ABSTRACT
Dementia is often characterized by age-dependent cerebrovascular pathology, neuroinflammation, and cognitive deficits with notable sex differences in risk, disease onset, progression and severity. Women bear a disproportionate burden of dementia, and the onset of menopause (i.e., perimenopause) may be a critical period conferring increased susceptibility. However, the contribution of early ovarian decline to the neuroinflammatory processes associated with cerebrovascular dementia risks, particularly at the initial stages of pathology that may be more amenable to proactive intervention, is unknown. To better understand the influence of early ovarian failure on dementia-associated neuroinflammation we developed a model of perimenopausal cerebral amyloid angiopathy (CAA), an important contributor to dementia. For this, accelerated ovarian failure (AOF) was induced by 4-vinylcyclohexene diepoxide (VCD) treatment to isolate early-stage ovarian failure comparable to human perimenopause (termed "peri-AOF") in transgenic SWDI mice expressing human vasculotropic mutant amyloid beta (Aß) precursor protein, that were also tested at an early stage of amyloidosis. We found that peri-AOF SWDI mice showed increased astrocyte activation accompanied by elevated Aß in select regions of the hippocampus, a brain system involved in learning and memory that is severely impacted during dementia. However, although SWDI mice showed signs of increased hippocampal microglial activation and impaired cognitive function, this was not further affected by peri-AOF. In sum, these results suggest that elevated dysfunction of key elements of the neurovascular unit in select hippocampal regions characterizes the brain pathology of mice at early stages of both CAA and AOF. However, neurovascular unit pathology may not yet have passed a threshold that leads to further behavioral compromise at these early periods of cerebral amyloidosis and ovarian failure. These results are consistent with the hypothesis that the hormonal dysregulation associated with perimenopause onset represents a stage of emerging vulnerability to dementia-associated neuropathology, thus providing a selective window of opportunity for therapeutic intervention prior to the development of advanced pathology that has proven difficult to repair or reverse.
ABSTRACT
OBJECTIVES/HYPOTHESIS: The primary objective of this investigation was to determine rates of abnormal coagulation panels and diagnoses of coagulopathies in children with post-tonsillectomy hemorrhage (PTH). Secondary objectives identified patient demographics and hemorrhage event characteristics that correlated with a coagulopathy diagnosis. STUDY DESIGN: Case series with chart review. METHODS: Patients requiring operative control of PTH at a tertiary children's hospital between 2015 and 2019 were included. Details of tonsillectomy procedures and hemorrhage events were reviewed along with screening labs for coagulopathy, referrals to hematology and bleeding disorder diagnoses. RESULTS: There were 250 children included. Mean age was 8.8 years (95% CI: 8.2-9.4) and 53.6% were males. PTH events occurred at a median of postoperative day six (mean: 5.9, 95% CI: 5.4-6.3), and 14.8% occurred within 24 hours of surgery. In this series, 23 patients (9.2%) had a second PTH, and three (1.2%) had a third PTH. Single and multiple PTH patients were similar with respect to age, gender, postoperative day, and technique (P > .05). Screening coagulation panels were obtained on presentation in 67.8% of children with one PTH and abnormally elevated in 38.3%. All children with multiple PTHs had labs drawn with 34.8% having elevated levels. No child with a single PTH was diagnosed with a bleeding disorder. Conversely, 87.0% of children with multiple PTHs saw hematology and three (13.0%) were diagnosed with a bleeding disorder (P < .001). CONCLUSIONS: Obtaining coagulation panels in pediatric patients presenting with PTH is rarely useful and diagnosing a coagulopathy is uncommon. However, among children with a second PTH, referral to hematology is reasonable as this group has a significantly higher, albeit small, incidence of undiagnosed bleeding disorders. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E2069-E2073, 2021.
