Hyperpolarized (129)Xe spectra from C6 glioma cells implanted in rat brains.

Tumor cell density is dramatically different from normal tissue. Since the chemical shift of hyperpolarized (129)Xe reflects local cell structure, we hypothesized that the presence of tumor cells could potentially be determined from (129)Xe spectra. Spectra and washout decay rate from three rats implanted with C6 glioma cells were compared with eight control rats. No significant differences between normal and tumor spectra were observed. The decay time of the C6 rats (mean 13.5 ± 1.9 s) was not significantly different from normal rats (mean 11.7 ± 1.8 s). These results suggest that hyperpolarized Xe may not be a superior tracer for detection of tumor cells in the intact brain.

Quantitative accuracy of delayed hyperperfusion in MRI of transient ischemia in rats.

A strong hyperperfusion was reported in transient ischemic tissue between 48 and 72 hours after middle cerebral artery occlusion (MCAO). Cerebral blood flow (CBF) estimated by continuous arterial spin labeling (CASL) with short delay after tagging was sensitive to cerebral blood volume (CBV) change. The delayed hyperperfusion may indicate a CBV increase after MCAO. For confirmation of the delayed hyperperfusion, we investigated a transit-time dependency in CASL at two days after MCAO. We also acquired CBF using the dynamic susceptibility contrast (DSC) at the same day. We have confirmed the CBF in transient ischemic tissue is quite higher (179.1+/-21.6 ml/100g/min) than normal tissue (121.0+/-6.9 ml/100g/min) with CASL using tagging delay of 0.4 sec. CBF estimated by DSC also show delayed hyperperfusion in transient ischemic tissue. These results confirm existence of physiological delayed hyperperfusion in transient ischemic area.

Clinical diagnosis of vascular dementia.

Vascular dementia (VaD) is a heterogeneous clinical entity based on various vascular pathophysiological processes underlying the subtypes of cerebrovascular disease (CVD). Several diagnostic criteria are currently being used for the clinical diagnosis of VaD, but they are mostly more than 10 years old and need to be renovated including the use of functional brain imaging methods such as single photon emission computerized tomography (SPECT). There is a limitation in the diagnosis based on the strict dichotomy between AD and VaD, and the concept of "AD with CVD" or "mixed dementia" should be included in the clinical diagnosis of VaD.

Confirming the existence of five peaks in 129Xe rat head spectra.

A series of experiments were performed to investigate why two peaks (D and E) of the five dissolved phase peaks in hyperpolarized (129)Xe rat head spectra appeared inconsistently in previous work. Specifically, spectra were acquired under conditions of various shim states, anaesthetics, and arterial ligation. The shimming experiments showed that slice-shimming can be used to improve resolution of the dissolved phase peaks, but even so, subtle changes in the shim state that may dramatically alter the shape of peak E remain poorly understood. Also, the inability to shim gas spaces and tissue simultaneously may explain why inconsistent chemical shift values have been reported in the literature. A possible solution for this problem is suggested. The results of pre- and postligation spectra from the same animal indicated that two peaks (A and E) originate from brain. Changing the anaesthetic was found to have no effect on the number of dissolved peaks in xenon spectra.

Loss of M5 muscarinic acetylcholine receptors leads to cerebrovascular and neuronal abnormalities and cognitive deficits in mice.

The M5 muscarinic acetylcholine receptor (M5R) has been shown to play a crucial role in mediating acetylcholine-dependent dilation of cerebral blood vessels. We show that male M5R-/- mice displayed constitutive constriction of cerebral arteries using magnetic resonance angiography in vivo. Male M5R-/- mice exhibited a significantly reduced cerebral blood flow (CBF) in the cerebral cortex, hippocampus, basal ganglia, and thalamus. Cortical and hippocampal pyramidal neurons from M5R-/- mice showed neuronal atrophy. Hippocampus-dependent spatial and nonspatial memory was also impaired in M5R-/- mice. In M5R-/- mice, CA3 pyramidal cells displayed a significantly attenuated frequency of the spontaneous postsynaptic current and long-term potentiation was significantly impaired at the mossy fiber-CA3 synapse. Our findings suggest that impaired M5R signaling may play a role in the pathophysiology of cerebrovascular deficits. The M5 receptor may represent an attractive novel therapeutic target to ameliorate memory deficits caused by impaired cerebrovascular function.

Transplantation of neural cells derived from retinoic acid-treated cynomolgus monkey embryonic stem cells successfully improved motor function of hemiplegic mice with experimental brain injury.

We induced neural cells by treating cynomolgus monkey embryonic stem (ES) cells with retinoic acid. The treated cells mainly expressed betaIIItubulin. They further differentiated into neurons expressing neurofilament middle chain (NFM) in elongated axons. Half of the cells differentiated into Islet1+ motoneurons in vitro. The monkey ES-derived neural cells were transplanted to hemiplegic mice with experimental brain injury mimicking stroke. The neural cells that had grafted into periventricular area of the mice distributed extensively over the injured cortex. Some of the transplanted cells expressed the neural stem/progenitor marker nestin 2 days after transplantation. The cells expressed markers characteristic of mature motoneurons 28 days after transplantation. Mice with the neural cell graft gradually recovered motor function, whereas control animals remained hemiplegic. This is the first demonstration that neural cells derived from nonhuman primate ES cells have the ability to restore motor function in an animal model of brain injury.

A method for measuring the decay time of hyperpolarized 129Xe magnetization in rat brain without estimation of RF flip angles.

PURPOSE: The decay time of hyperpolarized 129Xe in brain tissue depends on the cerebral blood flow (CBF) as well as the longitudinal relaxation time in the tissue (T(1,tissue)). Therefore, the decay time is an important parameter for investigating the potential of Xe for cerebral studies. Previous attempts to measure the decay time have been performed after correction of the MR signal for the costheta decay induced by multiple radiofrequency (RF) excitation pulses. However, since this method requires accurate knowledge of the RF pulse flip angle, the use of a surface coil is restricted because of its nonuniform RF power, distribution. We present a two-pulse protocol for estimating the decay time without the need for flip-angle estimation and demonstrate it in the rat brain. METHOD: After rat inhalation of hyperpolarized Xe, two MR spectra of the rat head were obtained at various delay times (4-16 s) and the logarithmic ratio of the two amplitudes was calculated. The decay time was obtained from the slope of the logarithmic ratio against the delay time. The MR measurements were performed with a 4.7T imaging spectrometer with a surface coil located over the head of the anesthetized rat. The gas (25 cc) was smoothly introduced to the lung for 40 s before each measurement began. RESULT: From 18 experiments on 11 rats, the decay time was estimated to be 17.7+/-1.9 s. DISCUSSION: Assuming a normal rat CBF value, T(1,tissue) can be estimated from the decay time to be 26+/-4 s.

129Xe spectra from the heads of rats with and without ligation of the external carotid and pterygopalatine arteries.

After rats inhaled hyperpolarized (129)Xe gas, in vivo spectra from their heads revealed a dominant peak around 195 ppm, another easily resolvable peak near 189 ppm, a broad peak around 210 ppm, and two minor peaks around 198 ppm and 192 ppm. However, the source of each peak remains controversial. To further study the origin of each peak, we compared spectra obtained from the heads of normal rats with spectra taken from the heads of rats that had undergone ligation of the external carotid (ECA) and pterygopalatine (PPA) arteries, the major feeding vessels of nonbrain tissue in the rat head. The amplitude of the peak at around 189 ppm was greatly reduced in the ECA/PPA-ligated rats, while the peak around 195 ppm persisted. We conclude that the signal that originates from the rat brain after inhalation of (129)Xe gas is overwhelmingly dominated by the single resonance at 195 ppm.

Therapeutic efficacy of basic fibroblast growth factor on experimental focal ischemia studied by magnetic resonance imaging.

The purpose of this study was to evaluate the effect of intravenous infusion of basic fibroblast growth factor (bFGF) in a permanent ischemia model at the subacute phase (2 weeks) as well as at 24 hours and 1 week using T2-weighted magnetic resonance imaging (MRI). The middle cerebral artery (MCA) in Sprague-Dawley rats was occluded using an intraluminal suture method. The rats were randomly divided into 2 groups to receive either bFGF (45 mircrog/kg/hr) or saline solution. The infusion was started 30 minutes after MCA occlusion (MCAO) and continued for 3 hours. Regional cerebral blood flow (rCBF) was measured using laser Doppler flowmetry throughout the infusion. T2-weighted MRI was carried out before MCAO, 24 hours after MCAO, and days 7 and 14 after MCAO. Although an elevation in rCBF was seen after the infusion, no significant change between the groups was observed. A significant difference between the bFGF and saline groups in T2-derived lesion volume was observed at 24 hours (P < .05), on day 7 (P < .05), and on day 14 (P < .01). The percentage of lesion area calculated from the ipsilateral hemisphere using hematoxylin and eosin staining on day 14 showed a significant difference between the bFGF and saline groups (P < .05). No significant change in the number of bromodeoxyuridine (BrdU)-labeled cells between the groups was observed. This study demonstrates that bFGF, infused intravenously starting 30 minutes after the induction of permanent MCAO, significantly reduces region volume even at day 14, as well as at days 1 and 7, compared with the corresponding saline group.

Magnetic resonance spectra of hyperpolarized (129)xe in human blood and living rat chest.

We constructed a gas polarization system to test the feasibility of using hyperpolarized (129)Xe gas as an NMR (nuclear magnetic resonance) probe to explore brain function. Both in vitro and in vivo experiments were performed with a 4.7 T NMR spectrometer. Xenon spectra from human blood confirmed the existence of two peaks corresponding to red blood cells and plasma. In rat studies, three peaks at around 200 ppm were observed. Our results are consistent with previously reported data.

Hemodynamic aspects of Alzheimer's disease.

Neuroradiological functional imaging techniques demonstrate the patterns of hypoperfusion and hypometabolism that are thought to be useful in the differential diagnosis of Alzheimer's disease (AD) from other dementing disorders. Besides the distribution patterns of perfusion or energy metabolism, vascular transit time (VTT), vascular reactivity (VR), and oxygen extraction fraction (OEF), which can be measured with positron emission tomography (PET), provide hemodynamic aspects of brain pathophysiology. In order to evaluate the hemodynamic features of AD, PET studies were carried out in 20 patients with probable AD and 20 patients with vascular dementia (VaD). The PET findings were not included in their diagnostic process of AD. Using oxygen-15-labeled compounds, cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO(2)), OEF, cerebral blood volume, and VTT were measured quantitatively during resting state. To evaluate VR, CBF was also measured during CO(2) inhalation. There was a significant increase in OEF in and around the parietotemporal cortices, but both VTT and VR were well preserved in patients with AD. By contrast, VR was markedly depressed and VTT was mildly prolonged in patients with VaD. Thus, from the hemodynamic point of view, the preservation of vascular reserve may be a distinct difference between AD and VaD. Furthermore, this indicates a hemodynamic integrity of the vasculature in the level of arterioles in AD.