Multifarious roles of mTOR signaling in cognitive aging and cerebrovascular dysfunction of Alzheimer's disease.

Age-related cognitive failure is a main devastating incident affecting even healthy people. Alzheimer's disease (AD) is the utmost common form of dementia among the geriatric community. In the pathogenesis of AD, cerebrovascular dysfunction is revealed before the beginning of the cognitive decline. Mounting proof shows a precarious impact of cerebrovascular dysregulation in the development of AD pathology. Recent studies document that the mammalian target of rapamycin (mTOR) acts as a crucial effector of cerebrovascular dysregulation in AD. The mTOR contributes to brain vascular dysfunction and subsequence cerebral blood flow deficits as well as cognitive impairment. Furthermore, mTOR causes the blood-brain barrier (BBB) breakdown in AD models. Inhibition of mTOR hyperactivity protects the BBB integrity in AD. Furthermore, mTOR drives cognitive defect and cerebrovascular dysfunction, which are greatly prevalent in AD, but the central molecular mechanisms underlying these alterations are obscure. This review represents the crucial and current research findings regarding the role of mTOR signaling in cognitive aging and cerebrovascular dysfunction in the pathogenesis of AD.

Circ-camk4 involved in cerebral ischemia/reperfusion induced neuronal injury.

Stroke and subsequent cerebral ischemia/reperfusion (I/R) injury is a frequently occurring disease that can have serious consequences in the absence of timely intervention. Circular RNAs (circRNAs) in association with microRNAs (miRNAs) and RNA-binding proteins (RBPs) can influence gene expression. However, whether circRNAs have a role in cerebral I/R injury pathogenesis, especially soon after onset, is unclear. In this study, we used the SD rat middle cerebral artery occlusion (MCAO) model of stroke to examine the role of circRNAs in cerebral I/R injury. We used high-throughput sequencing (HTS) to compare the expression levels of circRNAs in cerebral cortex tissue from MCAO rats during the occlusion-reperfusion latency period 3 hours after I/R injury with those in control cerebral cortices. Our sequencing results revealed that expression levels of 44 circRNAs were significantly altered after I/R, with 16 and 28 circRNAs showing significant up- and down-regulation, respectively, relative to levels in control cortex. We extended these results in vitro in primary cultured neuron cells exposed to oxygen-glucose deprivation/reperfusion (OGD/R) using qRT-PCR to show that levels of circ-camk4 were increased in OGD/R neurons relative to control neurons. Bioinformatics analyses predicted that several miRNAs could be associated with circ-camk4 and this prediction was confirmed in a RNA pull-down assay. KEGG analysis to predict pathways that involve circ-camk4 included the glutamatergic synapse pathway, MAPK signaling pathway, and apoptosis signaling pathways, all of which are known to be involved in brain injury after I/R. Our results also demonstrate that levels of the human homolog to circ-camk4 (hsa-circ-camk4) are elevated in SH-SY5Y cells exposed to OGD/R treatment. Overexpression of hsa-circ-camk4 in SH-SY5Y cells significantly increased the rate of cell death after OGD/R, suggesting that circ-camk4 may play a key role in progression of cerebral I/R injury.

3-Aminobenzamide protects against cerebral artery injury and inflammation in rats with intracranial aneurysms.

This study aimed to investigate the treatment effects and molecular mechanism of 3-aminobenzamide (3-AB) on intracranial aneurysms (IA). The IA model was established in male Sprague-Dawley (SD) rats and sham group was set up without ligation. The rats were intraperitoneally injected with normal saline in sham and model control groups and 10 mg/kg, 20 mg/kg and 40 mg/kg 3-AB for low, middle and high 3-AB groups for 3 months, respectively. The rates in and blood pressures of caudal artery were measured and anterior cerebral artery and olfactory artery were stained with hematoxylin and eosin (HE) for morphology observation. Besides, the effects of 3-AB on inflammatory cells, macrophages, neutrophils and T cells, were evaluated using immunohistochemistry. Gene expressions of TNF-α, MMP-9, MMP-2, iNOS, TLR4, PARP-1 and p65 were measured using qRT-PCR and the protein levels of TLR4, PARP-1 and p-p65 were evaluated using western blotting. Blood pressures of rats in 3-AB treatment groups were decreased in a dose-dependent manner. The damage of cerebral artery wall was alleviated and the inflammatory cells (macrophages, neutrophils and T cells) were reduced to some extent in 3-AB high-dose groups. The gene expression of TNF-α, MMP-9, MMP-2, iNOS, TLR4, PARP-1 and p65, as well as the protein expression of TLR4, PARP-1 and p-p65 in 3-AB treatment groups were decreased in a dose-dependent manner (P < 0.01).3-AB exhibited therapeutic effects on IA through inhibiting the secretions of inflammatory cytokines and MMPs.

Misery perfusion and amyloid deposition in atherosclerotic major cerebral artery disease.

Although experimental studies have shown that global cerebral hypoperfusion leads to amyloid deposition in the hemisphere with carotid artery occlusion in rodents, the results of such occurrence are controversial in humans. Hence, we aim to determine whether global cerebral hypoperfusion leading to decreased blood flow relative to metabolic demand [increased oxygen extraction fraction (OEF), misery perfusion] is associated with increases in amyloid deposition in the hemisphere with atherosclerotic major cerebral artery disease in patients. We evaluated the distribution of ß-amyloid plaques using positron emission tomography and a [18F]-pyridylbenzofuran derivative (18F-FPYBF-2) in 13 patients with unilateral atherosclerotic disease of the internal carotid artery (ICA) or middle cerebral artery (MCA) disease and no cortical infarction. The distribution volume ratio (DVR) of 18F- FPYBF-2 was calculated using dynamic data and Logan graphical analysis with reference tissue and was correlated with the cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2), and OEF, obtained from 15O-gas PET. The mean cortical value was calculated as the mean value within the frontal, posterior cingulate, precuneus, parietal, and lateral temporal cortical regions. Significant reductions in CBF and CMRO2 and increases in OEF were found in the hemisphere ipsilateral to the arterial lesion compared with the contralateral hemisphere. There was no significant difference for 18F-FPYBF-2 DVR between hemispheres. The ipsilateral to contralateral ratio of the 18F- FPYBF-2 DVR was increased in 3 patients, while the ipsilateral to contralateral OEF ratio was increased in 4 patients. The incidence of an increased hemispheric DVR ratio was significantly higher in patients with an increased hemispheric OEF ratio (3/4) than in patients without (0/9) (p < 0.02). Although the 18F- FPYBF-2 DVR in the ipsilateral hemisphere was positively correlated with OEF after adjustment for the 18F- FPYBF-2 DVR in the contralateral hemisphere using multiple regression analysis (p < 0.05), the contribution rate of OEF was small (R2 = 5.5%). Only one of the 4 patients with an increased hemispheric OEF ratio showed amyloid positivity based on the DVR value. In atherosclerotic major cerebral artery disease, misery perfusion accompanied only small increases of amyloid deposition at best. Misery perfusion was not associated with amyloid positivity.

Inhibition of the NLRP3-inflammasome as a potential approach for neuroprotection after stroke.

Activation of the NOD-like receptor protein (NLRP3)-inflammasome has been postulated to mediate inflammatory responses to brain damage during ischemic/reperfusion (I/R) injury. We therefore hypothesized that MCC950, a selective NLRP3-inflammasome inhibitor provides protection in mouse model of transient middle cerebral artery occlusion (tMCAO). Focal cerebral ischemia was induced by 60 min tMCAO followed by intraperitoneal administration of MCC950 (50 mg/kg) or saline at 1 h and 3 h post-occlusion. After 24 h of I/R, mice were tested for neurological outcome and were sacrificed for the analysis of infarct size and estimating NLRP3-inflammasome and apoptotic markers as well. Spectrophotometric method was used to determine hemoglobin (Hb) content as a marker of intracerebral hemorrhage. MCC950-treated mice showed a substantial reduction in infarction, edema and Hb content compared to saline controls in parallel with improved neurological deficits. MCC950 reduced expression of NLRP3-inflammasome cleavage products Caspase-1 and interlukin-1ß (IL-1ß) in penumbral region. These protective effects of MCC950 were associated with decreased TNF-α levels as well as poly (ADP-ribose) polymerase (PARP) and Caspase-3 cleavage and paralleled less phosphrylated NFκBp65 and IκBα levels. Taken together, these data indicate that inhibition of NLRP3-inflammasome with MCC950 has therapeutic potential in ischemic stroke models. Further investigations into the therapeutic efficacy and protocols are needed to confirm whether MCC950 treatment could be a promising candidate for clinical trials.

Nocturnal oxyhemoglobin desaturation and arteriopathy in a pediatric sickle cell disease cohort.

OBJECTIVE: The purpose of this study of sickle cell disease (SCD) was to determine whether arteriopathy, measurable as intracranial vessel signal loss on magnetic resonance angiography (MRA), was associated with low nocturnal hemoglobin oxygen saturation (SpO2) or hemolytic rate, measurable as reticulocytosis or unconjugated hyperbilirubinemia. METHODS: Ninety-five East London children with SCD without prior stroke had overnight pulse oximetry, of whom 47 (26 boys, 39 hemoglobin SS; mean age 9.1 ± 3.1 years) also had MRA, transcranial Doppler (TCD), steady-state hemoglobin, and reticulocytes within 34 months. Two radiologists blinded to the other data graded arteriopathy on MRA as 0 (none) or as increasing severity grades 1, 2, or 3. RESULTS: Grades 2 or 3 arteriopathy (n = 24; 2 with abnormal TCD) predicted stroke/TIA compared with grades 0 and 1 (log-rank χ2 [1, n = 47] = 8.1, p = 0.004). Mean overnight SpO2 correlated negatively with reticulocyte percentage (r = -0.387; p = 0.007). Despite no significant differences across the degrees of arteriopathy in genotype, mean overnight SpO2 was higher (p < 0.01) in those with grade 0 (97.0% ± 1.6%) than those with grades 2 (93.9 ± 3.7%) or 3 (93.5% ± 3.0%) arteriopathy. Unconjugated bilirubin was not associated but reticulocyte percentage was lower (p < 0.001) in those with grade 0 than those with grades 2 and 3 arteriopathy. In multivariable logistic regression, lower mean overnight SpO2 (odds ratio 0.50, 95% confidence interval 0.26-0.96; p < 0.01) predicted arteriopathy independent of reticulocyte percentage (odds ratio 1.47, 95% confidence interval 1.15-1.87; p = 0.003). CONCLUSION: Low nocturnal SpO2 and reticulocytosis are associated with intracranial arteriopathy in children with SCD. Preventative strategies might reduce stroke risk.

A study on effect of curcumin on anticerebral aneurysm in the male albino rats.

INTRODUCTION: This study investigated the curcumin effect on the cerebral aneurysm. Apoptosis is known to play a fundamental role in the pathogenesis of a cerebral aneurysm. Therefore, we investigated the effect of curcumin on apoptosis of smooth muscle cells of a cerebral aneurysm-induced male albino rats. METHODS: In this study, the cerebral aneurysm has been induced in the male albino rats by the CaCl2 administration. After cerebral aneurysm induction, smooth muscle cells were isolated. Cells were treated with curcumin (25 & 50 mg/kg bwt) for 48 hr. RESULTS: Curcumin reduced altered mitochondrial morphology significantly, evidenced through fluorescence and confocal study. Curcumin treatment reduced the expression of p53, caspase-3, and bax/bxl-2 ratio significantly. Curcumin treatment also reversed the cellular architecture of smooth muscle cell wall significantly. Fluorescence and the confocal study confirmed the reduction in apoptosis in a cerebral aneurysm-induced smooth muscle cells of male albino rats. CONCLUSION: Taking all these data together, it may suggest that the curcumin could significantly reduce the CaCl2-induced cerebral aneurysm through the inhibition of cell apoptosis in the cells.

Optimal Brain 99mTc-Ethyl Cysteinate Dimer SPECT Imaging and Analysis to Detect Misery Perfusion on 15O PET Imaging in Patients With Chronic Occlusive Disease of Unilateral Major Cerebral Artery.

PURPOSE: Misery perfusion is defined as marginally sufficient cerebral blood supply relative to cerebral metabolic demand. The aim of the present study was to determine the optimal brain Tc-ethyl cysteinate dimer (ECD) SPECT imaging and analysis to detect misery perfusion on O PET imaging in patients with chronic occlusive disease of unilateral internal carotid or middle cerebral artery (MCA). METHODS: For 97 patients, cerebral blood flow, cerebral metabolic rate of oxygen, and oxygen extraction fraction were measured using O PET; Tc-ECD SPECT was performed using dynamic scanning with a scan duration of 10 minutes each for 50 minutes after tracer administration. A region of interest was placed in the bilateral MCA territories and in the bilateral cerebellar hemispheres in all standardized images using a 3-dimensional stereotaxic region-of-interest template and affected-to-contralateral asymmetry ratio in the MCA territory (ARMCA) and contralateral-to-affected asymmetry ratio in the cerebellar hemisphere (ARcbl) were calculated. RESULTS: The ARMCA or ARcbl on Tc-ECD SPECT with a scan time of 20 to 30 minutes after tracer administration (ARMCA20-30 or ARcbl20-30) was correlated with ARMCA on PET cerebral blood flow (r = 0.654) or ARMCA on PET cerebral metabolic rate of oxygen (r = 0.576), respectively, more strongly than with other scan times. The area under the receiver operating characteristic curve for detecting abnormally elevated ARMCA on PET oxygen extraction fraction was significantly greater for ARcbl20-30/ARMCA20-30 (0.947) than for ARMCA20-30 alone (0.780) (difference between areas, 0.167; P = 0.0001) on Tc-ECD SPECT. CONCLUSIONS: Combination of asymmetries in the cerebellar and cerebral hemispheres on Tc-ECD SPECT in a scan time of 20 to 30 minutes after tracer administration optimally detects misery perfusion in unilateral internal carotid artery or MCA occlusive disease.

Cerebral Arteriopathy in a Newborn With Incontinentia Pigmenti.

BACKGROUND: Incontinentia pigmenti is a rare X-linked neurocutaneous disorder that can present in the neonatal period with seizures and encephalopathy. Brain magnetic resonance imaging and magnetic resonance angiography may reveal cerebral infarction and arteriopathy. PATIENT DESCRIPTION: We describe a neonate with the typical rash of incontinentia pigmenti along with seizures and brain magnetic resonance imaging abnormalities. RESULTS: Brain magnetic resonance imaging, magnetic resonance angiography, and magnetic resonance spectroscopy at age one week revealed chronic and acute brain injury, arteriopathy of the small and medium-sized cerebral vessels, and elevation of a lactate metabolite peak. By age six months, her magnetic resonance angiogram had normalized. At age 2.5 years, she has well-controlled complex partial seizures, global developmental delay, and residual hemiplegia. CONCLUSION: Despite extensive cerebral arteriopathy in association with incontinentia pigmenti, this girl had a relatively stable early clinical course, steady developmental progress over time, and seizures that have been well controlled. Later brain imaging revealed resolution of the arteriopathy.

Differential regulation of matrix metalloproteinases in varicella zoster virus-infected human brain vascular adventitial fibroblasts.

Upon reactivation, varicella zoster virus (VZV) spreads transaxonally, infects cerebral arteries and causes ischemic or hemorrhagic stroke, as well as aneurysms. The mechanism(s) of VZV-induced aneurysm formation is unknown. However, matrix metalloproteinases (MMPs), which digest extracellular structural proteins in the artery wall, play a role in cerebral and aortic artery aneurysm formation and rupture. Here, we examined the effect of VZV infection on expression of MMP-1, -2, -3, and -9 in primary human brain vascular adventitial fibroblasts (BRAFS). At 6 days post-infection, VZV- and mock-infected BRAFs were analyzed for mRNA levels of MMP-1, -2, -3 and -9 by RT-PCR and for corresponding total intra- and extracellular protein levels by multiplex ELISA. The activity of MMP-1 was also measured in a substrate cleavage assay. Compared to mock-infected BRAFs, MMP-1, MMP-3 and MMP-9 transcripts, cell lysate protein and conditioned supernatant protein were all increased in VZV-infected BRAFs, whereas MMP-2 transcripts, cell lysate protein and conditioned supernatant protein were decreased. MMP-1 from the conditioned supernatant of VZV-infected BRAFs showed increased cleavage activity on an MMP-1-specific substrate compared to mock-infected BRAFs. Differential regulation of MMPs in VZV-infected BRAFs may contribute to aneurysm formation in VZV vasculopathy.

Role of high sensitivity C-reactive protein and other risk factors in intracranial and extracranial artery occlusion in patients with ischaemic stroke.

OBJECTIVE: A retrospective case-control study to identify stroke-associated risk factors and quantify serum C-reactive protein in patients with ischaemic stroke, with or without intracranial and/or extracranial artery occlusion (IEAO). METHODS: Patients with ischaemic stroke and internal carotid artery occlusion (ICAO), middle cerebral artery occlusion (MCAO), ICAO + MCAO, or no IEAO (control patients) were retrospectively recruited. Data regarding stroke-associated risk factors were retrieved from medical records. High sensitivity (hs)-CRP was quantified within 3 days of hospital admission. RESULTS: Patients with ICAO (n = 89), MCAO (n = 74) and ICAO + MCAO (n = 29) had significantly higher serum hs-CRP concentrations, and were significantly more likely to have coronary heart disease, a history of stroke, and more than three stroke-associated risk factors than control patients (n = 84). CONCLUSIONS: Coronary heart disease and a history of stroke are risk factors for ischaemic stroke with IEAO. Hs-CRP may be used as a marker for IEAO.

Cytoskeletal reorganization evoked by Rho-associated kinase- and protein kinase C-catalyzed phosphorylation of cofilin and heat shock protein 27, respectively, contributes to myogenic constriction of rat cerebral arteries.

Our understanding of the molecular events contributing to myogenic control of diameter in cerebral resistance arteries in response to changes in intravascular pressure, a fundamental mechanism regulating blood flow to the brain, is incomplete. Myosin light chain kinase and phosphatase activities are known to be increased and decreased, respectively, to augment phosphorylation of the 20-kDa regulatory light chain subunits (LC20) of myosin II, which permits cross-bridge cycling and force development. Here, we assessed the contribution of dynamic reorganization of the actin cytoskeleton and thin filament regulation to the myogenic response and serotonin-evoked constriction of pressurized rat middle cerebral arteries. Arterial diameter and the levels of phosphorylated LC(20), calponin, caldesmon, cofilin, and HSP27, as well as G-actin content, were determined. A decline in G-actin content was observed following pressurization from 10 mm Hg to between 40 and 120 mm Hg and in three conditions in which myogenic or agonist-evoked constriction occurred in the absence of a detectable change in LC20 phosphorylation. No changes in thin filament protein phosphorylation were evident. Pressurization reduced G-actin content and elevated the levels of cofilin and HSP27 phosphorylation. Inhibitors of Rho-associated kinase and PKC prevented the decline in G-actin; reduced cofilin and HSP27 phosphoprotein content, respectively; and blocked the myogenic response. Furthermore, phosphorylation modulators of HSP27 and cofilin induced significant changes in arterial diameter and G-actin content of myogenically active arteries. Taken together, our findings suggest that dynamic reorganization of the cytoskeleton involving increased actin polymerization in response to Rho-associated kinase and PKC signaling contributes significantly to force generation in myogenic constriction of cerebral resistance arteries.

Role of BK(Ca) channels in diabetic vascular complications.

OBJECTIVE: This review focuses on the role of the large conductance calcium-activated potassium (BKCa) channels in diabetic vascular complications. DATA SOURCES: Relevant articles published in English or Chinese from 1981 to present were selected from PubMed. The search terms were "BKCa channels" and "diabetes". Important references from selected articles were also retrieved. STUDY SELECTION: Articles regarding the role of BKCa channels in diabetic vascular complications and relevant mechanisms were selected. RESULTS: The BKCa channels are abundantly expressed in vascular smooth cells and play an important role in regulation of vascular tone. Multiple studies indicated that the expression and function of BKCa channels are altered by different mechanisms in diabetic vascular diseases such as coronary arterial disease, cerebral arterial disease, and diabetic retinopathy. CONCLUSION: BKCa channels may play an important role in diabetic vascular complications and may be an effective therapeutic target for relieving and reducing the burden of diabetic vascular complications.

The early stage formation of PI3K-AMPAR GluR2 subunit complex facilitates the long term neuroprotection induced by propofol post-conditioning in rats.

Previously, we have shown that the phosphoinositide-3-kinase (PI3K) mediated acute (24 h) post-conditioning neuroprotection induced by propofol. We also found that propofol post-conditioning produced long term neuroprotection and inhibited the internalization of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor GluR2 subunit up to 28 days post middle cerebral artery occlusion (MCAO). However, the relationship between PI3K with AMPA receptor GluR2 subunit trafficking in propofol post-conditioning has never been explored. Here we showed that propofol post-conditioning promoted the binding of PI3K to the C-terminal of AMPA receptor GluR2 subunit and formed a complex within 1 day after transient MCAO. Interestingly, the enhanced activity of PI3K was observed in the hippocampus of post-conditioning rats at day 1 post ischemia, whereas the decrease of AMPA receptor GluR2 subunit internalization was found up to 28 days in the same group. Administration of PI3K selective antagonist wortmannin inhibited the improvement of spatial learning memory and the increase of neurogenesis in the dentate gyrus up to 28 days post ischemia. It also reversed the inhibition of AMPA receptor GluR2 internalization induced by propofol post-conditioning. Together, our data indicated the critical role of PI3K in regulating the long term neuroprotection induced by propofol post-conditioning. Moreover, this role was established by first day activation of PI3K and formation of PI3K-AMPA receptor GluR2 complex, thus stabilized the structure of postsnaptic AMPA receptor and inhibited the internalization of GluR2 subunit during the early stage of propofol post-conditioning.

Review: cerebral amyloid angiopathy, prion angiopathy, CADASIL and the spectrum of protein elimination failure angiopathies (PEFA) in neurodegenerative disease with a focus on therapy.

Failure of elimination of proteins from the brain is a major feature in many neurodegenerative diseases. Insoluble proteins accumulate in brain parenchyma and in walls of cerebral capillaries and arteries. Cerebral amyloid angiopathy (CAA) is a descriptive term for amyloid in vessel walls. Here, we adopt the term protein elimination failure angiopathy (PEFA) to focus on mechanisms involved in the pathogenesis of a spectrum of disorders that exhibit both unique and common features of protein accumulation in blood vessel walls. We review (a) normal pathways and mechanisms by which proteins and other soluble metabolites are eliminated from the brain along 100- to 150-nm-thick basement membranes in walls of cerebral capillaries and arteries that serve as routes for lymphatic drainage of the brain; (b) a spectrum of proteins involved in PEFA; and (c) changes that occur in artery walls and contribute to failure of protein elimination. We use accumulation of amyloid beta (Aß), prion protein and granular osmiophilic material (GOM) in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) as examples of different factors involved in the aetiology and pathogenesis of PEFA. Finally, we discuss how knowledge of factors involved in PEFA may help to focus on new therapies for neurodegenerative diseases. When Aß (following immunotherapy) and prion protein are released from brain parenchyma they deposit in walls of cerebral capillaries and arteries; GOM in CADASIL accumulates primarily in artery walls. Therefore, the focus of therapy for protein clearance in neurodegenerative disease should perhaps be on facilitating perivascular elimination of proteins and reducing PEFA.

A mechanistic investigation into non-infarcted brain injury induced by cerebral artery microemboli.

To establish a rat brain injury by non-infarction process model induced by cerebral artery microemboli which would be used to further explore the neural injury mechanisms of cerebral artery microemboli. Seventy-two Sprague-Dawley rats were randomly divided into the microemboli group and the sham group; 100 25-50 µm microemboli in 300 µl or the same amount of saline were injected into the left carotid artery, respectively. The severity of neuron damage was assessed 3 and 7 days after the operation, using haematoxylin-eosin (HE) staining and immunohistochemical staining for caspase-3. Immunohistochemical staining for CD11b and GFAP were used to quantitatively analyse hyperplasia and the activation of microglia and astrocytes. TNF-α expression was detected by using ELISA and the NF-κB expression was detected by employing Western blotting. The results of HE staining had shown that ischaemic infarct foci were not detected in either the microemboli group or sham group. Only a few apoptotic cells and a few cells with the positive expression of CD11b and GFAP were detected in the sham group. And compared with that of the sham group, the number of apoptotic cells and the positive expression of CD11b and GFAP in the microemboli group were significantly increased (P < 0.001). These parameters were also significantly increased 7 days after the operation compared to rats 3 days after surgery (P < 0.001). The expressions of TNF-α and NF-κB were significantly increased in the microemboli group (P < 0.001), and the increase of the expression of TNF-α and NF-κB on the 3 days was more significant compared to that of TNF-α and NF-κB on 7 days (P < 0.001). Injection of 25-50 µm microemboli at a dose of 100 microemboli in 300 µl into the carotid artery of rats did not result in cerebral infarction, but led to neuronal apoptosis, hyperplasia and activation of microglia and astrocytes. This leads us to conclude that TNF-α and NF-κB may play important roles in the pathogenesis of neuronal apoptosis induced by microemboli in the cerebral arteries.

Cerebral tissue hemoglobin saturation in children with sickle cell disease.

BACKGROUND: Desaturation of hemoglobin (Hb) in cerebral tissue, a physiologic marker of brain vulnerable to ischemic injury, can be detected non-invasively by transcranial oximetry. Absolute cerebral oximetry has not been studied in sickle cell disease (SCD), a group at very high risk of cerebral infarction in whom prevention of brain injury is key. PROCEDURE: We measured absolute Hb saturation in cerebral tissue (S(CT)O(2)) in children with SCD using near-infrared spectrophotometry and investigated the contributions of peripheral Hb saturation (S(P)O(2)), hematologic measures, cerebral arterial blood flow velocity, and cerebral arterial stenosis to S(CT)O(2). We also assessed the effects of transfusion. RESULTS: We studied 149 children with SCD (112 HbSS/Sß(0); 37 HbSC/Sß(+)). S(CT)O(2) was abnormally low in 75% of HbSS/Sß(0) and 35% of HbSC/Sß(+) patients. S(CT)O(2) (mean ± SD) was 53.2 ± 14.2 in HbSS/Sß(0) and 66.1 ± 9.2% in SC/Sß(+) patients. S(CT)O(2) correlated with age, sex, Hb concentration, reticulocytes, Hb F, and S(P)O(2), but not transcranial Doppler arterial blood flow velocities as continuous measures. In multivariable models, S(P)O(2), Hb concentration, and age were significant independent determinants of S(CT)O(2). Cerebral vasculopathy was associated with ipsilateral cerebral desaturation. Transfusion increased S(CT)O(2) and minimized the inter-hemispheric differences in S(CT)O(2) due to vasculopathy. CONCLUSIONS: Cerebral desaturation, a physiologic marker of at-risk brain, is common in SCD, more severe in HbSS/Sß(0) patients, and associated with peripheral desaturation, more severe anemia, and increasing age. Cerebral oximetry has the potential to improve the identification of children with SCD at highest risk of neurologic injury and possibly serve as a physiologic guide for neuroprotective therapy.

Accuracy of central benzodiazepine receptor binding potential/cerebral blood flow SPECT imaging for detecting misery perfusion in patients with unilateral major cerebral artery occlusive diseases: comparison with cerebrovascular reactivity to acetazolamide and cerebral blood flow SPECT imaging.

PURPOSE: The aim of the present study was to determine whether central benzodiazepine receptor binding potential (BRBP)/cerebral blood flow (CBF) or a combination of CBF and cerebrovascular reactivity (CVR) to acetazolamide on single-photon emission computed tomography (SPECT) more accurately detects misery perfusion, indicating elevation of absolute value of oxygen extraction fraction (OEF) on positron emission tomography (PET), in patients with unilateral major cerebral artery occlusive diseases. METHODS: In 84 patients, OEF, CBF, CVR to acetazolamide, and BRBP were assessed using ¹5O-PET and N-isopropyl-p-[¹²³I]-iodoamphetamine and [¹²³I]-iomazenil SPECT, respectively. A region of interest was automatically placed in the middle cerebral artery territory using a 3-dimensional stereotactic region of interest template. RESULTS: Sensitivity, specificity, and positive and negative predictive values for the affected side-to-contralateral side asymmetry on SPECT-BRBP/CBF to detect the abnormally elevated PET-OEF in the affected hemisphere were 100%, 86.4%, 66.7%, and 100%, respectively. Area under the receiver operating characteristic curve in detecting the abnormally elevated PET-OEF in the affected hemisphere did not differ between analysis of the combination of SPECT-CBF and SPECT-CVR in the affected hemisphere (0.89; 95% confidence interval, 0.80-0.94) and that of the affected side-to-contralateral side asymmetry on SPECT-BRBP/CBF (0.93; 95% confidence interval, 0.86-0.97). The combination of the 3 detected abnormally elevated PET-OEF with 97.0% specificity and 90.0% positive predictive value. CONCLUSIONS: The accuracy of central BRBP/CBF asymmetry on SPECT is equivalent to that of the combination of CBF and CVR to acetazolamide on SPECT for detecting misery perfusion in patients with unilateral major cerebral artery occlusive disease.