Jasmeet Pannu Hayes

Head injury has emerged as a significant environmental risk factor for dementia. Demyelination, defined as the loss of the fatty protective layer surrounding axons, may be associated with neurodegenerative processes following head injury, especially in cortical regions. Although many neuroimaging studies have investigated demyelination in deep subcortical white matter tracts following head injury, these methods do not readily capture myelinated axons that also extend to the cortical surface. To address this gap, the present study used a structural neuroimaging method (T1-weighted [T1w]/T2-weighted [T2w] ratio) as a proxy measure for intracortical myelin content and related these values to history of traumatic brain injury (TBI) and/or repetitive head impacts (RHIs). The sample included 73 older adults (42% male; mean age = 64.8 years; range: 51–86 years) categorized based on TBI ( n = 31) and RHI ( n = 23) exposure. Rank-transformed analyses of covariance compared whole-brain and regional T1w/T2w values between exposed and nonexposed groups. Partial Spearman’s correlations tested monotonic associations between continuous numbers of TBI and RHI exposures and T1w/T2w values. Linear regression models explored interaction effects between head injury and age on T1w/T2w values. Covariates in all analyses included sex, education, and image signal intensity variables. Results revealed that RHI exposure and head injury frequency, including lifetime RHI estimates and number of TBI events, were associated with lower global T1w/T2w values. Regionally, RHI was linked to lower T1w/T2w values in the lateral occipital gyrus. Age further moderated these effects, with stronger associations between RHI and whole-brain myelination observed in younger individuals. These findings provide in vivo evidence linking repetitive impacts to cortical-level myelination and highlight the modifying role of age on these processes.

INTRODUCTION: Modifiable lifestyle variables, such as cardiorespiratory fitness, may attenuate age‐related brain atrophy. Although recent studies have investigated the relationship between cardiorespiratory fitness and cortical thickness across the adult lifespan, to our knowledge, none have considered nonlinear relationships with age. The current cross‐sectional study explored the nonlinear effects of age on the relationship between cardiorespiratory fitness and cortical thickness across the adult lifespan. METHODS: Young, middle‐aged, and older adults ( n = 159; age range = 18–86 years, mean age = 54.2 years) were selected from the Fitness, Aging, Stress, and TBI Exposure Repository (FASTER; Hayes & Hayes). Cardiorespiratory fitness (VO ₂ peak) was assessed via progressive maximal exercise testing on a stationary bike. T ₁ ‐ and T ₂ ‐weighted magnetic resonance imaging (MRI) scans were processed and analyzed using FreeSurfer. Surface‐based analyses were used to identify regions showing a main effect of VO ₂ peak on cortical thickness in older adults (55+ years). Average cortical thickness was extracted from regions of interest, and Generalized additive models (GAMs) were used to identify the optimal relationship between continuous age and VO ₂ peak on cortical thickness. RESULTS: Positive and negative associations between VO ₂ peak and cortical thickness were observed in older adults. GAMs demonstrated effects with varying linearity and showed an Age × VO ₂ peak interaction in the left superior temporal gyrus, parahippocampal cortex, superior parietal lobe, and inferior parietal lobe, and the right pars orbitalis and lateral orbitofrontal cortex. The relationship between VO ₂ peak and cortical thickness became more positive in older adults, but it varied and was nonlinear across age. DISCUSSION: These findings highlight the complex relationship between cardiorespiratory fitness and cortical thickness across the adult lifespan. Among older adults, cardiorespiratory fitness may be an important variable contributing to higher cortical thickness in aging.

Background and Objectives: Perceived stress is associated with poor health outcomes, including accelerated cognitive decline and increased risk for dementia. Prior research suggests that emotion regulation may determine the extent to which stress impairs cognition with age. This study extends this work by examining the moderating role of two emotion regulation strategies (cognitive reappraisal; expressive suppression) on the relationship between perceived stress and cognitive decline over 10 years in a sample of older adults. Research Design and Methods: The sample was drawn from the Midlife in the United States Study (MIDUS; N = 468; Mean age at baseline = 60.24), providing measures of perceived stress, emotion regulation, and cognition at baseline and follow-up (episodic memory; executive functioning). Moderation analyses with 5,000 bootstrapped samples were conducted in the PROCESS Macro and statistically adjusted for age, sex, education, household income, medications, and baseline cognition. Results: Results revealed that perceived stress interacted with expressive suppression to predict later episodic memory performance. As stress levels increased, only individuals endorsing regular use of expressive suppression exhibited significant memory decline. By contrast, cognitive reappraisal did not significantly moderate relationships between stress and later cognition. Discussion and Implications: Findings highlight that habitual suppression of emotional expression may amplify the consequences of perceived stress on memory decline in late life. Promotion of adaptive emotion regulation may play a role in mitigating the effects of stress on cognitive outcomes among older adults.

Background: Identifying biomarkers of Alzheimer's disease (AD) is critical for early diagnosis and AD risk assessment. Objective: We examined the hypothesis that the plasma amyloid-β 42 and 40 (Aβ _42:40 ) ratio has a curvilinear relationship with age among individuals who are at higher genetic risk for AD. Methods: This study investigated the relationship between plasma amyloid-β 42 and 40 (Aβ _42:40 ) ratio and age in 315 men and women Veterans, including those at genetic risk for AD. Hierarchical regression models investigated linear and nonlinear relationships between age, genetic risk, and Aβ _42:40 . Results: We observed a curvilinear relationship between age and Aβ _42:40 in individuals with higher genetic risk, characterized by an increase in the Aβ _42:40 during midlife followed by a decrease in older age. Conclusions: These findings highlight distinct patterns in Aβ metabolism among genetically predisposed individuals, suggesting that early metabolic shifts may play a role in the progression of AD. Understanding these nuanced changes is essential for refining the use of Aβ _42:40 ratio as a biomarker, potentially leading to more accurate risk stratification and earlier intervention strategies in AD.

Childhood maltreatment is recognized as a risk factor for cognitive decline in adulthood. However, the mechanisms underlying this association, particularly the role of systemic inflammation, remain understudied. To address this gap, this study investigated the indirect effects of inflammation on the associations between childhood maltreatment and both episodic memory (EM) and executive functioning (EF) performance 10 years after inflammatory measurement in older adults. We selected 590 participants ( M _age = 65.5 years) from the Midlife in the United States Study based on available childhood maltreatment, inflammation, and composite cognitive data. Spearman's rank correlations were calculated to test associations among childhood maltreatment, cognition, and inflammation. The results informed follow‐up analyses testing the indirect effects of inflammation on the associations between childhood maltreatment and cognition. Correlations demonstrated that inflammation was associated with overall childhood maltreatment as well as with specific domains of childhood maltreatment (i.e., physical abuse, sexual abuse, emotional abuse, and physical neglect), p s = .002–.010. Inflammation was negatively associated with EF, p = .001, and EM, p = .028. Follow‐up analyses revealed significant indirect pathways linking overall childhood maltreatment, β = −.0088, SE = 0.0058, 95% CI [−0.0223, −0.00000], to EM performance through inflammation, but no specific domain of maltreatment drove this association. The results suggest that inflammation may help explain links between childhood maltreatment exposure and EM deficits in adulthood. These results elucidate the importance of evaluating childhood maltreatment as a risk factor for later‐life cognitive decline, particularly within the context of heightened inflammatory biomarkers.

This cross-sectional study examined associations between multiple fluid biomarkers of neuronal and glial dysfunction (plasma neurofilament light chain, CSF growth-associated protein 43 and CSF soluble triggering receptor expressed on myeloid cells 2), total white matter hyperintensity volume and episodic memory and executive function performance in the context of Alzheimer’s disease biomarker status. A total of 563 participants (mean age = 71.9 years, standard deviation = 7.2) from the Alzheimer’s Disease Neuroimaging Initiative were classified by the amyloid-β/tau/neurodegeneration framework into no Alzheimer’s disease pathology (n = 176), suspected non-Alzheimer’s disease pathophysiology (n = 87) or Alzheimer’s disease continuum (n = 300) groups. Participants completed baseline neuropsychological assessment, plasma/CSF biomarker collection and MRI. Analyses explored the relative contributions of biomarkers to episodic memory and executive function performance and whether relationships varied by amyloid-β/tau/neurodegeneration group status. Across all participants, neurofilament light chain (β^= −0.14, P < 0.001) and growth-associated protein 43 (β^= −0.13, P < 0.001) were the strongest biomarkers associated with episodic memory performance, such that greater levels were associated with worse episodic memory. There was a group by growth-associated protein 43 interaction with episodic memory: greater growth-associated protein 43 was associated with lower episodic memory performance in participants classified as Alzheimer’s disease continuum relative to the no Alzheimer’s disease pathology group (β^= −0.26, P < 0.001). No robust associations between biomarkers and executive function performance or between soluble triggering receptor expressed on myeloid cells 2, white matter hyperintensity volume and cognition were observed. Biomarkers of neuro-axonal injury and synaptic dysfunction may independently contribute to episodic memory performance across participants with differing amyloid-β/tau/neurodegeneration profiles. Growth-associated protein 43 may predict worse episodic memory performance in participants with greater Alzheimer’s disease pathology. These biomarkers of neuronal dysfunction may serve as domain-specific cognitive correlates in the context of Alzheimer’s disease biomarker status.

Traumatic brain injuries (TBIs) may increase the risk for Alzheimer’s disease (AD) and its neuropathological correlates, although the mechanisms of this relationship are unclear. The current study examined the synergistic effects of TBI and genetic risk for AD on β-amyloid (Aβ) levels among Vietnam War Veterans. We hypothesized that the combination of TBI and higher polygenic risk score (PRS) for AD would be associated with lower cerebrospinal fluid (CSF) Aβ _42/40 . Data were obtained from the Department of Defense Alzheimer’s Disease Neuroimaging Initiative. Participants included Vietnam War Veterans without dementia who identified as White non-Hispanic/Latino and had available demographic, clinical assessment, genetic, and CSF biomarker data. Lifetime TBI history was assessed using The Ohio State University TBI Identification Method. Participants were categorized into those with and without TBI. Among those with a prior TBI, injury severity was defined as either mild or moderate/severe. CSF Aβ _42/40 ratios were calculated. Genetic propensity for AD was assessed using PRSs. Hierarchical linear regression models examined the interactive effects of TBI and PRS for AD on Aβ _42/40 . Exploratory analyses examined the interaction between TBI severity and PRS. The final sample included 88 male Vietnam War Veterans who identified as White non-Hispanic/Latino ( M _age = 68.3 years), 49 of whom reported a prior TBI. There was a significant interaction between TBI and PRS, such that individuals with TBI and higher PRS for AD had lower Aβ _42/40 ( B = −0.45, 95% CI: −0.86 to −0.05, p = 0.03). This relationship may be stronger with increasing TBI severity ( p = 0.05). Overall, TBI was associated with lower Aβ _42/40 , indicating greater amyloid deposition in the brain, in the context of greater polygenic risk for AD. These findings highlight who may be at increased risk for AD neuropathology following TBI.

Background: Alzheimer’s disease (AD) is associated with the accumulation of neuropathological beta‐amyloid (Ab) plaques, which is thought to be caused by an imbalance between Ab overproduction and dysfunctional Ab clearance. Both animal and human studies have shown that increased cerebrospinal fluid (CSF) levels of Ab peptides, especially Ab‐40 and Ab‐38 due to their high solubility, may be indicative of overall Ab dysregulation in preclinical AD, years before pathological Ab plaques begin to aggregate. The apolipoprotein E (APOE) e4 allele, which is the strongest genetic risk factor for AD, has been linked to impaired Ab clearance and disruption of the amyloid precursor protein (APP) pathway that is responsible for Ab production. However, the association between early Ab dysregulation and other genetic risk variants remains understudied. Thus, we aimed to explore whether genetic risk for AD is related to early markers of Ab overproduction by examining associations between polygenic risk scores (PRS) and CSF Ab‐40 and Ab‐38 in an AD‐vulnerable population.Method: We selected 88 non‐demented Veterans (Age: M = 68.22, SD = 3.75 years) from the Alzheimer’s Disease Neuroimaging Initiative‐Department of Defense (ADNI‐DOD) database with available genetic markers and CSF measures for Ab‐40 and Ab‐38. Genetic propensity for AD was assessed using genome‐wide PRS, both with and without the APOE region, employing a p‐value threshold < 0.01. CSF Ab concentrations were measured using a 2D‐UPLC‐tandem mass spectrometry method outlined by ADNI‐DOD. Partial spearman’s correlations related PRS to CSF Ab‐38 and Ab‐40 levels adjusting for age.Result: CSF Ab‐40 levels were positively associated with PRS for AD (rho_partial = 0.22, p = 0.037). When variants in the APOE region were excluded from the score, the relationship between CSF Ab‐40 and PRS remained significant (rho_partial = 0.23, p = 0.035). The relationship between PRS for AD and CSF Ab‐38 levels was not significant, regardless of whether APOE regions were included in the score (all p’s > 0.1).Conclusion: Genetic risk for AD may lead to early Ab overproduction, as evidenced by elevated CSF Ab levels, particularly Ab‐40. Other genetic variants, in addition to APOE, may play an integral role in disrupting the APP pathway and dysregulating Ab production.

Background: There is a broad and diverse range of symptoms after a concussion, from irritability to nausea. This heterogeneity of symptoms is a challenge for clinicians managing the different presentations among injuries. Prior research has investigated the structure of postconcussive symptoms to determine if they can be grouped into clusters of related symptoms. Purpose/Hypothesis: The purpose of this study was to identify symptom clusters during the acute phase after a sports-related concussion using exploratory factor analysis and to understand the relationship between risk factors for postconcussion symptoms (ie, demographics, injury characteristics, mental health, and sleep qualities) and different symptom clusters. We hypothesized that certain factors would be predictive of specific symptom clusters. Study Design: Cross-sectional study; Level of evidence, 3. Methods: Collegiate athletes (N = 1104) from the Concussion, Assessment, Research, and Education (CARE) Consortium completed the Sport Concussion Assessment Tool–Third Edition symptom assessment tool 24 to 48 hours after concussion. Exploratory factor analysis was conducted on the symptom evaluation to determine symptom clusters 24 to 48 hours after concussion. Regression analysis was used to examine the effects of pre- and postinjury characteristics. Results: Exploratory factor analysis revealed a 4-cluster structure for acute postconcussive symptoms that explained 62% of the variance in symptom reporting: vestibular-cognitive, migrainous, cognitive fatigue, and affective. Delayed reporting, less sleep before assessment, female sex, and being hurt outside of competition (during practice/training) was correlated with increased symptoms for 4 symptom clusters. Depression predicted higher vestibular-cognitive and affective symptoms. Amnesia was correlated with higher vestibular-cognitive and migrainous symptoms, whereas migraine history was associated with more migrainous and affective symptoms. Conclusion: Symptoms can be grouped into 1 of 4 distinct clusters. Certain variables were associated with increased symptoms across multiple clusters and may be indicative of greater injury severity. Other factors (ie, migraine history, depression, amnesia) were associated with a more specific symptom presentation and may be mechanistically related to concussion outcomes and biological markers.