Dataset Information

Cerebral microbleeds in a neonatal rat model.

ABSTRACT:

Background

In adult humans, cerebral microbleeds play important roles in neurodegenerative diseases but in neonates, the consequences of cerebral microbleeds are unknown. In rats, a single pro-angiogenic stimulus in utero predisposes to cerebral microbleeds after birth at term, a time when late oligodendrocyte progenitors (pre-oligodendrocytes) dominate in the rat brain. We hypothesized that two independent pro-angiogenic stimuli in utero would be associated with a high likelihood of perinatal microbleeds that would be severely damaging to white matter.

Methods

Pregnant Wistar rats were subjected to intrauterine ischemia (IUI) and low-dose maternal lipopolysaccharide (mLPS) at embryonic day (E) 19. Pups were born vaginally or abdominally at E21-22. Brains were evaluated for angiogenic markers, microhemorrhages, myelination and axonal development. Neurological function was assessed out to 6 weeks.

Results

mRNA (Vegf, Cd31, Mmp2, Mmp9, Timp1, Timp2) and protein (CD31, MMP2, MMP9) for angiogenic markers, in situ proteolytic activity, and collagen IV immunoreactivity were altered, consistent with an angiogenic response. Vaginally delivered pups exposed to prenatal IUI+mLPS had spontaneous cerebral microbleeds, abnormal neurological function, and dysmorphic, hypomyelinated white matter and axonopathy. Pups exposed to the same pro-angiogenic stimuli in utero but delivered abdominally had minimal cerebral microbleeds, preserved myelination and axonal development, and neurological function similar to naïve controls.

Conclusions

In rats, pro-angiogenic stimuli in utero can predispose to vascular fragility and lead to cerebral microbleeds. The study of microbleeds in the neonatal rat brain at full gestation may give insights into the consequences of microbleeds in human preterm infants during critical periods of white matter development.

SUBMITTER: Theriault BC

PROVIDER: S-EPMC5291518 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Publications

Cerebral microbleeds in a neonatal rat model.

Theriault Brianna C BC Woo Seung Kyoon SK Karimy Jason K JK Keledjian Kaspar K Stokum Jesse A JA Sarkar Amrita A Coksaygan Turhan T Ivanova Svetlana S Gerzanich Volodymyr V Simard J Marc JM

PloS one 20170203 2

<h4>Background</h4>In adult humans, cerebral microbleeds play important roles in neurodegenerative diseases but in neonates, the consequences of cerebral microbleeds are unknown. In rats, a single pro-angiogenic stimulus in utero predisposes to cerebral microbleeds after birth at term, a time when late oligodendrocyte progenitors (pre-oligodendrocytes) dominate in the rat brain. We hypothesized that two independent pro-angiogenic stimuli in utero would be associated with a high likelihood of per ...[more]

PMID: 28158198

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Project description:Background and purposeCerebral microbleeds (CMBs) are represented by small areas of hemosiderin deposition, detected on brain magnetic resonance imaging (MRI), and found in ≈23% of the cognitively normal population over age of 60 years. CMBs predict risk of hemorrhagic and ischemic stroke. They correlate with increased cardiovascular mortality. In this article, we sought to determine in a population-based study whether antithrombotic medications correlate with CMBs and, if present, whether the association was direct or mediated by another variable.MethodsThe study consisted of 1253 participants from the population-based Mayo Clinic Study of Aging who underwent T2* gradient-recalled echo magnetic resonance imaging. We tested the relationship between antithrombotic medications and CMB presence and location, using multivariable logistic-regression models. Ordinal logistic models tested the relationship between antithrombotics and CMB frequency. Using structural equation models, we assessed the effect of antithrombotic medications on presence/absence of CMBs and count of CMBs in the CMB-positive group, after considering the effects of age, sex, vascular risk factors, amyloid load by positron emission tomography, and apoE.ResultsTwo hundred ninety-five participants (26.3%) had CMBs. Among 678 participants taking only antiplatelet medications, 185 (27.3%) had CMBs. Among 95 participants taking only an anticoagulant, 43 (45.3%) had CMBs. Among 44 participants taking an anticoagulant and antiplatelet therapy, 21 (48.8%) had CMBs. Anticoagulants correlated with the presence and frequency of CMBs, whereas antiplatelet agents were not. Structural equation models showed that predictors for presence/absence of CMBs included older age at magnetic resonance imaging, male sex, and anticoagulant use. Predictors of CMB count in the CMB-positive group were male sex and amyloid load.ConclusionsAnticoagulant use correlated with presence of CMBs in the general population. Amyloid positron emission tomography correlated with the count of CMBs in the CMB-positive group.

Project description:ImportanceCerebral microbleeds (CMBs) are collections of blood breakdown products that are a common incidental finding in magnetic resonance imaging of elderly individuals. Cerebral microbleeds are associated with cognitive deficits, but the mechanism is unclear. Studies show that individuals with CMBs related to symptomatic cerebral amyloid angiopathy have abnormal vascular reactivity and cerebral blood flow (CBF), but, to our knowledge, abnormalities in cerebral blood flow have not been reported for healthy individuals with incidental CMBs.ObjectiveTo evaluate the association of incidental CMBs with resting-state CBF, cerebral metabolism, cerebrovascular disease, β-amyloid (Aβ), and cognition.Design, setting, and participantsA cross-sectional study of 55 cognitively normal individuals with a mean (SD) age of 86.8 (2.7) years was conducted from May 1, 2010, to May 1, 2013, in an academic medical center in Pittsburgh; data analysis was performed between June 10, 2013, and April 9, 2015.Interventions3-Tesla magnetic resonance imaging was performed with susceptibility-weighted imaging or gradient-recalled echo to assess CMBs, arterial spin labeling for CBF, and T1- and T2-weighted imaging for atrophy, white matter hyperintensities, and infarcts. Positron emission tomography was conducted with fluorodeoxyglucose to measure cerebral metabolism and Pittsburgh compound B for fibrillar Aβ. Neuropsychological evaluation, including the Clinical Dementia Rating scale, was performed.Main outcomes and measuresMagnetic resonance images were rated for the presence and location of CMBs. Lobar CMBs were subclassified as cortical or subcortical. Measurements of CBF, metabolism, and Aβ were compared with the presence and number of CMBs with voxelwise and region-of-interest analyses.ResultsThe presence of cortical CMBs was associated with significantly reduced CBF in multiple regions on voxelwise and region-of-interest analyses (percentage difference in global CBF, -25.3%; P = .0003), with the largest reductions in the parietal cortex (-37.6%; P < .0001) and precuneus (-31.8%; P = .0006). Participants with any CMBs showed a nonsignificant trend toward reduced CBF. Participants with cortical CMBs had a significant association with greater prevalence of infarcts (24% vs 6%; P = .047) and demonstrated a trend to greater prevalence of deficits demonstrated on the Clinical Dementia Rating scale (45% vs 19%; P = .12). There was no difference in cortical amyloid (measured by Pittsburgh compound B positron emission tomography) between participants with and without CMBs (P = .60).Conclusions and relevanceIn cognitively normal elderly individuals, incidental CMBs in cortical locations are associated with widespread reductions in resting-state CBF. Chronic hypoperfusion may put these people at risk for neuronal injury and neurodegeneration. Our results suggest that resting-state CBF is a marker of CMB-related small-vessel disease.

Project description:Background and Purpose- Cerebral microbleeds (CMBs) have been observed using magnetic resonance imaging in patients with cardiovascular risk factors, cognitive deterioration, small vessel disease, and dementia. They are a well-known consequence of cerebral amyloid angiopathy, chronic hypertension, and diffuse axonal injury, among other causes. However, the frequency and location of new CMBs postadult cardiac surgery, in association with cognition and perioperative risk factors, have yet to be studied. Methods- Pre- and postsurgery magnetic resonance susceptibility-weighted images and neuropsychological tests were analyzed from a total of 75 patients undergoing cardiac surgery (70 men; mean age, 63±10 years). CMBs were identified by a neuroradiologist blinded to clinical details who independently assessed the presence and location of CMBs using standardized criteria. Results- New CMBs were identified in 76% of patients after cardiac surgery. The majority of new CMBs were located in the frontal lobe (46%) followed by the parietal lobe (15%), cerebellum (13%), occipital lobe (12%), and temporal lobe (8%). Patients with new CMBs typically began with a higher prevalence of preexisting CMBs ( P=0.02). New CMBs were associated with longer cardiopulmonary bypass times ( P=0.003), and there was a borderline association with lower percentage hematocrit ( P=0.04). Logistic regression analysis suggested a ?2% increase in the odds of acquiring new CMBs during cardiac surgery for every minute of bypass time (odds ratio, 1.02; 95% CI, 1.00-1.05; P=0.04). Postoperative neuropsychological decline was observed in 44% of patients and seemed to be unrelated to new CMBs. Conclusions- New CMBs identified using susceptibility-weighted images were found in 76% of patients who underwent cardiac surgery. CMBs were globally distributed with the highest numbers in the frontal and parietal lobes. Our regression analysis indicated that length of cardiopulmonary bypass time and lowered hematocrit may be significant predictors for new CMBs after cardiac surgery. Clinical Trial Registration- URL: http://www.isrctn.com . Unique identifier: 66022965.

Dataset Information

Cerebral microbleeds in a neonatal rat model.

Background

Methods

Results

Conclusions

Publications

Cerebral microbleeds in a neonatal rat model.

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