Impaired hippocampal-cortical coupling but preserved local synchrony during sleep in APP/PS1 mice modeling Alzheimer's disease.

Sleep, in addition to its brain restorative processes, plays an important role in memory transfer from its temporary store in the hippocampus to the more permanent storage in the neocortex. Alzheimer's disease (AD) affects memory and sleep. The aim of this study was to explore disturbances in global and local synchrony patterns between brain regions in the APP/PS1 mouse model of the AD during natural sleep. We used 8 male APPswe/PS1dE9 mice and 6 wild-type littermates, aged 5-6 months, with multiple electrode bundles implanted into cortical regions, thalamus and hippocampus. We measured video-EEG in freely moving animals and analyzed synchrony during NREM vs REM sleep. Global synchrony between medial frontal cortex and hippocampus measured with magnitude-squared coherence was slightly decreased in delta range during NREM stage of sleep in APP/PS1 mice. In contrast, local hippocampal synchrony measured with cross-frequency coupling remained intact. Ripple structure or frequency did not differ between the genotypes. However, the coupling of the spindle-band power peak in the medial prefrontal cortex to hippocampal ripples was significantly decreased compared to wild-type animals. The delicate timing of hippocampal ripples, frontal delta, and corticothalamic spindle oscillations may be the first sign of impaired memory in amyloid plaque-forming transgenic mice.

Effect of collagen cross-linking on quantitative MRI parameters of articular cartilage.

OBJECTIVE: To investigate the sensitivity of quantitative magnetic resonance imaging (MRI) parameters to increase of collagen cross-linking in articular cartilage, a factor possibly contributing to the aging-related development of osteoarthritis (OA). The issue has not been widely studied although collagen cross-links may significantly affect the evaluation of cartilage imaging outcome. DESIGN: Osteochondral samples (n = 14) were prepared from seven bovine patellae. To induce cross-linking, seven samples were incubated in threose while the other seven served as non-treated controls. The specimens were scanned at 9.4 T for T1, T1Gd (dGEMRIC), T2, adiabatic and continuous wave (CW) T1ρ, adiabatic T2ρ and T1sat relaxation times. Specimens from adjacent tissue were identically treated and used for reference to determine biomechanical properties, collagen, proteoglycan and cross-link contents, fixed charge density (FCD), collagen fibril anisotropy and water concentration of cartilage. RESULTS: In the threose-treated sample group, cross-links (pentosidine, lysyl pyridinoline (LP)), FCD and equilibrium modulus were significantly (P < 0.05) higher as compared to the non-treated group. Threose treatment resulted in significantly greater T1Gd relaxation time constant (+26%, P < 0.05), although proteoglycan content was not altered. Adiabatic and CW-T1ρ were also significantly increased (+16%, +28%, P < 0.05) while pre-contrast T1 was significantly decreased (-10%, P < 0.05) in the threose group. T2, T2ρ and T1sat did not change significantly. CONCLUSION: Threose treatment induced collagen cross-linking and changes in the properties of articular cartilage, which were detected by T1, T1Gd and T1ρ relaxation time constants. Cross-linking should be considered especially when interpreting the outcome of contrast-enhanced MRI in aging populations.

Imaging microstructural damage and plasticity in the hippocampus during epileptogenesis.

Epileptogenesis refers to the development and extension of tissue capable of generating spontaneous seizures, resulting in the development of an epileptic condition and/or progression of epilepsy after the condition is established. The hippocampus is the seizure-initiating zone in many epilepsy patients as well as in animal models of epilepsy. During epileptogenesis, the hippocampus undergoes structural changes, including mossy fiber sprouting; alterations in dendritic branching, spine density, and shape; and neurogenesis. In vivo magnetic resonance imaging (MRI) techniques provide insights into the microstructural organization of the hippocampus. An assessment of the structural plasticity of the hippocampus may provide parameters that could be used as biomarkers for epileptogenesis. Here we review conventional and more advanced MRI methods for detecting hippocampal tissue changes related to epileptogenesis. In addition, we summarize how diffusion tensor imaging can reveal cellular damage and plasticity, even at the level of hippocampal subfields. Finally, we discuss challenges and future directions for using novel MRI techniques in the search of biomarkers associated with epileptogenesis after brain injury.

Effect of lacosamide on structural damage and functional recovery after traumatic brain injury in rats.

In a subgroup of patients, traumatic brain injury (TBI) results in the occurrence of acute epileptic seizures or even status epilepticus, which are treated with antiepileptic drugs (AEDs). Recent experimental data, however, suggest that administration of AEDs at the early post-injury phase can compromise the recovery process. The present study was designed to assess the profile of a novel anticonvulsant, lacosamide (Vimpat) on post-TBI structural, motor and cognitive outcomes. Moderate TBI was induced by lateral fluid-percussion injury in adult rats. Treatment with 0.9% saline or lacosamide (30 mg/kg, i.p.) was started at 30 min post-injury and continued at 8h intervals for 3d (total daily dose 90 mg/kg/d). Rats were randomly assigned to 4 treatment groups: sham-operated controls treated with vehicle (Sham-Veh) or lacosamide (Sham-LCM) and injured animals treated with vehicle (TBI-Veh) or lacosamide (TBI-LCM). As functional outcomes we tested motor recovery with composite neuroscore and beam-walking at 2, 7, and 15 d post-injury. Cognitive recovery was tested with the Morris water-maze at 12-14 d post-TBI. To assess the structural outcome, animals underwent magnetic resonance imaging (MRI) at 2 d post-TBI. At 16d post-TBI, rats were perfused for histology to analyze cortical and hippocampal neurodegeneration and axonal damage. Our data show that at 2 d post-TBI, both the TBI-Veh and TBI-LCM groups were equally impaired in neuroscore. Thereafter, motor recovery occurred similarly during the first week. At 2 wk post-TBI, recovery of the TBI-LCM group lagged behind that in the TBI-VEH group (p<0.05). Performance in beam-walking did not differ between the TBI-Veh and TBI-LCM groups. Both TBI groups were similarly impaired in the Morris water-maze at 2 wk post-TBI. MRI and histology did not reveal any differences in the cortical or hippocampal damage between the TBI-Veh and TBI-LCM groups. Taken together, acute treatment with LCM had no protective effects on post-TBI structural or functional impairment. Composite neuroscore in the TBI-LCM group lagged behind that in the TBI-Veh group at 15 d post-injury, but no compromise was found in other indices of post-TBI recovery in the LCM treated animals.

In vivo magnetic resonance imaging and spectroscopy identifies oncolytic adenovirus responders.

At present, it is not possible to reliably identify patients who will benefit from oncolytic virus treatments. Conventional modalities such as computed tomography (CT), which measure tumor size, are unreliable owing to inflammation-induced tumor swelling. We hypothesized that magnetic resonance imaging (MRI) and spectroscopy (MRS) might be useful in this regard. However, little previous data exist and neither oncolytic adenovirus nor immunocompetent models have been assessed by MRS. Here, we provide evidence that in T2-weighted MRI a hypointense core area, consistent with coagulative necrosis, develops in immunocompetent Syrian hamster carcinomas that respond to oncolytic adenovirus treatment. The same phenomenon was observed in a neuroblastoma patient while he responded to the treatment. With relapse at a later stage, however, the tumor of this patient became moderately hyperintense. We found that MRS of taurine, choline and unsaturated fatty acids can be useful early indicators of response and provide detailed information about tumor growth and degeneration. In hamsters, calprotectin-positive inflammatory cells (heterophils and macrophages) were found in abundance; particularly surrounding necrotic areas in carcinomas and T cells were significantly increased in sarcomas, when these had been treated with a granulocyte-macrophage colony-stimulating factor-producing virus, suggesting a possible link between oncolysis, necrosis (seen as a hypointense core in MRI) and/or immune response. Our study indicates that both MRI and MRS could be useful in the estimation of oncolytic adenovirus efficacy at early time points after treatment.

Cortical spreading depression induces oxidative stress in the trigeminal nociceptive system.

Indirect evidence suggests the increased production of reactive oxygen species (ROS) in migraine pathophysiology. In the current study we measured lipid peroxidation product in the rat cortex, trigeminal ganglia and meninges after the induction of cortical spreading depression (CSD), a phenomenon known to be associated with migraine aura, and tested nociceptive firing triggered by ROS in trigeminal nerves ex vivo. Application of KCl to dura mater in anesthetized rats induced several waves of CSD recorded by an extracellular electrode in the cortex. Following CSD, samples of cortex (affected regions were identified with blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI)), meninges from left and right hemispheres and trigeminal ganglia were taken for biochemical analysis. We found that CSD increased the level of the lipid peroxidation product malondialdehyde (MDA) in the ipsilateral cerebral cortex and meninges, but also in both ipsi- and contralateral trigeminal ganglia. In order to test the pro-nociceptive action of ROS, we applied the mild oxidant hydrogen peroxide to isolated rat hemiskull preparations including preserved trigeminal innervations. Application of hydrogen peroxide to meninges transiently enhanced electrical spiking activity of trigeminal nerves showing a pro-nociceptive action of ROS. In the presence of hydrogen peroxide trigeminal nerves still responded to capsaicin by burst of spiking activity indicating integrity of neuronal structures. The action of hydrogen peroxide was mediated by TRPA1 receptors as it was abolished by the specific TRPA1 antagonist TCS-5861528. Using dorsal root ganglion sensory neurons as test system we found that hydrogen peroxide promoted the release of the migraine mediator calcitonin gene-related peptide (CGRP), which we previously identified as a trigger of delayed sensitization of trigeminal neurons. Our data suggest that, after CSD, oxidative stress spreads downstream within the trigeminal nociceptive system and could be involved in the coupling of CSD with the activation of trigeminovascular system in migraine pathology.

Mild cognitive impairment associates with concurrent decreases in serum cholesterol and cholesterol-related lipoprotein subclasses.

BACKGROUND AND OBJECTIVE: Accumulating evidence suggests that serum lipids are associated with cognitive decline and dementias. However, majority of the existing information concerns only serum total cholesterol (TC) and data at the level of lipoprotein fractions and subclasses is limited. The aim of this study was to explore the levels and trends of main cholesterol and triglyceride measures and eight lipoprotein subclasses during normal aging and the development of mild cognitive impairment by following a group of elderly for six years. DESIGN: Longitudinal. SETTING: City of Kuopio, Finland. PARTICIPANTS: 45 elderly individuals of which 20 developed mild cognitive impairment (MCI) during the follow-up. MEASUREMENTS: On each visit participants underwent an extensive neuropsychological and clinical assessment. Lipoprotein levels were measured via 1H NMR from native serum samples. RESULTS: Serum cholesterol and many primarily cholesterol-associated lipoprotein measures clearly decreased in MCI while the trends were increasing for those elderly people who maintained normal cognition. CONCLUSION: These findings suggest that a decreasing trend in serum cholesterol measures in elderly individuals may suffice as an indication for more detailed inspection for potential signs of cognitive decline.

Galactolipid deficiency in the early pathogenesis of neuronal ceroid lipofuscinosis model Cln8mnd : implications to delayed myelination and oligodendrocyte maturation.

AIMS: CLN8 deficiency underlies one of a group of devastating childhood neurodegenerative disorders, the neuronal ceroid lipofuscinoses. The function of the CLN8 protein is currently unknown, but a role in lipid metabolism has been proposed. In human CLN8 diseased brains, alterations in lipid composition have been detected. To further investigate the connection of CLN8 to lipid metabolism, we characterized the lipid composition of early symptomatic Cln8-deficient mouse (Cln8(mnd)) brains. METHODS: For lipid profiling, Cln8(mnd) cerebral cortical tissue was analysed by liquid chromatography/mass spectrometry. Galactolipid synthesis was measured through enzyme activity and real-time mRNA expression analyses. Based on the findings, myelination and white matter integrity were studied by immunohistochemistry, stereological methods, electron microscopy and magnetic resonance imaging. The development of myelin-forming oligodendrocytes was also studied in vitro. RESULTS: Sphingolipid profiling showed a selective reduction in myelin-enriched galactolipids. The mRNA expression and activity of UDP-galactose:ceramide galactosyltransferase (CGT), the key enzyme in the galactolipid synthesis, was reduced in the Cln8(mnd) brain. Expression of oligodendrocyte markers suggests a maturation defect. The amount of myelin was reduced in 1-month-old Cln8(mnd) mice, but reached normal levels by 5 months of age. The level of Cln8 gene expression followed the developmental pattern of myelin formation and was high in primary oligodendrocytes. CONCLUSIONS: Taken together, these observations suggest that galactolipid deficiency and delayed myelin maturation characterize the early CLN8 disease pathogenesis through a maturation defect of oligodendrocytes.

Cotargeting of VEGFR-1 and -3 and angiopoietin receptor Tie2 reduces the growth of solid human ovarian cancer in mice.

Despite optimal surgery and chemotherapy, the prognosis of ovarian cancer patients remains poor and new treatments are urgently needed. Solid tumors require the formation of new vessels for growth and metastasis. In the present study, we have used soluble vascular endothelial growth factor (sVEGF) receptors sVEGFR-1 and -3, soluble receptors Tie1 and Tie2 and their combinations in an ovarian cancer xenograft model. Human ovarian cancer cells were injected intraperitoneally into nude mice (n=42) and magnetic resonance imaging (MRI) was used for confirming tumors before gene delivery. Treatment with combined AdsVEGFR-1, AdsVEGFR-3 and AdsTie2 significantly decreased the size of the intraperitoneal tumors compared with the controls (AdLacZ; P=0.038) with significantly less microvessels and vascular area. Unexpectedly, treatment with combined AdsTie1 and AdsTie2 led to a dramatic shortening of the survival which was not observed in the groups receiving either of the soluble receptors alone (P=0.031). The only difference to other treatments was liver toxicity observed after the combined Tie receptor treatment. In conclusion, combined inhibition of VEGFR-1, VEGFR-3 and Tie2 pathways was safe and provided efficient therapy for ovarian cancer in mice.

Vascular changes in epilepsy: functional consequences and association with network plasticity in pilocarpine-induced experimental epilepsy.

Angiogenesis and blood-brain-barrier (BBB) damage have been proposed to contribute to epileptogenesis and/or ictogenesis in experimental and human epilepsy. We tested a hypothesis that after brain injury angiogenesis occurs in the most damaged hippocampal areas with the highest need of tissue repair, and associates with formation of epileptogenic neuronal networks. We induced status epilepticus (SE) with pilocarpine in adult rats, and investigated endothelial cell proliferation (BrdU and rat endothelial cell antigen-1 (RECA-1) double-labeling), vessel length (unbiased stereology), thrombocyte aggregation (thrombocyte immunostaining), neurodegeneration (Nissl staining), neurogenesis (doublecortin (DCX) immunohistochemistry), and mossy fiber sprouting (Timm staining) in the hippocampus at different time points post-SE. As functional measures we determined BBB leakage (quantified immunoglobulin G (IgG) immunostaining), and hippocampal blood volume (CBV) and flow (CBF) in vivo (magnetic resonance imaging, MRI). The total length of hippocampal blood vessels was decreased by 17% at 2 d after status epilepticus (SE) induced by pilocarpine in adult rats (P<0.05 as compared to controls) which was not accompanied by alterations in hippocampal blood volume (BV) and flow (BF). Number of proliferating endothelial cells peaked at 4 d post-SE and correlated with an increase in vessel length (r=0.900, P<0.05). Vessels length had recovered to control level or even higher at 2 wk post-SE, angiogenesis being most prominent in the CA3 (128% as compared to that in controls, P<0.05), and was associated with increased BV (178% as compared to that in controls, P<0.05). Enlargement of vessel diameter in the hippocampal fissure was associated with thrombocyte aggregation in distal capillaries. BBB was most leaky during the first 4 d post-SE and increased IgG extravasation was observed for 60 d. Our data show that magnitude of endothelial cell proliferation is not associated with severity of acute post-SE neurodegeneration or formation of abnormal neuronal network. This encourages identification of molecular targets that initiate and maintain specific aspects of tissue reorganization, including preservation and proliferation of endothelial cells to reduce the risk of epileptogenesis and enhance recovery after brain injury.

(Strept)avidin-displaying lentiviruses as versatile tools for targeting and dual imaging of gene delivery.

Lentiviruses have shown great promise for human gene therapy. However, no optimal strategies are yet available for noninvasive imaging of virus biodistribution and subsequent transduction in vivo. We have developed a dual-imaging strategy based on avidin-biotin system allowing easy exchange of the surface ligand on HIV-derived lentivirus envelope. This was achieved by displaying avidin or streptavidin fused to the transmembrane anchor of vesicular stomatitis virus G protein on gp64-pseudotyped envelopes. Avidin and streptavidin were efficiently incorporated on virus particles, which consequently showed binding to biotin in ELISA. These vectors, conjugated to biotinylated radionuclides and engineered to express a ferritin transgene, enabled for the first-time dual imaging of virus biodistribution and transduction pattern by single-photon emission computed tomography and magnetic resonance imaging after stereotactic injection into rat brain. In addition, vector retargeting to cancer cells overexpressing CD46, epidermal growth factor and transferrin receptors using biotinylated ligands and antibodies was demonstrated in vitro. In conclusion, we have generated novel lentivirus vectors for noninvasive imaging and targeting of lentivirus-mediated gene delivery. This study suggests that these novel vectors could be applicable for the treatment of central nervous system disorders and cancer.

Water spin dynamics during apoptotic cell death in glioma gene therapy probed by T1rho and T2rho.

Longitudinal and transverse relaxations in the rotating frame, with characteristic time constants T1rho and T2rho, respectively, have potential to provide unique MRI contrast in vivo. On-resonance spin-lock T1rho with different spin-lock field strengths and adiabatic T2rho with different radiofrequency-modulation functions were measured in BT4C gliomas treated with Herpes Simplex Virus thymidine kinase (HVS-tk) gene therapy causing apoptotic cell death. These NMR tools were able to discriminate different treatment responses in tumor tissue from day 4 onward. An equilibrium two-site exchange model was used to calculate intrinsic parameters describing changes in water dynamics. Observed changes included increased correlation time of water associated with macromolecules and a decreased fractional population of this pool. These results are consistent with destructive intracellular processes associated with cell death and the increase of extracellular space during the treatment. Furthermore, association between longer exchange correlation time and decreased pH during apoptosis is discussed. In this study, we demonstrated that T1rho and T2rho MR imaging are useful tools to quantify early changes in water dynamics reflecting treatment response during gene therapy.

T2, Carr-Purcell T2 and T1rho of fat and water as surrogate markers of trabecular bone structure.

Magnetic resonance imaging (MRI) techniques have been developed for non-invasive assessment of the structural properties of trabecular bone. These measurements, however, suffer from relatively long acquisition times and low resolution compared to the trabecular size. Spectroscopic measurement of relaxation times could be applied for more detailed and faster assessment of relaxation properties of bone marrow and also provide surrogate information on trabecular structure. In the present study, bovine trabecular bone was investigated with spectroscopic NMR (nuclear magnetic resonance) methods to determine the relationship between structural parameters as measured with micro-CT and T(2), Carr-Purcell T(2) and T(1rho) relaxation times of fat and water. To compare bone with a sample matrix with magnetic susceptibility interfaces, phantoms consisting of glass beads with different diameters in oil or water were used. The behavior of T(2) measured with different sequences and T(1rho) at different magnitudes of spin-lock fields were characterized, and relaxation times were correlated with structural parameters. T(2) and T(1rho) showed significant associations with structural bone parameters. Strongest linear correlations (r = 0.81, p < 0.01) were established between R(1rho) (1/T(1rho)) of fat component and structural model index. For glass beads, the behavior of T(2) and T(1rho) was similar to that of the water compartment of bone marrow. The present results suggest feasibility of spectroscopic NMR measurements to assess trabecular structure. However, further studies are required to determine the sensitivity of this approach to fat content of bone marrow and to lower the field strengths used in clinical devices.

Proton exchange as a relaxation mechanism for T1 in the rotating frame in native and immobilized protein solutions.

T1 relaxation in the rotating frame (T1rho) is a sensitive magnetic resonance imaging (MRI) contrast for acute brain insults. Biophysical mechanisms affecting T1rho relaxation rate (R1rho) and R1rho dispersion (dependency of R1rho on the spin-lock field) were studied in protein solutions by varying their chemical environment and pH in native, heat-denatured, and glutaraldehyde (GA) cross-linked samples. Low pH strongly reduced R1rho in heat-denatured phantoms displaying proton resonances from a number of side-chain chemical groups in high-resolution 1H NMR spectra. At pH of 5.5, R1rho dispersion was completely absent. In contrast, in the GA-treated phantoms with very few NMR visible side chain groups, acidic pH showed virtually no effect on R1rho. The present data point to a crucial role of proton exchange on R1rho and R1rho dispersion in immobilized protein solution mimicking tissue relaxation properties.

Assessment of brain tissue viability in acute ischemic stroke by BOLD MRI.

The introduction of new neuroprotective treatment strategies for acute stroke patients has provided a requirement for neuroimaging methods capable of identifying salvageable tissue in acute stroke patients. Substantial positron emission tomography evidence points to the fact that a peri-infarct zone with blood flow of 20-45% of normal, metabolic rate of oxygen of >35% of normal and oxygen extraction ratio (OER) of >0.7 are indices of tissue at risk of infarction, yet with potential for recovery. The sensitivity of T(2) to blood oxygen level dependent (BOLD) effects allows the mismatch between oxygen delivery and consumption in the brain to be imaged. Previous evidence from animal models of cerebral hypoperfusion and ischemic stroke strongly suggest that T(2) BOLD MRI highlights viable and salvageable brain regions. The Hahn-echo T(2) and diffusion show distinct flow thresholds in the rat brain so that the former parameter probes areas with high OER and the latter genuine ischemia. In the flow-compromised tissue showing negative T(2) BOLD, substantial residual perfusion is evident as revealed by bolus-tracking perfusion MRI, in agreement with the idea that tissue metabolic viability must be preserved for expression of BOLD. It is concluded that BOLD MRI may have potential for the assessment of tissue viability in acute ischemic stroke.

Cerebral T1rho relaxation time increases immediately upon global ischemia in the rat independently of blood glucose and anoxic depolarization.

Time-dependent changes of T1 in the rotating frame (T1rho), diffusion, T2, and magnetization transfer contrast on cardiac arrest-induced global ischemia in rat were investigated. T1rho, as acquired with spin lock amplitudes >0.6 G, started to increase 10-20 sec after cardiac arrest followed by an increase within 3-4 min to a level that was 6-8% greater than in normal brain. The ischemic T1rho response coincided with the drop of water diffusion coefficient in normoglycemic animals. However, unlike the rate of diffusion, the kinetics of T1rho were not affected by either preischemic hypoglycemia or hyperglycemia. Similar to diffusion, the kinetics of anoxic depolarization were dependent on preischemic blood glucose levels. Ischemia caused a reduction in the Hahn spin echo T2 as a result of blood oxygenation level-dependent (BOLD) effect; maximal negative BOLD seen by 40 sec. In the animals injected with an ironoxide particle contrast agent, AMI-227, prior to the insult, both T1rho and T2 immediately increased in concert on induction of ischemia. In contrast to the T1rho and diffusion changes, a much slower change in magnetization transfer contrast was evident over the first 20 min of ischemia. These data demonstrate that T1rho immediately increases following ischemia and that the pathophysiological mechanisms affecting this relaxation time may not directly involve magnetization transfer. The mechanisms prolonging T1rho differ from those affecting water diffusion with respect to their sensitivities to glucose and are apparently independent of membrane depolarization.

Use of spin echo T(2) BOLD in assessment of cerebral misery perfusion at 1.5 T.

Inadequate blood supply relative to metabolic demand, a haemodynamic condition termed as misery perfusion, often occurs in conjunction with acute ischaemic stroke. Misery perfusion results in adaptive changes in cerebral physiology including increased cerebral blood volume (CBV) and oxygen extraction ratio (OER) to secure substrate supply for the brain. It has been suggested that the presence of misery perfusion may be an indication of reversible ischaemia, thus detection of this condition may have clinical impact in acute stroke imaging. The ability of single spin echo T(2) to detect misery perfusion in the rat brain at 1.5 T owing to its sensitivity to blood oxygenation level dependent (BOLD) contrast was studied both theoretically and experimentally. Based on the known physiology of misery perfusion, tissue morphometry and blood relaxation data, T(2) behaviour in misery perfusion was simulated. The interpretation of these computations was experimentally assessed by quantifying T(2) in a rat model for cerebral misery perfusion. CBF was quantified with the H(2) clearance method. A drop of CBF from 58+/-8 to 17+/-3 ml/100 g/min in the parieto-frontal cortex caused shortening of T(2) from 66.9+/-0.4 to 64.6+/-0.5 ms. Under these conditions, no change in diffusion MRI was detected. In contrast, the cortex with CBF of 42+/-7 ml/100 g/min showed no change in T(2). Computer simulations accurately predicted these T(2) responses. The present study shows that the acute drop of CBF by 70% causes a negative BOLD that is readily detectable by T(2) MRI at 1.5 T. Thus BOLD may serve as an index of misery perfusion thus revealing viable tissue with increased OER.

Interrelations of T(1) and diffusion of water in acute cerebral ischemia of the rat.

Interrelation of T(1) and diffusion of water was studied in rat models of acute global and focal cerebral ischemia. Cortical T(1), as quantified with an inversion recovery method, increased by 4-7% within a few minutes of global ischemia at 4.7 and 9.4 T, but a significantly smaller change was detected at 1.5 T. The initial T(1) change occurred within seconds of cardiac arrest, much earlier than the extensive diffusion drop after 1-2 min. Thus, the initial increase in T(1) upon acute cerebral ischemia is directly caused by cessation of blood flow. In transient middle cerebral artery occlusion (MCAO), prolonged T(1) relaxation was detected within 10 min, with a subsequent increase during the course of ischemia. Spin density did not change during the first hour, showing that T(1) increase was not caused by net accumulation of water. Interestingly, partial recovery of T(1) upon release of MCAO, occurring independent of long-term tissue outcome, was observed only in concert with diffusion recovery.

Transgenic mice overexpressing truncated trkB neurotrophin receptors in neurons show increased susceptibility to cortical injury after focal cerebral ischemia.

It has been suggested that the increased production of endogenous BDNF after brain insults supports the survival of injured neurons and limits the spread of the damage. In order to test this hypothesis experimentally, we have produced transgenic mouse lines that overexpress the dominant-negative truncated splice variant of BDNF receptor trkB (trkB.T1) in postnatal cortical and hippocampal neurons. When these mice were exposed to transient focal cerebral ischemia by occluding the middle cerebral artery for 45 min and the damage was assessed 24 h later, transgenic mice had a significantly larger damage than wild-type littermates in the cerebral cortex (204 +/- 32% of wild-type, P = 0.02), but not in striatum, where the transgene is not expressed. Our results support the notion that endogenously expressed BDNF is neuroprotective and that BDNF signaling may have an important role in preventing brain damage after transient ischemia.

Graded reduction of cerebral blood flow in rat as detected by the nuclear magnetic resonance relaxation time T2: a theoretical and experimental approach.

The ability of transverse nuclear magnetic resonance relaxation time, T2, to reveal acutely reduced CBF was assessed using magnetic resonance imaging (MRI). Graded reduction of CBF was produced in rats using a modification of Pulsinelli's four-vessel occlusion model. The CBF in cerebral cortex was quantified using the hydrogen clearance method, and both T2 and the trace of the diffusion tensor (Dav = 1/3TraceD) in the adjacent cortical tissue were determined as a function of reduced CBF at 4.7 T. A previously published theory, interrelating cerebral hemodynamic parameters, hemoglobin, and oxygen metabolism with T2, was used to estimate the effects of reduced CBF on cerebral T2. The MRI data show that T2 reduces in a U-shape manner as a function of CBF, reaching a level that is 2.5 to 2.8 milliseconds (5% to 6%) below the control value at CBF, between 15% and 60% of normal. This reduction could be estimated by the theory using the literature values of cerebral blood volume, oxygen extraction ratio, and precapillary oxygen extraction during compromised CBF. Dav dropped with two apparent flow thresholds, so that a small 11% to 17% reduction occurred between CBF values of 16% to 45% of normal, followed by a precipitous collapse by more than 20% at CBF below 15% of normal. The current data show that T2 can be used as an indicator of acute hypoperfusion because of its ability to indicate blood oxygenation level-dependent phenomena on reduced CBF.