White Matter Injury Due to Experimental Chronic Cerebral Hypoperfusion Is Associated with C5 Deposition

Liu, Qinghai; He, Shuhan; Groysman, Leonid; Shaked, David; Russin, Jonathan J.; Cen, Steven; Mack, William J.

doi:10.1371/journal.pone.0084802

Cited by 23 publications

(31 citation statements)

References 37 publications

(35 reference statements)

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“…Ours and other groups have demonstrated that the BCAS model of CCH employed in this study results in reproducible white matter injury [2,3,11]. Histopathologically, ischemic damage has been confirmed in the corpus callosum, anterior commissure, external capsule and optic tracts [3,4, 26–29].…”

Section: Discussionsupporting

confidence: 55%

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Chronic cerebral hypoperfusion induced by bilateral carotid artery stenosis causes selective recognition impairment in adult mice

Patel

Moalem

Cheng

et al. 2017

Neurological Research

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Objectives Chronic cerebral hypoperfusion (CCH) can result in vascular dementia and small vessel white matter ischemic injury. These findings have previously been demonstrated in a murine experimental model of CCH secondary to bilateral common carotid artery stenosis (BCAS). This study sought to elucidate the effects of CCH on recognition memory as assessed by the novel object recognition (NOR) test and histological analysis of the hippocampus and perirhinal cortex. Methods Studies were performed on ten-week-old male mice using bilateral 0.18 mm microcoils to narrow the carotid arteries in accordance with prior publications. Following surgery, BCAS (n = 6) and sham (n = 6) mice were evaluated using NOR and 8-arm radial maze testing paradigms. Tissue damage was assessed using H&E staining on a parallel cohort of mice (n = 6 BCAS, n = 7 sham). Results In the NOR paradigm, BCAS mice demonstrated significant deficits in short-term memory. Consistent with prior studies, BCAS mice also performed significantly worse on 8-arm radial maze testing. BCAS mice exhibited significantly more neuronal injury in the perirhinal cortex when compared to sham-operated mice. However, no significant differences in neuronal damage were observed in the CA1 region of the hippocampus. Discussion Experimental CCH secondary to BCAS results in recognition memory deficits on NOR testing. Damage to the perirhinal cortex, rather than to the hippocampus, may underlie this impairment.

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Section: Discussionsupporting

confidence: 55%

“…No mice died during the 0.18 mm BCAS surgical operation and no post-operative mortality occurred (Table 1). For comparison, combined surgical and post-operative mortality were previously reported by other groups at 10–15% for the 0.18 mm BCAS group and 0% for the Sham-operated group [3,11]. …”

Section: Resultsmentioning

confidence: 99%

Chronic cerebral hypoperfusion induced by bilateral carotid artery stenosis causes selective recognition impairment in adult mice

Patel

Moalem

Cheng

et al. 2017

Neurological Research

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“…Bilateral white matter susceptibility follows a vascular distribution that more closely aligns with patterns of chronic, global cerebral hypoxia, rather than acute, localized hypoxia. Chronic hypoperfusion caused by the narrowing of the carotid arteries, in both human patients and animal models, shows selective injury to oligodendrocytes in white matter tissue in‐between the distal ends of penetrating arteries . The spatial patterns of injury following global hypoxia occurs diffusely within watershed regions, and has a relatively symmetrical appearance across brain hemispheres .…”

Section: Discussionmentioning

confidence: 99%

Anemia predicts lower white matter volume and cognitive performance in sickle and non‐sickle cell anemia syndrome

et al. 2019

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Severe chronic anemia is an independent predictor of overt stroke, white matter damage, and cognitive dysfunction in the elderly. Severe anemia also predisposes to white matter strokes in young children, independent of the anemia subtype. We previously demonstrated symmetrically decreased white matter (WM) volumes in patients with sickle cell disease (SCD). In the current study, we investigated whether patients with non-sickle anemia also have lower WM volumes and cognitive dysfunction. Magnetic Resonance Imaging was performed on 52 clinically asymptomatic SCD patients (age = 21.4 ± 7.7; F = 27, M = 25; hemoglobin = 9.6 ± 1.6 g/dL), 26 non-sickle anemic patients (age = 23.9 ± 7.9; F = 14, M = 12; hemoglobin = 10.8 ± 2.5 g/dL) and 40 control subjects (age = 27.7 ± 11.3; F = 28, M = 12; hemoglobin = 13.4 ± 1.3 g/dL). Voxel-wise changes in WM brain volumes were compared to hemoglobin levels to identify brain regions that are vulnerable to anemia. White matter volume was diffusely lower in deep, watershed areas proportionally to anemia severity. After controlling for age, sex, and hemoglobin level, brain volumes were independent of disease. WM volume loss was associated with lower Full Scale Intelligence Quotient (FSIQ; P = .0048; r 2 = .18) and an abnormal burden of silent cerebral infarctions (P = .029) in males, but not in females.Hemoglobin count and cognitive measures were similar between subjects with and without white-matter hyperintensities. The spatial distribution of volume loss suggests chronic hypoxic cerebrovascular injury, despite compensatory hyperemia. Neurocognitive consequences of WM volume changes and silent cerebral infarctionwere strongly sexually dimorphic. Understanding the possible neurological consequences of chronic anemia may help inform our current clinical practices.

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“…BCAS in mice triggers a proinflammatory milieu and impairs microvascular dysfunction, as evident by the increased gene expression of ICAM-1 and VCAM-1 (Fig. 2 ) [ 20 ]. ICAM-1 and VCAM-1 promote adhesion phenomena resulting into disintegration of BBB and increased infiltration of proinflammatory immune cells, which amplifies the neuro-glial inflammation, WM degeneration, and cell death (Figs.…”

Section: Discussionmentioning

confidence: 99%

Remote Ischemic Postconditioning: Harnessing Endogenous Protection in a Murine Model of Vascular Cognitive Impairment

Khan

Hoda

Vaibhav

et al. 2014

Transl. Stroke Res.

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We previously reported that remote limb ischemic conditioning (RLIC; PERconditioning) during acute stroke confers neuroprotection, possibly due to increased cerebral blood flow (CBF). Vascular cognitive impairment (VCI) is a growing threat to public health without any known treatment. The bilateral common carotid artery stenosis (BCAS) mouse model is regarded as the most valid model for VCI. We hypothesized that RLIC (postconditioning; RIPostC) will augment CBF during chronic cerebral hypoperfusion (CCH) and prevent cognitive impairment in the BCAS model. BCAS using customized microcoil was performed in C57/B6 male mice to establish CCH. A week after the BCAS surgery, mice were treated with RIPostC-therapy once daily for 2 weeks. CBF was measured with laser speckle contrast imager at different time points. Cognitive testing was performed at 4-week post-BCAS, and brain tissue was harvested for biochemistry. BCAS led to chronic hypoperfusion resulting into impaired cognitive function as tested by novel object recognition (NOR). Histological examinations revealed that BCAS triggered inflammatory responses and caused frequent vacuolization and cell death. BCAS also increased the generation and accumulation of amyloid beta protein (Aβ), resulting into the loss of white matter (WM) and myelin basic protein (MBP). RIPostC-therapy showed both acute increase as well as sustained improvement in CBF even after the cessation of therapy for a week. RIPostC improved cognitive function, inhibited inflammatory responses, prevented the cell death, reduced the generation and accumulation of Aβ, and protected WM integrity. RIPostC is effective in the BCAS model and could be an attractive low-cost conventional therapy for aged individuals with VCI. The mechanisms by which RIPostC improves CBF and attenuates tissue damage need to be investigated in the future.Electronic supplementary materialThe online version of this article (doi:10.1007/s12975-014-0374-6) contains supplementary material, which is available to authorized users.

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White Matter Injury Due to Experimental Chronic Cerebral Hypoperfusion Is Associated with C5 Deposition

Cited by 23 publications

References 37 publications

Chronic cerebral hypoperfusion induced by bilateral carotid artery stenosis causes selective recognition impairment in adult mice

Chronic cerebral hypoperfusion induced by bilateral carotid artery stenosis causes selective recognition impairment in adult mice

Anemia predicts lower white matter volume and cognitive performance in sickle and non‐sickle cell anemia syndrome

Remote Ischemic Postconditioning: Harnessing Endogenous Protection in a Murine Model of Vascular Cognitive Impairment

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