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Many ischaemic stroke patients who have a mechanical removal of their clot (thrombectomy) do not get reperfusion of tissue despite the thrombus being removed. One hypothesis for this ‘no-reperfusion’ phenomenon is micro-emboli fragmenting off the large clot during thrombectomy and occluding smaller blood vessels downstream of the clot location. This is impossible to observe in-vivo and so we here develop an in-silico model based on in-vitro experiments to model the effect of micro-emboli on brain tissue. Through in-vitro experiments we obtain, under a variety of clot consistencies and thrombectomy techniques, micro-emboli distributions post-thrombectomy. Blood flow through the microcirculation is modelled for statistically accurate voxels of brain microvasculature including penetrating arterioles and capillary beds. A novel micro-emboli algorithm, informed by the experimental data, is used to simulate the impact of micro-emboli successively entering the penetrating arterioles and the capillary bed. Scaled-up blood flow parameters–permeability and coupling coefficients–are calculated under various conditions. We find that capillary beds are more susceptible to occlusions than the penetrating arterioles with a 4x greater drop in permeability per volume of vessel occluded. Individual microvascular geometries determine robustness to micro-emboli. Hard clot fragmentation leads to larger micro-emboli and larger drops in blood flow for a given number of micro-emboli. Thrombectomy technique has a large impact on clot fragmentation and hence occlusions in the microvasculature. As such, in-silico modelling of mechanical thrombectomy predicts that clot specific factors, interventional technique, and microvascular geometry strongly influence reperfusion of the brain. Micro-emboli are likely contributory to the phenomenon of no-reperfusion following successful removal of a major clot.

Sustained silencing of gene expression throughout the brain using small interfering RNAs (siRNAs) has not been achieved. Here we describe an siRNA architecture, divalent siRNA (di-siRNA), that supports potent, sustained gene silencing in the central nervous system (CNS) of mice and nonhuman primates following a single injection into the cerebrospinal fluid. Di-siRNAs are composed of two fully chemically modified, phosphorothioate-containing siRNAs connected by a linker. In mice, di-siRNAs induced the potent silencing of huntingtin, the causative gene in Huntington’s disease, reducing messenger RNA and protein throughout the brain. Silencing persisted for at least 6 months, with the degree of gene silencing correlating to levels of guide strand tissue accumulation. In cynomolgus macaques, a bolus injection of di-siRNA showed substantial distribution and robust silencing throughout the brain and spinal cord without detectable toxicity and with minimal off-target effects. This siRNA design may enable RNA interference-based gene silencing in the CNS for the treatment of neurological disorders. A divalent siRNA architecture enables sustained silencing of gene expression in deep regions of the brain.

Intravascular imaging has emerged as a valuable tool for the treatment of coronary and peripheral artery disease; however, no solution is available for safe and reliable use in the tortuous vascular anatomy of the brain. Endovascular treatment of stroke is delivered under image guidance with insufficient resolution to adequately assess underlying arterial pathology and therapeutic devices. High-resolution imaging, enabling surgeons to visualize cerebral arteries' microstructure and micron-level features of neurovascular devices, would have a profound impact in the research, diagnosis, and treatment of cerebrovascular diseases. Here, we present a neurovascular high-frequency optical coherence tomography (HF-OCT) system, including an imaging console and an endoscopic probe designed to rapidly acquire volumetric microscopy data at a resolution approaching 10 microns in tortuous cerebrovascular anatomies. Using a combination of in vitro, ex vivo, and in vivo models, the feasibility of HF-OCT for cerebrovascular imaging was demonstrated. High resolution intravascular imaging in the brain is limited by the high tortuosity of the vasculature. Here the authors present a fiber optic imaging technology using high-frequency optical coherence tomography (HF-OCT) to provide volumetric high resolution images in the highly tortuous cerebral vasculature.

Our aim was to assess the utility of a novel machine learning software (Orbit Image Analysis) in the histological quantification of acute ischemic stroke (AIS) clots. We analyzed 50 AIS blood clots retrieved using mechanical thrombectomy procedures. Following H&E staining, quantification of clot components was performed by two different methods: a pathologist using a reference standard method (Adobe Photoshop CC) and an experienced researcher using Orbit Image Analysis. Following quantification, the clots were categorized into 3 types: RBC dominant (≥60% RBCs), Mixed and Fibrin dominant (≥60% Fibrin). Correlations between clot composition and Hounsfield Units density on Computed Tomography (CT) were assessed. There was a significant correlation between the components of clots as quantified by the Orbit Image Analysis algorithm and the reference standard approach (ρ = 0.944**, p < 0.001, n = 150). A significant relationship was found between clot composition (RBC-Rich, Mixed, Fibrin-Rich) and the presence of a Hyperdense artery sign using the algorithmic method (X2(2) = 6.712, p = 0.035*) but not using the reference standard method (X2(2) = 3.924, p = 0.141). Orbit Image Analysis machine learning software can be used for the histological quantification of AIS clots, reproducibly generating composition analyses similar to current reference standard methods.

BackgroundClot mechanical properties are influenced by composition and the arrangement of components within the clot. This work investigates the effects of platelet-driven contraction on blood clot microstructure and mechanical behavior, and provides insight into some implications for mechanical thrombectomy.MethodsPlatelet-contracted clot analogues (PCCs) and non-contracted clot analogues (NCCs) were prepared from blood mixtures of various hematocrits (%H), that is, the volume percentage of red blood cells (RBCs) in the mixture. Mechanical testing was performed to compare the behavior of the analogues with previously tested human thromboemboli. Scanning electron microscopy and histology investigated the clot microstructure and composition. The association between clot properties and their behavior during mechanical behavior was also investigated.ResultsOverall, PCCs were found to be stiffer than NCCs, across all hematocrits. PCCs with a low %H resisted complete ingestion via contact aspiration alone or complete retrieval with stent-retrievers. PCCs with a higher %H and all NCCs were fully retrievable, although the likelihood of fragmentation was increased in clots with a greater %H. Histologically, there was little difference in the RBC and fibrin content between PCCs and NCCs with the same %H. However, the microstructure of the two groups differed significantly.ConclusionA selection of repeatable clot analogues with a range of mechanical properties have been developed for in vitro modeling of acute ischemic stroke. Platelet contraction significantly affects clot volume and microstructure, and in turn clot stiffness. The significant difference in mechanical properties and microstructure, but without an appreciable difference in histology, implies that histological studies of explanted human clots alone may not prove to be predictive of the mechanical behavior of the clots in thrombectomy.

Background and objectives Vascular disease is a known risk factor for Alzheimer’s disease (AD). Endothelial dysfunction has been linked to reduced cerebral blood flow. Endothelial nitric oxide synthase pathway (eNOS) upregulation is known to support endothelial health. This single-center, proof-of-concept study tested whether the use of three medications known to augment the eNOS pathway activity improves cognition and cerebral blood flow (CBF). Methods Subjects with mild AD or mild cognitive impairment (MCI) were sequentially treated with the HMG-CoA reductase synthesis inhibitor simvastatin (weeks 0–16), l -arginine (weeks 4–16), and tetrahydrobiopterin (weeks 8–16). The primary outcome of interest was the change in CBF as measured by MRI from baseline to week 16. Secondary outcomes included standard assessments of cognition. Results A total of 11 subjects were deemed eligible and enrolled. One subject withdrew from the study after enrollment, leaving 10 subjects for data analysis. There was a significant increase in CBF from baseline to week 8 by ~13% in the limbic and ~15% in the cerebral cortex. Secondary outcomes indicated a modest but significant increase in the MMSE from baseline (24.2±3.2) to week 16 (26.0±2.7). Exploratory analysis indicated that subjects with cognitive improvement (reduction of the ADAS-cog 13) had a significant increase in their respective limbic and cortical CBF. Conclusions Treatment of mild AD/MCI subjects with medications shown to augment the eNOS pathway was well tolerated and associated with modestly increased cerebral blood flow and cognitive improvement. Trial registration This study is registered in https://www.clinicaltrials.gov ; registration identifier: NCT01439555; date of registration submitted to registry: 09/23/2011; date of first subject enrollment: 11/2011.

Introduction Flow diversion is being increasingly used to treat cerebral aneurysms. We present our experience using these stents to treat aneurysms distal to the circle of Willis with parent arteries smaller than 2.5 mm. Methods Aneurysms treated with a Pipeline™ Embolization Device in vessels less than 2.5 mm between June 2012 and August 2014 were included. We evaluated risk factors, family history of aneurysms, aneurysm characteristics, National Institute of Health Stroke Scale (NIHSS), and modified Rankin scale (mRS) on admission and angiography and clinical outcome at discharge, 6 months, and 1 year. Results We included seven patients with a mean age of 65 years. The parent vessel size ranged from 1.5 to 2.3 mm; mean 1.9 mm. Location of the aneurysms was as follows: two aneurysms centered along the pericallosal artery (one left, one right), one on the right angular artery, one aneurysm at the anterior communicating artery (ACom), one at the ACom-right A2 anterior cerebral artery (ACA), one at the lenticulostriate artery, and one at the A1-A2 ACA artery. Aneurysms ranged from 1 to 12 mm in diameter. All aneurysms were treated with a single Pipeline™ Embolization Device (PED). No peri- or post-procedural complications or mortality occurred. The patients were discharged with no change in NIHSS or mRS score. Angiographic follow-up was available in six patients. Angiography showed complete aneurysm occlusion in all. NIHSS and mRS remained unchanged at follow-up. Conclusion Our preliminary results show that flow diversion technology is an effective and safe therapy for aneurysms located on small cerebral arteries. Larger studies with long-term follow-up are needed to validate our promising results.

Cardiovascular disease is the leading cause of death in Western cultures. The vast majority of cardiovascular events, including stroke and myocardial infarction, result from the rupture of vulnerable atherosclerotic plaques, which are characterized by high and active macrophage content. Current imaging modalities including magnetic resonance imaging (MRI) aim to characterize anatomic and structural features of plaques rather than their content. Previously, we reported that macrophage-targeted delivery of gadolinium (Gd)-based contrast agent (GBCA-HDL) using high density lipoproteins (HDL)-like particles significantly enhances the detection of plaques in an apolipoprotein (apo) E knockout (KO) mouse model, with an atherosclerotic wall/muscle normalized enhancement ratio (NER) of 120% achieved. These particles are comprised of lipids and synthetic peptide fragments of the major protein of HDL, apo A-I, that contain a naturally occurring modification which targets the particles to macrophages. Targeted delivery minimizes the Gd dose and thus reduces the adverse effects of Gd. The aims of the current study were to test whether varying the GBCA-HDL particle shape and composition can further enhance atherosclerotic plaque MRI and control organ clearance of these agents. We show that the optimized GBCA-HDL particles are efficiently delivered intracellularly to and uptaken by both J774 macrophages in vitro and more importantly, by intraplaque macrophages in vivo, as evidenced by NER up to 160% and higher. This suggests high diagnostic power of our GBCA-HDL particles in the detection of vulnerable atherosclerotic plaques. Further, in contrast to discoidal, spherical GBCA-HDL exhibit hepatic clearance, which could further diminish adverse renal effects of Gd. Finally, activated macrophages are reliable indicators of any inflamed tissues and are implicated in other areas of unmet clinical need such as rheumatoid arthritis, sepsis and cancer, suggesting the expanded diagnostic and prognostic use of this method.

BackgroundCurrent studies on clot characterization in acute ischemic stroke focus on fibrin and red blood cell composition. Few studies have examined platelet composition in acute ischemic stroke clots. We characterize clot composition using the Martius Scarlet Blue stain and assess associations between platelet density and CT density.Materials and methodHistopathological analysis of the clots collected as part of the multi-institutional STRIP registry was performed using Martius Scarlet Blue stain and the composition of the clots was quantified using Orbit Image Analysis (www.orbit.bio) machine learning software. Prior to endovascular treatment, each patient underwent non-contrast CT (NCCT) and the CT density of each clot was measured. Correlations between clot components and clinical information were assessed using the χ2 test.ResultsEighty-five patients were included in the study. The mean platelet density of the clots was 15.7% (2.5–72.5%). There was a significant correlation between platelet-rich clots and the absence of hyperdensity on NCCT, (ρ=0.321, p=0.003*, n=85). Similarly, there was a significant inverse correlation between the percentage of platelets and the mean Hounsfield Units on NCCT (ρ=−0.243, p=0.025*, n=85).ConclusionMartius Scarlet Blue stain can identify patients who have platelet-rich clots. Platelet-rich clots are isodense on NCCT.

Progress in clinical development of magnetic resonance imaging (MRI) substrate-sensors of enzymatic activity has been slow partly due to the lack of human efficacy data. We report here a strategy that may serve as a shortcut from bench to bedside. We tested ultra high-resolution 7T MRI (µMRI) of human surgical histology sections in a 3-year IRB approved, HIPAA compliant study of surgically clipped brain aneurysms. µMRI was used for assessing the efficacy of MRI substrate-sensors that detect myeloperoxidase activity in inflammation. The efficacy of Gd-5HT-DOTAGA, a novel myeloperoxidase (MPO) imaging agent synthesized by using a highly stable gadolinium (III) chelate was tested both in tissue-like phantoms and in human samples. After treating histology sections with paramagnetic MPO substrate-sensors we observed relaxation time shortening and MPO activity-dependent MR signal enhancement. An increase of normalized MR signal generated by ultra-short echo time MR sequences was corroborated by MPO activity visualization by using a fluorescent MPO substrate. The results of µMRI of MPO activity associated with aneurysmal pathology and immunohistochemistry demonstrated active involvement of neutrophils and neutrophil NETs as a result of pro-inflammatory signalling in the vascular wall and in the perivascular space of brain aneurysms.