Background Childhood adversity is linked to psychopathology risk and dysregulated stress reactivity; however, unified underlying neural mechanisms are unclear. A central visceral network, including the bed nucleus of the stria terminalis (BNST), amygdala and subgenual anterior cingulate cortex (sgACC), is implicated in affective processes and proximally controls stress reactivity. We examined relationships among childhood adversity, stressor-evoked neural activity/connectivity and affective and cardiovascular outcomes. Methods Participants were adults (n=97, mean age=27.32, SD=4.02, 57 females) uniformly distributed across physical abuse severity. Childhood adversity was assessed by threat (abuse or traumatic events) and socioeconomic deprivation (SED). Participants performed an fMRI stress task with cardiovascular recordings. Linear/curvilinear regressions were performed with threat and deprivation together as predictors of stressor-evoked activity/connectivity. Neural variables showing significant adversity associations were examined as predictors of affective symptoms/diagnoses or cardiovascular responses. Results Threat and SED displayed opposing curvilinear relationships with stressor-evoked amygdala and sgACC activity, respectively: at low and high adversity, amygdala reactivity was greater, whereas sgACC reactivity was blunted. Greater SED was associated with weaker BNST-sgACC connectivity. Blunted amygdala reactivity and lower sgACC reactivity were associated with greater post-traumatic stress symptoms. Affective diagnoses peaked at near-zero BNST-sgACC connectivity. Greater amygdala reactivity was associated with blunted diastolic blood pressure reactivity and recovery. Conclusions The curvilinear relationships suggest adversity-related vulnerability thresholds. Blunted amygdala, lower sgACC reactivity and weaker BNST-sgACC connectivity may confer affective risk, whereas heightened amygdala reactivity may confer cardiovascular risk. Our findings support a central visceral network pathway by which childhood adversity may contribute to affective and cardiovascular health.
N. Kasibhatla, C. W. Peng, H. Karim et al.· medRxiv· 0 citations
BACKGROUND AND OBJECTIVES
Plasma glial fibrillary acidic protein (GFAP), a marker of astrocyte reactivity, is elevated across multiple neurodegenerative conditions, including Alzheimer disease. However, its role in neurodegeneration and cognitive decline driven by cerebrovascular pathology, independent of β-amyloid (Aβ) copathology, remains poorly characterized. We investigated whether plasma GFAP is associated with medial temporal atrophy and cognition across a spectrum of cerebrovascular burden in Aβ-negative cognitively impaired individuals.
METHODS
In this cross-sectional multicenter study, Aβ PET-negative cognitively impaired participants were recruited from South Korean memory clinics. Plasma GFAP was measured using ultrasensitive Simoa assays. White matter hyperintensity burden was graded using the Fazekas scale and stratified into low (LVP: Fazekas 1) and high (HVP: Fazekas 2-3) cerebrovascular burden groups. Medial temporal gray matter density was assessed using voxel-based morphometry, and hippocampal and amygdalar volumes were derived from T1-weighted MRI adjusted for intracranial volume. Linear regression, interaction, and bootstrap mediation models were used to assess associations among GFAP, brain structure, and cognition.
RESULTS
A total of 324 participants were included (LVP n = 203; HVP n = 121; median age 73 years [interquartile range 66-78]; 67.9% female). Compared with LVP, HVP participants were older (75 vs 71 years; p < 0.0001), had lower Mini-Mental State Examination (MMSE) scores (22.7 vs 24.5; p = 0.005), and higher plasma GFAP (136.7 vs 112.1 pg/mL; p = 0.001). Higher GFAP was associated with lower medial temporal gray matter density in HVP (β = -0.311; p = 0.001) but not LVP (β = -0.012; p = 0.858), with a significant GFAP-vascular burden interaction (β = -0.309; p = 0.008). In HVP, higher GFAP was associated with smaller hippocampal (β = -0.179; p = 0.044) and amygdalar volumes (β = -0.169; p = 0.049) and lower MMSE (β = -0.194; p = 0.039). Medial temporal atrophy statistically explained the GFAP-MMSE association (indirect β = -0.071, 95% CI -0.140 to -0.010; p = 0.016). Vascular comorbidities (diabetes, dyslipidemia, hypertension) did not modify the GFAP-cognition association.
DISCUSSION
In Aβ-negative cognitively impaired individuals with high cerebrovascular burden, elevated plasma GFAP is associated with medial temporal atrophy and cognitive decline, suggesting GFAP may capture astrocyte-reactivity relevant to vascular cognitive impairment beyond amyloid pathology. These cross-sectional findings require confirmation in longitudinal and ethnically diverse cohorts.
M. S. Oliveira-Junior, M. Rodrigues, Livia Amaral et al.· Neurology· 0 citations
