Plasminogen Activator Inhibitor-1 in the Pathophysiology of Late Life Depression.

Introduction: Late life depression (LLD) is characterized by specific clinical features including a high frequency of vascular form and frequent antidepressant treatment resistance. The expression and functions of the serine protease inhibitor, Plasminogen Activator Inhibitor-1 (PAI-1) is known to be altered by aging, vascular damage, insulin levels associated with a sedentary lifestyle, chronic stress leading to hypercortisolemia, and inflammatory changes linked to stress responses. These phenomena would be implicated in LLD like vascular depression.

Reliable infarction of the middle cerebral artery territory in C57BL/6 mice using pterygopalatine artery ligation and filament optimization - The PURE-MCAo model.

Current techniques for inducing intraluminal filamentous middle cerebral artery occlusion (fMCAo) in mice produce highly variable results and often cause additional infarcts in the posterior cerebral artery (PCA) territory. The aim of the current study was to develop a novel procedure to overcome these shortcomings. Male C57BL/6 mice were subjected to 60 min of fMCAo with cerebral blood flow monitored by laser Doppler flowmetry.

Endogenous tPA levels: A biomarker for discriminating hemorrhagic stroke from ischemic stroke and stroke mimics.

Objective: Stroke is the leading cause of death and disability. Timely differentiation between ischemic stroke, hemorrhagic stroke, and stroke mimics is critical for tailored treatment and triage. To accelerate the identification of stroke's subtype, we propose to use the levels of circulating tPA as a biomarker.

MRI-based microthrombi detection in stroke with polydopamine iron oxide.

In acute ischemic stroke, even when successful recanalization is obtained, downstream microcirculation may still be obstructed by microvascular thrombosis, which is associated with compromised brain reperfusion and cognitive decline. Identifying these microthrombi through non-invasive methods remains challenging. We developed the PHySIOMIC (Polydopamine Hybridized Self-assembled Iron Oxide Mussel Inspired Clusters), a MRI-based contrast agent that unmasks these microthrombi.

Bradykinin 2 Receptors Mediate Long-Term Neurocognitive Deficits After Experimental Traumatic Brain Injury.

The kallikrein-kinin system is one of the first inflammatory pathways to be activated following traumatic brain injury (TBI) and has been shown to exacerbate brain edema formation in the acute phase through activation of bradykinin 2 receptors (B2R). However, the influence of B2R on chronic post-traumatic damage and outcome is unclear. In the current study, we assessed long-term effects of B2R-knockout (KO) after experimental TBI.

To see or not to see: In vivo nanocarrier detection methods in the brain and their challenges.

Nanoparticles have a great potential to significantly improve the delivery of therapeutics to the brain and may also be equipped with properties to investigate brain function. The brain, being a highly complex organ shielded by selective barriers, requires its own specialized detection system. However, a significant hurdle to achieve these goals is still the identification of individual nanoparticles within the brain with sufficient cellular, subcellular, and temporal resolution.

Pharmacological preclinical comparison of tenecteplase and alteplase for the treatment of acute stroke.

Alteplase (rtPA) remains the standard thrombolytic drug for acute ischemic stroke. However, new rtPA-derived molecules, such as tenecteplase (TNK), with prolonged half-lives following a single administration, have been developed. Although TNK is currently under clinical evaluation, the limited preclinical data highlight the need for additional studies to elucidate its benefits.

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

Recanalization is the mainstay of ischemic stroke treatment. However, even with timely clot removal, many stroke patients recover poorly. Leptomeningeal collaterals (LMCs) are pial anastomotic vessels with yet-unknown functions.

Improving stroke outcomes in hyperglycemic mice by modulating tPA/NMDAR signaling to reduce inflammation and hemorrhages.

The pharmacological intervention for ischemic stroke hinges on intravenous administration of the recombinant tissue-type plasminogen activator (rtPA, Alteplase/Actilyse) either as a standalone treatment or in conjunction with thrombectomy. However, despite its clinical significance, broader use of rtPA is constrained because of the risk of hemorrhagic transformations (HTs). Furthermore, the presence of diabetes or chronic hyperglycemia is associated with an elevated risk of HT subsequent to thrombolysis.

Thrombolytic therapy based on lyophilized platelet-derived nanocarriers for ischemic stroke.

Background: Intravenous administration of fibrinolytic drugs, such as recombinant tissue plasminogen activator (rtPA) is the standard treatment of acute thrombotic diseases. However, current fibrinolytics exhibit limited clinical efficacy because of their short plasma half-lives and risk of hemorrhagic transformations. Platelet membrane-based nanocarriers have received increasing attention for ischemic stroke therapies, as they have natural thrombus-targeting activity, can prolong half-life of the fibrinolytic therapy, and reduce side effects.

Continued dysfunction of capillary pericytes promotes no-reflow after experimental stroke in vivo.

Incomplete reperfusion of the microvasculature ('no-reflow') after ischaemic stroke damages salvageable brain tissue. Previous ex vivo studies suggest pericytes are vulnerable to ischaemia and may exacerbate no-reflow, but the viability of pericytes and their association with no-reflow remains under-explored in vivo. Using longitudinal in vivo two-photon single-cell imaging over 7 days, we showed that 87% of pericytes constrict during cerebral ischaemia and remain constricted post reperfusion, and 50% of the pericyte population are acutely damaged.

Dynamics of cerebral blood volume during and after middle cerebral artery occlusion in rats - Comparison between ultrafast ultrasound and dynamic susceptibility contrast-enhanced MRI measurements.

Tomographic perfusion imaging techniques are integral to translational stroke research paradigms that advance our understanding of the disease. Functional ultrasound (fUS) is an emerging technique that informs on cerebral blood volume (CBV) through ultrasensitive Doppler and flow velocity (CBFv) through ultrafast localization microscopy. It is not known how experimental results compare with a classical CBV-probing technique such as dynamic susceptibility contrast-enhanced perfusion MRI (DSC-MRI).

A multi-disciplinary commentary on preclinical research to investigate vascular contributions to dementia.

Although dementia research has been dominated by Alzheimer's disease (AD), most dementia in older people is now recognised to be due to mixed pathologies, usually combining vascular and AD brain pathology. Vascular cognitive impairment (VCI), which encompasses vascular dementia (VaD) is the second most common type of dementia. Models of VCI have been delayed by limited understanding of the underlying aetiology and pathogenesis.

Targeting NMDA Receptors at the Neurovascular Unit: Past and Future Treatments for Central Nervous System Diseases.

The excitatory neurotransmission of the central nervous system (CNS) mainly involves glutamate and its receptors, especially N-methyl-D-Aspartate receptors (NMDARs). These receptors have been extensively described on neurons and, more recently, also on other cell types. Nowadays, the study of their differential expression and function is taking a growing place in preclinical and clinical research.

Scanning laser-induced endothelial injury: a standardized and reproducible thrombosis model for intravital microscopy.

Vascular injury models are indispensable for studying thrombotic processes in vivo. Amongst the available methods for inducing thrombosis, laser-induced endothelial injury (LIEI) has several unique advantages. However, a lack of methodological standardization and expensive instrumentation remain significant problems decreasing reproducibility and impeding the adoption of LIEI in the wider scientific community.

PKCδ-positive GABAergic neurons in the central amygdala exhibit tissue-type plasminogen activator: role in the control of anxiety.

Tissue plasminogen activator (tPA) is a serine protease expressed in several brain regions and reported to be involved in the control of emotional and cognitive functions. Nevertheless, little is known about the structure-function relationships of these tPA-dependent behaviors. Here, by using a new model of constitutive tPA-deficient mice (tPA), we first show that tPA controls locomotor activity, spatial cognition and anxiety.

Molecular Magnetic Resonance Imaging of Vascular Inflammation After Recanalization in a Rat Ischemic Stroke Model.

Background And Purpose: Brain imaging has become central in the management of acute ischemic stroke. Detection of parenchymal injury and perfusion enables characterization of the extent of ischemic damage, which guides treatment decision-making. Additional assessment of secondary events, such as inflammation, which may particularly arise after recanalization, may improve diagnosis and (supplementary) treatment selection.

Sex-specificities in anxiety and depressive symptoms across the lifespan and their links with multimodal neuroimaging.

Background: Anxiety and depressive symptoms are associated with impaired well-being, higher risk of developing psychoaffective disorders and are risk factors for Alzheimer's disease (AD). To further understand their relevance and the mechanisms underlying their link with AD, our aims were to assess how anxiety and depressive symptoms changed with age and related to AD neuroimaging biomarkers across the adult lifespan, while also exploring sex specificities.

Methods: 210 cognitively normal participants aged 19-86 years (101 men, 109 women) completed assessments of anxiety and depressive symptoms with the STAI-A and MADRS respectively, and neuroimaging measurements including structural MRI, FDG-PET and amyloid-PET.

Thrombolysis by PLAT/tPA increases serum free IGF1 leading to a decrease of deleterious autophagy following brain ischemia.

Cerebral ischemia is a pathology involving a cascade of cellular mechanisms, leading to the deregulation of proteostasis, including macroautophagy/autophagy, and finally to neuronal death. If it is now accepted that cerebral ischemia induces autophagy, the effect of thrombolysis/energy recovery on proteostasis remains unknown. Here, we investigated the effect of thrombolysis by PLAT/tPA (plasminogen activator, tissue) on autophagy and neuronal death.

Magnetic Resonance Imaging of Blood-Brain Barrier permeability in Dementia.

Alzheimer's disease (AD) and cerebral small vessel disease (cSVD) are the two main causes of dementia with blood-brain barrier (BBB) breakdown being a common contributor. Recent advances in neuroimaging techniques offer new possibilities to understand how the brain functions in health and disease. This includes methods such as dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) which allows the detection of subtle regional changes in the BBB integrity.

Preventing the Long-term Effects of General Anesthesia on the Developing Brain: How Translational Research can Contribute.

In 2017, the Food and Drug Administration published a safety recommendation to limit the exposure to general anesthesia as much as possible below the age of three. Indeed, several preclinical and clinical studies have questioned the possible toxicity of general anesthesia on the developing brain. Since then, recent clinical studies tried to mitigate this alarming issue.

New Opportunities for Diagnosis and Prognosis of Stroke: The Benefits of Across Border Approaches.

Ischemic stroke is a leading cause of disability, with its treatment not yet optimal. It is thus mandatory to make preclinical research on this topic more efficient. This review summarizes current development of research aimed to improve diagnosis and prognosis of ischemic stroke.