Cerebral Blood Flow Deficits Research Articles

Effect of stroke thrombolysis predicted by distal vessel occlusion detection

Among ischemic stroke patients with negative CT angiography (CTA), we aimed to determine the predictive value of enhanced distal vessel occlusion detection using CT perfusion postprocessing (waveletCTA) for the treatment effect of IV thrombolysis (IVT). Patients were selected from 1,851 consecutive patients who had undergone CT perfusion. Inclusion criteria were (1) significant cerebral blood flow (CBF) deficit, (2) no occlusion on CTA, and (3) infarction confirmed on follow-up. Favorable morphologic response was defined as smaller values of final infarction volume divided by initial CBF deficit volume (FIV/CBF). Favorable functional outcome was defined as modified Rankin Scale score of ≤2 after 90 days and decrease in NIH Stroke Scale score of ≥3 from admission to 24 hours (∆NIHSS). Among patients with negative CTA (n = 107), 58 (54%) showed a distal occlusion on waveletCTA. There was no difference between patients receiving IVT (n = 57) vs supportive care (n = 50) regarding symptom onset, early ischemic changes, perfusion mismatch, or admission NIHSS score (all p > 0.05). In IVT-treated patients, the presence of an occlusion was an independent predictor of a favorable morphologic response (FIV/CBF: β -1.43; 95% confidence interval [CI] -1.96, -0.83; p = 0.001) and functional outcome (90-day modified Rankin Scale: odds ratio 7.68; 95% CI 4.33-11.51; p = 0.039; ∆NIHSS: odds ratio 5.76; 95% CI 3.98-8.27; p = 0.013), while it did not predict outcome in patients receiving supportive care (all p > 0.05). In stroke patients with negative CTA, distal vessel occlusions as detected by waveletCTA are an independent predictor of a favorable response to IVT.

Dynamic Cerebral Autoregulation Impairment Persists Past Resolution of Symptoms in Collegiate Athletes Following Concussion

ObjectivesDespite 3.8 million concussions occurring annually in the United States, the pathophysiological sequelae of the injury are still poorly understood. Animal and human studies have consistently reported deficits in cerebral blood flow (CBF) following concussion suggesting impairments in CBF regulation. Reductions in CBF are also associated with functional outcomes. The purpose of the study was to examine dynamic cerebral autoregulation (dCA) in an ongoing prospective cohort of collegiate athletes 3 days, 21 days, and 90 days following a concussion and compare them with non‐injured controls.Materials and MethodsTwenty‐seven NCAA and recreational athletes (20±1 years) with a physician diagnosed sports‐related concussions were enrolled in the study. For the injured athletes, data was collected on days 3,21, and 90 following concussion. Twenty‐five age and sports matched non‐injured controls (20±1 years) were also enrolled. For non‐injured controls, data was collected at one time point. Symptom number and severity was measured using the Sports Concussion Assessment Tool (SCAT‐3). Depression scores were assessed with Patient Health Questionnaire‐9 (PHQ‐9). Continuous mean arterial blood pressure (MBP) was obtained with finger photoplethysmography and middle cerebral artery blood flow velocity (MCAV) was obtained with a 2 MHz transcranial Doppler ultrasonography while subjects were seated in an upright position. dCA was estimated from transfer function (Tf) analysis of beat‐to‐beat spontaneous fluctuations in MBP and MCAV within the low (LF, 0.07–0.20 Hz) and high (HF, 0.20–0.35 Hz) frequency ranges. Effective dCA would attenuate spontaneous changes in MCAV in response to variations in MBP, which would correspond to relatively low transfer function gain. Independent and paired t‐tests were used to compare dCA between days 3, 21, and 90 following concussion with the non‐injured controls.ResultsCompare to the controls, concussed athletes exhibited greater symptom number on day‐3 (12.2±6.8 vs. 2.4±3.4; p<0.001) and higher PHQ‐9 score (8.7±5.6 vs. 2.1±2.1; p<0.001). LF Tf gain was higher on day‐3 (1.26±0.34U vs. 1.04±0.28U; p=0.016) compared to the controls. LF Tf gain continued to be high on day‐21 (1.30±0.45U; p=0.025) compared to the non‐injured controls despite no differences in symptoms number or depression scores between the groups. LF Tf gain was comparable to the controls on day‐90.ConclusionsDynamic cerebral autoregulation appears to be impaired at least up to 21 days following concussion despite improvement in symptom and depression. Cerebral autoregulation estimated from transcranial Doppler ultrasonography may be useful as a potential vascular biomarker for return‐to‐play decisions following a concussion preventing the risk of second‐impact syndrome.Support or Funding InformationThis work was supported by SMU University Research Council Grant, Spring 2015 & Texas Institute for Brain Injury and Repair (TIBIR) Pilot Grant 2016.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Thalamic Diaschisis in Acute Ischemic Stroke: Occurrence, Perfusion Characteristics, and Impact on Outcome.

Ipsilateral thalamic diaschisis (ITD) describes the reduction of thalamic function, metabolism, and perfusion resulting from a distant lesion of the ipsilateral hemisphere. Our aim was to evaluate the perfusion characteristics and clinical impact of ITD in acute middle cerebral artery stroke, which does not directly affect the thalamus. One hundred twenty-four patients with middle cerebral artery infarction were selected from a prospectively acquired cohort of 1644 patients who underwent multiparametric computed tomography (CT), including CT perfusion for suspected stroke. Two blinded readers evaluated the occurrence of ITD, defined as ipsilateral thalamic hypoperfusion present on ≥2 CT perfusion maps. Perfusion alterations were defined according to the Alberta Stroke Program Early CT Score regions. Final infarction volume and subacute complications were assessed on follow-up imaging. Clinical outcome was quantified using the modified Rankin Scale. Multivariable linear and ordinal logistic regression analysis were applied to identify independent associations. ITD was present in 25/124 subjects (20.2%, ITD+). In ITD+ subjects, perfusion of the caudate nucleus, internal capsule, and lentiform nucleus was more frequently affected than in ITD- patients (each with P<0.001). In the ITD+ group, larger cerebral blood flow (P=0.002) and cerebral blood volume (P<0.001) deficit volumes, as well as smaller cerebral blood flow-cerebral blood volume mismatch (P=0.021) were observed. There was no independent association of ITD with final infarction volume or clinical outcome at discharge in treatment subgroups (each with P>0.05). ITD had no influence on the development of subacute stroke complications. ITD in the form of thalamic hypoperfusion is a frequent CT perfusion finding in the acute phase in middle cerebral artery stroke patients with marked involvement of subcortical areas. ITD does not result in thalamic infarction and had no independent impact on patient outcome. Notably, ITD was misclassified as part of the ischemic core by automated software, which might affect patient selection in CT perfusion-based trials.

Detrimental effects of 2-arachidonoylglycerol on whole blood platelet aggregation and on cerebral blood flow after a focal ischemic insult in rats.

2-Arachidonoylglycerol (2-AG) is a major modulator of blood flow and platelet aggregation and a potential neuroprotectant. The present study investigated, for the first time, the effects of 2-AG on cerebral blood flow (CBF) in the first critical hours during middle cerebral artery occlusion (MCAO) and on platelet aggregation in rats. Adult male Sprague-Dawley rats ( n = 30) underwent permanent MCAO under isoflurane anesthesia and were randomly assigned to receive either 2-AG (6 mg/kg iv), monoacylglycerol lipase inhibitor JZL-184 (10 mg/kg iv), or vehicle ( n = 6 rats/group) treatment. CBF and cardiovascular responses were measured, by a blinded investigator, for up to 4 h. In separate experiments, platelet aggregation by 2-AG (19-300 µM) was assessed by whole blood aggregometry ( n = 40). 2-AG and JZL-184 significantly increased the severity of the CBF deficit versus vehicle (20.2 ± 8.8% and 22.7 ± 6.4% vs. 56.4 ± 12.1% of pre-MCAO baseline, respectively, P < 0.05) but had no effect on blood pressure or heart rate. While JZL-184 significantly increased the number of thrombi after MCAO, this did not reach significance by 2-AG. 2-AG induced platelet aggregation in rat whole blood in a similar manner to arachidonic acid and was significantly reduced by the cyclooxygenase inhibitors indomethacin and flurbiprofen and the thromboxane receptor antagonist ICI 192,605 ( P < 0.05). This is the first study showing that 2-AG increases the severity of the CBF deficit during MCAO, and further interrogation confirmed 2-AG-induced platelet aggregation in rats. These findings are important because 2-AG had previously been shown to exert neuroprotective actions and therefore force us to reevaluate the circumstances under which 2-AG is beneficial. NEW & NOTEWORTHY 2-Arachidonoylglycerol (2-AG) has neuroprotective properties; however, the present study revealed that 2-AG increases the severity of the cerebral blood flow deficit during middle cerebral artery occlusion in rats. Further interrogation showed that 2-AG induces platelet aggregation in rats. These findings force us to reevaluate the circumstances under which 2-AG is beneficial.

Brain functional and perfusional alterations in schizophrenia: an arterial spin labeling study

Schizophrenia is a severe mental disorder that affects the anatomy and function of the brain, with an impact on one's thoughts, feelings, and behavior. The purpose of the study was to investigate cerebral blood flow (CBF) and brain connectivity in a group of patients with schizophrenia. Pseudo-continuous arterial spin labeling (pCASL) images were acquired from 28 patients in treatment and 28 age-matched healthy controls. Mean CBF and connectivity patterns were assessed. Schizophrenia patients had decreased CBF in the bilateral frontal pole and superior frontal gyrus, right medial frontal gyrus, triangular and opercular parts of the inferior frontal gyrus, posterior division of the left supramarginal gyrus, superior and inferior divisions of the left lateral occipital cortex, and bilateral occipital pole. Moreover, through different methods to assess connectivity, our results showed abnormal connectivity patterns in regions involved in motor, sensorial, and cognitive functions. Using pCASL, a non-invasive technique, we found CBF deficits and altered functional organization of the brain in schizophrenia patients that are associated with the symptoms and characteristics of the disorder.

Assessment of cerebral perfusional and functional connectivity in schizophrenia using magnetic resonance imaging

Schizophrenia is a significant mental disorder that compromises structural and functional aspects of the brain, with an extreme effect on the patient’s thoughts, feelings, and behavior. Physiologically, in addition to functional and structural abnormalities, changes in neuronal activity are reported. Since the cerebral blood flow (CBF) is directly related to neuronal activity, the magnetic resonance imaging (MRI) technique called arterial spin labeling (ASL), which allows the quantification of CBF, is a useful tool in brain perfusional evaluation. In addition, ASL can be used to assess functional connectivity, which is efficient in investigating functional impairment between regions of the brain. Pseudo-continuous arterial spin labeling (pCASL) images were acquired from 28 schizophrenia patients in treatment and 28 age-matched healthy controls. Static CBF and connectivity patterns were assessed. Decreased CBF and functional connectivity were observed in regions that forms two resting brain networks, default mode (DMN) and salience (SN), for schizophrenia patients. Previous studies related the features of this pathology with altered resting CBF and functional disconnections. Therefore, using a noninvasive technique, we were able to find CBF deficits and altered functional organization of the brain in schizophrenia patients that are associated with the symptoms and characteristics of the disorder.

Investigating structural and perfusion deficits due to repeated head trauma in active professional fighters.

Repeated head trauma experienced by active professional fighters results in various structural, functional and perfusion damage. However, whether there are common regions of structural and perfusion damage due to fighting and whether these structural and perfusion differences are associated with neuropsychological measurements in active professional fighters is still unknown. To that end, T1-weighted and pseudocontinuous arterial spin labeling MRI on a group of healthy controls and active professional fighters were acquired. Voxelwise group comparisons, in a univariate and multivariate sense, were performed to investigate differences in gray and white matter density (GMD, WMD) and cerebral blood flow (CBF) between the two groups. A significantly positive association between global GMD and WMD was obtained with psychomotor speed and reaction time, respectively, in our cohort of active professional fighters. In addition, regional WMD deficit was observed in a cluster encompassing bilateral pons, hippocampus, and thalamus in fighters (0.49 ± 0.04 arbitrary units (a.u.)) as compared to controls (0.51 ± 0.05a.u.). WMD in the cluster of active fighters was also significantly associated with reaction time. Significantly lower CBF was observed in right inferior temporal lobe with both partial volume corrected (46.9 ± 14.93 ml/100 g/min) and non-partial volume corrected CBF maps (25.91 ± 7.99 ml/100 g/min) in professional fighters, as compared to controls (65.45 ± 22.24 ml/100 g/min and 35.22 ± 12.18 ml/100 g/min respectively). A paradoxical increase in CBF accompanying right cerebellum and fusiform gyrus in the active professional fighters (29.52 ± 13.03 ml/100 g/min) as compared to controls (19.43 ± 12.56 ml/100 g/min) was observed with non-partial volume corrected CBF maps. Multivariate analysis with both structural and perfusion measurements found the same clusters as univariate analysis in addition to a cluster in right precuneus. Both partial volume corrected and non-partial volume corrected CBF of the cluster in the thalamus had a significantly positive association with the number of fights. In addition, GMD of the cluster in right precuneus was significantly associated with psychomotor speed in our cohort of active professional fighters. Our results suggest a heterogeneous pattern of structural and CBF deficits due to repeated head trauma in active professional fighters. This finding indicates that investigating both structural and CBF changes in the same set of participants may help to understand the pathophysiology and progression of cognitive decline due to repeated head trauma.

MTOR drives cerebral blood flow and memory deficits in LDLR−/− mice modeling atherosclerosis and vascular cognitive impairment

We recently showed that mTOR attenuation blocks progression and abrogates established cognitive deficits in Alzheimer’s disease (AD) mouse models. These outcomes were associated with the restoration of cerebral blood flow (CBF) and brain vascular density (BVD) resulting from relief of mTOR inhibition of NO release. Recent reports suggested a role of mTOR in atherosclerosis. Because mTOR drives aging and vascular dysfunction is a universal feature of aging, we hypothesized that mTOR may contribute to brain vascular and cognitive dysfunction associated with atherosclerosis. We measured CBF, BVD, cognitive function, markers of inflammation, and parameters of cardiovascular disease in LDLR−/− mice fed maintenance or high-fat diet ± rapamycin. Cardiovascular pathologies were proportional to severity of brain vascular dysfunction. Aortic atheromas were reduced, CBF and BVD were restored, and cognitive dysfunction was attenuated potentially through reduction in systemic and brain inflammation following chronic mTOR attenuation. Our studies suggest that mTOR regulates vascular integrity and function and that mTOR attenuation may restore neurovascular function and cardiovascular health. Together with our previous studies in AD models, our data suggest mTOR-driven vascular damage may be a mechanism shared by age-associated neurological diseases. Therefore, mTOR attenuation may have promise for treatment of cognitive impairment in atherosclerosis.

Crossed cerebellar diaschisis in acute ischemic stroke: Impact on morphologic and functional outcome

Crossed cerebellar diaschisis (CCD) is the phenomenon of hypoperfusion and hypometabolism of the contralateral cerebellar hemisphere caused by dysfunction of the related supratentorial region. Our aim was to analyze its influence on morphologic and functional outcome in acute ischemic stroke. Subjects with stroke caused by a large vessel occlusion of the anterior circulation were selected from an initial cohort of 1644 consecutive patients who underwent multiparametric CT including whole-brain CT perfusion. Two experienced readers evaluated the posterior fossa in terms of CCD absence (CCD−) or presence (CCD+). A total of 156 patients formed the study cohort with 102 patients (65.4%) categorized as CCD− and 54 (34.6%) as CCD+. In linear and logistic regression analyses, no significant association between CCD and final infarction volume (β = −0.440, p = 0.972), discharge mRS ≤ 2 (OR = 1.897, p = 0.320), or 90-day mRS ≤ 2 (OR = 0.531, p = 0.492) was detected. CCD+ patients had larger supratentorial cerebral blood flow deficits (median: 164 ml vs. 115 ml; p = 0.001) compared to CCD−patients. Regarding complications, CCD was associated with a higher rate of parenchymal hematomas (OR = 4.793, p = 0.035). In conclusion, CCD is frequently encountered in acute ischemic stroke caused by large vessel occlusion of the anterior circulation. CCD was associated with the occurrence of parenchymal hematoma in the ipsilateral cerebral infarction but did not prove to significantly influence patient outcome.

Focal cerebral ischemia in rats with estrogen deficiency and endothelial dysfunction

To assess an effect of ovariectomy (OE) on the cerebral blood flow, endothelium-dependent vasodilation, neurological, cognitive and locomotor deficit as markers of brain damage after focal ischemia in rats. The study was conducted in 48 female Wistar rats. Ovariectomy was performed with ovaries and uterine body extirpation, cerebral ischemia was performed by middle cerebral artery occlusion (MCAO) in rats. To assess brain damage, Combs and Garcia scores, 'open field' test (OFT), 'extrapolatory escape test' (EET), 'passive avoidance test' (PAT), 'beam-walking test' were used. Cerebral blood flow was measured using ultrasonic flowmetry. After 7 days of MCAO, the cerebral blood flow in ovarioectomized animals was reduced by 20% compared to sham-ovariectomized animals. Ovariectomized animals with MCAO showed a three-fold endothelium-dependent vasodilation reduction (the reaction of cerebral vessels to the introduction of acetylcholine and N-L-arginine), indicating the presence of severe endothelial dysfunction. In ovarioectomized animals, the cerebral blood flow was reduced by 34% compared to sham-operated animals. MCAO and OE taken together resulted in more than 2-fold increase in neurological, motor disturbances, 3-fold decrease in motor activity of the animals in the OP test. Focal ischemia in ovarioectomized animals with endothelial dysfunction led to memory decrease by 1/5 fold in PAT and by 2-fold in EET.

Detection of single-phase CTA occult vessel occlusions in acute ischemic stroke using CT perfusion-based wavelet-transformed angiography.

To determine the detection rate of intracranial vessel occlusions using CT perfusion-based wavelet-transformed angiography (waveletCTA) in acute ischemic stroke patients, in whom single-phase CTA (spCTA) failed to detect an occlusion. Subjects were selected from a cohort of 791 consecutive patients who underwent multiparametric CT including whole-brain CT perfusion. Inclusion criteria were (1) significant cerebral blood flow (CBF) deficit, (2) no evidence of vessel occlusion on spCTA and (3) follow-up-confirmed acute ischemic infarction. waveletCTA was independently analysed by two readers regarding presence and location of vessel occlusions. Logistic regression analysis was performed to identify predictors of waveletCTA-detected occlusions. Fifty-nine patients fulfilled the inclusion criteria. Overall, an occlusion was identified using waveletCTA in 31 (52.5%) patients with negative spCTA. Out of 47 patients with middle cerebral artery infarction, 27 occlusions (57.4%) were detected by waveletCTA, mainly located in the M2 (15) and M3 segments (8). The presence of waveletCTA-detected occlusions was associated with larger CBF deficit volumes (odds ratio (OR) = 1.335, p = 0.010) and shorter times from symptom onset (OR = 0.306, p = 0.041). waveletCTA is able to detect spCTA occult vessel occlusions in about half of acute ischemic stroke patients and may potentially identify more patients eligible for endovascular therapy. • waveletCTA is able to detect spCTA occult vessel occlusions in stroke patients. • waveletCTA-detected occlusions are associated with larger cerebral blood flow deficits. • waveletCTA has the potential to identify more patients eligible for endovascular therapy. • waveletCTA implies neither additional radiation exposure nor extra contrast agent.

Changes of Cerebral Perfusion andFunctional Brain Network Organization inPatients with Mild Cognitive Impairment.

Disruptions of the functional brain network and cerebral blood flow (CBF) have been revealed in patients with mild cognitive impairment (MCI). However, the neurophysiological mechanism of hypoperfusion as well as the reorganization of the intrinsic whole brain network due to the neuropathology of MCI are still unclear. In this study, we aimed to investigate the changes of CBF and the whole brain network organization in MCI by using a multimodal MRI approach. Resting state ASL MRI and BOLD MRI were used to evaluate disruptions of CBF and underlying functional connectivity in 27 patients with MCI and 35 cognitive normal controls (NC). The eigenvector centrality mapping (ECM) was used to assess the whole brain network reorganization in MCI, and a seed-based ECM approach was proposed to reveal the contributions of the whole brain network on the ECM alterations. Significantly decreased perfusion in the posterior parietal cortex as well as its connectivity within the default mode network and occipital cortex were found in the MCI group compared to the NC group. The ECM analysis revealed decreased EC in the middle cingulate cortex, parahippocampal gyrus, medial frontal gyrus, and increased EC in the right calcarine sulcus, superior temporal gyrus, and supplementary motor area in the MCI group. The results of this study indicate that there are deficits in cerebral blood flow and functional connectivity in the default mode network, and that sensory-processing networks might play a compensatory role to make up for the decreased connections in MCI.

Perfusion Deficits and Functional Connectivity Alterations in Memory-Related Regions of Patients with Post-Traumatic Stress Disorder.

To explore the potential alterations in cerebral blood flow (CBF) and functional connectivity of recent onset post-traumatic stress disorder (PTSD) induced by a single prolonged trauma exposure, we recruited 20 survivors experiencing the same coal mining flood disaster as the PTSD (n = 10) and non-PTSD (n = 10) group, respectively. The pulsed arterial spin labeling (ASL) images were acquired with a 3.0T MRI scanner and the partial volume (PV) effect in the images was corrected for better CBF estimation. Alterations in CBF were analyzed using both uncorrected and PV-corrected CBF maps. By using altered CBF regions as regions-of-interest, seed-based functional connectivity analysis was then performed. While only one CBF deficit in right corpus callosum of PTSD patients was detected using uncorrected CBF, three more regions (bilateral frontal lobes and right superior frontal gyrus) were identified using PV-corrected CBF. Furthermore, the regional CBF of right superior frontal gyrus exhibited significantly negative correlation with the symptom severity (r = −0.759, p = 0.018). The resting-state functional connectivity analysis revealed increased connectivity between left frontal lobe and right parietal lobe. The results indicated the symptom-specific perfusion deficits and an aberrant connectivity in memory-related regions of PTSD patients when using PV-corrected ASL data. It also suggested that PV-corrected CBF exhibits more subtle changes that may be beneficial to perfusion and connectivity analysis.

Implications of Electrical Communication in Brain Blood Flow Regulation and Stroke Injury

An integrated network of cerebral arteries actively coordinates brain blood flow in accordance with metabolic demands. Large regional changes require synchronised vasomotor responses across vessel segments starting at the origin of a stimulus and spreading to the major upstream resistors. The coordination of vasomotor tone is intimately tied to the spread of charge through gap junctions, a process that equalizes membrane potential, [Ca2+] and myosin light chain phosphorylation among thousands of smooth muscle cells. Coordinated responses are critically important during cerebrovascular accidents (i.e. stroke) where the synchronized dilation of collateral vessels diverts flow into ischemic tissue. We hypothesized that electrical communication, via gap junctions, plays a central role and that dysfunctional communication between vascular cells impairs collateral responses, increasing stroke injury. Using isolated cerebral arteries from mouse, hamster and resected human tissue, we show that electrical stimuli can effectively spread along vascular cells in an endothelium dependant manner. Genetic deletion of Connexin40 (Cx40−/−), a component protein of gap junctions, compromised electrical communication in the cerebral arteries. Subjecting Cx40−/− mice to focal cerebral ischemia induced greater deficit in cerebral blood flow than in wild type controls, during stroke and the subsequent reperfusion period. This attenuation of blood flow translated to augmented stroke injury in the Cx40−/− mice. In closing, our study illustrates the presence of robust electrical communication and that compromising this integrated process restricts the ability of the cerebral circulation to respond to, and moderate injury from vascular accidents, including stroke.Support or Funding InformationThis work is supported by an operating grant to Dr Welsh from the Natural Science and Engineering Council of Canada (NSERC). Dr Welsh is the Roraback Chair in Neuroscience and Vascular Biology at the University of Western Ontario. A. Zechariah is supported by Canadian Institutes of Health Research (CIHR) Postdoctoral scholarship, Alberta Innovates Postdoctoral scholarship and Eyes High Postdoctoral fellowship. Dr. Tuor is supported by a grant from CIHR.

Finding the optimal deconvolution algorithm for MR perfusion in carotid stenosis: Correlations with angiographic cerebral circulation time

The aim of our study is to explore the impacts of different deconvolution algorithms on correlations between CBF, MTT, CBV, TTP, Tmax from MR perfusion (MRP) and angiography cerebral circulation time (CCT). Retrospectively, 30patients with unilateral carotid stenosis, and available pre-stenting MRP and angiography were included for analysis. All MRPs were conducted in a 1.5-T MR scanner. Standard singular value decomposition, block-circulant, and two delay-corrected algorithms were used as the deconvolution methods. All angiographies were obtained in the same bi-plane flat-detector angiographic machine. A contrast bolus of 12mL was administrated via angiocatheter at a rate of 8mL/s. The acquisition protocols were the same for all cases. CCT was defined as the difference between time to peak from the cavernous ICA and the parietal vein in lateral view. Pearson correlations were calculated for CCT and CBF, MTT, CBV, TTP, Tmax. The correlation between CCT and MTT was highest with Tmax (r=0.65), followed by MTT (r=0.60), CBF (r=-0.57), and TTP (r=0.33) when standard singular value decomposition was used. No correlation with CBV was noted. MRP using a singular value decomposition algorithm confirmed the feasibility of quantifying cerebral blood flow deficit in steno-occlusive disease within the angio-room. This approach might further improve patient safety by providing immediate cerebral hemodynamics without extraradiation and iodine contrast.

Reducing Timp3 or vitronectin ameliorates disease manifestations in CADASIL mice

CADASIL is a genetic paradigm of cerebral small vessel disease caused by NOTCH3 mutations that stereotypically lead to the extracellular deposition of NOTCH3 ectodomain (Notch3(ECD) ) on the vessels. TIMP3 and vitronectin are 2 extracellular matrix proteins that abnormally accumulate in Notch3(ECD) -containing deposits on brain vessels of mice and patients with CADASIL. Herein, we investigated whether increased levels of TIMP3 and vitronectin are responsible for aspects of CADASIL disease phenotypes. Timp3 and vitronectin expression were genetically reduced in TgNotch3(R169C) mice, a well-established preclinical model of CADASIL. A mouse overexpressing human TIMP3 (TgBAC-TIMP3) was developed. Disease-related phenotypes, including cerebral blood flow (CBF) deficits, white matter lesions, and Notch3(ECD) deposition, were evaluated between 6 and 20 months of age. CBF responses to neural activity (functional hyperemia), topical application of vasodilators, and decreases in blood pressure (CBF autoregulation) were similarly reduced in TgNotch3(R169C) and TgBAC-TIMP3 mice, and myogenic responses of brain arteries were likewise attenuated. These defects were rescued in TgNotch3(R169C) mice by haploinsufficiency of Timp3, although the number of white matter lesions was unaffected. In contrast, haploinsufficiency or loss of vitronectin in TgNotch3(R169C) mice ameliorated white matter lesions, although CBF responses were unchanged. Amelioration of cerebrovascular reactivity or white matter lesions in these mice was not associated with reduced Notch3(ECD) deposition in brain vessels. Elevated levels of TIMP3 and vitronectin, acting downstream of Notch3(ECD) deposition, play a role in CADASIL, producing divergent influences on early CBF deficits and later white matter lesions.

Altered resting-state cerebral blood flow and its connectivity in schizophrenia

Small sample sizes and large inter-subject variations result in inconsistent findings in resting-state cerebral blood flow (CBF) in schizophrenia. The CBF connectivity alterations in schizophrenia remain unclear. Recently, three-dimensional pseudo-continuous arterial spin labeling (pcASL) imaging was performed to measure the resting-state CBF in 100 schizophrenia patients and 94 healthy comparison subjects. The normalized CBF was used to reduce the inter-subject variations. Both group comparisons in the CBF and correlations between the CBF alterations and clinical parameters were assessed. The CBF connectivity of the brain regions with regional CBF differences was also compared between the groups. Compared with the healthy controls, the schizophrenia patients exhibited increased CBF in the bilateral inferior temporal gyri, thalami and putamen and decreased CBF in the left insula and middle frontal gyrus and the bilateral anterior cingulate cortices and middle occipital gyri. In the schizophrenia patients, significant correlations were identified between the CBF and clinical parameters. Importantly, the schizophrenia patients exhibited CBF disconnections between the left thalamus and right medial superior frontal gyrus and between the left insula and left postcentral gyrus. Our results suggest that schizophrenia patients may exhibit both regional CBF abnormalities and deficits in CBF connectivity, which may underlie the clinical symptoms of schizophrenia.

Granulocyte-Colony Stimulating Factor Increases Cerebral Blood Flow via a NO Surge Mediated by Akt/eNOS Pathway to Reduce Ischemic Injury.

Granulocyte-colony stimulating factor (G-CSF) protects brain from ischemic/reperfusion (I/R) injury, and inhibition of nitric oxide (NO) synthases partially reduces G-CSF protection. We thus further investigated the effects of G-CSF on ischemia-induced NO production and its consequence on regional cerebral blood flow (rCBF) and neurological deficit. Endothelin-1 (ET-1) microinfused above middle cerebral artery caused a rapid reduction of rCBF (ischemia) which lasted for 30 minutes and was followed by a gradual recovery of blood flow (reperfusion) within the striatal region. Regional NO concentration increased rapidly (NO surge) during ischemia and recovered soon to the baseline. G-CSF increased rCBF resulting in shorter ischemic duration and an earlier onset of reperfusion. The enhancement of the ischemia-induced NO by G-CSF accompanied by elevation of phospho-Akt and phospho-eNOS was noted, suggesting an activation of Akt/eNOS. I/R-induced infarct volume and neurological deficits were also reduced by G-CSF treatment. Inhibition of NO synthesis by L-NG-Nitroarginine Methyl Ester (L-NAME) significantly reduced the effects of G-CSF on rCBF, NO surge, infarct volume, and neurological deficits. We conclude that G-CSF increases rCBF through a NO surge mediated by Akt/eNOS, which partially contributes to the beneficial effect of G-CSF on brain I/R injury.

Cerebral amyloid angiopathy increases susceptibility to infarction after focal cerebral ischemia in Tg2576 mice.

We and others have shown that soluble amyloid β-peptide (Aβ) and cerebral amyloid angiopathy (CAA) cause significant cerebrovascular dysfunction in mutant amyloid precursor protein (APP) mice, and that these deficits are greater in aged APP mice having CAA compared with young APP mice lacking CAA. Amyloid β-peptide in young APP mice also increases infarction after focal cerebral ischemia, but the impact of CAA on ischemic brain injury is unknown. To determine this, we assessed cerebrovascular reactivity, cerebral blood flow (CBF), and extent of infarction and neurological deficits after transient middle cerebral artery occlusion in aged APP mice having extensive CAA versus young APP mice lacking CAA (and aged-matched littermate controls). We found that aged APP mice have more severe cerebrovascular dysfunction that is CAA dependent, have greater CBF compromise during and immediately after middle cerebral artery occlusion, and develop larger infarctions after middle cerebral artery occlusion. These data indicate CAA induces a more severe form of cerebrovascular dysfunction than amyloid β-peptide alone, leading to intra- and postischemic CBF deficits that ultimately exacerbate cerebral infarction. Our results shed mechanistic light on human studies identifying CAA as an independent risk factor for ischemic brain injury.

Abstract 064: Toll-like Receptor 2 Signaling Contributes To Cerebrovascular Dysfunction And Decreased Cerebral Blood Flow In Type-1 And Type-2 Diabetes.

We have shown that type 2 diabetic Goto-Kakizaki (GK) rats develop cerebrovascular endothelial dysfunction, impaired cerebral blood flow (CBF) and mild cognitive deficits. It is increasingly recognized that vascular cognitive impairment may be a new complication of the disease in both type 1 and type 2 diabetes. Toll-like receptor-2 (TLR2) plays a role in cardiovascular complications of diabetes but its involvement in diabetic cerebrovascular disease is unknown. Since brain function heavily depends on constant perfusion, and decreased CBF precedes development of inflammation and cognitive deficits, we hypothesized that enhanced TLR2 signaling in both type 1 and 2 diabetes would contribute to cerebrovascular dysfunction and decreased CBF. Endothelium-dependent relaxation was assessed by measuring acetylcholine (ACh, 10-9 -10-4 M) induced dilatory response in basilar arteries from GK rats in the presence and absence of an anti-TLR2 (1μg) antibody. Vascular contractility to serotonin (10-9 -10-5 M) stimulation was also assessed. Area under the curve (AUC) and maximal effective concentration (Emax as % of max KCl response) were calculated as indices of total relaxation and total contraction, respectively. Basilar artery relaxation was significantly improved in the vessels preincubated (30’) with antiTLR2 (184.8± 24.0 vs. 87.7± 4, p =0.007). The EMax in response to serotonin stimulation in the anti-TLR2 treated vessels was not significantly different than the vessels from the untreated diabetic GK rats (110.6± 4.9% vs 99.4.±4.5%). To further assess the in vivo functional effects of TLR2 signaling, CBF (relative intensity) was measured using laser speckle imaging in wild type and TLR2-knockout (KO) mice using an STZ induced diabetes model. Six weeks after induction of diabetes, wild-type diabetic mice exhibited a significant decrease in CBF vs. control (210±22.5 vs. 300.3±18.4, p&lt;0.05). This decrease in cerebral perfusion was attenuated in the TLR2-KO diabetic mice compared to TLR2 KO control (322.6±10.1 vs. 344. 5±11. 04). These findings suggest that TLR2 signaling leads to vascular dysfunction through decreased endothelium dependent relaxation, and could contribute to decreased CBF in diabetes predisposing to vascular cognitive impairment.