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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.

A series of experiments were performed to investigate why two peaks (D and E) of the five dissolved phase peaks in hyperpolarized 129Xe 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. Magn Reson Med 57:791–797, 2007. © 2007 Wiley-Liss, Inc.

We induced neural cells by treating cynomolgus monkey embryonic stem (ES) cells with retinoic acid. The treated cells mainly expressed βIIItubulin. 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.

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.

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.

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 (T1,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 cosθ 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, T1,tissue can be estimated from the decay time to be 26±4 s.

The effects of an intracellular calcium antagonist fasudil (HA 1077) on protein synthesis, ion derangement, brain edema, and the neurological signs associated with focal cerebral ischemia, were investigated via a nine-hour occlusion of the left common carotid artery (CCA) in Mongolian gerbils. Protein synthesis was evaluated by the amount of incorporation of [14C]methionine into the tissue. Intravenous infusion of fasudil hydrochloride (1 mg kg-1) just after CCA ligation was effective in reducing neurological deficits six and nine hours after CCA ligation, as well as loss of tissue potassium. However, fasudil did not ameliorate the brain edema or the accumulation of sodium in the tissue. On the other hand, fasudil improved the uptake of [14C]methionine, but not its incorporation into the tissue. The improved uptake of tracer into the tissue may indicate the facilitation of collateral blood flow by fasudil. These results suggest that fasudil may mitigate ischemic damage in the penumbral zone, possibly by ameliorating collateral blood flow and preventing calcium-related cell damage.

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.

The anabolism of isotopically labeled amino acids was compared between the cerebrum and the cerebellum in conscious rat at three feeding conditions. After l -[2- 18 F]fluorophenylalanine and l -[2,6- 3 H]phenylalanine injections, the incorporation rate of both radioactivity into protein fraction showed no difference between the cerebrum and the cerebellum at normal condition, but the lipid fraction in the cerebellum was higher than that in the cerebrum in any conditions. These results show the usefulness of l -[2- 18 F]fluorophenylalanine as a positron emission tomography tracer and different anabolic rate of the amino acids to lipid between the cerebrum and cerebellum.

The transport rates of L-[2-18F]fluorophenylalanine ([18F]Phe) and L-[U-14C]phenylalanine ([14C]Phe) across the blood-brain barrier were compared in saline, large neutral amino acids (NAA) and large basic amino acids (BAA) loaded rats. The fraction of transported tracer (FTT) was expressed as the ratio of brain radioactivity to integrated plasma radioactivity at 5 min after injection of the tracers. Cerebral FTTs of [18F]Phe and [14C]Phe in the control group were 0.042 and 0.045, respectively, and decreased to 0.016 and 0.019 in the NAA loaded group. The ratios of FTT of [18F]Phe and that of [14C]Phe were approx. 0.90, and did not differ among the three groups. These results indicate that the transport of [18F]Phe from the blood to the brain can be considered to be mediated by the NAA transport system and that its transport rate is almost the same as that of [14C]Phe.

Using positron emission tomography (PET), cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMR02) were measured in 32 healthy volunteers aged from 27 to 67 years. In bilateral putamen, left supratemporal\ left infrafrontal and left parietal cortices, CMR02 showed a significant decline during aging. The age-related decline of CBF was seen only at the left superior temporal cortex. The mean CMR02 was significantly lower in the elder group (over 51 years old) than in the younger group (under 50 years old), whereas no significant difference in mean CBF between the two groups. The poor correlation of CBF to the age could be explained partly by the fact that CBF is easily influenced by the physiological, psychological and/or environmental factors. The age-related changes of CMR02 were more marked in the association cortices of the left hemisphere than in that of the right hemisphere.

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.

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.

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.

Vascular and metabolic reserve were analyzed in probable Alzheimer’s disease (AD) and vascular dementia (VaD). Cerebral blood flow (CBF), cerebral blood volume (CBV), cerebral metabolic rate of oxygen (CMRO2), and oxygen extraction fraction (OEF) were measured quantitatively with positron emission tomography (PET). Vascular reactivity (VR) was also calculated by comparing the CBF during 5% CO2 inhalation with the CBF during normal breathing. Vascular transit time (VTT) that was calculated as a ratio of CBV/CBF and VR reflect vasodilating capacity of the small resistance vessels, whereas OEF designates metabolic (oxygen-extraction) reserve in threatening brain ischemia. Significant increase in OEF was seen in the parieto-temporal cortex and both VTT and VR were preserved in AD patients. By constrast, there was no significant increase in OEF whereas VTT was prolonged and VR was markedly depressed in VaD patients. The increase of OEF and preserved VTT and VR seen in AD patients indicate the possible participation of vascular factors in the pathogenesis of AD perhaps at the capillary level.

To elucidate the hemodynamic pathophysiology underlying Alzheimer's disease (AD), cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2) and oxygen extraction fraction (OEF) were measured with positron emission tomography in 10 patients with probable AD and in 20 age-matched normal volunteers. By the 15O intravenous bolus injection method, CBF was measured during resting state, CO2 inhalation (hypercapnia) and hyperventilation (hypocapnia), and the vascular reactivity (VR) was estimated by comparing the CBF changes (delta CBF%/PaCO2 mmHg) in the hyper- or hypocapnic to the resting state. By the 15O2 single-breath method or 15O steady-state method, CMRO2 and OEF were measured during resting state. Based on 26 regions of interest, local CBF, CMRO2 and OEF were compared statistically between the two groups. As compared with the control group, the mean CBF and CMRO2 decreased to as low as 77.0% and 88.4% of the normal values, respectively, while the mean OEF increased by 12.1% (p < 0.05) in AD patients. These changes were most pronounced in the supramarginal and superior temporal gyri. There was no focal change in VR in the AD group, and no significant difference was seen in VR to either hyper- or hypocapnia between AD and control groups. The results may suggest a vascular involvement, possibly at the capillary level, that might cause a relative misery perfusion syndrome accompanied by preserved vascular reactivity in AD.

The distribution of functionally active monoamine oxidase type A (MAO-A) was investigated by in vivo quantitative autoradiography using [14C]clorgyline in normal, conscious rat brain. [14C]clorgyline was synthesized by the methylation reaction of N-desmethylclorgyline using [14C]methyliodide. Sixty minutes after [14C]clorgyline administration (1.58 MBq/animal i.v.), the brains were removed and prepared for autoradiography by washing the brain sections with 5% trichloroacetic acid solution to remove the nonbinding free tracer. The amount of MAO-A was calculated from the regional acid-insoluble tissue radioactivity and the specific activity of the tracer. The highest amount of MAO-A (5.84 nmol/g tissue) was found in the locus coeruleus. The interpeduncular nucleus, habenular nucleus, fasciculus retroflexus, and solitary tract nucleus possessed over 1.6 nmol/g tissue of MAO-A. Among 23 regions of interest, the lowest amount of MAO-A (0.37 nmol/g tissue) was found in the globus pallidus. The findings of this study suggest that the pattern of MAO-A parallels both in neuroanatomical distribution and in density that of norepinephrine and serotonin innervation. The MAO-A concentration was, however, relatively low in the dopamine-related areas. This corresponded to the previous results obtained by histochemical analysis. In addition, among the white matter structures, a high amount of MAO-A was found specifically in the fasciculus retroflexus.

To evaluate the effect of the novel intracellular calcium antagonist fasudil hydrochloride, cerebral blood flow (CBF) was measured quantitatively with positron emission tomography following the intravenous administration of fasudil in five patients with chronic cerebral infarction. The hemispheric mean CBF increased significantly on both hemispheres 30, 60, and 90 min after the administration of fasudil when the CBF values were corrected according to PaCO2 level, although there was no significant change in raw CBF data. A significant increase of CBF was seen in the cerebellar hemisphere and thalamus at 30 min and in the occipital cortex at 90 min. There was no significant fall in the systemic blood pressure after the administration of fasudil.

The availability of clorgyline for regional monoamine oxidase-A (MAO-A) determination was examined using [ 14 C]clorgyline in rat. [ 14 C]Clorgyline was synthesized by the methylation reaction of N -desmethylclorgyline and [ 14 C]methyliodide in dimethylformamide with high radiochemical yield. The MAO-A distribution map by autoradiography correlated with that by histochemical technique and its quantity was consistent with the calculated MAO-A amount based on previous reports. The combination of labeled clorgyline and autoradiographic technique will promise the quantitative measurement of regional MAO-A distribution.

The effect of HA1077, an intracellular calcium antagonist, on neurotransmitter metabolism in rat brain was investigated in vivo. After administration of HA1077, at doses of 0.1, 0.3, and 3 mg/kg, 5-hydroxyindoleacetic acid (5-HIAA) levels increased in most regions except midbrain. In the striatum, parallel increases of both serotonin (5-HT) and 5-HIAA levels were observed at 0.3 mg/kg, but only the 5-HT level increased at 0.1 mg/kg. These results suggest that HA1077 may activate the turnover or synthesis of 5-HT. After administration of HA1077 at 0.3, 1, and 3 mg/kg, the dopamine (DA) level was increased in the striatum, but 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid levels were unchanged. After HA1077 administration at 1 mg/kg, both DA and DOPAC levels increased in the hypothalamus and only DA level increased in the cerebral cortex. By contrast, DOPAC level decreased in the midbrain after HA1077 treatment at 0.1 and 0.3 mg/kg, and in the brainstem at 0.1 and 10 mg/kg. The ratio of [3H]-N-methylspiperone accumulation relative to that in the cerebellum did not change after HA1077 treatment at any of the doses employed. Thus, the effects of HA1077 on neurotransmitter metabolism are complex and vary depending on the dosage and sites of the brain. Although the dose-dependent effects of HA1077 on neurotransmitter metabolism are similar to those of calcium entry blockers, HA1077 can facilitate DA synthesis in the hypothalamus and striatum, unlike the calcium entry blockers.

The effect of thyrotropin-releasing hormone (TRH) was studied on local CBF (LCBF) in normal conscious rats. LCBF was measured by the autoradiographic [14C]iodoantipyrine method 5 min after TRH (5 mg/kg, i.v.) administration. TRH significantly increased LCBF in 22 of 33 brain regions. This increase of LCBF exceeded 100% of the control values in the cerebral cortices, whereas there was no significant increase in white matter or in some gray matter structures. The increase of CBF following TRH administration was abolished by pretreatment with indomethacin (5 mg/kg, i.v.). The mechanisms underlying the increase of CBF following TRH administration are discussed in relation to prostaglandin metabolism.

Effects of an antihypertensive drug, guanfacine, on brain regional cyclic AMP and cyclic GMP levels were studied in anesthetized rats. Cyclic nucleotides were analyzed in seven brain regions. Guanfacine decreased blood pressure and heart rate 20 min after administration. Yohimbine inhibited these hemodynamic effects of guanfacine. Guanfacine reduced cyclic AMP levels in the hypothalamus. The reducing effect of guanfacine on cyclic AMP was antagonized by yohimbine in the hypothalamus. Guanfacine lowered cyclic GMP in the cerebellum, medulla oblongata and hypothalamus. Yohimbine inhibited the effect of guanfacine on cyclic GMP in the cerebellum, medulla oblongata and hypothalamus. Prazosin showed no effect on guanfacine induced change of cyclic nucleotides in any brain region. From these results, it is concluded that guanfacine decreased cyclic AMP and cyclic GMP in the hypothalamus. In addition, it is suggested that alpha-2 adrenoceptors mainly modulate these changes of cyclic nucleotides.

The effect of methotrexate (MTX) on local cerebral blood flow (I-CBF) was studied with autoradiographic [14C]-iodoantipyrine methods in normal conscious rats. I-CBF was reduced by 30-57% in the rats given MTX (100 mg or 200 mg/body) as compared to that in the saline injected control group, but no dose-dependent effect was observed. The mechanism of I-CBF reduction by MTX was discussed.

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.

KONDOH, Y., MURAKAMI, M., TAKAHASHI, K., ITOH, I., MIZUSAWA, S., NAKAMICHI, H., SASAKI, H., WATANABE, K., TAGAWA, K. and UEMURA, K. Evaluation of N-Isopropyl-[125I] p-Iodoamphetamine Affinity Sites in Rat Brain by Autoradiography. Tohoku J. exp. Med., 1986, 149 (2), 229-230-Affinity sites of N-isopropyl-[125I] p-iodoamphetamine (IMP) were studied in rat brain employing in vitro technique of receptor autoradiography. High degrees of IMP accumulation were observed in almost regions of white matter and some of gray matter. Phenethylamine, glutamic acid and serotonin suppressed IMP accumulation in all brain regions, in cerebral cortex and in hypothalamus, respectively. These results indicated that IMP was accumulated mainly due to its physicochemical property of lipophilicity and might have some interactions with neurotransmitter receptors.