Improving acute stroke assessment in non-enhanced computed tomography: automated tool for early ischemic lesion volume detection.

BACKGROUND AND OBJECTIVES: ASPECTs is a widely used marker to identify early stroke signs on non-enhanced computed tomography (NECT), yet it presents interindividual variability and it may be hard to use for non-experts. We introduce an algorithm capable of automatically estimating the NECT volumetric extension of early acute ischemic changes in the 3D space. We compared the power of this marker with ASPECTs evaluated by experienced practitioner in predicting the clinical outcome. METHODS: We analyzed and processed neuroimaging data of 153 patients admitted with acute ischemic stroke. All patients underwent a NECT at admission and on follow-up. The developed algorithm identifies the early ischemic hypodense region based on an automatic comparison of the gray level in the images of the two hemispheres, assumed to be an approximate mirror image of each other in healthy patients. RESULTS: In the two standard axial slices used to estimate the ASPECTs, the regions identified by the algorithm overlap significantly with those identified by experienced practitioners. However, in many patients, the regions identified automatically extend significantly to other slices. In these cases, the volume marker provides supplementary and independent information. Indeed, the clinical outcome of patients with volume marker = 0 can be distinguished with higher statistical confidence than the outcome of patients with ASPECTs = 10. CONCLUSION: The volumetric extension and the location of acute ischemic region in the 3D-space, automatically identified by our algorithm, provide data that are mostly in agreement with the ASPECTs value estimated by expert practitioners, and in some cases complementary and independent.

Computed diffusion-weighted imaging in patients with transient neurovascular symptoms with and without ischemic infarction.

PURPOSE: Detection of ischemic lesions in patients with transient neurovascular symptoms is relevant for the estimation of the risk of a subsequent stroke and etiological classification. To improve detection rates, different technical approaches have been used, such as diffusion-weighted imaging (DWI) with high b-values or higher magnetic field strength. Here, we sought to investigate the value of computed DWI (cDWI) with high b-values in these patients. METHODS: From an MRI report database we identified patients with transient neurovascular symptoms who underwent repeated MRI including DWI. cDWI was calculated with a monoexponential model with high b-values (2000, 3000, and 4000 s/mm2) and compared to the routinely used standard DWI with regard to presence of ischemic lesions and lesion detectability. RESULT: Overall 33 patients with transient neurovascular symptoms (71 [IQR 57-83.5] years; 21 [63.6%] male) were included. On DWI, acute ischemic lesions were observed in 22 (78.6%). Acute ischemic lesions were observed in 17 (51.5%) patients on initial DWI, and in 26 (78.8%) patients on follow-up DWI. Lesion detectability was rated significantly better on cDWI at 2000s/mm2 compared to standard DWI. In 2 (9.1%) patients, cDWI at 2000s/mm2 revealed an acute ischemic lesion proven on follow-up standard DWI which was not detected with certainty on the initial standard DWI. CONCLUSION: cDWI might be a valuable addition to routinely acquired standard DWI in patients with transient neurovascular symptoms since its use might result in improved ischemic lesion detection. A b-value of 2000s/mm2 seems most promising for clinical practice.

Mimic of transient ischemic attack by anemia-induced asterixis: A novel differential diagnosis of stroke with critical pitfalls.

As most cases of asterixis with metabolic causes are asymptomatic, they have not been considered in the differential diagnosis of stroke. However, an asterixis occasionally resembles a transient ischemic attack (TIA). On the other hand, reports have indicated that anemia is an independent risk factor for brain ischemia. Therefore, both asterixis and anemia are important considerations for stroke diagnosis. A 79-year-old man with frequent leg palsy was initially diagnosed with recurrent TIA at the anterior cerebral artery (ACA) with a tiny callosal infarction and aspirin was prescribed immediately. However, subsequent careful physical examination revealed asterixis at both the wrist and knee joints. Laboratory testing and colonoscopy revealed severe anemia secondary to colon cancer. Blood transfusion immediately improved the asterixis and gait, thus confirming that anemia contributed to the patient's symptoms. This novel etiology of asterixis may be accompanied by misleading anemia-induced brain ischemic lesions detectable on magnetic resonance imaging (MRI). Anemia-induced asterixis should be considered as a novel differential diagnosis of a stroke to avoid pitfalls leading to unnecessary stroke treatment for patients with anemia.

Variability assessment of manual segmentations of ischemic lesion volume on 24-h non-contrast CT.

PURPOSE: Infarct lesion volume (ILV) may serve as an imaging biomarker for clinical outcomes in the early post-treatment stage in patients with acute ischemic stroke. The aim of this study was to evaluate the inter- and intra-rater reliability of manual segmentation of ILV on follow-up non-contrast CT (NCCT) scans. METHODS: Fifty patients from the Prove-IT study were randomly selected for this analysis. Three raters manually segmented ILV on 24-h NCCT scans, slice by slice, three times. The reference standard for ILV was generated by the Simultaneous Truth And Performance Level estimation (STAPLE) algorithm. Intra- and inter-rater reliability was evaluated, using metrics of intraclass correlation coefficient (ICC) regarding lesion volume and the Dice similarity coefficient (DSC). RESULTS: Median age of the 50 subjects included was 74.5 years (interquartile range [IQR] 67-80), 54% were women, median baseline National Institutes of Health Stroke Scale was 18 (IQR 11-22), median baseline ASPECTS was 9 (IQR 6-10). The mean reference standard ILV was 92.5 ml (standard deviation (SD) ± 100.9 ml). The manually segmented ILV ranged from 88.2 ± 91.5 to 135.5 ± 119.9 ml (means referring to the variation between readers, SD within readers). Inter-rater ICC was 0.83 (95%CI: 0.76-0.88); intra-rater ICC ranged from 0.85 (95%CI: 0.72-0.92) to 0.95 (95%CI: 0.91-0.97). The mean DSC among the three readers ranged from 65.5 ± 22.9 to 76.4 ± 17.1% and the mean overall DSC was 72.8 ± 23.0%. CONCLUSION: Manual ILV measurements on follow-up CT scans are reliable to measure the radiological outcome despite some variability.

Effects of MgSO4 Alone or Associated with 4-PBA on Behavior and White Matter Integrity in a Mouse Model of Cerebral Palsy: A Sex- and Time-Dependent Study.

Cerebral palsy (CP) is defined as permanent disorders of movement and posture. Prematurity and hypoxia-ischemia (HI) are risk factors of CP, and boys display a greater vulnerability to develop CP. Magnesium sulfate (MgSO4) is administered to mothers at risk of preterm delivery as a neuroprotective agent. However, its effectiveness is only partial at long term. To prolong MgSO4 effects, it was combined with 4-phenylbutyrate (4-PBA). A mouse model of neonatal HI, generating lesions similar to those reported in preterms, was realized. At short term, at the behavioral and cellular levels, and in both sexes, the MgSO4/4-PBA association did not alter the total prevention induced by MgSO4 alone. At long term, the association extended the MgSO4 preventive effects on HI-induced motor and cognitive deficits. This might be sustained by the promotion of oligodendrocyte precursor differentiation after HI at short term, which led to improvement of white matter integrity at long term. Interestingly, at long term, at a behavioral level, sex-dependent responses to HI were observed. This might partly be explained by early sex-dependent pathological processes that occur after HI. Indeed, at short term, apoptosis through mitochondrial pathways seemed to be activated in females but not in males, and only the MgSO4/4-PBA association seemed to counter this apoptotic process.

The benefit of deferred carotid revascularization in patients with moderate-severe disabling cerebral ischemic stroke.

OBJECTIVE: Symptomatic carotid artery stenosis needs revascularization within 2 weeks by carotid endarterectomy (CEA) to reduce the risk of symptom recurrence; however, the optimal timing of intervention is yet to be defined in patients with large-volume cerebral ischemic lesion (LVCIL) and modified Rankin scale (mRS) score ≥3. The aim of this study was to determine the most appropriate timing for CEA in patients with a recent stroke and LVCIL. METHODS: Data from patients with symptomatic carotid stenosis with LVCIL and mRS score of 3 or 4 from 2007 to 2017 were considered. Patients were submitted to CEA if they had a stable clinical condition and life expectancy >1 year. LVCIL was defined as a cerebral ischemic lesion of volume >4000 mm3. Perioperative stroke and death were evaluated by stratifying for timing of CEA by χ2 test and multiple logistic regression. Patients with similar characteristics (LVCIL and mRS score of 3 or 4) unfit for CEA served as the control group for recurrence of stroke at 1-year follow-up. RESULTS: In an 11-year period, of a total 4020 CEAs, 126 (2.9%) were performed in patients with a moderate stroke and LVCIL occurring in the same admission. The patients' median age was 69 years (interquartile range [IQR], 10 years); 72% (91) were male, with mRS score of 3 (IQR, 1) and LVCIL volume of 20,000 mm3 (IQR, 47,000 mm3). The median time elapsed from symptoms to CEA was 7 weeks (IQR, 8 weeks). Overall perioperative stroke/death was 7.3% (eight strokes and one death). By selective timing evaluation of the postoperative events, CEA performed within 4 weeks was associated with a significantly higher rate of stroke/death compared with patients operated on after 4 weeks: 11.9% (8/67) vs 1.7% (1/59; P = .03). By logistic regression, CEA within 4 weeks was an independent (from sex, cerebral ischemic lesion volume, dyslipidemia, and carotid stenosis) predictor of postoperative stroke/death (odds ratio, 8.2; 95% confidence interval, 1.01-73). In the same period, 101 patients were considered unfit for CEA for dementia (n = 22), severe comorbidities (n = 55), or short (<1-year) life expectancy (n = 24), and 43 (43%) survived at 1 year. At 1 year, the perioperative/recurrent stroke after CEA vs patients unfit for CEA was similar (6.2% vs 13.9%; P = .11), but CEA performed after 4 weeks led to significantly lower perioperative/recurrent stroke (1.7% vs 13.9%; P = .02). CONCLUSIONS: The surgical risk of CEA in patients with a recent moderate-severe ischemic stroke and LVCIL is high. However, if the intervention is delayed >4 weeks, its benefit seems significant.

Changing Ischemic Lesion Patterns and Hemodynamics of the Posterior Cerebral Artery in Moyamoya Disease.

OBJECTIVE: The aim of this study was to determine how hemodynamics of the posterior cerebral artery (PCA) are associated with cerebral ischemic lesions in moyamoya disease (MMD). METHODS: Thirty-six patients with ischemic MMD (Suzuki grade IV-V) were retrospectively analyzed. Hemodynamic parameters of the PCA were measured by transcranial color-coded sonography. We classified the range of ischemic lesions into 3 grades and perfusion levels into 3 grades according to computed tomography (CT) results. PCA steno-occlusion and leptomeningeal collaterals were confirmed by digital subtraction angiography. Ultrasonographic parameters in the PCA were compared with these radiographic findings. RESULTS: The velocity in the involved PCA (mean flow velocity [MFV] median, 42.00 [range, 34.50-58.00] cm/s) was significantly lower than that in the normal PCA (MFV median, 95.00 [range, 76.50-119.50] cm/s) (P < .001). The velocity in the PCA increased significantly as the leptomeningeal collateral stage advanced (MFV stage 1: median, 38.50 [range, 29.75-63.50] cm/s; stage 2: median, 55.00 [range, 44.00-96.00] cm/s; stage 3: median, 94.00 [range, 54.00-118.25] cm/s; stage 4: median, 85.50 [range, 70.50-117.75] cm/s, respectively) (P < .05). Decreased PCA velocities were associated with a larger ischemic area on CT (P ≤ .001). PCA velocity had no correlation with CT perfusion level of the temporal and frontal lobes. PCA velocity had significant correlations with perfusion level in the occipital (P < .001) and parietal lobes (P < .05). CONCLUSIONS: Our results suggest ischemic lesion patterns (as demonstrated on CT imaging) are associated with PCA velocity measurements in the advanced stage of MMD. Thus, monitoring PCA velocity in patients with advanced MMD may provide additional information to assist in managing these patients.

Reduced Ischemic Lesion Growth with Heparin in Acute Ischemic Stroke.

OBJECTIVE: The role of heparin in acute ischemic stroke is controversial. We investigated the effect of heparin on ischemic lesion growth. METHODS: Data were analyzed on nonthrombolyzed ischemic stroke patients in whom diffusion-weighted imaging (DWI)/perfusion-weighted imaging (PWI) MRI was performed less than 12 hours of last known well and showed a PWI-DWI lesion mismatch, and who underwent follow-up neuroimaging at least 4 days after admission. Lesion growth was assessed by (1) absolute lesion growth and (2) percentage mismatch lost (PML). Univariate and multivariate regression analysis, and propensity score matching, were used to determine the effects of heparin on ischemic lesion growth. RESULTS: Of the 113 patients meeting study criteria, 59 received heparin within 24 hours. Heparin use was associated with ∼5-fold reductions in PML (3.5% versus 19.2%, P = .002) and absolute lesion growth (4.7 versus 20.5 mL, P = .009). In multivariate regression models, heparin independently predicted reduced PML (P = .04) and absolute lesion growth (P = .04) in the entire cohort, and in multiple subgroups (patients with and without proximal artery occlusion; DWI volume greater than 5 mL; cardio-embolic mechanism; DEFUSE-3 target mismatch). In propensity score matching analysis where patients were matched by admission NIHSS, DWI volume and proximal artery occlusion, heparin remained an independent predictor of PML (P = .048) and tended to predict absolute lesion growth (P = .06). Heparin treatment did not predict functional outcome at discharge or 90 days. CONCLUSION: Early heparin treatment in acute ischemic stroke patients with PWI-DWI mismatch attenuates ischemic lesion growth. Clinical trials with careful patient selection are warranted to investigate the potential ischemic protective effects of heparin.

Time- and sex-dependent efficacy of magnesium sulfate to prevent behavioral impairments and cerebral damage in a mouse model of cerebral palsy.

Cerebral lesions acquired in the perinatal period can induce cerebral palsy (CP), a multifactorial pathology leading to lifelong motor and cognitive deficits. Several risk factors, including perinatal hypoxia-ischemia (HI), can contribute to the emergence of CP in preterm infants. Currently, there is no international consensus on treatment strategies to reduce the risk of developing CP. A meta-analysis showed that magnesium sulfate (MgSO4) administration to mothers at risk of preterm delivery reduces the risk of developing CP (Crowther et al., 2017). However, only a few studies have investigated the long-term effects of MgSO4 and it is not known whether sex would influence MgSO4 efficacy. In addition, the search for potential deleterious effects is essential to enable broad use of MgSO4 in maternity wards. We used a mouse model of perinatal HI to study MgSO4 effects until adolescence, focusing on cognitive and motor functions, and on some apoptosis and inflammation markers. Perinatal HI at postnatal day 5 (P(5)) induced (1) sensorimotor deficits in pups; (2) increase in caspase-3 activity 24 h after injury; (3) production of proinflammatory cytokines from 6 h to 5 days after injury; (4) behavioral and histological alterations in adolescent mice with considerable interindividual variability. MgSO4 prevented sensorimotor alterations in pups, with the same efficacy in males and females. MgSO4 displayed anti-apoptotic and anti-inflammatory effects without deleterious side effects. Perinatal HI led to motor coordination impairments in female adolescent mice and cognitive deficits in both sexes. MgSO4 tended to prevent these motor and cognitive deficits only in females, while it prevented global brain tissue damage in both sexes. Moreover, interindividual and intersexual differences appeared regarding the lesion size and neuroprotection by MgSO4 in a region-specific manner. These differences, the partial prevention of disorders, as well as the mismatch between histological and behavioral observations mimic clinical observations. This underlines that this perinatal HI model is suitable to further analyze the mechanisms of sex-dependent perinatal lesion susceptibility and MgSO4 efficacy.

Different Clinical Phenotypes of Embolic Stroke of Undetermined Source: A Subgroup Analysis of 86 Patients.

INTRODUCTION AND STUDY AIM: Embolic strokes of undetermined source (ESUS) represent a rather recent diagnostic entity under clinical research for relapse prevention in cryptogenic stroke patients. Despite strict diagnostic criteria, ESUS definition ignores major clinical and radiological aspects, so including heterogeneous cases and probably influencing trial results. This study researches clinically relevant phenotypes among ESUS patients. PATIENTS AND METHODS: We evaluated ESUS patients admitted at Trento Stroke Unit over a 4-year period. Vascular risk factors (RFs), neurological deficit severity, presence of potential embolic sources, and ASCOD phenotype were recorded. Ischemic lesions were categorized considering their extension in 4 groups. Subgroup comparisons by predefined differences in age, amount of RFs, history of previous stroke, deficit severity, and stroke lesion extension were done. RESULTS: ESUS cases were 86. Patients younger than 50 years old (n = 17) had a lower prevalence of RFs, left atrial enlargement, left ventricle diastolic dysfunction, a higher proportion of ASCOD score A0 (P < .05). Patients without RFs (n = 18) differed from those with greater than or equal to 3 RFs (n = 23) for a younger age and a lower prevalence of potential causes of embolism (P < .05). Patients without a previous stroke (n = 70) were younger, had a lower prevalence of RFs, left ventricle diastolic dysfunction, a higher prevalence of ASCOD score A0 (P < .05). No differences were observed comparing minor and major clinical and radiological strokes. DISCUSSION AND CONCLUSIONS: ESUS patients can be distinguished in 2 opposite phenotypes defined by a lower and a higher load of atherosclerotic pathology. They may suggest possible underlying pathogenic mechanisms and support interpretation of ongoing trials results.

What influenced the lesion patterns and hemodynamic characteristics in patients with internal carotid artery stenosis? A retrospective study.

OBJECTIVES: This study aimed to explore the dynamic changes of lesion patterns and hemodynamic characteristics in patients with internal carotid artery stenosis (ICAS). PATIENTS AND METHODS: Patients who had suffered an acute ischemic stroke in the distribution of ipsilateral ICAS were included. Computed tomography (CT) and transcranial doppler ultrasound (TCD) were conducted to evaluate the degree of ICAS and the hemodynamic characteristics of the intracranial and extracranial arteries. RESULT: A total of 424 patients were included in the study. With the aggravation of ICAS, blood velocity in ipsilateral ICA was increased, while blood flow in the ipsilateral middle cerebral artery (MCA) was decreased. In the same degree of ICAS, patients with opened communicating arteries showed relatively higher blood perfusion in MCA compared with those without communicating arteries. In the average stage of ICAS, small lesions (D=0-1.5cm), middle lesions (1.5cm3.0cm) commonly existed. The number of small and large lesions significantly increased when the blood flow of ipsilateral MCA decreased. In the same degree of stenosis, the number of small lesions and large lesions, and the total area of all lesions, evidently increased with the decrease of ipsilateral MCA blood velocity. CONCLUSION: Hypoperfusion is an independent risk factor for ischemic lesions in patients with ICAS. Whether or not the communicating arteries are open influences the blood flow of the intracranial arteries. TCD was a convenient and rapid tool to assess intracranial perfusion and vascular compensatory status.

Successful Reperfusion With Mechanical Thrombectomy Is Associated With Reduced Disability and Mortality in Patients With Pretreatment Diffusion-Weighted Imaging-Alberta Stroke Program Early Computed Tomography Score ≤6.

BACKGROUND AND PURPOSE: In acute ischemic stroke patients, diffusion-weighted imaging (DWI)-Alberta Stroke Program Early Computed Tomography Score (ASPECTS) is correlated with infarct volume and is an independent factor of functional outcome. Patients with pretreatment DWI-ASPECTS ≤6 were excluded or under-represented in the recent randomized mechanical thrombectomy trials. Our aim was to assess the impact of reperfusion in pretreatment DWI-ASPECTS ≤6 patients treated with mechanical thrombectomy. METHODS: We analyzed data collected between January 2012 and August 2015 in a bicentric prospective clinical registry of consecutive acute ischemic stroke patients treated with mechanical thrombectomy. Every patient with a documented internal carotid artery or middle cerebral artery occlusion with pretreatment DWI-ASPECTS ≤6 was eligible for this study. The primary end point was a favorable outcome defined by a modified Rankin Scale score ≤2 at 90 days. RESULTS: Two hundred and eighteen patients with a DWI-ASPECTS ≤6 were included. Among them, 145 (66%) patients had successful reperfusion at the end of mechanical thrombectomy. Reperfused patients had an increased rate of favorable outcome (38.7% versus 17.4%; P=0.002) and a decreased rate of mortality at 3 months (22.5% versus 39.1%; P=0.013) compared with nonreperfused patients. The symptomatic intracranial hemorrhage rate was not different between the 2 groups (13.0% versus 14.1%; P=0.83). However, in patients with DWI-ASPECTS <5, favorable outcome was low (13.0% versus 9.5%; P=0.68) with a high mortality rate (45.7% versus 57.1%; P=0.38) with or without successful reperfusion. CONCLUSIONS: Successful reperfusion is associated with reduced mortality and disability in patients with a pretreatment DWI-ASPECTS ≤6. Further data from randomized studies are needed, particularly in patients with DWI-ASPECTS <5.

Post-Stroke Seizures Is Associated with Low Alberta Stroke Program Early CT Score.

BACKGROUND: Ischemic stroke is a leading cause of new-onset seizures. Cortical ischemia and large ischemic lesion size are among the most consistently reported risk factors for post-stroke seizures. Alberta Stroke Program Early CT Score (ASPECTS) is a simple and reliable tool for quantifying the extent of cerebral ischemia and may function as a screening tool for patients with high risk of seizure development. We investigated the association of post-stroke seizures with the extent of ischemia assessed by ASPECTS and with cortical involvement identified on non-contrast CT (NCCT). METHODS: This cohort study was based on a prospectively maintained clinical database of acute ischemic stroke patients who were given intravenous tissue plasminogen activator treatment. We included patients with anterior circulation stroke admitted between January 2008 and October 2014. Patients with pre-stroke seizures were excluded. Clinical data and seizure follow-up data were collected. NCCT scans acquired both on stroke admission and at 24 h were analyzed. Logistic regression and cox regression were performed in statistical analysis. RESULTS: A total of 348 patients (median age 73 years, interquartile range [IQR] 63-80, 55% male) were included. During follow-up (median duration 559 days, IQR 107.5-1188.5 days), 22 (6.3%) patients developed post-stroke seizures. Median time from stroke to seizure onset was 138 days (IQR 10-342 days). In univariate logistic regression, both ASPECTS on admission (OR 0.69 per 1-point increase; 95% CI 0.55-0.86; p = 0.001) and at 24 h (OR 0.80 per 1-point increase; 95% CI 0.70-0.92; p = 0.002) were significantly associated with post-stroke seizures. Cortical involvement at 24 h also correlated with seizure occurrence (OR 3.01; 95% CI 1.08-8.34; p = 0.03). Cox regression confirmed the higher risk of developing seizures at any time point in patients with lower ASPECTS value and cortical ischemia. Of note, ASPECTS was the only independent predictor for post-stroke seizures in multivariate logistic regression. CONCLUSION: The extent of ischemia assessed by ASPECTS and cortical involvement identified on NCCT were associated with the development of post-stroke seizures.

Parkinson's disease might increase the risk of cerebral ischemic lesions.

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disease in the elderly. Cerebrovascular diseases such as cerebral ischemic lesion (CIL) also commonly occur in elderly adults. However, previous studies on the relationship between PD and cerebrovascular disease have not found consistent results. Therefore, we conducted this study to evaluate whether or not PD is related to an increased prevalence of ischemic cerebrovascular lesions. METHODS: This study recruited 241 patients with PD and 112 healthy controls (HCs). All subjects underwent brain magnetic resonance imaging and general neuropsychological tests. The motor severity of PD was evaluated according to the Hoehn and Yahr stage (HY stage), and the severity of CIL in all subjects was classified according to Fazekas grade. The PD patients were classified into two subgroups according to HY stage (Group 1 - HY 1, 2; Group 2 - HY 3 to 5). RESULTS: Among all PD patients, 76% had small vessel disease, while 44% of all HCs had small vessel disease (p<0.001). Regarding the difference between the two subgroups according to motor severity, group 2 showed significantly higher Fazekas scale score and more severe CIL, indicating a higher prevalence of small vessel disease compared to group 1. CONCLUSION: This study demonstrates that PD patients have a significantly higher prevalence of CIL compared to HCs. Therefore, although the present study is not a large-scale study, we cautiously suggest that PD can play an important role as a risk factor in the occurrence of ischemic cerebrovascular disease.

Cerebral Hyperperfusion after Revascularization Inhibits Development of Cerebral Ischemic Lesions Due to Artery-to-Artery Emboli during Carotid Exposure in Endarterectomy for Patients with Preoperative Cerebral Hemodynamic Insufficiency: Revisiting the "Impaired Clearance of Emboli" Concept.

The purpose of the present study was to determine whether cerebral hyperperfusion after revascularization inhibits development of cerebral ischemic lesions due to artery-to-artery emboli during exposure of the carotid arteries in carotid endarterectomy (CEA). In patients undergoing CEA for internal carotid artery stenosis (≥70%), cerebral blood flow (CBF) was measured using single-photon emission computed tomography (SPECT) before and immediately after CEA. Microembolic signals (MES) were identified using transcranial Doppler during carotid exposure. Diffusion-weighted magnetic resonance imaging (DWI) was performed within 24 h after surgery. Of 32 patients with a combination of reduced cerebrovascular reactivity to acetazolamide on preoperative brain perfusion SPECT and MES during carotid exposure, 14 (44%) showed cerebral hyperperfusion (defined as postoperative CBF increase ≥100% compared with preoperative values), and 16 (50%) developed DWI-characterized postoperative cerebral ischemic lesions. Postoperative cerebral hyperperfusion was significantly associated with the absence of DWI-characterized postoperative cerebral ischemic lesions (95% confidence interval, 0.001-0.179; p = 0.0009). These data suggest that cerebral hyperperfusion after revascularization inhibits development of cerebral ischemic lesions due to artery-to-artery emboli during carotid exposure in CEA, supporting the "impaired clearance of emboli" concept. Blood pressure elevation following carotid declamping would be effective when embolism not accompanied by cerebral hyperperfusion occurs during CEA.

Biochemical and immunomorphological evaluation of hepatocyte growth factor and c-Met pathway in patients with critical limb ischemia.

OBJECTIVES: Hepatocyte growth factor (HGF), the c-Met receptor, and hypoxia-inducible factor (HIF) are crucial for regenerative processes including ischemic wound healing. The aims of the present study are (a) to analyze the tissue c-Met and HIF-1α expression in skin from patients with critical limb ischemia (CLI); (b) to compare the serum HGF levels of CLI and control subjects. METHODS: This is a prospective, controlled, single-center study. Thirty-seven patients were enrolled. A skin sample adjacent to the ischemic lesion was taken from 20 patients with CLI; skin samples were taken from the surgical wounds of 17 patients surgically treated for abdominal aortic aneurysm as healthy controls. Serum samples were taken in all cases. Samples were formalin fixed, paraffin embedded, and routinely processed. Tissue inflammation was histologically assessed. Immunohistochemistry was performed with antibodies against total c-Met receptor, activated Met (p-Met), and HIF-1α. RT-polymerase chain reaction was used to quantify HIF-1α mRNA. The enzyme-linked immunosorbent assay was performed to evaluate serum HGF levels. RESULTS: With immunohistochemistry, while total c-Met was unchanged, different patterns of p-Met positivity were observed between CLI and control cases (p < .001). In particular, CLI skin showed a total negativity or membrane positivity for p-Met (19/20 cases), while control skin mainly showed cytoplasmic positivity in the epidermal basal layer (16/17 cases). HIF-1α was diffusely lost in CLI, but HIF-1α mRNA was threefold higher than in controls. Finally, mean serum HGF levels were 590.5 pg/mL and 2380.0 pg/mL in CLI and control groups respectively (p < .001). CONCLUSIONS: In CLI patients a significant decrease in serum HGF levels, concomitant with a loss of skin HIF-1α stabilization and a lack of c-Met phosphorylation were seen, probably driving a decrease in wound-healing functions. The next hypothesis is that HGF application might reactivate the c-Met receptor, stabilizing the normal wound healing process.

Nε-(carboxymethyl)lysine in debris from carotid artery stenting: multiple versus nonmultiple postoperative lesions.

BACKGROUND: No predictor of postoperative ischemic events has been identified in patients undergoing carotid artery stenting (CAS). We aimed to determine whether N(ε)-(carboxymethyl)lysine (CML) in debris trapped by an embolic protection filter device is a predictor of postoperative ischemic events. METHODS: We enrolled 27 patients (73.4 ± 7.2 years; 22 male, 5 female) who underwent CAS for carotid artery stenosis. Diffusion-weighted magnetic resonance imaging was performed before and after the procedure. Protein samples were extracted from the debris. CML and myeloperoxidase were examined by solid phase enzyme-linked immunosorbent assay and Western blot analysis. RESULTS: Seventeen patients had 0 or 1 new lesion (nonmultiple lesions) postoperatively, whereas 10 patients had 2 or more new lesions postoperatively (multiple lesions). The CML concentration of the protein sample was significantly higher in patients with multiple lesions than in those with nonmultiple lesions (6.26 ± 2.77 ng/mg protein and 3.36 ± 1.57 ng/mg protein, respectively; P = .010). Statin therapy for dyslipidemia was associated with a lower incidence of multiple lesions and a lower concentration of CML in the protein sample (P = .004 and P = .02, respectively). Receiver operating characteristic analysis showed that the area under the curve for CML was significantly greater than .5 (.877; 95% confidence interval, .742-1.00). CONCLUSIONS: CML derived from debris may distinguish between patients with postoperative multiple ischemic lesions and those with postoperative nonmultiple lesions who undergo CAS.

Brain-wide continuous functional ultrasound imaging for real-time monitoring of hemodynamics during ischemic stroke.

Ischemic stroke occurs abruptly causing sudden neurologic deficits, and therefore, very little is known about hemodynamic perturbations in the brain immediately after stroke onset. Here, functional ultrasound imaging was used to monitor variations in relative cerebral blood volume (rCBV) compared to baseline. rCBV levels were analyzed brain-wide and continuously at high spatiotemporal resolution (100 µm, 2 Hz) until 70mins after stroke onset in rats. We compared two stroke models, with either a permanent occlusion of the middle cerebral artery (MCAo) or a tandem occlusion of both the common carotid and middle cerebral arteries (CCAo + MCAo). We observed a typical hemodynamic pattern, including a quick drop of the rCBV after MCAo, followed by spontaneous reperfusion of several brain regions located in the vicinity of the ischemic core. The severity and location of the ischemia were variable within groups. On average, the severity of the ischemia was in good agreement with the lesion volume (24 hrs after stroke) for MCAo group, while larger for the CCAo + MCAo model. For both groups, we observed that infarcts extended to initially non-ischemic regions located rostrally to the ischemic core. These regions strongly colocalize with the origin of transient hemodynamic events associated with spreading depolarizations.

Neuropilin-1 modulates vascular endothelial growth factor-induced poly(ADP-ribose)-polymerase leading to reduced cerebrovascular apoptosis.

Cerebral ischemia is encompassed by cerebrovascular apoptosis, yet the mechanisms behind apoptosis regulation are not fully understood. We previously demonstrated inhibition of endothelial apoptosis by vascular endothelial growth factor (VEGF) through upregulation of poly(ADP-ribose)-polymerase (PARP) expression. However, PARP overactivation through oxidative stress can lead to necrosis. This study tested the hypothesis that neuropilin-1 (NP-1), an alternative VEGF receptor, regulates the response to cerebral ischemia by modulating PARP expression and, in turn, apoptosis inhibition by VEGF. In endothelial cell culture, NP-1 colocalized with VEGF receptor-2 (VEGFR-2) and acted as its coreceptor. This significantly enhanced VEGF-induced PARP mRNA and protein expression demonstrated by receptor-specific inhibitors and VEGF-A isoforms. NP-1 augmented the inhibitory effect of VEGF/VEGFR-2 interaction on apoptosis induced by adhesion inhibition through the αV-integrin inhibitor cRGDfV. NP-1/VEGFR-2 signal transduction involved JNK and Akt. In rat models of permanent and temporary middle cerebral artery occlusion, the ischemic cerebral hemispheres displayed endothelial and neuronal apoptosis next to increased endothelial NP-1 and VEGFR-2 expression compared to non-ischemic cerebral hemispheres, sham-operated or untreated controls. Increased vascular superoxide dismutase-1 and catalase expression as well as decreased glycogen reserves indicated oxidative stress in the ischemic brain. Of note, protein levels of intact PARP remained stable despite pro-apoptotic conditions through increased PARP mRNA production during cerebral ischemia. In conclusion, NP-1 is upregulated in conditions of imminent cerebrovascular apoptosis to reinforce apoptosis inhibition and modulate VEGF-dependent PARP expression and activation. We propose that NP-1 is a key modulator of VEGF maintaining cerebrovascular integrity during ischemia. Modulating the function of NP-1 to target PARP could help to prevent cellular damage in cerebrovascular disease.

[18F]FDG PET-MR in the Evaluation and Follow-Up of Incidental Bone Ischemic Lesions in a Mono-Center Cohort of Pediatric Patients Affected by Hodgkin's Lymphoma.

Hodgkin's lymphoma (HL) is one of the neoplasms with the best prognosis in children, adolescents and young adults, but sufferers are burdened by the possibility of developing adverse effects such as Bone Ischemic Lesions (BILs) which are lesions of the bone caused by the loss of/reduction in blood flow. The main goal of this retrospective study was to evaluate the role of [18F]FDG-PET-MR in the early detection of BILs in a single-center cohort of uniformly treated pediatric HL patients. BILs were assessed through PET-MR images as the appearance of medullary lesion surrounded by a serpiginous, tortuous border. From 2017 to 2022, 10/53 (18.9%) HL patients developed BILs which were mostly (8/10 patients) multifocal. Overall, 30 lesions were identified in the 10 asymptomatic patients, all with the above-mentioned features at MR and with very low [18F]FDG uptake. BILs were incidentally detected during HL therapy (n = 6) and follow-up (n = 4), especially in the long bones (66.7%). No factors correlated with the occurrence of BIL were identified. No patients developed complications. PET-MR is a sensitive combined-imaging technique for detecting BILs that are asymptomatic and self-limiting micro-ischemic lesions. BILs can be monitored by clinical follow-up alone both during and after therapy.