Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
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J. Cereb. Blood Flow Metab. · Aug 2013
The APOE ɛ4/ɛ4 genotype potentiates vascular fibrin(ogen) deposition in amyloid-laden vessels in the brains of Alzheimer's disease patients.
Evidence indicates a critical role for cerebrovascular dysfunction in Alzheimer's disease (AD) pathophysiology. We have shown that fibrin(ogen), the principal blood-clotting protein, is deposited in the AD neurovasculature and interacts with beta-amyloid (Aβ), resulting in increased formation of blood clots. As apolipoprotein E (ApoE), a lipid-transporting protein with three human isoforms (E2, E3, and E4), also binds to Aβ, we hypothesized that ApoE and fibrin(ogen) may have a combined effect on the vascular pathophysiology in AD. ⋯ An increased deposition of fibrin(ogen) was observed in AD cases compared with non-demented controls, and there was a strong correlation between cerebral amyloid angiopathy (CAA) severity and fibrin(ogen) deposition. Moreover, brains from AD cases homozygous for APOE ɛ4 showed increased deposition of fibrin(ogen), specifically in CAA- and oligomeric Aβ-positive vessels compared with AD APOE ɛ2 and ɛ3 allele carriers, an effect that was not directly linked to CAA severity and cerebrovascular atherosclerosis. These data further support a role for fibrin(ogen) in AD pathophysiology and link the APOE ɛ4/ɛ4 genotype with increased thrombosis and/or impaired fibrinolysis in the human AD brain.
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J. Cereb. Blood Flow Metab. · Jul 2013
Clinical TrialLaser speckle imaging allows real-time intraoperative blood flow assessment during neurosurgical procedures.
Currently, there is no adequate technique for intraoperative monitoring of cerebral blood flow (CBF). To evaluate laser speckle imaging (LSI) for assessment of relative CBF, LSI was performed in 30 patients who underwent direct surgical revascularization for treatment of arteriosclerotic cerebrovascular disease (ACVD), Moyamoya disease (MMD), or giant aneurysms, and in 8 control patients who underwent intracranial surgery for reasons other than hemodynamic compromise. The applicability and sensitivity of LSI was investigated through baseline perfusion and CO2 reactivity testing. ⋯ The applicability and sensitivity of LSI was shown by a significantly reduced CO2 reactivity in ACVD (9.6±9%) and MMD (8.5±8%) compared with control (31.2±5%; P<0.0001). In high- and intermediate-flow bypass patients, LSI was characterized by a dynamic real-time response to acute perfusion changes and ultimately confirmed a sufficient flow substitution through the bypass graft. Thus, LSI can be used for sensitive and continuous, non-invasive real-time visualization and measurement of relative cortical CBF in excellent spatial-temporal resolution.
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J. Cereb. Blood Flow Metab. · Jul 2013
Early inhibition of MMP activity in ischemic rat brain promotes expression of tight junction proteins and angiogenesis during recovery.
In cerebral ischemia, matrix metalloproteinases (MMPs) have a dual role by acutely disrupting tight junction proteins (TJPs) in the blood-brain barrier (BBB) and chronically promoting angiogenesis. Since TJP remodeling of the neurovascular unit (NVU) is important in recovery and early inhibition of MMPs is neuroprotective, we hypothesized that short-term MMP inhibition would reduce infarct size and promote angiogenesis after ischemia. Adult spontaneously hypertensive rats had a transient middle cerebral artery occlusion with reperfusion. ⋯ The GM6001, which reduced tissue loss at 3 to 4 weeks, significantly increased new vessel formation with expression of TJPs and MMPs. Our results show that pericytes and astrocytes act spatiotemporally, contributing to extraendothelial TJP formation, and that MMPs are involved in BBB restoration during recovery. Early MMP inhibition benefits neurovascular remodeling after stroke.
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J. Cereb. Blood Flow Metab. · Jun 2013
'Hit & Run' model of closed-skull traumatic brain injury (TBI) reveals complex patterns of post-traumatic AQP4 dysregulation.
Cerebral edema is a major contributor to morbidity associated with traumatic brain injury (TBI). The methods involved in most rodent models of TBI, including head fixation, opening of the skull, and prolonged anesthesia, likely alter TBI development and reduce secondary injury. We report the development of a closed-skull model of murine TBI, which minimizes time of anesthesia, allows the monitoring of intracranial pressure (ICP), and can be modulated to produce mild and moderate grade TBI. ⋯ This AQP4 dysregulation peaked at 7 days after injury and was largely indistinguishable between mild and moderate grade TBI for the first 2 weeks after injury. Within the same model, blood-brain barrieranalysis of variance permeability, cerebral edema, and ICP largely normalized within 7 days after moderate TBI. These findings suggest that changes in AQP4 expression and localization may not contribute to cerebral edema formation, but rather may represent a compensatory mechanism to facilitate its resolution.
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J. Cereb. Blood Flow Metab. · Jun 2013
Microstructural basis of contusion expansion in traumatic brain injury: insights from diffusion tensor imaging.
Traumatic brain injury (TBI) is often exacerbated by events that lead to secondary brain injury, and represent potentially modifiable causes of mortality and morbidity. Diffusion tensor imaging was used to characterize tissue at-risk in a group of 35 patients scanned at a median of 50 hours after injury. Injury progression was assessed in a subset of 16 patients with two scans. ⋯ In patients who underwent serial imaging, the rim of ADC hypointensity was subsumed into the high ADC region as the contusion enlarged. Overall contusion enlargement tended to be more frequent with early lesions, but its extent was unrelated to the time of initial imaging, initial contusion size, or the presence of hemostatic abnormalities. This rim of hypointensity may characterize a region of microvascular failure resulting in cytotoxic edema, and may represent a 'traumatic penumbra' which may be rescued by effective therapy.