Recent studies support the hypothesis that the adverse effects of early-life adversity and transgenerational stress on neural plasticity and behavior are mediated by inflammation. The objective of the present study was to investigate the immune and behavioral programing effects of intranasal (IN) vasopressin (AVP) and oxytocin (OXT) treatment of chronic social stress (CSS)-exposed F1 dams on F2 juvenile female offspring. It was hypothesized that maternal AVP and OXT treatment would have preventative effects on social stress-induced deficits in offspring anxiety and social behavior and that these effects would be associated with changes in interferon-γ (IFNγ). Control and CSS-exposed F1 dams were administered IN saline, AVP, or OXT during lactation and the F2 juvenile female offspring were assessed for basal plasma IFNγ and perseverative, anxiety, and social behavior. CSS F2 female juvenile offspring had elevated IFNγ levels and exhibited increased repetitive/perseverative and anxiety behaviors and deficits in social behavior. These effects were modulated by AVP and OXT in a context- and behavior-dependent manner, with OXT exhibiting preventative effects on repetitive and anxiety behaviors and AVP possessing preventative effects on social behavior deficits and anxiety. Basal IFNγ levels were elevated in the F2 offspring of OXT-treated F1 dams, but IFNγ was not correlated with the behavioral effects. These results support the hypothesis that maternal AVP and OXT treatment have context- and behavior-specific effects on peripheral IFNγ levels and perseverative, anxiety, and social behaviors in the female offspring of early-life social stress-exposed dams. Both maternal AVP and OXT are effective at preventing social stress-induced increases in self-directed measures of anxiety, and AVP is particularly effective at preventing impairments in overall social contact. OXT is specifically effective at preventing repetitive/perseverative behaviors, yet is ineffective at preventing deficits in overall social behavior.

Similar to the multi-hit theory of schizophrenia, social behavior pathologies are mediated by multiple factors across generations, likely acting additively, synergistically, or antagonistically. Exposure to social adversity, especially during early life, has been proposed to induce depression symptoms through immune mediated mechanisms. Basal immune factors are altered in a variety of neurobehavioral models. In the current study, we assessed two aspects of a transgenerational chronic social stress (CSS) rat model and its effects on the immune system. First, we asked whether exposure of F0 dams and their F1 litters to CSS changes basal levels of IL-6, TNF, IFN-γ, and social behavior in CSS F1 female juvenile rats. Second, we asked whether the F2 generation could generate normal immunological responses following vaccination with Mycobacterium bovis Bacillus Calmette–Guérin (BCG). We report several changes in the associations between social behaviors and cytokines in the F1 juvenile offspring of the CSS model. It is suggested that changes in the immune–behavior relationships in F1 juveniles indicate the early stages of immune mediated disruption of social behavior that becomes more apparent in F1 dams and the F2 generation. We also report preliminary evidence of elevated IL-6 and impaired interferon-gamma responses in BCG-vaccinated F2 females. In conclusion, transgenerational social stress alters both immune–behavior associations and responses to vaccination. It is hypothesized that the effects of social stress may accumulate over generations through changes in the immune system, establishing the immune system as an effective preventative or treatment target for social behavior pathologies.

Introduction: Hematocrit at both low and high extremes can result in both hypoxia and thrombosis respectively. While both scenarios may predispose to ischemia, it is unclear whether hematocrit associates with small vessel cerebrovascular lacunar infarcts. Hypothesis: Hematocrit levels will associate with both asymptomatic and symptomatic cerebrovascular lacunar infarcts in stroke-free participants and ischemic stroke patients, respectively. Methods: A cross sectional observational analysis of a prospective, population-based cohort study of stroke-free, older adult (>50) participants from the Northern Manhattan study (NOMAS) receiving baseline hematocrit testing and MRI between 2003-2008 were analyzed. A second, single center prospective cohort of admitted adult ischemic stroke patients receiving baseline hematocrit testing and MRI between 2005-2018 was evaluated. Associations of hematocrit with covert, asymptomatic chronic lacunar infarcts from stroke-free participants in NOMAS were assessed using general additive models after adjusting for relevant covariates. Separate analyses were performed to assess associations of hematocrit with symptomatic acute lacunar infarct stroke etiology using similar adjusted models for patients admitted and enrolled into the ischemic stroke registry. Results: Of 1218 NOMAS participants analyzed, 6% had covert chronic lacunar infarcts. The association between hematocrit and covert chronic lacunar infarcts was U-shaped (X2: 9.21; p-value: 0.03). In the 1489 patients from the ischemic stroke registry, 23% were identified to have symptomatic acute lacunar infarcts. Linear relationships were identified with higher hematocrit and symptomatic acute lacunar infarct etiology (adjusted coefficient beta: 0.020; standard error: 0.009; p=0.03). Conclusions: We identified relationships of hematocrit with both asymptomatic and symptomatic lacunar infarcts in both stroke-free and ischemic stroke cohorts, respectively. There may be a relevant role of red blood cell volumes with ischemic cerebral small vessel disease pathophysiology. However, further studies are required to clarify the mechanisms behind these relationships.

Introduction: Intracranial artery calcification (IAC) is a common radiological finding on Computed Tomography (CT) scan. Although IAC occurs with aging, it is uncertain whether IAC varies by stroke subtypes. Method: We included patients admitted to our hospital with acute stroke. We quantified calcification volume of both clinoid and siphon carotid arteries, vertebral arteries at the V4 segment, and the basilar artery using an in-house quantification tool for non-contrast brain CT. Stroke etiological subtypes were determined according to the Trial of Organon in Acute Stroke Trial (TOAST) classification system independent of the calcification quantification. Demographic and clinical information was extracted from the medical records. We determined the prevalence of IAC in 51% of patients. (31% anterior, 7% posterior, and 14 % in both circulations) Result: We included 694 patients with stroke history (mean age 68 ± 16, range 21-101, 55% women, 71% nonwhite or mixed). IAC was associated with male sex (OR 1.47 [95%-CI 1.41-2.08), older age (OR 1.05 [95%-CI, 1.04-1.06]), hypertension (OR 1.55 [95%-CI, 1.01-2.36], dyslipidemia (OR 1.54 [95%-CI, 1.06-2.25]), and smoking (OR 1.79 [95%-CI, 1.18-2.71]). Anterior IAC was associated with dyslipidemia (OR 1.57 [95%-CI, 1.08-2.28], smoking (1.9 [95%-CI, 1.25-2.88]), and older age (OR 1.05 [95%-CI, 1.36-1.66). Posterior IAC was associated with myocardial infarction (OR 1.58 [95%-CI, 1.01-2.47] and older age (OR 1.02 [95%-CI, 1.01-1.03]. In multivariate analyses, any IAC was associated with small artery disease stroke (OR 1.01[95%-CI, 1.41-3.98]). Stratifying by circulations, however, demonstrated that the association was only with posterior (OR 1.22[95%-CI, 1.02-2.28]) and not anterior IAC (OR 1.20[95%-CI, 0.86-1.1.69]). There was no association between IAC and intracranial large artery stenoses OR (1.22[95%-CI, 0.78-1.1.92]). Conclusion: IAC is a marker of arterial disease, and its prevalence relates to vascular risk factors and small artery disease strokes. Understanding the mechanism by which IAC may relate to small artery disease may help us understand small artery stroke physiopathology and discover novel therapies for its treatment.

Introduction: Early neurological deterioration (END) in patients with acute stroke is associated with poorer outcomes. We aim to investigate whether higher acute phase reactants in blood are associated with END. Identifying predictors of END could help select patient at the highest risk of END for possible interventions. Methods: In this cross-sectional study, we included 242 patients with acute onset of ischemic stroke admitted to Columbia University Irving Medical Center-New York-Presbyterian Hospital from 2006 to 2015. We focused on retrieving C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) when they were collected on admission. Risk factors and comorbidities were also captured from the charts. END was defined as any neurologic deterioration referable to ischemic stroke and not related to a medical or non-cerebrovascular neurological complication. We considered significant associations by a P-value <.05. We built separate logistic regression models with END as the outcome and CRP and ESR as the main exposure variables, progressively adjusting for confounders. Results: The study included 242 patients with a mean age of 64.2 ± 17.2, of which 108 (50%) were women, 89 (41%) were Hispanic and 40 (19%) were African American or black. The prevalence of END was 47 (19%). The most common stroke mechanism was penetrating artery infarct, 103 (43%). CRP level was associated with END, and it remained an independent predictor of END even after progressively adjusting for confounders (OR = 1.01; 95% CI 1.01 to 1.02, P <0.001). ESR was not associated with END (table 1). Among patients with acute stroke and CRP>10, there was a 28% risk of END compared with only 13% among those with CRP 10 or lower. Conclusions: Our results suggest that high CRP levels are associated with END. A cutoff of 10 or greater identifies patients at the highest risk of END. Replication studies are needed to understand the mechanisms behind this and further replicate these findings.