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We analyzed interrelations between the cerebral blood flow, cardiac output, and condition of the brain substance in 530 patients with ischemic stroke. Dependencies between the linear blood flow velocities in all arteries supplying the brain, as well as between the total volume blood flow through the internal carotid arteries and left ventricular stroke volume were revealed. The severity of atrophy was maximum in the parietal lobes (median 1.5 (1.0; 2.0)) and minimum in the occipital lobes (median 0.5 (0; 1.0)). Temporal lobes cortical atrophy significantly correlated with changes in the limbic system and in the periventricular and deep white matter; a significant weak inverse correlation of this parameter with blood flow in the middle cerebral artery was also found. Changes in the periventricular white matter (but not in deep white matter) demonstrated a significant inverse correlation with blood flow in the middle and anterior cerebral arteries.

Sleep deficiency increases the risk of cerebrovascular diseases. However, the effects of sleep deprivation (SD) on cerebral blood flow have been poorly studied. We examined the effect of 24-h of SD on the resting posterior cerebral artery (PCA) and middle cerebral artery (MCA) flow velocities (FV), the visually evoked FV response in the PCA (neurovascular coupling), and the hypercapnia-induced FV response in the MCA (cerebral vasoreactivity). Visual evoked potential (VEP) and transcranial Doppler examinations were performed in 25 healthy adults before and after 24-h of SD. Cerebral vasoreactivity was measured by breath-holding test in left and right MCA. The visually evoked FV response was evaluated in left and right PCA. There was a tendency for increased resting mean FV in PCA ( p  = 0.08) and MCA ( p  = 0.07) after SD. Both the visually evoked FV response in the PCA and the hypercapnia-induced FV increase in the MCA were significantly lower after than before SD, however, no change in VEP amplitudes was found. Our study suggested that the impaired functional stimulation-evoked FV response after SD was not due to a reduced neuronal activation, but probably to a decreased vasodilatory response. Negative effects of SD on cerebral hemodynamics were also demonstrated by reduced cerebral vasoreactivity.

Protein aggregation critically affects cell viability in neurodegenerative diseases, but whether this also occurs in ischemic brain injury remains elusive. Prior studies report the post-ischemic aggregation of ubiquitin, small ubiquitin-related modifier (SUMO) and ribosomes, however whether other proteins are also affected is unknown. Here we employed a proteomic approach to identify the insoluble, aggregated proteome after cerebral ischemia. Mice underwent transient middle cerebral artery occlusion or sham-surgery. After 1-hour reperfusion, prior to apparent brain injury, mice were sacrificed and detergent-insoluble proteins were obtained and identified by nanoLC-MS/MS. Naturally existing insoluble proteins were determined in sham controls and aggregated proteins after cerebral ischemia/reperfusion were identified. Selected aggregated proteins found by proteomics were biochemically verified and aggregation propensities were studied during ischemia with or without reperfusion. We found that ischemia/reperfusion induces the aggregation of RNA-binding and heat-shock proteins, ubiquitin, SUMO and other proteins involved in cell signalling. RNA-binding proteins constitute the largest group of aggregating proteins in ischemia. These include TDP43, FUS, hnRNPA1, PSF/SFPQ and p54/NONO, all of which have been linked to neurodegeneration associated with amyotrophic lateral sclerosis and frontotemporal dementia. The aggregation of neurodegeneration-related disease proteins in cerebral ischemia unveils a previously unappreciated molecular overlap between neurodegenerative diseases and ischemic stroke.

Cerebrovascular hemodynamics are believed to play an important role in the development of ischemic stroke (IS). However, the relationships between hemodynamics and prognosis are not fully understood. Four-dimensional (4D) flow cardiovascular magnetic resonance (CMR) enables comprehensive characteristics of cerebrovascular hemodynamics. This study aims to investigate the associations of the different hemodynamics derived from 4D flow CMR with IS functional outcomes. Ninety-one patients (median age 64 years, 62 males) with unilateral IS in middle cerebral artery (MCA) territory were included. All subjects underwent a CMR scan, including 4D flow, three-dimensional (3D) time-of-flight magnetic resonance angiography, and 3D whole brain black-blood high-resolution vessel wall imaging of the MCA. Six hemodynamic parameters, including flow rate, velocity, pulsatility index, time-averaged wall shear stress (TAWSS), oscillatory shear index, and relative residence time (RRT), were calculated for the lesion site, pre-bifurcation M1 (pM1) segment, and the distal M1 and/or first branches of M2 (dM1/M2) segments. Vessel characteristics, such as lumen area, vessel area, wall area, maximum wall thickness, and the degree of stenosis, were calculated at the most stenotic lesion site. The modified Rankin Scale (mRS) scores were assessed at 90 days and 1 year, and an mRS >2 was considered as a poor functional outcome. Lower segment-level TAWSS (odds ratio [OR]: 0.24, P = 0.006 and OR: 0.29, P = 0.014), higher RRT (OR: 2.74, P = 0.007 and OR: 2.40, P = 0.011) of dM1/M2 segments, and lower segment- and lesion-level velocity (OR: 0.40, P = 0.019 and OR: 0.41, P = 0.025; OR: 0.41, P = 0.030 and OR: 0.42, P = 0.040) of pM1 segment were observed to be associated with poor functional outcome at both 90 days and 1 year. Using the cut-off value of 3.58 Pa and 0.29, respectively, TAWSS and RRT of dM1/M2 segments showed moderate performance in distinguishing poor functional outcome from favorable outcome (area under the curve ranging from 0.642–0.687) both at 90 days and 1 year. Distal segmental TAWSS and RRT of dM1/M2 segments were associated with poor functional outcomes. Such alterations in hemodynamics might help in the identification of patients with potentially unfavorable prognosis. [Display omitted]

Although platelet-derived growth factors (PDGFs) and receptors (PDGFRs) are abundantly expressed in the central nervous system, their functions largely remain elusive. We investigated the role of PDGFR-β in tissue responses and functional recovery after photothrombolic middle cerebral artery occlusion (MCAO). In the normal adult mouse brain, PDGFR-β was mainly localized in neurons and in pericyte/vascular smooth muscle cells (PC/vSMCs). From 3 to 28 days after MCAO, postnatally induced systemic PDGFR-β knockout mice (Esr-KO) exhibited the delayed recovery of body weight and behavior, and larger infarction volume than controls. In Esr-KO, PC/vSMC coverage was decreased and vascular leakage of infused fluorescent-labeled albumin was extensive within the ischemic lesion, but not in the uninjured cerebral cortex. Angiogenesis levels were comparable between Esr-KO and controls. In another PDGFR-β conditional KO mouse (Nestin-KO), PDGFR-β was deleted in neurons and astrocytes from embryonic day 10.5, but was preserved in PC/vSMCs. After MCAO, vascular leakage and infarction volume in Nestin-KO were worse than controls, but partly improved compared with Esr-KO. Astroglial scar formation in both Esr-KO and Nestin-KO was similarly reduced compared with controls after MCAO. These data suggested that PDGFR-β signaling is crucial for neuroprotection, endogenous tissue repair, and functional recovery after stroke by targeting neurons, PC/vSMCs, and astrocytes.

The brain vascular system has an autoregulatory mechanism that maintains blood perfusion within normal limits at the capillary level. Partially due to its clinical importance, it is of interest to better understand the mechanisms involved in vascular regulation. Therefore, using functional magnetic resonance imaging (fMRI), we quantitatively investigated hemodynamic response characteristics of regions supplied by the main cerebral arteries, during two breath holding tests (BHT): after inspiration and after expiration. We used an auto-regressive method capable of estimating four signal parameters: onset delay, full width at half maximum (FWHM), time-to-peak and amplitude. The onset delay was significantly longer for the posterior cerebral artery (PCA) than for middle cerebral artery (MCA) and anterior arteries (ACA). FWHM and time-to-peak were larger in the ACA territory, indicating a slower blood flow in this region. Differences were also observed in the amplitude among the three areas, where MCA and PCA territories showed the smallest and the highest amplitudes, respectively. Moreover, differences were found in amplitude and onset when BHT was performed after inspiration as compared to BHT after expiration. Time-to-peak and FWHM showed no statistical differences between these two challenges. Such results are related to regional anatomical specificities and biochemical mechanisms responsible for vasodilation, such as those related to vascularity and vessel sizes.

BackgroundAlthough systemic endothelial function is unimpaired in migraine, it is unknown whether cerebral endothelial function impairment exists in migraineurs.Materials and methodsWe conducted a prospective study to assess endothelial function in migraineurs (n=45) and healthy volunteers (n=44). Cerebral endothelial function was assessed by Breath Holding Index (BHI) on transcranial Doppler in bilateral middle cerebral artery (MCA at 30–60 mm), posterior cerebral artery (PCA at 60–80 mm) and basilar artery (BA at 80–120 mm) using bilateral monitoring probes fixed on headband. Brachial artery flow-mediated dilation (FMD) was used as measure of systemic endothelial function.ResultsThere was no difference in baseline mean velocities of MCA, PCA, BA among migraineurs and controls. Mean BHI was significantly lower in PCA (p<0.001) and BA (p<0.001) in patients with migraine with no difference in MCA (p=0.909, 0.450). Cerebral endothelial dysfunction (BHI<1.15) was present in 62.2% of migraineurs in the right PCA (p<0.001), 57.8% in left PCA (p<0.001) and 77.8% in BA (BHI <0.83, p<0.001). There was no difference in BHI among migraineurs without and with aura (n=15). Cerebral and systemic endothelial function had no correlation in migraineurs. Increasing BMI was identified as a predictor of impaired BHI in the BA in migraineurs (p=0.020). Age, sex, presence of aura, lateralisation of headache, headache frequency, time to last attack and impaired FMD were not associated with impaired PCA and BA BHI in migraineurs.ConclusionsMigraineurs may have isolated cerebral endothelial dysfunction restricted to the posterior circulation in the absence of systemic endothelial dysfunction.

Progress in experimental stroke and translational medicine could be accelerated by high-resolution in vivo imaging of disease progression in the mouse cortex. Here, we introduce optical microscopic methods that monitor brain injury progression using intrinsic optical scattering properties of cortical tissue. A multi-parametric Optical Coherence Tomography (OCT) platform for longitudinal imaging of ischemic stroke in mice, through thinned-skull, reinforced cranial window surgical preparations, is described. In the acute stages, the spatiotemporal interplay between hemodynamics and cell viability, a key determinant of pathogenesis, was imaged. In acute stroke, microscopic biomarkers for eventual infarction, including capillary non-perfusion, cerebral blood flow deficiency, altered cellular scattering, and impaired autoregulation of cerebral blood flow, were quantified and correlated with histology. Additionally, longitudinal microscopy revealed remodeling and flow recovery after one week of chronic stroke. Intrinsic scattering properties serve as reporters of acute cellular and vascular injury and recovery in experimental stroke. Multi-parametric OCT represents a robust in vivo imaging platform to comprehensively investigate these properties.

Abstract Clinical and experimental studies have been focused on the pathophysiological mechanisms induced by brain ischemia-reperfusion injury. Recovery events, such as neurogenesis, angiogenesis and the growth of new blood vessels from the preexisting vascular tree, have been intensively studied in the last decades to clarify the vascular remodeling crucial for stroke outcome. This review aims to discuss the cerebral microcirculation remodeling induced by ischemia-reperfusion and the mechanisms involved in angiogenesis and vasculogenesis. The first in vivo observations were focused on anastomotic shunting of cerebral blood flow (CBF) in experimental and clinical models. Thereafter, vascular remodeling induced by cerebral ischemia-reperfusion was reported in mice and rats. Successively, other studies have assessed that within 30 days of middle cerebral artery (MCA) occlusion in rats, there is an increase in CBF and recovery from stroke. Recently, rats submitted to transient MCA occlusion showed pial microcirculation remodeling with the formation of new arterioles sprouting from penumbra vessels and overlapping the ischemic core. This review focuses on the production and/or activation of vasculotrophic factors able to trigger and facilitate microvascular remodeling. Vascular endothelial growth factor and endothelium-released nitric oxide appear to be the main factors involved in the formation of new vessels during microvascular remodeling. These studies are fundamental for consequent interventions on molecular targets, useful for fostering vascular remodeling and the recovery of functions.

Time-of-flight (TOF) angiography detects embolic occlusion of arteries in patients with acute ischemic stroke due to the absence of blood flow in the occluded vessel. In contrast, susceptibility weighted imaging (SWI) directly enables intravascular clot visualization due to hypointense susceptibility vessel signs (SVS) in the occluded vessel. The aim of this study was to compare the diagnostic accuracy of both methods to determine vessel occlusion in patients with acute stroke. 94 patients were included who presented with clinical symptoms for acute stroke and displayed a delay on the time-to-peak perfusion map in the territory of the anterior (ACA), middle (M1, M1/M2, M2/M3) or posterior (PCA) cerebral artery. The frequency of SVS on SWI and vessel occlusion or stenosis on TOF-angiography was compared using the McNemar-Test. 87 of 94 patients displayed a clearly definable SVS on SWI. In 72 patients the SVS was associated with occlusion or stenosis on TOF-angiography. Fifteen patients exclusively displayed SVS on SWI (14 M2/M3, 1 M1), whereas no patient revealed exclusively occlusion or stenosis on TOF-angiography. Sensitivity for detection of embolic occlusion within major vessel segments (M1, M1/M2, ACA, and PCA) did not show any significant difference between both techniques (97% for SWI versus 96% for TOF-angiography) while the sensitivity for detection of embolic occlusion within M2/M3 was significantly different (84% for SWI versus 39% for TOF-angiography, p<0.00012). SWI and TOF-angiography provide similar sensitivity for central thrombi while SWI is superior for the detection of peripheral thrombi in small arterial vessel segments.