Leptomeningeal collaterals regulate reperfusion in ischemic stroke and rescue the brain from futile recanalization

Binder, Nadine Felizitas; El Amki, Mohamad; Glück, Chaim; Middleham, William; Reuss, Anna Maria; Bertolo, Adrien; Thurner, Patrick; Deffieux, Thomas; Lambride, Chryso; Epp, Robert; Handelsmann, Hannah-Lea; Baumgartner, Philipp; Orset, Cyrille; Bethge, Philipp; Kulcsar, Zsolt; Aguzzi, Adriano; Tanter, Mickael; Schmid, Franca; Vivien, Denis; Wyss, Matthias Tasso; Luft, Andreas; Weller, Michael; Weber, Bruno; Wegener, Susanne

doi:10.1016/j.neuron.2024.01.031

Cited by 12 publications

(6 citation statements)

References 76 publications

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“…Importantly, Pia-FLOW revealed that only collaterals showed significant increases in flow speed to redistribute blood supply to the affected arterial territory while the flow in ACA segments remained unchanged. These data are in line with previous TPLSM studies that discovered the engagement of collateral to reroute blood flow in stroke conditions ( 22 , 23 ). In contrast to Pial-FLOW, LSCI was not sensitive enough to specifically detect the flow increase in collaterals but surprisingly showed flow reductions in both pial collaterals and ACA segments ( Fig.…”

Section: Resultssupporting

confidence: 92%

“…As pial collaterals are a natural bypass that can redistribute blood flow to ischemic regions, we primarily focused on these vascular segments. Previous work of us and others showed that after arterial occlusion, collaterals dilate and change flow direction ( 22 , 23 ). However, it is unknown whether all pial collaterals change flow direction after stroke and to what extent collaterals are capable of compensating blood flow in the affected region.…”

Section: Resultsmentioning

confidence: 93%

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Pia-FLOW: Deciphering hemodynamic maps of the pial vascular connectome and its response to arterial occlusion

Glück,

Zhou,

Droux

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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The pial vasculature is the sole source of blood supply to the neocortex. The brain is contained within the skull, a vascularized bone marrow with a unique anatomical connection to the brain meninges. Recent developments in tissue clearing have enabled detailed mapping of the entire pial and calvarial vasculature. However, what are the absolute flow rate values of those vascular networks? This information cannot accurately be retrieved with the commonly used bioimaging methods. Here, we introduce Pia-FLOW, a unique approach based on large-scale transcranial fluorescence localization microscopy, to attain hemodynamic imaging of the whole murine pial and calvarial vasculature at frame rates up to 1,000 Hz and spatial resolution reaching 5.4 µm. Using Pia-FLOW, we provide detailed maps of flow velocity, direction, and vascular diameters which can serve as ground-truth data for further studies, advancing our understanding of brain fluid dynamics. Furthermore, Pia-FLOW revealed that the pial vascular network functions as one unit for robust allocation of blood after stroke.

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Section: Resultssupporting

confidence: 92%

Section: Resultsmentioning

confidence: 93%

Pia-FLOW: Deciphering hemodynamic maps of the pial vascular connectome and its response to arterial occlusion

Glück,

Zhou,

Droux

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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“…During M 4 clipping and repetency, we found in situ PSD magnitude of δ (0 - 3 Hz) and θ bands (4 - 7 Hz) were closely related to LMCs’ RFR (101.7 ±4.2 vs. 97.7 ±4.7 dB, P < 0.001; 88.9 ±4.4 vs. 86.6 ±3.4 dB, P < 0.001, Figure 1C), while δ band was positively correlated with LMCs’ RFR (R 2 = 0.09, P < 0.001, Figure 1D), representing the neural activity related to LMCs recruitment.…”

Section: Resultsmentioning

confidence: 92%

“…Incomplete reperfusion of the microvasculature is about eighty percent of acute ischemic stroke (AIS) patients, even after successful recanalization of the occluded vessel 1 . It has been verified in rodent models that abundant leptomeningeal collaterals (LMCs) provided hemodynamic support during AIS and reperfusion, acted as key components regulating reperfusion and preventing futile recanalization 2 . Although the regulation details in microcirculation have been deeply acquired from animal models, human cortex may share limited hemodynamic patterns due to the thicker layers, more collateral networks and larger physical scale.…”

Section: Introductionmentioning

confidence: 99%

Roles and mechanisms of leptomeningeal collaterals in human distal MCA territory ischemia

Zou,

Mei,

et al. 2024

Preprint

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Objective: Leptomeningeal collaterals (LMCs) provided hemodynamic support and reperfusion during acute ischemic stroke (AIS). Although regulation details have been deeply acquired from animal models, human cortex may share limited hemodynamic patterns due to larger physical scale that needs further investigation. Approach and Results: We performed 'sequential hierarchical blocking' during awake craniotomy on fourteen human subjects to mimic AIS in middle cerebral artery (MCA) M4 segment territory. Widefield microscope was applied to reveal microcirculation of LMCs. Relative flow rate (RFR) was measured to evaluate the impact of LMCs hierarchy on microcirculation maintenance. Single-cell sequencing and spatial transcriptomics were further performed to analyze the mechanism of different LMCs recruitment abilities. LMCs RFR decreased to 30.75% immediately (95% CI, 6.64 - 54.86%, P < 0.001), and about 80.25% RFR was finally recovered within 5 minutes (95% CI, 55.2 - 105.3%, P = 0.0034) during M4 occlusion. For M5 and pial branches occlusion, RFR decreased to 55.78% with no further recovery (95% CI, 22.50-89.05%, P = 0.014), and 4 in 11 subjects had no valid microcirculation. For subjects with better recruitment ability, the proportion of arteriole is much higher in leptomeninx (76 - 79% vs. 36 - 56%). There were more significant interaction pairs associated with key signaling pathways between arteriole and neuron/astrocyte (TGF-beta signaling pathway, ECM-receptor interaction). Conclusion: Abundant LMCs supported hemodynamic stability during AIS in human subjects. The proportion of arteriole is much higher in leptomeninx for subjects with better recruitment ability. The Active neuron/astrocyte - arteriole interaction may improve LMCs recruitment.

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“…The following supporting information can be downloaded at: , Supplemental Information S1 Background on Futile Recanalization: Definition, Prevalence, Predictors, and Outcomes after Futile Recanalization; Supplementary Information S2: Python Code. References [ 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 ...…”

mentioning

confidence: 99%

Introducing the Futile Recanalization Prediction Score (FRPS): A Novel Approach to Predict and Mitigate Ineffective Recanalization after Endovascular Treatment of Acute Ischemic Stroke

Shen,

Huasen,

Killingsworth

et al. 2024

Neurology International

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Objective: This study aims to develop and validate the Futile Recanalization Prediction Score (FRPS), a novel tool designed to predict the severity risk of FR and aid in pre- and post-EVT risk assessments. Methods: The FRPS was developed using a rigorous process involving the selection of predictor variables based on clinical relevance and potential impact. Initial equations were derived from previous meta-analyses and refined using various statistical techniques. We employed machine learning algorithms, specifically random forest regression, to capture nonlinear relationships and enhance model performance. Cross-validation with five folds was used to assess generalizability and model fit. Results: The final FRPS model included variables such as age, sex, atrial fibrillation (AF), hypertension (HTN), diabetes mellitus (DM), hyperlipidemia, cognitive impairment, pre-stroke modified Rankin Scale (mRS), systolic blood pressure (SBP), onset-to-puncture time, sICH, and NIHSS score. The random forest model achieved a mean R-squared value of approximately 0.992. Severity ranges for FRPS scores were defined as mild (FRPS < 66), moderate (FRPS 66–80), and severe (FRPS > 80). Conclusions: The FRPS provides valuable insights for treatment planning and patient management by predicting the severity risk of FR. This tool may improve the identification of candidates most likely to benefit from EVT and enhance prognostic accuracy post-EVT. Further clinical validation in diverse settings is warranted to assess its effectiveness and reliability.

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Leptomeningeal collaterals regulate reperfusion in ischemic stroke and rescue the brain from futile recanalization

Cited by 12 publications

References 76 publications

Pia-FLOW: Deciphering hemodynamic maps of the pial vascular connectome and its response to arterial occlusion

Pia-FLOW: Deciphering hemodynamic maps of the pial vascular connectome and its response to arterial occlusion

Roles and mechanisms of leptomeningeal collaterals in human distal MCA territory ischemia

Introducing the Futile Recanalization Prediction Score (FRPS): A Novel Approach to Predict and Mitigate Ineffective Recanalization after Endovascular Treatment of Acute Ischemic Stroke

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