Background and Purpose— The aim of the present study was to investigate the impact of different stroke subtypes on the glymphatic system using MRI. Methods— We first improved and characterized an in vivo protocol to measure the perfusion of the glymphatic system using MRI after minimally invasive injection of a gadolinium chelate within the cisterna magna. Then, the integrity of the glymphatic system was evaluated in 4 stroke models in mice including subarachnoid hemorrhage (SAH), intracerebral hemorrhage, carotid ligature, and embolic ischemic stroke. Results— We were able to reliably evaluate the glymphatic system function using MRI. Moreover, we provided evidence that the glymphatic system was severely impaired after SAH and in the acute phase of ischemic stroke, but was not altered after carotid ligature or in case of intracerebral hemorrhage. Notably, this alteration in glymphatic perfusion reduced brain clearance rate of low-molecular-weight compounds. Interestingly, glymphatic perfusion after SAH can be improved by intracerebroventricular injection of tissue-type plasminogen activator. Moreover, spontaneous arterial recanalization was associated with restoration of the glymphatic function after embolic ischemic stroke. Conclusions— SAH and acute ischemic stroke significantly impair the glymphatic system perfusion. In these contexts, injection of tissue-type plasminogen activator either intracerebroventricularly to clear perivascular spaces (for SAH) or intravenously to restore arterial patency (for ischemic stroke) may improve glymphatic function.

The CSF actively penetrates within the brain parenchyma in the gyrencephalic brain, as described for the glymphatic system in rodent. This parenchymal CSF circulation is severely impaired by SAH.

Stroke and Alzheimer's disease (AD) are cerebral pathologies with high socioeconomic impact that can occur together and mutually interact. Vascular factors predisposing to cerebrovascular disease have also been specifically associated with development of AD, and acute stroke is known to increase the risk to develop dementia. Despite the apparent association, it remains unknown how acute cerebrovascular disease and development of AD are precisely linked and act on each other. It has been suggested that this interaction is strongly related to vascular deposition of amyloid-β (Aβ), i.e., cerebral amyloid angiopathy (CAA). Furthermore, the blood-brain barrier (BBB), perivascular space, and the glymphatic system, the latter proposedly responsible for the drainage of solutes from the brain parenchyma, may represent key pathophysiological pathways linking stroke, Aβ deposition, and dementia. In this review, we propose a hypothetic connection between CAA, stroke, perivascular space integrity, and dementia. Based on relevant pre-clinical research and a few clinical case reports, we speculate that impaired perivascular space integrity, inflammation, hypoxia, and BBB breakdown after stroke can lead to accelerated deposition of Aβ within brain parenchyma and cerebral vessel walls or exacerbation of CAA. The deposition of Aβ in the parenchyma would then be the initiating event leading to synaptic dysfunction, inducing cognitive decline and dementia. Maintaining the clearance of Aβ after stroke could offer a new therapeutic approach to prevent post-stroke cognitive impairment and development into dementia.

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Background Intracranial aneurysms may be associated with an underlying arteriopathy, leading to arterial wall fragility. Arterial tortuosity is a major characteristic of some connective tissue disease. Aim To determine whether intracranial aneurysm is associated with an underlying arteriopathy. Methods Using a case-control design, from May 2012 to May 2013, we selected intracranial aneurysm cases and controls from consecutive patients who had conventional cerebral angiography in our center. Cases were patients with newly diagnosed intracranial aneurysm. Controls were patients who had diagnostic cerebral angiography and free of aneurysm. The prevalence of tortuosity, retrospectively assessed according to standard definitions, was compared between cases and controls and, association between tortuosity and some aneurysm characteristics was examined, in cases only. Results About 659 arteries from 233 patients (112 cases and 121 controls) were examined. Tortuosity was found in 57 (51%) cases and 31 (26%) controls (adjusted OR = 2.71; 95%CI, 1.53-4.80). The same trend was found when looking at each tortuosity subtype (simple tortuosity, coil, kink) or at carotid or vertebral territory separately. In contrast, no association between tortuosity and rupture status, aneurysm number or neck size was found. Conclusions Cervical artery tortuosity is significantly associated with intracranial aneurysm, although not related to main aneurysm characteristics. Our results support the presence of an underlying diffuse arteriopathy in intracranial aneurysm patients.

Background Solutes distribution by the intracranial cerebrospinal fluid (CSF) fluxes along perivascular spaces and through interstitial fluid (ISF) play a key role in the clearance of brain metabolites, with essential functions in maintaining brain homeostasis. Objective To investigate the impact of decompressive craniectomy (DC) and cranioplasty (CP) on the efficacy of solutes distribution by the intracranial CSF and ISF flux. Methods Mice were allocated in 3 groups: sham surgery, DC, and DC followed by CP. The solutes distribution in the brain parenchyma was assessed using T1 magnetic resonance imaging after injection of DOTA-Gadolinium in the cisterna magna. This evaluation was performed at an early time point following DC (after 2 d) and at a later time point (after 15 d). We evaluated the solutes distribution in the whole brain and in the region underneath the DC area. Results Our results demonstrate that the global solutes distribution in the brain parenchyma is impaired after DC in mice, both at early and late time-points. However, there was no impact of DC on the solutes distribution just under the craniectomy. We then provide evidence that this impairment was reversed by CP. Conclusion The solute distribution in the brain parenchyma by the CSF and ISF is impaired by DC, a phenomenon reversed by CP.

Altogether, this preclinical study demonstrates that the tPA present in the blood stream is a key player of the formation of IAs. Thus, tPA should be considered as a possible new target for the prevention of IAs formation and rupture.

Intracerebral hemorrhage (ICH) is the most severe form of stroke. Catheter-delivered thrombolysis with recombinant tissue-type plasminogen activator (rtPA) for the drainage of ICH is currently under evaluation in a phase III clinical trial (MISTIE III). However, in a pig model of ICH, in situ fibrinolysis with rtPA was reported to increase peri-lesional edema by promoting N-methyl-D-aspartate (NMDA)-dependent excitotoxicity. In the present study, we engineered a non-neurotoxic tPA variant, OptPA, and investigated its safety and efficacy for in situ fibrinolysis in a rat model of ICH. Magnetic resonance imaging analyses of hematoma and edema volumes, behavioral tasks and histological analyses were performed to measure the effects of treatments. In vitro, OptPA was equally fibrinolytic as rtPA without promoting NMDA-dependent neurotoxicity. In vivo, in situ fibrinolysis using OptPA reduced hematoma volume, like rtPA, but it also reduced the evolution of peri-hematomal neuronal death and subsequent edema progression. Overall, this preclinical study demonstrates beneficial effects of OptPA compared to rtPA for the drainage of ICH.