Chunyan Lei

Association between cerebral microbleeds and cognitive function: a systematic review

Background Cerebral microbleeds (MBs), defined as haemorrhagic microvascular lesions or microangiopathy in the brain, have traditionally been considered clinically silent. Recent studies, however, suggest that MBs are associated with a decline in cognitive function. Objective To determine whether an association between MBs and cognitive function exists, we conducted a systematic review of the literature using the Cochrane Library, MEDLINE, EMBASE and the China National Knowledge Infrastructure database. We also searched the reference lists of relevant studies and review articles. Results A total of seven studies were included. Qualitative meta-analysis of two studies suggested that the presence of MBs was significantly associated with cognitive impairment, while quantitative meta-analysis revealed an association between MBs and cognitive dysfunction in two studies (OR 3.06, 95% CI1.59 to 5.89) and implicated MBs as important in cognitive function decline in three other studies (standardised mean difference −1.06, 95% CI −2.10 to −0.02). MBs in the frontal or temporal region and the basal ganglia might also be related to cognitive dysfunction. Conclusions These results suggest that rather than being clinically silent, cerebral MBs might be a factor inducing cognitive function decline.

High-mobility group box1 protein promotes neuroinflammation after intracerebral hemorrhage in rats.

High-mobility group box1 (HMGB1) protein is massively released into the cytoplasm and induces inflammation following various insults such as sepsis, acute cerebral ischemia, and pancreatitis. However, whether HMGB1 can act as an early proinflammatory cytokine to promote inflammation after intracerebral hemorrhage (ICH) is unclear. We explored this question using a rat model of collagenase-induced ICH. We found that HMGB1 was released into the cytoplasm soon after ICH. Administration of ethyl pyruvate decreased the level of HMGB1 and microglia around the hematoma. Ethyl pyruvate also ameliorated ICH-induced neuronal apoptosis, cerebral edema, and neurological impairment. These findings suggest that HMGB1 may act as an early proinflammatory cytokine within the neurovascular unit to mediate inflammation during the acute phase of ICH.

Effects of high-mobility group box1 on cerebral angiogenesis and neurogenesis after intracerebral hemorrhage.

Neural stem cells, which reside mainly in the subventricular and subgranular zones of the hippocampus, can regenerate new neuroblasts after various brain insults. Aided by vascular remodeling, these new neuroblasts migrate long distances to injured brain regions. Studies have suggested that high-mobility group box1 (HMGB1), a nonhistone nuclear DNA-binding protein, may stimulate such remodeling in the late phase of some types of brain injury, but it is unclear whether this is true for intracerebral hemorrhage (ICH). Here we used a rat model of collagenase-induced ICH to determine whether HMGB1 can promote neurogenesis and angiogenesis in the late phase of injury. Daily administration of ethyl pyruvate, which inhibited HMGB1 expression, reduced the recovery of neurological function, decreased vascular endothelial growth factor (VEGF) and nerve growth factor (NGF) levels in the ipsilateral striatum, and decreased the numbers of 5-bromo-2-deoxyuridine (BrdU)- and doublecortin (DCX)-positive cells around the hematoma. These findings suggest that HMGB1 may promote angiogenesis and neurogenesis in the late phase of ICH.

Association between statin use and intracerebral hemorrhage: a systematic review and meta‐analysis

Accumulating evidence suggests that statins exert neuroprotective effects, but whether their use affects the outcomes of intracerebral hemorrhage (ICH) remains controversial. Therefore, we performed a systematic review and meta‐analysis to investigate whether statin use before spontaneous ICH affects unfavorable functional outcome or mortality.

HMGB1 may act via RAGE to promote angiogenesis in the later phase after intracerebral hemorrhage

Following intracerebral hemorrhage (ICH), high-mobility group box 1 protein (HMGB1) may promote vascular remodeling. Whether HMGB1 supports angiogenesis after ICH is unclear, as are the receptors and downstream signaling pathway(s) involved. We used the rat model of collagenase-induced ICH to determine whether HMGB1 acts via the receptor for advanced glycation end-products (RAGE) to upregulate vascular endothelial growth factor (VEGF), a potent mitogen of endothelial cells and key regulator of normal and abnormal angiogenesis in the late phase of injury. At 3d after ICH induction, rats were treated with saline, ethyl pyruvate (EP) or N-benzyl-4-chloro-N-cyclohexylbenzamide (FPS-ZM1). ICH induced the movement of HMGB1 from the nucleus into the cytoplasm. Levels of HMGB1 and RAGE in the ipsilateral striatum increased within a few days of induction and continued to rise for 7-14d afterward. By 14d after induction, levels of VEGF and vessel density were higher than in the Sham group. Administering EP 3 days after ICH induction prevented much of the stroke-induced increases in vessel density and in expression of HMGB1, RAGE, and VEGF. Administering FPS-ZM1 after ICH blocked much of the stroke-induced increases in vessel density and VEGF expression. Our results suggest that after ICH, HMGB1 may upregulate VEGF in the ipsilateral striatum predominantly via RAGE. Hence, targeting the HMGB1/RAGE signaling pathway may help reduce inappropriate angiogenesis after ICH.

Activation of cerebral recovery by matrix metalloproteinase-9 after intracerebral hemorrhage

Cerebral ischemia, traumatic brain injury, intracerebral hemorrhage and other brain insults trigger neurogenesis in the subventricular zone and hippocampal subgranular zone, and newly formed blood vessels promote the migration of these new neuronal cells to damaged brain regions. The molecular steps involved in brain injury-induced angiogenesis and neurogenesis are unclear. Here we used a rat model of collagenase-induced intracerebral hemorrhage (ICH) to examine whether matrix metalloproteinase-9 (MMP-9), a zinc endopeptidase that regulates growth factor levels during recovery from brain injury, is involved in neurogenesis and angiogenesis following ICH. Induction of ICH led to significant increases in the levels of MMP-9, vascular endothelial growth factor (VEGF), and nerve growth factor (NGF), as well as in the numbers of 5-bromo-2-deoxyuridine (BrdU)- and doublecortin (DCX)-positive cells, in the ipsilateral brain. Intracerebroventricular injection of MMP-9 siRNA reduced these ICH-induced increases. These findings suggest that MMP-9 may promote angiogenesis and neurogenesis during recovery from ICH.

Association between asymptomatic carotid stenosis and cognitive function: a systematic review.

BACKGROUND Asymptomatic carotid stenosis (CS), traditionally considered clinically silent, may be an independent risk factor for a cognitive impairment. METHODS To determine whether an association exists between asymptomatic CS and cognitive function, we systematically reviewed the literature in the Cochrane Library, MEDLINE, EMBASE and the China National Knowledge Infrastructure databases. RESULTS A total of 8 cross-sectional studies and 2 community-based cohort studies were included, comprising 763 participants in the CS group and 6308 participants in the non-CS group. All but one study supported the association between asymptomatic CS and cognitive impairment. Pooled analysis identified older age (2 studies) and cerebral hypoperfusion (2 studies) as additional factors in patients with asymptomatic CS that may linked to cognitive decline. CONCLUSIONS These results suggest that rather than being clinically silent, asymptomatic CS may be associated with cognitive impairment, and this should be further investigated in high-quality studies.

Activation of the High-Mobility Group Box 1 Protein-Receptor for Advanced Glycation End-Products Signaling Pathway in Rats During Neurogenesis After Intracerebral Hemorrhage

Background and Purpose— Following intracerebral hemorrhage (ICH), high-mobility group box 1 protein (HMGB1) may promote neurogenesis that supports functional recovery. How HMGB1 regulates or participates in this process is unclear, as are the pattern recognition receptors and signaling pathways involved. Methods— ICH was induced by injection of collagenase in Sprague–Dawley rats, which were treated 3 days later with saline, with the HMGB1 inhibitor ethyl pyruvate or with FPS-ZM1, an antagonist of the receptor for advanced glycation end-products. A Sham group was treated with saline solution instead of collagenase and then treated 3 days later with saline again or with ethyl pyruvate or N-benzyl-4-chloro-N-cyclohexylbenzamide (FPS-ZM1). Expression of the following proteins was measured by Western blot, immunohistochemistry, or immunofluorescence: HMGB1, receptor for advanced glycation end-products, toll-like receptor (TLR)-2, TLR4, brain-derived neurotrophic factor, and matrix metalloproteinase-9. The number of cells positive for 5-bromo-2-deoxyuridine or doublecortin was determined by immunohistochemistry and immunofluorescence. Results— Levels of HMGB1, receptor for advanced glycation end-products, TLR4, TLR2, brain-derived neurotrophic factor, and matrix metalloproteinase-9 were significantly higher 14 days after ICH than at baseline, as were the numbers of 5-bromo-2-deoxyuridine- or doublecortin-positive cells. At the same time, HMGB1 moved from the nucleus into the cytoplasm. Administering ethyl pyruvate significantly reduced all these ICH-induced increases, except the increase in TLR4 and TLR2. Administering FPS-ZM1 reduced the ICH-induced increases in the expression of brain-derived neurotrophic factor and matrix metalloproteinase-9 and in the numbers of 5-bromo-2-deoxyuridine- or doublecortin-positive cells. Conclusions— These findings suggest that HMGB1 acts via the receptor for advanced glycation end-products signaling pathway to promote neurogenesis in later phases of ICH.

Blockade of high mobility group box-1 signaling via the receptor for advanced glycation end-products ameliorates inflammatory damage after acute intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is a devastating disease with no specific treatment. Increasing evidence indicates that inflammatory response plays a critical role in ICH-induced damage. High mobility group box-1 protein (HMGB1) may trigger inflammatory response via three putative receptors: receptor for advanced glycation end-products (RAGE), toll-like receptor-2 (TLR2) and toll-like receptor-4 (TLR4). Which receptor participates in HMGB1-induced inflammation during acute ICH is unknown. Using a rat model to examine the early phase of injury in collagenase-induced ICH, we found that treating animals with HMGB1 antagonist significantly reduced the expression of all three receptors. Treating animals with the HMGB1 antagonist EP or RAGE antagonist FPS-ZM1 significantly reduced inflammatory cell infiltration and expression of IL-1β, matrix metalloproteinase-9 in the perihematoma after ICH. Treatment with EP or FPS-ZM1 also led to greater neurobehavioral function and less brain edema, hemorrhage volume and brain damage after ICH. In contrast, treatment with TLR2/4 antagonists did not significantly affect these post-ICH outcomes. Our results suggest that RAGE may play a specific role in the acute phase of ICH, so targeting the HMGB1-RAGE signaling pathway may be a promising therapeutic strategy.

Association of moyamoya disease with thyroid autoantibodies and thyroid function: a case-control study and meta-analysis.

Evidence suggests that elevated thyroid function and elevated levels of thyroid autoantibodies are associated with risk of moyamoya disease (MMD). Therefore a meta‐analysis of all available evidence was performed, including unpublished data from our own center, in order to assess this association.