Atsushi Tsuji

Estimation of Cerebral Perfusion Reserve by Blood Oxygenation Level—Dependent Imaging: Comparison with Single-Photon Emission Computed Tomography

Measurement of cerebrovascular reserve capacity predicts the risk of ischemic insult in patients with major vessel occlusion. Blood oxygenation level-dependent (BOLD) imaging has the potential to estimate reserve capacity of the cerebral circulation noninvasively based on changes in the signal that reflect differences in the magnetic susceptibility of intravascular oxyhemoglobin and deoxyhemoglobin. The authors examined the feasibility of using the BOLD technique to assess cerebrovascular reserve capacity in patients with cerebrovascular occlusive disease by comparing results with an established method of measuring CBF. Ten patients with severe or complete occlusion of the internal carotid artery were compared with 17 healthy subjects to evaluate regional differences and identify variables that indicate a change in the BOLD signal. Dilation of cerebral vessels was induced by breath holding, and the R2* change was examined with gradient-echo, echo-planar imaging. Before measuring the regional change in the BOLD signal, actual timing of “activated” and “rest” periods was corrected by shifting the phase of a sine-wave template to obtain the largest correlation coefficient. Percent signal change was calculated on a pixel-by-pixel basis and was compared with CBF measured by single-photon emission computed tomography (SPECT) before and after acetazolamide challenge. The degree of impairment and the distribution of impaired areas detected by the BOLD study correlated with the results of SPECT. Overall sensitivity and specificity of the BOLD technique by visual inspection were 100% and 98.4%, respectively. A negative response (decreased CBF) frequently was observed in areas of exhausted reserve capacity, suggesting that a “steal” phenomenon exists. The percent change and the ΔCBF were well correlated (P < 0.01). The mean percent change in most areas of impaired reserve capacity was more than 2 SD below the mean values in healthy subjects. The present method of semiquantitative BOLD analysis can be used to create a map of the cerebral hemodynamic state. Furthermore, the development of reliable, generally accessible techniques for evaluating cerebral hemodynamics opens the door for clinical studies to monitor and treat patients with compromised reserve. This study is an attempt to develop such analysis.

Intracranial solitary juvenile xanthogranuloma successfully treated with stereotactic radiosurgery

Juvenile xanthogranuloma (JXG) is a non-Langerhans cell histiocytosis, which primarily affects the skin in young children. Although intracranial involvement is rare, it differs from other systemic JXG because its responsiveness to non-surgical treatment is poor. We present the case of a 2-year-old boy with left abducens nerve palsy. Imaging studies revealed a mass in the left Meckel’s cave. Systemic examination showed no other abnormalities including his skin. After partial removal, JXG was diagnosed based on immunohistochemical evaluation. He underwent a stereotactic radiosurgery. Then, the mass decreased, and his abducens nerve palsy improved. This is the seventh case with isolated intracranial JXG, and the first case to be treated with radiosurgery. We consider that stereotactic radiosurgery is an excellent choice for treatment of intracranial JXG.

A whole-genome radiation hybrid panel and framework map of the rat genome

Linda C. McCarthy, * ** Marie-Therese Bihoreau,* Susanna L. Kiguwa,* Julie Browne, Takeshi K. Watanabe, Haretsugu Hishigaki, Atsushi Tsuji, Susanne Kiel, 2 Caleb Webber, Maria E. Davis, Catherine Knights, Angela Smith, Ricky Critcher, 1 Patrick Huxtall, 1 James R. Hudson, Jr., 4 Toshihide Ono, Hiroumi Hayashi, Toshihisa Takagi, Yusuke Nakamura, Akira Tanigami, 3 Peter N. Goodfellow, *** G. Mark Lathrop, 2 Michael R. James

Mossy fiber sprouting in the dentate gyrus in a newly developed epileptic mutant, Ihara epileptic rat.

We examined the correlation between seizure activity and development of mossy fiber sprouting in the hippocampal formation using Timm staining in a newly developed Ihara epileptic rat (IER). The sprouting of mossy fibers were clearly shown in the inner molecular portion of the dentate gyrus and in the stratum oriens of CA3 pyramidal cell layer with repeated seizures. A positive correlation between the frequency of generalized tonic and clonic convulsions and the Timm staining score in molecular layer of dentate gyrus was revealed. Sprouting of mossy fiber in IER seems to be linked with seizure activities resulting from epileptic bursts, not to the genetic mutation.

Neuronal microdysgenesis and acquired lesions of the hippocampal formation connected with seizure activities in Ihara epileptic rat.

The present study was designed to examine the morphological features of the hippocampal formation in the Ihara epileptic rat (IER), and to characterize genetically programmed lesions and acquired lesions connected with seizure activities. Neuropathological investigation of the hippocampal formation was performed in four separate groups, 2-month-old IERs with neither abnormal behaviors nor any seizure activity, and 12-month-old IERs of both sexes with abnormal behaviors, circling seizures or generalized tonic-clonic convulsions. In every IER examined, there were invariable and fundamental neuropathological findings consisting of abnormal neuronal clusters in the CA1 of the hippocampal formation. Moreover, disarrangement of neuronal cells, such as dispersion and gaps in lamination of pyramidal neurons, were observed. These changes were thought to represent genetically programmed lesions, neuronal microdysgenesis, because they were common findings in 2-month-old and 12-month-old IERs of both sexes. An enlargement of the dentate gyrus was also found in rats that experienced generalized tonic-clonic convulsions or circling seizures. This enlargement of the dentate gyrus, on the other hand, was categorized as a secondary and acquired lesion connected with seizure activities. It is suggested that the neuronal microdysgenesis in the hippocampal formation of IER has an intimate relationship with epileptogenesis and/or an enhancement of seizure susceptibility.

Genetic analysis of cataract in Ihara epileptic rat

Abstract. We analyzed the mode of inheritance of cataract in the Ihara epileptic rat (IER) by crossing experiments, and mapped cataract-related genes by linkage analysis. Cataract did not develop in the F1 animals, but it developed in both male and female animals of backcross and F2. The occurrence rate of cataract was 48.5% in the backcross progeny and 19.4% in the F2 progeny. Thus, the character was considered to be inherited by the autosomal recessive mode. We found two groups that differed according to the time of onset among the backcross and F2 progeny: an early-onset group (EOG), in which cataracts developed by about 4 months after birth, and a late-onset group (LOG), in which cataracts developed 8 months or more after birth. Linkage analysis indicated the presence of one cataract gene each on Chromosome (Chr) 8 and Chr 15, and the cataract was demonstrated to be governed by more than one gene. The gene on Chr 8 was named Cati1, and that on Chr 15, Cati2. Cati1 was involved in the occurrence of cataract, and the conditions required for cataract to develop were Cati1i/Cati1i or Cati1i/Cati1w. However, in the cataract rats with Cati1i/Cati1w, the allele of Cati2 was always Cati2i/Cati2i. Cati2 was involved in the timing of onset of the cataract, and the precondition for early onset was Cati2i/Cati2i.

Genetic analysis of pancreatic duct hyperplasia in Otsuka Long-Evans Tokushima Fatty rats : Possible association with a region on rat chromosome 14 that includes the disrupted cholecystokinin-A receptor gene

An Otsuka Long–Evans Tokushima Fatty (OLETF) strain of rat spontaneously developed hyperglycemia, hyperinsulinemia, insulin resistance and mild obesity, which had been studied as animal model for type II diabetes mellitus (T2DM). Recently, we observed that this strain coincidentally developed atypical hyperplasia of the choledocho‐pancreatic ductal epithelium with a complete incidence. In an effort to locate genes responsible for this hyperplasia, we prepared 288 backcross progeny from a mating between OLETF rats and BN rats (which do not develop hyperplasia), and performed a genome‐wide scan using 207 polymorphic genetic markers. We observed a prominent association of hyperplasia with a region involving a marker locus D14Mit4 (P = 0.00020, Fishers exact test) and Cckar (the cholecystokinin‐A receptor gene; P = 0.00025, Fishers exact test) which is known to be disrupted in an OLETF strain. Our findings indicated that epithelial hyperplasia of the choledocho‐pancreatic duct is associated with a region on rat chromosome 14 around the Cckar gene in an additive fashion with another two susceptible loci, each on chromosome 9 and 7. This implied the possibility that Cckar deficiency could result in a predisposition towards pancreatic duct hyperplasia.

Macrophage Imaging of Cerebral Aneurysms with Ferumoxytol: an Exploratory Study in an Animal Model and in Patients

OBJECTIVE The purpose of this study is to assess the validity and feasibility of macrophage imaging using an ultrasmall superparamagnetic iron oxide nanoparticle, ferumoxytol, in the cerebral aneurysmal wall in an animal model and in humans. MATERIALS AND METHODS Engulfment of ferumoxytol by primary culture of macrophages and RAW264.7 cells was assessed. Uptake of ferumoxytol was evaluated histologically in a cerebral aneurysmal model in rats. In an exploratory clinical study of magnetic resonance macrophage imaging, 17 unruptured aneurysms in 17 patients were imaged using thin-slice gapless magnetic resonance images of 2D-gradient-recalled echo (2D-GRE) and 3D-T1-fast-spin echo sequences on day 0 and of the same sequences with infusion of ferumoxytol 24 hours after the first imaging. Pre- and postinfusion images were evaluated independently by 2 medical doctors. RESULTS Engulfment of ferumoxytol was confirmed in vitro, but the amount of ferumoxytol uptake was independent of the activation state or the differentiation state. Ferumoxytol uptake in CD68-positive cells was observed in the cerebral arterial walls of 4 out of 15 (26.7%) experimentally induced aneurysms in rats. In a clinical study, 17 aneurysms were enrolled and 2 aneurysms were not assessed because of incomplete images. Eleven aneurysms without oral intake of recent anti-inflammatory agents of the remaining 15 aneurysms showed ferumoxytol uptake on 2D-GRE subtraction images, and the size of the aneurysms was significantly related to positive images. CONCLUSIONS Ferumoxytol uptake was confirmed in cultured macrophages and in the cerebral aneurysmal wall in rats. Thin-slice gapless magnetic resonance imaging with ferumoxytol in human cerebral aneurysmal walls may reflect macrophages in the cerebral aneurysmal wall, but its application to small-sized lesions may be restricted.

A Prospective and Retrospective Study of Cerebral AVM Treatment Strategies 1990-2014.

Although treatment options for cerebral arteriovenous malformations (AVMs) have changed since the advent of endovascular surgery and radiosurgery, microsurgery is still the major treatment option since it is effective for immediate cure. We proposed, and have applied, a revised treatment strategy to patients at our institution from February 2008 to May 2014, in which the final goal was disappearance of the nidus on angiography in patients who underwent surgical intervention. We followed 67 patients with cerebral AVMs, and in the 59 patients who had surgical intervention, the cure rate was 89.8 % (53 of 59). In all 67 patients, the surgical extirpation rate was 70.1 % (47/67). These rates were significantly higher than those between 1990 and 2008 at our institute. Microsurgical extirpation-related complications were a postoperative fatal hemorrhage in one patient, and visual field defects in two. In the endovascular treatment, two patients experienced hemiparesis, and radiosurgery-related complications were a fatal hemorrhage in one patient. Two patients from the non-surgical intervention group suffered from fatal hemorrhage. To achieve lower morbidity and mortality in AVM microsurgery, complete treatment until disappearance of the lesion, and an effective combination of available treatment modalities, are mandatory.