Compromised microvascular oxygen delivery increases brain tissue vulnerability with age

Moeini, Mohammad; Lu, Xuecong; Avti, Pramod K.; Damseh, Rafat; Bélanger, Samuel; Picard, Frédéric; Boas, David A.; Kakkar, Ashok; Lesage, Frédéric

doi:10.1038/s41598-018-26543-w

Cited by 88 publications

(174 citation statements)

References 96 publications

(96 reference statements)

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“…Stoppages in the capillary network were all- or-none and highly heterogeneous, and may have even more severe metabolic consequences on local scales. Tissue oxygenation drops off exponentially over distances of tens of microns from the capillaries and pre-capillary arterioles (65, 66), an effect normally countered by dense branching within the capillary network that places most neurons within 15 μm of a vessel (67). However, the widespread and prolonged stoppages caused by injury may substantially increase this distance and create localized pockets of metabolic starvation.…”

Section: Discussionmentioning

confidence: 99%

Rapid disruption of the cortical microcirculation after mild traumatic brain injury

Witkowski¹,

Erdener²,

Kılıç³

et al. 2019

Preprint

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Keywords: traumatic brain injury, mouse, weight drop injury, cerebral blood flow, capillary, in 21 vivo, laser speckle contrast imaging, optical coherence tomography, two-photon imaging 22 23 24 Acknowledgments: We thank Tim Otchy, Jennifer Morgan, and members of the Davison and 25 Boas laboratories for comments and discussion. This work was supported by Boston University 26 startup funds.Abstract 30 Traumatic brain injury (TBI) is a major source of cognitive deficits affecting millions annually. The 31 bulk of human injuries are mild, causing little or no macroscopic damage to neural tissue, yet can 32 still lead to long-term neuropathology manifesting months or years later. Although the cellular 33 stressors that ultimately lead to chronic pathology are poorly defined, one notable candidate is 34 metabolic stress due to reduced cerebral blood flow (CBF), which is common to many forms of 35 TBI. Here we used high-resolution in vivo intracranial imaging in a rodent injury model to 36 characterize deficits in the cortical microcirculation during both acute and chronic phases after 37 mild TBI. We found that CBF dropped precipitously during immediate post-injury periods, 38 decreasing to less than half of baseline levels within minutes and remaining suppressed for 1.5-39 2 hours. Repeated time-lapse imaging of the cortical microvasculature revealed further striking 40 flow deficits in the capillary network, where 18% of vessels were completely occluded for 41 extended periods after injury, and an additional >50% showed substantial stoppages. Decreased 42 CBF was paralleled by extensive vasoconstriction that is likely to contribute to loss of flow. Our 43 data indicate a major role for vascular dysfunction in even mild forms of TBI, and suggest that 44 acute post-injury periods may be key therapeutic windows for interventions that restore flow 45 and mitigate metabolic stress. 46 47 88 dysfunction across the cortical microvasculature, where a large fraction of individual capillaries 89were occluded for periods of minutes or longer, leading to localized regions with complete loss 90 5 of perfusion. CBF largely returned to normal by 3 hours after injury and showed no measurable 91 deficits when tracked until 3 weeks. Reduced CBF was paralleled by pronounced 92 vasoconstriction, identifying a potential mechanism contributing to disrupted flow. This rapid 93 and extensive vascular dysfunction highlights the importance of immediate post-injury periods 94 for delivering interventions, and suggests that relieving vasoconstriction will be a promising 95 avenue for countering the effects of mild injury. 96 97 Methods 98 99 Animals and surgical procedures 100 All experiments were performed in 2-5 month-old male and female C57BL6/J mice in accordance 101 with guidelines of the Boston University Institutional Animal Care and Use Committee. Animals 102 were group housed on a 12-hour light/dark cycle with ad libitum access to food and water. 103 Chronic cranial windows were implanted using standard procedures (30, 31). Brie...

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Section: Discussionmentioning

confidence: 99%

Rapid disruption of the cortical microcirculation after mild traumatic brain injury

Witkowski¹,

Erdener²,

Kılıç³

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…By expanding our previous observations under physiological conditions (17), we see that the capillary RBC flow is extremely irregular and intermittent in the ischemic penumbra, with cells repeatedly getting stuck and released in the microcirculation. We already know that within brain tissue, capillary flow velocities are very different from each other, plasma and red blood cells are differentially partitioned at bifurcations (58), causing a spatial heterogeneity which can lower oxygen extraction efficiency (16,(59)(60)(61)(62). Simulations have revealed that the flow kinetics and partitioning in the tight lumen of capillaries are dominated by complex physical cell-cell interactions and rheological parameters which are influenced by temporal events affecting the incidental cell distributions (58).…”

Section: Discussionmentioning

confidence: 99%

Neutrophil-mediated dynamic capillary stalls in ischemic penumbra: persistent traffic jams after reperfusion contribute to injury

Erdener

Tang

Kılıç

et al. 2019

Preprint

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the study objectives, designed and performed the experiments, acquired, processed and analyzed the data, wrote the manuscript. J.T. set up and optimized the OCT equipment, wrote acquisition codes and processing algorithms. K.K. designed surgical procedures and performed experiments. D.P set up and optimized the laser speckle imaging equipment, S.K wrote data analysis codes, analyzed data. A.C and J.G. set up and optimized two-photon microscope, prepared data analysis codes and performed the experiments. T.V. performed experiments, acquired and analyzed data. S.S. and C.B.S. contributed to study objectives and experimental design and critically evaluated the manuscript. D.A.B. supervised the project in overall, contributed to study objectives and experimental design, and critically evaluated the manuscript. AbstractEver since the introduction of thrombolysis and the subsequent expansion of endovascular treatments for acute ischemic stroke, it remains to be identified why the actual outcomes are less favorable despite recanalization. Here, by high spatio-temporal resolution imaging of capillary circulation in mice, we introduce the pathological phenomenon of dynamic flow stalls in cerebral capillaries, occurring persistently in the salvageable penumbra after recanalization. These stalls, which are distinct from permanent cellular plugs that can lead to no-flow, were temporarily and repetitively occurring in the capillary network, impairing the overall circulation like small focal traffic jams. In vivo microscopy in the ischemic penumbra revealed leukocytes traveling through capillary lumen or getting stuck, while red blood cell flow was being disturbed in the neighboring segments, within 3 hours after stroke onset. Stall dynamics could be modulated, by injection of an anti-Ly6G antibody specifically targeting neutrophils. By decreasing the number and duration of stalls, we were able to improve the blood flow in the penumbra within 2-24 hours after reperfusion, increase capillary oxygenation, decrease cellular damage and improve functional outcome. Thereby the dynamic microcirculatory stall phenomenon contributes to the ongoing penumbral injury and is a potential hyperacute stage mechanism adding on previous observations of detrimental effects of activated neutrophils in ischemic stroke. SignificanceThis work provides in vivo evidence that, even in perfused capillaries, abnormal capillary flow patterns in the form of dynamic stalls can contribute to ongoing tissue injury in the salvageable penumbra in very early hours of cerebral ischemia. These events resembling micro traffic jams in a complex road network, are mediated by passage of neutrophils through the microcirculation and persist despite recanalization of the occluded artery.

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“…Nocturnal hypoxia was associated with a poor prognosis for cardiovascular events [9], and patients with ischemic stroke have a high risk of obstructive sleep apnea, with lowest overnight SpO 2 values < 80% in more than half of observed patients [10]. Furthermore, in the clinical setting of HD therapy, cognitive impairment is common in patients undergoing HD and the pathogenesis of cognitive impairment would be associated with hemodynamic factors including changes in BP or anemia [11]. In particular, both intradialytic hypotension and anemia reportedly induced the deterioration of cerebral oxygenation [12,13].…”

Section: Discussionmentioning

confidence: 99%

Sleep apnea syndrome caused lowering of cerebral oxygenation in a hemodialysis patient: a case report and literature review

Ookawara

Fueki³

et al. 2018

Ren Replace Ther

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Background: Sleep apnea syndrome (SAS) is a sleep disturbance, which is frequently comorbid in dialysis patients. SAS induces hypoxia, and therefore, systemic and cerebral oxygenation would be low. Near-infrared spectroscopy (NIRS) has recently been used to measure regional saturation of oxygen (rSO 2), as a marker of tissue oxygenation. Although cerebral rSO 2 was measured in patients in various clinical settings, few reports have previously shown the associations of changes in cerebral rSO 2 and systemic oxygenation using measurement of peripheral arterial oxygen saturation (SpO 2) in patients undergoing hemodialysis (HD) with SAS. We herein report a first HD case with SASinduced reduction in cerebral oxygenation during sleep. Case presentation: A 74-year-old woman underwent HD therapy for 1 month, because of advanced CKD caused by hypertension and obesity. In addition, she was diagnosed with obstructive sleep apnea with polysomnography about 4 years prior. Her apnea-hypopnea index (AHI) was 77.5 per hour, and therefore, continuous positive airway pressure (CPAP) was started. Thereafter, her AHI was improved to 3 to 6 per hour. However, she discontinued CPAP therapy at HD initiation. Since her oxygenation without CPAP would deteriorate, we evaluated her SpO 2 and cerebral rSO 2 by NIRS monitoring during sleep. We confirmed the deterioration in cerebral rSO 2 according to the SpO 2 decrease, and furthermore, the improvement in cerebral rSO 2 was apparently delayed even after the improvement in her SpO 2. The patient's cerebral oxygenation under CPAP therapy could not be evaluated because she refused to receive CPAP therapy after HD initiation. Therefore, as a comparison, we evaluated a 69-year-old male HD patient without SAS and found that in contrast to a patient with SAS, his SpO 2 and cerebral rSO 2 were maintained throughout sleep. Conclusion: We observed deterioration in cerebral oxygenation during sleep in addition to a decrease in systemic oxygenation in a patient with SAS undergoing HD. Real-time cerebral NIRS monitoring during sleep might be a useful method for detection of SAS.

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Compromised microvascular oxygen delivery increases brain tissue vulnerability with age

Cited by 88 publications

References 96 publications

Rapid disruption of the cortical microcirculation after mild traumatic brain injury

Rapid disruption of the cortical microcirculation after mild traumatic brain injury

Neutrophil-mediated dynamic capillary stalls in ischemic penumbra: persistent traffic jams after reperfusion contribute to injury

Sleep apnea syndrome caused lowering of cerebral oxygenation in a hemodialysis patient: a case report and literature review

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