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This study was performed to estimate the corpse age using histological examinations of the fourth and sixth ribs by a morphometric method. One hundred samples of referred bodies of the Legal Medicine Organization of Lorestan province, Iran, were examined. The sampling was performed from the fourth and sixth ribs. The transverse sections of the samples were prepared, in which various variables such as the diameter of the haversian system (DHC), haversian system perimeter (PHS), haversian system area (AHS), and the thickness of the haversian lamellae (TH) were measured using a Motic microscope video system and the Motic Image Plus 2 software. To predict age from sex and the morphometric parameters a stepwise multiple linear regression was used. Accordingly, AHS in rib 4, DHC with lens 10 in rib 4, DHC with lens 10 in rib 6 and TH in rib 6 remained in the model at significance level 0.05 (R square = 0.1654). Although age was associated with some of the studied parameters, the obtained equation was not fit enough to predict the exact age. Further parameters should be studied for prediction of age in corpse.

To review the recent developments on the effect of chronic high mean arterial blood pressure (MAP) on cerebral blood flow (CBF) autoregulation and supporting the notion that CBF autoregulation impairment has connection with chronic cerebral diseases.

Alzheimer&rsquo, s disease (AD) is the result of the deposition of amyloid &beta, (A&beta, ) peptide into amyloid fibrils and tau into neurofibrillary tangles. At the present time, there are no possible treatments for the disease. We have recently shown that diets enriched in phytonutrients show protection or limit the extent of damage in a number of neurological disorders. GrandFusion (GF) diets have attenuated the outcomes in animal models of traumatic brain injury, cerebral ischemia, and chronic traumatic encephalopathy. In this study, we investigated the effect of GF diets in a mouse model of AD prior to the development of amyloid plaques to show how this treatment paradigm would alter the accumulation of A&beta, peptide and related pathologic changes (i.e., inflammation, cathepsin B, and memory impairment). Administration of GF diets (2&ndash, 4%) over a period of four months in APP/&Delta, PS1 double-transgenic mice resulted in attenuation in A&beta, peptide levels, reduction of amyloid load, and inflammation, increased cathepsin B expression, and improved spatial orientation. Additionally, treatment with GF diets increased nerve growth factor (NGF) levels in the brain and tempered the memory impairment in the animal model. These data suggest that GF diets may alter the development and progression of the mechanisms associated with the disease process to effectively modify AD pathogenesis.

Serum amyloid A (SAA) proteins are acute-phase reactant associated with high-density lipoprotein (HDL) particles and increase in the plasma 1000-fold during inflammation. Recent studies have implicated SAAs in innate immunity and various disorders; however, the precise mechanism eludes us. Previous studies have shown SAAs are elevated following stroke and cerebral ischemia, and our studies demonstrated that SAA-deficient mice reduce inflammation and infarct volumes in a mouse stroke model. Our studies demonstrate that SAA increases the cytokine interleukin-1β (IL-1β), which is mediated by Nod-like receptor protein 3 (NLRP3) inflammasome, cathepsin B, and caspase-1 and may play a role in the pathogenesis of neurological disorders. SAA induced the expression of NLRP3, which mediated IL-1β induction in murine BV-2 cells and both sex primary mouse microglial cells, in a dose- and time-dependent fashion. Inhibition or KO of the NLRP3 in microglia prevented the increase in IL-1β.N-acetyl-l-cysteine and mito-TEMPO blocked the induction of IL-1β by inhibiting ROS with SAA treatment. In addition, inhibition of cathepsin B with different drugs or microglia from CatB-deficient mice attenuated inflammasome activation. Our studies suggest that the impact of SAA on inflammasome stimulation is mediated in part by the receptor for advanced glycation endproducts and Toll-like receptor proteins 2 and 4. SAA induced inflammatory cytokines and an M1 phenotype in the microglial cells while downregulating anti-inflammation M2 phenotype. These studies suggest that brain injury to can elicit a systemic inflammatory response mediated through SAA that contributes to the pathological outcomes.SIGNIFICANCE STATEMENTIn the present study, serum amyloid A can induce that activation of the inflammasome in microglial cells and give rise to IL-1β release, which can further inflammation in the brain following neurological diseases. The also presents a novel target for therapeutic approaches in stroke.

This paper proposes a comprehensive bilevel model for the maintenance scheduling of power units including wind farms in a restructured environment. The maintenance-scheduling problem of generating companies (GENCOs) is constrained by technical and security constraints set by the independent system operator (ISO), who has the responsibility of operating the power system. To consider the impact of these constraints on the scheduling problem, we propose a bilevel approach with a strategic GENCO at the upper level and an ISO at the lower level. In the upper level, the scheduling problem considering the participation of wind farms is presented. The lower level, also called the ISO level, maximizes the social welfare with network security constraints. This bilevel problem is modeled as a mathematical program with equilibrium constraints (MPEC), which is then transformed into a mixed-integer linear problem through a linearization procedure. The resultant model is tested on the IEEE 24-Bus Reliability Test System considering various case studies to illustrate the effectiveness of the proposed model. The results show that the proposed model can properly schedule the outages under different strict conditions preserving system’s security.

Nowadays, utilities aim to find methods for improving the reliability of distribution systems and satisfying the customers by providing the continuity of power supply. Different methodologies exist for utilities to improve the reliability of network. In this paper, demand response (DR) programs and smart charging/discharging of plug-in electric vehicles (PEVs) are investigated for improving the reliability of radial distribution systems adopting particle swarm optimization (PSO) algorithm. Such analysis is accomplished due to the positive effects of both DR and PEVs for dealing with emerging challenges of the world such as fossil fuel reserves reduction, urban air pollution and greenhouse gas emissions. Additionally, the prioritization of DR and PEVs is presented for improving the reliability and analyzing the characteristics of distribution networks. The reliability analysis is performed in terms of loss of load expectation (LOLE) and expected energy not served (EENS) indexes, where the characteristics contain load profile, load peak, voltage profile and energy loss. Numerical simulations are accomplished to assess the effectiveness and practicality of the proposed scheme.

Despite existing strong evidence on oxidative markers overproduction following ischemia/reperfusion (I/R), the mechanism by which oxidative enzyme Cytochrome P450-2E1 (CYP2E1) contributes to I/R outcomes is not clear. In this study, we sought to evaluate the functional significance of CYP2E1 in I/R. CYP2E1 KO mice and controls were subjected to middle cerebral artery occlusion (MCAo-90 min) followed by 24 h of reperfusion to induce focal I/R injury as an acute stage model. Then, histological and chemical analyses were conducted to investigate the role of CYP2E1 in lesion volume, oxidative stress, and inflammation exacerbation. Furthermore, the role of CYP2E1 on the blood-brain barrier (BBB) integrity was investigated by measuring 20-hydroxyecosatetraenoic acid (20-HETE) activity, as well as, in vivo BBB transfer rate. Following I/R, the CYP2E1 KO mice exhibited a significantly lower lesion volume, and neurological deficits compared to controls (p &lt, 0.005). Moreover, reactive oxygen species (ROS) production, apoptosis, and neurodegeneration were significantly lower in the CYP2E1(&minus, /&minus, ) I/R group (p &lt, 0.001). The BBB damage was significantly lower in CYP2E1(&minus, ) mice compared to wild-type (WT) (p &lt, 0.001), while 20-HETE production was increased by 41%. Besides, inflammatory cytokines expression and the number of activated microglia were significantly lower in CYP2E1(&minus, ) mice following I/R. CYP2E1 suppression ameliorates I/R injury and protects BBB integrity by reducing both oxidative stress and inflammation.

Plant-based nutritional supplementation has been shown to attenuate and reduce mortality in the processes of both acute and chronic disorders, including diabetes, obesity, cardiovascular disease, cancer, inflammatory diseases, and neurological and neurodegenerative disorders. Low-level systemic inflammation is an important contributor to these afflictions and diets enriched in phytochemicals can slow the progression. The goal of this study was to determine the impact of lipopolysaccharide (LPS)-induced inflammation on changes in glucose and insulin tolerance, performance enhancement, levels of urinary neopterin and concentrations of neurotransmitters in the striatum in mouse models. Both acute and chronic injections of LPS (2 mg/kg or 0.33 mg/kg/day, respectively) reduced glucose and insulin tolerance and elevated neopterin levels, which are indicative of systemic inflammatory responses. In addition, there were significant decreases in striatal neurotransmitter levels (dopamine and DOPAC), while serotonin (5-HT) levels were essentially unchanged. LPS resulted in impaired execution in the incremental loading test, which was reversed in mice on a supplemental plant-based diet, improving their immune function and maintaining skeletal muscle mitochondrial activity. In conclusion, plant-based nutritional supplementation attenuated the metabolic changes elicited by LPS injections, causing systemic inflammatory activity that contributed to both systemic and neurological alterations.

Even though the Persian leopard Panthera pardus saxicolor is an endangered subspecies with the main population inhabiting in Iran (Khorozyan and Abramov, Zool Middle East 41:11–24, 2007; Kiabi et al., Zool Middle East 26(1):41–47, 2002), earlier studies (Sanei et al., Assessment of the Persian leopard mortality rate in Iran. In: Proceedings from UMT 11th International Annual Symposium on Sustainability Science and Management (pp. 1458–1462, 2012). Terengganu, Malaysia: Universiti Malaysia Terengganu) demonstrated that the majority of leopard mortalities are recorded to be as a result of intentional hunting, revenge killing, and poisoning of the specimens. To mitigate livestock–carnivore conflicts and reduce the subsequent revenge killings, an innovative model including a medium and a long-term insurance schemes together with awareness raising, trust building, and participatory conservation strategies is designed. Accordingly, the medium term insurance scheme addresses three main subjects of (1) improving conservation practices in the areas of leopard mortality hot spots, (2) medical payments and wergild for possible human injuries/maim/death because of human–leopard conflicts and (3) recompensing livestock depredation. Also, since the wolf Canis lupus distribution is comparable with the leopard range in the country, because of conservation concerns, damages caused by wolf depredation are also planned to be recompensed partially in the first type (i.e. medium term) insurance scheme and fully recompensed in the long term (i.e. second type) insurance program. Introducing sessions about the relative regulations and instructions were conducted for provincial wildlife wardens and DoE staff who are well familiar with wildlife sign surveys and have a quick access to the habitats in each region. Subsequently, they took the responsibility for identification of wildlife species in livestock–carnivore conflicts. Improvements in husbandry practices, linking the payments to the acceptable husbandry enhancements and participation in reducing risk of damages by local people are some of the instructions considered in the model to improve the efficacy and outcomes. So far, Department of Environment of Iran together with a private insurance company has partially launched the short term insurance scheme since 2016 and launching other sections of this model is in progress.

In this paper, interfacial and elastic properties of polymer-based nanocomposites reinforced by carbon nanocones (CNCs) are investigated. The CNCs are transitional structures from graphene to carbon nanotubes and, depending on their apex angles, show either more graphene or more nanotube behavior. Due to the importance of the interphase layer and its impact on the elastic properties of nanocomposites, the molecular dynamics method is used to investigate the behavior of polyethylene polymer in the interface of the CNCs. The MD simulation results reveal that there are two distinct interphase layers, i. e. the inner interphase region inside the CNCs and the outer interphase region outside the CNCs. While the outer interphase regions are the same in all cases, the size and properties of the inner interphase depend on the geometries of CNCs. Using the results of MD simulations, the finite element method is used to simulate CNC-reinforced polyethylene nanocomposites in larger dimensions. In finite element modeling, the effects of different orientations of nanofillers, various volume fractions, and geometrical parameters of the CNCs are studied.

Vascular cognitive impairment and dementia (VCID) is a diagnostic term applied to cognitively impaired individuals with heterogeneous cerebrovascular conditions affecting large and/or small vessels. Individual biomarkers have been identified as instrumental in relating VCID to specific underlying pathologies to better characterize this syndrome. Emerging research to refine panels of biomarkers will increase classification sensitivity and specificity. Refined VCID clustering based on the severity and pathology of vascular injury will permit the development of optimal prevention and treatment strategies. Here, we review recently reported data concerning the diversity of VCID-related pathology and attempts for VCID clustering based on biomarkers obtained from different sets of measurements. We discuss three major sets of biomarkers: 1) neuroimaging biomarkers, 2) neuropsychological performance measures, and 3) biochemical markers in current VCID clustering. Finally, we highlight the effect of blood-brain barrier health on cerebrovascular disease trajectory.

Physiological and pathological processes that increase or decrease the central nervous system's need for nutrients and oxygen via changes in local blood supply act primarily at the level of the neurovascular unit (NVU). The NVU consists of endothelial cells, associated blood–brain barrier tight junctions, basal lamina, pericytes, and parenchymal cells, including astrocytes, neurons, and interneurons. Knowledge of the NVU is essential for interpretation of central nervous system physiology and pathology as revealed by conventional and advanced imaging techniques. This article reviews current strategies for interrogating the NVU, focusing on vascular permeability, blood volume, and functional imaging, as assessed by ferumoxytol an iron oxide nanoparticle.

Transmission expansion planning (TEP) is a sophisticated decision-making problem, especially in an oligopolistic electricity market in which a number of strategic (price-maker) producers compete together. A transmission system planner, who is in charge of making TEP decisions, requires considering the future generation investment actions. However, in such an oligopolistic market, each producer makes its own strategic generation investment decisions. This motivates the transmission system planner to consider the generation investment decision-making problem of all producers within its TEP model. The strategic generation investment problem of each producer can be represented by a complementarity bi-level model. The joint consideration of all bi-level models, one per producer, characterizes the generation investment equilibrium that identifies the future evolution of generation investment in the market. This paper proposes a tri-level TEP decision-making model to be solved by the transmission system planner, whose objective is to maximize the social welfare of the market minus the expansion costs, and whose constraints are the transmission expansion limits as well as the generation investment equilibrium problem. This model is then recast as a mixed-integer linear programming problem and solved. Numerical results from an illustrative example and a case study based on the IEEE 14-bus test system demonstrate the usefulness of the proposed approach.

Studies have shown that supplementation with extracts from various sources, including fruits and vegetables reverse the age-related changes in movement and cognition. We hypothesized that these beneficial effects result from the presence of anti-oxidants and anti-inflammatory compounds in the fruits and vegetables that contribute to reduced oxidative stress, inflammation and cell death while potentially enhancing neurogenesis. The present study was performed to determine the impact of supplementation with GrandFusion®(GF) to aged Fisher 344 rats for 4 months to determine the impact on attenuation or reversal of the age-related deficits. When the aged rats consumed a diet enriched with the extracts the results showed an improved motor performance, and enhanced cognitive functions. In addition, the rats showed reduced oxidative stress and inflammation, and enhanced neurogenesis, Nrf2 and anti-oxidant expression. The effect of GF extracts on the augmentation of memory and learning is significant and may function through the modulation of antioxidant enzymes, signaling pathways and additional mechanisms to improve the aging process. These studies further support the recommendation of USDA for the consumption of fruits and vegetables to improve healthy aging.

In this paper, transversely isotropic elastic properties of carbon nanocones are studied using molecular dynamics simulation implemented in the large-scale atomic/molecular massively parallel simulator (LAMMPS). All atomic interactions are calculated based on the Adaptive Intermolecular Reactive Empirical Bond Order (AIREBO) potential energy functions. To determine the five independent elastic constants, four distinct loading conditions, i. e. uniaxial tensile, longitudinal torsion, in-plane biaxial stretching, and in-plane shear are imposed. The results reveal that Young’s and axial shear moduli are dependent on the apex angle of carbon nanocones, while the effect of the length on them is negligible. Furthermore, the in-plane bulk modulus and in-plane shear constant of these structures increase as their apex angle increases.

Yearly preventive maintenance scheduling of generating units in a restructured power system is one of the most important problems that have to be solved in modern power systems. In this paper, a bilevel approach is used for modelling of the preventive maintenance scheduling problem. The upper level of this bilevel problem represents the revenue function of power units owned by a generation company (GENCO), whereas the lower-level problem represents the market-clearing process and is usually called the independent system operator (ISO) level. This bilevel problem is then formulated as a mathematical program with equilibrium constraints (MPEC) using the primal–dual theorem, which converts the problem into a single-level mixed-integer non-linear optimization problem that can be solved using programming software. Various case studies are conducted using the IEEE reliability test system (RTS) and the obtained results are compared.

Alzheimer’s disease (AD) results in the deposition of amyloid β (Aβ) peptide into amyloid fibrils and tau into neurofibrillary tangles. Regardless of whether or not these entities are a cause or consequence of the disease process, preventing their accumulation or accelerating their clearance may slow the rate of AD onset. Motoneuronotrophic factor (MNTF) is an endogenous neurotrophin that is specific for the human nervous system, and some of the observed effects of MNTF include motoneuron differentiation, maintenance, survival, and reinnervation of target muscles and organs. GM6 is a six-amino-acid component of MNTF that appears to replicate its activity spectrum. In this study, we investigated the effect of GM6 in a mouse model of AD before the development of amyloid plaques and determined how this treatment affected the accumulation of Aβ peptide and related pathologic changes (e.g., inflammation, nerve growth factor (NGF) expression, cathepsin B, and memory impairment). Application of GM6 over a 4-month period in young APP/ΔPS1 double-transgenic mice resulted in attenuation in Aβ peptide levels, reduction of inflammation and amyloid load, increased cathepsin B expression, and improved spatial orientation. In addition, treatment with GM6 increased brain NGF levels and tempered memory impairment by ∼ 50% at the highest dose. These data suggest that GM6 may modulate disease-determining pathways at an early stage to slow the histological and clinical progression of AD.

Background Repetitive mild traumatic brain injuries (rmTBI) are associated with cognitive deficits, inflammation, and stress-related events. We tested the effect of nutrient intake on the impact of rmTBI in an animal model of chronic traumatic encephalopathy (CTE) to study the pathophysiological mechanisms underlying this model. We used a between group design rmTBI closed head injuries in mice, compared to a control and nutrient-treated groups. Methods Our model allows for controlled, repetitive closed head impacts to mice. Briefly, 24-week-old mice were divided into five groups: control, rmTBI, and rmTBI with nutrients (2% of NF-216, NF-316 and NF-416). rmTBI mice received four concussive impacts over 7 days. Mice were treated with NutriFusion diets for 2 months prior to the rmTBI and until euthanasia (6 months). Mice were then subsequently euthanized for macro- and micro-histopathologic analysis for various times up to 6 months after the last TBI received. Animals were examined behaviorally, and brain sections were immunostained for glial fibrillary acidic protein (GFAP) for astrocytes, iba-1 for activated microglia, and AT8 for phosphorylated tau protein. Results Animals on nutrient diets showed attenuated behavioral changes. The brains from all mice lacked macroscopic tissue damage at all time points. The rmTBI resulted in a marked neuroinflammatory response, with persistent and widespread astrogliosis and microglial activation, as well as significantly elevated phospho-tau immunoreactivity to 6 months. Mice treated with diets had significantly reduced inflammation and phospho-tau staining. Conclusions The neuropathological findings in the rmTBI mice showed histopathological hallmarks of CTE, including increased astrogliosis, microglial activation, and hyperphosphorylated tau protein accumulation, while mice treated with diets had attenuated disease process. These studies demonstrate that consumption of nutrient-rich diets reduced disease progression.

The locus coeruleus (LC) noradrenergic system regulates arousal and modulates attention through its extensive projections across the brain. LC dysfunction has been implicated in a broad range of neurodevelopmental, neurodegenerative and psychiatric disorders, as well as in the cognitive changes observed during normal aging. Magnetic resonance imaging (MRI) has been used to characterize the human LC (elevated contrast relative to surrounding structures), but there is limited understanding of the factors underlying putative LC contrast that are critical to successful biomarker development and confidence in localizing nucleus LC. We used ultra-high-field 7 T magnetic resonance imaging (MRI) to acquire T1-weighted microscopy resolution images (78 μm in-plane resolution) of the LC from post-mortem tissue samples. Histological analyses were performed to characterize the distribution of tyrosine hydroxylase (TH) and neuromelanin in the scanned tissue, which allowed for direct comparison with MR microscopy images. Our results indicate that LC-MRI contrast corresponds to the location of neuromelanin cells in LC; these also correspond to norepinephrine neurons. Thus, neuromelanin appears to serve as a natural contrast agent for nucleus LC that can be used to localize nucleus LC and may have the potential to characterize neurodegenerative disease.

Studies have shown that supplementation with extracts from various sources, including fruits and vegetables reverse the age-related changes in movement and cognition. We hypothesized that these beneficial effects result from the presence of anti-oxidants and anti-inflammatory compounds in the fruits and vegetables that contribute to reduced oxidative stress, inflammation and cell death while potentially enhancing neurogenesis. The present study was performed to determine the impact of supplementation with GrandFusion®(GF) to aged Fisher 344 rats for 4 months to determine the impact on attenuation or reversal of the age-related deficits. When the aged rats consumed a diet enriched with the extracts the results showed an improved motor performance, and enhanced cognitive functions. In addition, the rats showed reduced oxidative stress and inflammation, and enhanced neurogenesis, Nrf2 and anti-oxidant expression. The effect of GF extracts on the augmentation of memory and learning is significant and may function through the modulation of antioxidant enzymes, signaling pathways and additional mechanisms to improve the aging process. These studies further support the recommendation of USDA for the consumption of fruits and vegetables to improve healthy aging.

Stroke is a leading cause of adult morbidity and mortality with very limited treatment options. Evidence from preclinical models of ischemic stroke has demonstrated that the antioxidant N-acetylcysteine (NAC) effectively protects the brain from ischemic injury. Here, we evaluated a new pathway through which NAC exerted its neuroprotection in a transient cerebral ischemia animal model. Our results demonstrated that pretreatment with NAC increased protein levels of hypoxia-inducible factor-1α (HIF-1α), the regulatable subunit of HIF-1, and its target proteins erythropoietin (EPO) and glucose transporter (GLUT)-3, in the ipsilateral hemispheres of rodents subjected to 90 min middle cerebral artery occlusion (MCAO) and 24 h reperfusion. Interestingly, after NAC pretreatment and stroke, the contralateral hemisphere also demonstrated increased levels of HIF-1α, EPO, and GLUT-3, but to a lesser extent. Suppressing HIF-1 activity with two widely used pharmacological inhibitors, YC-1 and 2ME2, and specific knockout of neuronal HIF-1α abolished NAC’s neuroprotective effects. The results also showed that YC-1 and 2ME2 massively enlarged infarcts, indicating that their toxic effect was larger than just abolishing NAC’s neuroprotective effects. Furthermore, we determined the mechanism of NAC-mediated HIF-1α induction. We observed that NAC pretreatment upregulated heat-shock protein 90 (Hsp90) expression and increased the interaction of Hsp90 with HIF-1α in ischemic brains. The enhanced association of Hsp90 with HIF-1α increased HIF-1α stability. Moreover, Hsp90 inhibition attenuated NAC-induced HIF-1α protein accumulation and diminished NAC-induced neuroprotection in the MCAO model. These results strongly indicate that HIF-1 plays an important role in NAC-mediated neuroprotection and provide a new molecular mechanism involved in the antioxidant’s neuroprotection in ischemic stroke.

The name of author “William Swindell” missed the midle initial “R.”. This should be written as “William R. Swindell” as corrected above.

The aim of this study is to quantitatively evaluate the behavior of CNS cavernous malformations (CCMs) using a dynamic contrast-enhanced MRI (DCEMRI) technique sensitive for slow transfer rates of gadolinium. The prospective study was approved by the institutional review board and was HIPPA compliant. Written informed consent was obtained from 14 subjects with familial CCMs (4 men and 10 women, ages 22-76 years, mean 48.1 years). Following routine anatomic MRI of the brain, DCEMRI was performed for six slices, using T1 mapping with partial inversion recovery (TAPIR) to calculate T1 values, following administration of 0.025 mmol/kg gadolinium DTPA. The transfer rate (Ki) was calculated using the Patlak model, and Ki within CCMs was compared to normal-appearing white matter as well as to 17 normal control subjects previously studied. All subjects had typical MRI appearance of CCMs. Thirty-nine CCMs were studied using DCEMRI. Ki was low or normal in 12 lesions and elevated from 1.4 to 12 times higher than background in the remaining 27 lesions. Ki ranged from 2.1E-6 to 9.63E-4 min(-1), mean 3.55E-4. Normal-appearing white matter in the CCM patients had a mean Ki of 1.57E-4, not statistically different from mean WM Ki of 1.47E-4 in controls. TAPIR-based DCEMRI technique permits quantifiable assessment of CCMs in vivo and reveals considerable differences not seen with conventional MRI. Potential applications include correlation with biologic behavior such as lesion growth or hemorrage, and measurement of drug effects.

In cerebral ischemia, matrix metalloproteinases (MMPs) have a dual role by acutely disrupting tight junction proteins (TJPs) in the blood-brain barrier (BBB) and chronically promoting angiogenesis. Since TJP remodeling of the neurovascular unit (NVU) is important in recovery and early inhibition of MMPs is neuroprotective, we hypothesized that short-term MMP inhibition would reduce infarct size and promote angiogenesis after ischemia. Adult spontaneously hypertensive rats had a transient middle cerebral artery occlusion with reperfusion. At the onset of ischemia, they received a single dose of the MMP inhibitor, GM6001. They were studied at multiple times up to 4 weeks with immunohistochemistry, biochemistry, and magnetic resonance imaging (MRI). We observed newly formed vessels in peri-infarct regions at 3 weeks after reperfusion. Dynamic contrast-enhanced MRI showed BBB opening in new vessels. Along with the new vessels, pericytes expressed zonula occludens-1 (ZO-1) and MMP-3, astrocytes expressed ZO-1, occludin, and MMP-2, while endothelial cells expressed claudin-5. The GM6001, which reduced tissue loss at 3 to 4 weeks, significantly increased new vessel formation with expression of TJPs and MMPs. Our results show that pericytes and astrocytes act spatiotemporally, contributing to extraendothelial TJP formation, and that MMPs are involved in BBB restoration during recovery. Early MMP inhibition benefits neurovascular remodeling after stroke.

Blood–brain barrier (BBB) disruption visualized in lesions by MRI is a major biomarker of disease activity in multiple sclerosis (MS). However, in MS, destruction occurs to a variable extent in lesions as well as in gray matter (GM) and in the normal appearing white matter (NAWM). A method to quantify the BBB disruption in lesions as well as in non-lesion areas would be useful for assessment of MS progression and treatments. The objective of this study was to quantify the BBB transfer rate (Ki) in WM lesions, in the NAWM, and in the full-brain of MS patients. Thirteen MS patients with active lesions and 10 healthy controls with age and gender matching were recruited for full-brain and WM Ki studies. Dynamic contrast-enhanced MRI (DCEMRI) scans were conducted using T1 mapping with partial inversion recovery (TAPIR), a fast T1 mapping technique, following administration of a quarter-dose of the contrast agent Gadolinium-DTPA (Gd-DTPA). The Patlak modeling technique was used to derive a voxel-based map of Ki. In all patients contrast-enhanced lesions, quantified by Ki maps, were observed. Compared with controls, patients with MS exhibited an increase in mean Ki of the full-brain (P-value

Background White matter hyperintensities (WMHs) are associated with vascular cognitive impairment (VCI) but fail to correlate with neuropsychological measures. As proton MR spectroscopy ( 1 H-MRS) can identify ischaemic tissue, we hypothesised that MRS detectable brain metabolites would be superior to WMHs in predicting performance on neuropsychological tests. Methods 60 patients with suspected VCI underwent clinical, neuropsychological, MRI and CSF studies. They were diagnosed as having subcortical ischaemic vascular disease (SIVD), multiple infarcts, mixed dementia and leukoaraiosis. We measured brain metabolites in a white matter region above the lateral ventricles with 1 H-MRS and WMH volume in this region and throughout the brain. Results We found a significant correlation between both total creatine (Cr) and N-acetylaspartyl compounds (NAA) and standardised neuropsychological test scores. Cr levels in white matter correlated significantly with executive function (p=0.001), attention (p=0.03) and overall T score (p=0.007). When lesion volume was added as a covariate, NAA also showed a significant correlation with executive function (p=0.003) and overall T score (p=0.015). Furthermore, while metabolite levels also correlated with total white matter lesion volume, adjusting the Cr levels for lesion volume did not diminish the strength of the association between Cr levels and neuropsychological scores. The lowest metabolite levels and neuropsychological scores were found in the SIVD group. Finally, lesion volume alone did not correlate significantly with any neuropsychological test score. Conclusion These results suggest that estimates of neurometabolite levels provide additional and useful information concerning cognitive function in VCI not obtainable by measurements of lesion load.

BACKGROUND Cerebral ionic homeostasis impairment, especially Ca2+, has been observed in Alzheimer's disease (AD) and also with hypertension. Hypertension and AD both have been implicated in impaired cerebral autoregulation. However, the relationship between the ionic homeostasis impairment in AD and hypertension and cerebral blood flow (CBF) autoregulation is not clear. OBJECTIVE To test the hypothesis that a high-salt diet regimen influences the accumulation of amyloid-β (Aβand CBF) and CBF, exacerbates cognitive decline, and increases the propensity to AD. METHODS Double transgenic mice harboring the amyloid-β protein precursor (APPswe), and presenilin-1 (PSEN1) along with control littermates, 2 months of age at initiation of special diet, were divided into 4 groups: Group A, APP/PS1 and Group B, controls fed a high-sodium (4.00%) chow diet for 3 months; Group C, APP/PS1 and Group D, controls fed a low-sodium (0.08%) regular chow diet for 3 months. Mean arterial blood pressure (MAP) and CBF were measured noninvasively using the tail MAP measurement device and magnetic resonance imaging, respectively. Aβ plaques numbers in the cortex and hippocampus of APP/PS1 were quantified. RESULTS In contrary to controls, APP/PS1 mice fed a high-salt diet did not show markedly elevated mean systolic and diastolic blood pressure (134±4.8 compared with 162±2.8 mmHg, and 114±5.0 compared with 137±20 mmHg, p

BACKGROUND Methadone intoxication can cause respiratory depression, leading to hypoxia with subsequent coma and death. Delayed postanoxic leukoencephalopathy (DAL) has been reported with intoxication by carbon monoxide, narcotics, and other toxins. OBJECTIVE To investigate the metabolic derangement of the white matter (WM) and blood–brain barrier (BBB) after DAL caused by methadone overdose. DESIGN, SETTING, AND PATIENTS Case report of 2 patients with DAL after a single dose of “diverted” methadone used for pain control. RESULTS In both cases brain magnetic resonance imaging (MRI) revealed initial extensive bilateral restricted diffusion lesions within the WM. Follow-up MRI using proton magnetic resonance spectroscopic imaging (1H-MRSI) showed markedly lower N-acetylaspartate and higher choline within the WM. BBB permeability, calculated by Patlak graphical analysis of MRI T1 data obtained after contrast agent injection, showed disruption of the BBB within the WM lesions, which persisted longer than a year in 1 patient. Neuropsychological evaluation showed executive dysfunction in both patients. After 1 year, one patient recovered whereas the second remained impaired. CONCLUSIONS Methadone overdose can cause DAL with profound disturbances of neural metabolism and the BBB. The time course of these disturbances can be monitored with MR methods.

Background and Purpose— Disruption of the blood–brain barrier has been proposed to be important in vascular cognitive impairment. Increased cerebrospinal fluid albumin and contrast-enhanced MRI provide supporting evidence, but quantification of the blood–brain barrier permeability in patients with vascular cognitive impairment is lacking. Therefore, we acquired dynamic contrast-enhanced MRI to quantify blood–brain barrier permeability in vascular cognitive impairment. Method— We studied 60 patients with suspected vascular cognitive impairment. They had neurological and neuropsychological testing, permeability measurements with dynamic contrast-enhanced MRI, and lumbar puncture to measure albumin index. Patients were separated clinically into subcortical ischemic vascular disease (SIVD), multiple and lacunar infarcts, and leukoaraiosis. Twenty volunteers were controls for the dynamic contrast-enhanced MRI studies, and control cerebrospinal fluid was obtained from 20 individuals undergoing spinal anesthesia for nonneurological problems. Results— Thirty-six patients were classified as SIVD, 8 as multiple and lacunar infarcts, and 9 as leukoaraiosis. The albumin index was significantly increased in the SIVD group compared with 20 control subjects. Permeabilities for the patients with vascular cognitive impairment measured by dynamic contrast-enhanced MRI were significantly increased over control subjects ( P P i values were elevated over control subjects in SIVD but were similar to multiple and lacunar infarcts. Conclusions— There was abnormal permeability in white matter in patients with SIVD as shown by dynamic contrast-enhanced MRI and albumin index. Future studies will be needed to determine the relationship of blood–brain barrier damage and development of white matter hyperintensities.

Breakdown of the blood-brain barrier (BBB), occurring in many neurological diseases, has been difficult to measure noninvasively in humans. Dynamic contrast-enhanced magnetic resonance imaging measures BBB permeability. However, important technical challenges remain and normative data from healthy humans is lacking. We report the implementation of a method for measuring BBB permeability, originally developed in animals, to estimate BBB permeability in both healthy subjects and patients with white matter pathology. Fast T(1) mapping was used to measure the leakage of contrast agent Gadolinium diethylene triamine pentaacetic acid (Gd-DTPA) from plasma into brain. A quarter of the standard Gd-DTPA dose for dynamic contrast-enhanced magnetic resonance imaging was found to give both sufficient contrast-to-noise and high T(1) sensitivity. The Patlak graphical approach was used to calculate the permeability from changes in 1/T(1). Permeability constants were compared with cerebrospinal fluid albumin index. The upper limit of the 95% confidence interval for white matter BBB permeability for normal subjects was 3 × 10(-4) L/g min. MRI measurements were not [corrected] correlated strongly with levels of cerebrospinal fluid albumin in those subjects undergoing lumbar puncture. Dynamic contrast-enhanced magnetic resonance imaging with low dose Gd-DTPA and fast T(1) imaging is a sensitive method to measure subtle differences in BBB permeability in humans and may have advantages over techniques based purely on the measurement of pixel contrast changes.

Increased permeability of the blood-brain barrier (BBB) is important in neurological disorders. Neuroinflammation is associated with increased BBB breakdown and brain injury. Tumor necrosis factor (TNF)-alpha is involved in BBB injury and edema formation through a mechanism involving matrix metalloproteinase (MMP) up-regulation. There is emerging evidence indicating that cyclooxygenase (COX) inhibition limits BBB disruption following ischemic stroke and bacterial meningitis, but the mechanisms involved are not known. We used intracerebral injection of TNF-alpha to study the effect of COX inhibition on TNF-alpha-induced BBB breakdown, MMP expression/activity, and oxidative stress. BBB disruption was evaluated by the uptake of (14)C-sucrose into the brain and by magnetic resonance imaging utilizing gadolinium-diethylenetriaminepentaacetic acid as a paramagnetic contrast agent. Using selective inhibitors of each COX isoform, we found that COX-1 activity is more important than COX-2 in BBB opening. TNF-alpha induced a significant up-regulation of gelatinase B (MMP-9), stromelysin-1 (MMP-3), and COX-2. In addition, TNF-alpha significantly depleted glutathione as compared with saline. Indomethacin (10 mg/kg i.p.), an inhibitor of COX-1 and COX-2, reduced BBB damage at 24 h. Indomethacin significantly attenuated MMP-9 and MMP-3 expression and activation and prevented the loss of endogenous radical scavenging capacity following intracerebral injection of TNF-alpha. Our results show for the first time that BBB disruption during neuroinflammation can be significantly reduced by administration of COX inhibitors. Modulation of COX in brain injury by COX inhibitors or agents modulating prostaglandin E(2) formation/signaling may be useful in clinical settings associated with BBB disruption.

Proteolytic disruption of the extracellular matrix with opening of the blood—brain barrier (BBB) because of matrix metalloproteinases (MMPs) occurs in reperfusion injury after stroke. Matrix metalloproteinase inhibition blocks the early disruption of the BBB, but the long-term consequences of short-term MMP inhibition are not known. Recently, a method to quantify BBB permeability by graphical methods was described, which provides a way to study both early disruption of the BBB and long-term effects on recovery in the same animal. We used a broad-spectrum MMP inhibitor, BB1101, to determine both the usefulness of the Magnetic resonance imaging (MRI) method for treatment studies and the long-term effects on recovery. Magnetic resonance imaging studies were performed in control ( N = 6) and drug-treated ( N = 8) groups on a dedicated 4.7-T MRI scanner. Adult Wistar—Kyoto underwent a 2-h middle cerebral artery occlusion followed by an MRI study after 3 h of reperfusion, which consisted of T2- and diffusion-weighted techniques. Additionally, a rapid T1 mapping protocol was also implemented to acquire one pre-gadolinium-diethylenetriaminepentaacetic acid baseline data set followed by postinjection data sets at 3-min intervals for 45 mins. The same animal was imaged again at 48 h for lesion size estimation. Data was postprocessed pixel-wise to generate apparent diffusion coefficient and permeability coefficient maps. Treatment with BB-1101 significantly reduced BBB permeability at 3 h, but failed to reduce lesion size at 48 h. Behavioral studies showed impairment in recovery in treated rats. Magnetic resonance imaging allowed for the monitoring of multiple parameters in the same animal. Our studies showed that BB-1101 was an excellent inhibitor of the BBB damage. However, results show that BB-1101 may be responsible for significant deterioration in neurologic status of treated animals. Although these preliminary results suggest that BB-1101 is useful in reducing early BBB leakage owing to reperfusion injury in stroke, further studies will be needed to determine whether the later detrimental effects can be eliminated by shorter time course of drug delivery.

The pharmacokinetics (PK) of the contrast agent Gd-DTPA administered intravenously (i.v.) for contrast-enhanced MR imaging (DCE-MRI) is an important factor for quantitative data acquisition. We studied the effect of various initial bolus doses on the PK of Gd-DTPA and analyzed population PK of a lower dose for intra-subject variations in DCE-MRI. First, fifteen subjects (23–85 years, M/F) were randomly divided into four groups for DCE-MRI with different Gd-DTPA dose: group-I, 0.1 mmol/kg, n = 4; group-II, 0.05 mmol/kg, n = 4; group-III, 0.025 mmol/kg, n = 4; and group-IV, 0.0125 mmol/kg, n = 3. Sequential fast T1 mapping sequence, after a bolus i.v. Gd-DTPA administered, and a linear T1-[Gd-DTPA] relationship were used to estimate the PK of Gd-DTPA. Secondly, MR-acquired PKs of Gd-DTPA from 58 subjects (28–80 years, M/F) were collected retrospectively, from an ongoing study of the brain using DCE-MRI with Gd-DTPA at 0.025 mmol/kg, to statistically analyze population PK of Gd-DTPA. We found that the PK of Gd-DTPA (i.v. 0.025 mmol/kg) had a half-life of 37.3 ± 6.6 min, and was a better fit into a linear T1-[Gd-DTPA] relationship than higher doses (up to 0.1 mmol/kg). The area under the curve (AUC) for 0.025 mmol/kg was 3.37 ± 0.46, which was a quarter of AUC of 0.1 mmol/kg. In population analysis, a dose of 0.025 mmol/kg of Gd-DTPA provided less than 5% subject-dependent variation in the PK of Gd-DTPA. Administration of 0.025 mmol/kg Gd-DTPA enabled us to estimate [Gd-DTPA] from T1 by using a linear relationship that has a lower estimation error compared to a non-linear relationship. DCE-MRI with a quarter dose of Gd-DTPA is more sensitive to detect changes in [Gd-DTPA].

Introduction: The impairment of Ca2+ homeostasis has been connected to the deleterious effect of abnormal beta-amyloid (Ab) on the calcium sensing receptors (CaSR) in Alzheimer’s disease (AD). Elevated extracellular Ca2+ can also induce relaxation of arteries and prevent the development of hypertension. Change in ionic strength reduces the effect of CaSR agonists, such as Ab, and regulates Ca2+ homeostasis. Na+ gradient also increase ionic strength and may regulate Ca2+ homeostasis through CaSR and Na+/Ca2+ antiporter exchange to affect blood pressure. In non-pathological conditions, the elevation of Na+ gradient through high-sodium diet is considered as a reason for imbalance of Na+/Ca2+, and one of the several causes of hypertension and cardiovascular complications. However, the effect of Na+ gradient on AD patients is unclear. The purpose of this study was to test the hypothesis that in AD the increase of Na+ gradient diminishes the Ab ability on activation of CaSR and does not induce the hypertension. Method: We examined the effect of Na+ load on the arterial blood pressure in double transgenic mice harboring Ab precursor protein (APPswe), and presenilin-1 (PSEN1) as mouse model of AD (10-20 weeks, 25-30g). Wild type littermates were used as controls. Four groups: Control + low sodium diet (n=6); Control + high sodium diet (n=12); APP + low sodium diet (n=12); APP + high sodium diet (n=12) were tested for both systolic arterial blood pressure (SAP) and diastolic arterial blood pressure (DAP). Mice were fed a low- (0.08% NaCl) or a high-sodium (4% NaCl) diet for 3 months. Heart rate and SAP and DAP were measured noninvasively using tail blood pressure measurement device after 3 months. Results: Compared with mice fed standard diet (0.08% NaCl), mice fed high sodium diet showed markedly elevated SAP and DAP (134±4.8 compared with 162±2.8 mmHg, and 114±5.0 compared with 137±20 mmHg) (p Conclusion: Data from this AD model suggest that APP transgenic mice is resistant to high sodium-induced increase in systolic and diastolic blood pressure.

Introduction The blood–brain barrier (BBB) plays an important role in the pathophysiology of a number of central nervous system disorders. In the past, a number of laboratory techniques have been proposed to quantify permeability coefficient k i , an important index of barrier function. Recently, magnetic resonance imaging (MRI) has been used to estimate k i based on graphical plot technique. The MR technique was found to be in good agreement with the gold standard, quantitative autoradiography (QAR). However, a reduced image signal-to-noise ratio, among other factors such as partial volume effects, did not allow reliable estimation of permeability coefficients. This proof-of-principle study proposes the use of Kalman filter as a filtering technique for a reliable estimation of permeability coefficients. The results are compared to those obtained using the Wiener filter technique. Materials and Methods MRI experiments were performed in Wistar rats ( N =2) using a 4.7-T Bruker Biospec MR system (Bruker Biospin, Billerica, MA). After acquiring localizer images, T 2 -weighted diffusion-weighted imaging images were acquired. Finally, a rapid T 1 mapping protocol was implemented to acquire one pre-gadolinium diethylenetriamine pentaacetic acid baseline data set followed by postinjection data sets at 3-min intervals for 45 min. Data were postprocessed with and without the application of Kalman and Wiener filters to obtain an estimate of k i . Results and Discussion Comparing T 1 maps, Patlak plots and permeability maps with and without the Kalman filtering presented several interesting observations. Kalman-filtered Patlak plots, compared to nonfiltered plots, showed that discrete data points on the plot were closer to the line fit. The number of time points used for the construction of the graphical plot had no effect on permeability coefficient estimates when the Kalman filter was used. A box-and-whiskers plot showed longer Y -error bars for nonfiltered and Wiener data compared to Kalman-filtered data. These observations suggest that it may be possible to obtain reliable permeability coefficient estimates in a short study time by applying the Kalman filter to the data. Future work involves investigating the application of this filter on a large-sample-size animal study and evaluating the role of partial volume effects on BBB permeability estimation.

Introduction Image contrast between tissue types can be generated based on their T 1/ T 2 ratio using spin-lock MRI techniques. An interesting application of such a concept would be to generate contrast in tissue with tissue relaxation times modified using exogenous contrast agents. An amplitude-modulated adiabatic waveform has been shown in the past to perform spin-lock MRI. However, implementation of this waveform may not prove to be efficient and practical in research or a clinical setup due to high radiofrequency power deposition. Recent advancement in software and hardware MR technology allows implementation of amplitude- and phase-modulated adiabatic waveforms on MR systems. The aim of this work was to explore role of adiabatic waveforms in performing ρ imaging and demonstrate that amplitude- and phase-modulated waveforms [e.g., hyperbolic secant, B1 independent rotation-4 (BIR-4) waveforms] can be used to distinguish materials that differ in T 1/ T 2 ratio. Methods and Results MR simulation was performed using computer routines implemented in MATLAB environment (Mathworks, Natick, MA). Modified Bloch equations with trapezoidal, hyperbolic secant and BIR-4 waveforms were used to perform MR simulation. Trapezoidal waveforms were only used for comparison to other waveforms. Gadolinium DTPA (Gad-DTPA) ( T 1/ T 2∼1) and manganese chloride (MnCl 2 ) ( T 1/ T 2∼10) were used as examples of contrast agents due to their routine use in clinical and research setups and more importantly because they provide good examples of materials differing in T 1/ T 2 ratios. Results of spin locking using trapezoidal waveform agree very well with the previously published results, thereby validating the computer routines used in this MR simulation. Plots of M ρ (magnetization vector in ρ domain) vs. offset frequency show distinct curves for these materials differing in T 1/ T 2 for the three waveforms. BIR-4 waveform demonstrated a 40% difference in M ρ (∼150 Hz) for the materials. Rate of spin lock with hyperbolic secant waveform was rapid compared to other waveforms. Discussion MR simulation using contrast agents Gad-DTPA and MnCl 2 provided a useful way to demonstrate that amplitude- and phase-modulated adiabatic waveforms can be used to perform spin-lock imaging. Future work involves implementation of these waveforms on MR scanners and performing in vivo imaging to generate tissue contrast based on relaxation times ratio.