), and for all interaction analyses. Longitudinally, we found a non-statistically significant association of those with remote mTBI (N = 11) having a faster rate of Aβ accumulation (B = 0.01, p = .08) than those without (N = 19). There was no significant interaction between remote mTBI and Aβ burden on cognition. In clinically normal older adults, history of mTBI is not associated with greater cortical Aβ burden and does not interact with Aβ burden to impact cognition. Longitudinal analyses suggest remote mTBI may be associated with more rapid cortical Aβ accumulation. This finding warrants further study in larger and more diverse samples with well-characterized lifelong head trauma exposure.

Background Traumatic brain injury (TBI) and repetitive head impacts (RHI) have been linked to increased risk for multiple types of neurodegenerative disease, higher dementia risk, and earlier age of dementia symptom onset, suggesting transdiagnostic implications for later-life brain health. Frontotemporal dementia (FTD) and primary progressive aphasia (PPA) represent a spectrum of clinical phenotypes that are neuropathologically diverse. FTD/PPA diagnoses bring unique challenges due to complex cognitive and behavioral symptoms that disproportionately present as an early-onset dementia (before age 65). We performed a detailed characterization of lifetime head trauma exposure in individuals with FTD and PPA compared to healthy controls to examine frequency of lifetime TBI and RHI and associated clinical implications. Methods We studied 132 FTD/PPA (age 68.9 ± 8.1, 65% male) and 132 sex-matched healthy controls (HC; age 73.4 ± 7.6). We compared rates of prior TBI and RHI (contact/collision sports) between FTD/PPA and HC (chi-square, logistic regression, analysis of variance). Within FTD/PPA, we evaluated associations with age of symptom onset (analysis of variance). Within behavioral variant FTD, we evaluated associations with cognitive function and neuropsychiatric symptoms (linear regression controlling for age, sex, and years of education). Results Years of participation were greater in FTD/PPA than HC for any contact/collision sport (8.5 ± 6.7yrs vs. 5.3 ± 4.5yrs, p  = .008) and for American football (6.2yrs ± 4.3yrs vs. 3.1 ± 2.4yrs; p  = .003). Within FTD/PPA, there were dose-dependent associations with earlier age of symptom onset for TBI (0 TBI: 62.1 ± 8.1, 1 TBI: 59.9 ± 6.9, 2 + TBI: 57.3 ± 8.4; p  = .03) and years of American football (0yrs: 62.2 ± 8.7, 1-4yrs: 59.7 ± 7.0, 5 + yrs: 55.9 ± 6.3; p  = .009). Within bvFTD, those who played American football had worse memory (z-score: -2.4 ± 1.2 vs. -1.4 ± 1.6, p  = .02, d  = 1.1). Conclusions Lifetime head trauma may represent a preventable environmental risk factor for FTD/PPA. Dose-dependent exposure to TBI or RHI influences FTD/PPA symptom onset and memory function in bvFTD. Clinico-pathological studies are needed to better understand the neuropathological correlates linking RHI or TBI to FTD/PPA onset and symptoms.

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).

Preclinical research has demonstrated a window of vulnerability in the immediate aftermath of concussion wherein continued activity and stimulation can impair or prolong neurobehavioral recovery. However, this concept has not been quantified in a human population.Context: To examine the effect of delayed reporting and removal from athletic activity after concussion on recovery time.Objective: Cross-sectional study.Design: A National Collegiate Athletic Association Division I university.Setting: Ninety-seven athletes who sustained a sport-related concussion between 2008 and 2015 were analyzed (age = 20.4 ± 1.3 years). Athletes were grouped as immediate removal from activity (I-RFA) or delayed removal from activity (D-RFA).Patients or Other Participants: Days missed was defined as the number of days between the concussion-causing event and clearance for return to contact. Associations between RFA group and prolonged (8 or more days') versus normal (7 or fewer days') recovery were also analyzed.Main Outcome Measure(s): Fifty (51.5%) of the 97 athletes did not immediately report concussion symptoms. The D-RFA athletes averaged 4.9 more days missed than the I-RFA athletes. Membership in the specific RFA group predicted days missed even after controlling for sex, concussion history, learning disability or attention-deficit/hyperactivity disorder diagnosis, diagnosed psychological disorder, and acute symptom severity ( R  2 change = 0.097, β = .319, P = .002). The D-RFA athletes were approximately 2.2 times more likely to have a prolonged recovery (8 or more days) compared with the I-RFA athletes (χ 2 = 10.268, P = .001, φ = 0.325).Results: Athletes who do not immediately report symptoms of a concussion and continue to participate in athletic activity are at risk for longer recoveries than athletes who immediately report symptoms and are immediately removed from activity. Continuing to participate in athletic activity during the immediate aftermath of a concussion potentially exposes the already injured brain to compounded neuropathophysiologic processes.Conclusions:

INTRODUCTION Factors underlying discordant visual and quantitative amyloid beta–positron emission tomography (Aβ‐PET) results and their clinical implications are not well understood. METHODS Participants from the 1Florida Alzheimer's Disease Research Center (1FLADRC) underwent Aβ‐PET, blood draw, brain magnetic resonance imaging (MRI), and neuropsychological testing. We evaluated differences in demographics, apolipoprotein E (APOE) status, biomarkers, and cognition among older adults with concordant and discordant visual‐quantitative Aβ‐PET. Discordance was defined as positive visual read (V) of Aβ‐PET with below‐threshold Centiloid quantification (Q; CL <25; V+/Q–) or negative visual read with CL ≥25 (V–/Q+). RESULTS We studied 386 participants (mean age ± SD: 70.7 ± 7.8, 55.2% female, 44.6% Hispanic White). Compared to V+/Q–, V–/Q+ had a higher frequency of APOE ε4 carriers (40%). Black/African American participants were overrepresented in V–/Q+ (40.9%). Both discordant groups had higher plasma phosphorylated tau 217 (p‐tau217) and glial fibrillary acidic protein (GFAP) than V–/Q– but lower than V+/Q+. Discordant groups had greater gray matter volume and better cognitive performance than V+/Q+. DISCUSSION Discordant Aβ‐PET findings likely hold clinical significance and may reflect early stages of neuropathological progression. Highlights Groups with concordant/discordant visual‐quantitative amyloid beta–positron emission tomography (Aβ‐PET) results were compared. Visual–/quant+ were more likely than visual+/quant– to be apolipoprotein E (APOE) ε4 carriers and Black/African American. Discordant groups had higher plasma phosphorylated tau 217 (p‐tau217) and glial fibrillary acidic protein (GFAP) than concordant negative. Discordant groups had less atrophy and better cognition than concordant positive. Centiloid quantification should supplement visual reads in clinical settings.

As cases of coronavirus disease 2019 (COVID-19) mount worldwide, attention is needed on potential long-term neurologic impacts for the majority of patients who experience mild to moderate illness managed as outpatients. To date, there has not been discussion of persistent neurocognitive deficits in patients with milder COVID-19. We present two cases of non-hospitalized patients recovering from COVID-19 with persistent neurocognitive symptoms. Commonly used cognitive screens were normal, while more detailed testing revealed working memory and executive functioning deficits. An observational cohort study of individuals recovering from COVID-19 (14 or more days following symptom onset) identified that among the first 100 individuals enrolled, 14 were non-hospitalized patients reporting persistent cognitive issues. These 14 participants had a median age of 39 years (interquartile range: 35–56), and cognitive symptoms were present for at least a median of 98 days (interquartile range: 71–120 following acute COVID-19 symptoms); no participants with follow-up evaluation reported symptom resolution. We discuss potential mechanisms to be explored in future studies, including direct viral effects, indirect consequences of immune activation, and immune dysregulation causing auto-antibody production.