Yasuko Tatewaki

Correlation of magnetic resonance imaging optic nerve parameters to optical coherence tomography and the visual field in glaucoma

To determine the viability of using magnetic resonance imaging measurement of optic nerve morphology as an objective analysis of glaucomatous damage.

Inotropic support against early brain injury improves cerebral hypoperfusion and outcomes in a murine model of subarachnoid hemorrhage.

Early brain injury/ischemia is a recent therapeutic target that contributes to triggering delayed cerebral ischemia (DCI) in the setting of subarachnoid hemorrhage (SAH). This study aimed to determine the role of dobutamine for inotropic cardiac support in improving cerebral blood flow (CBF) and outcomes after experimental SAH, mediated by hypoxia-inducible factor (HIF). Thirty-one mice were subjected to SAH by endovascular perforation, and assigned to either 2% isoflurane postconditioning performed between 1 and 2.5h after SAH induction or concomitant intravenous dobutamine infusion (15μg/kg/min) with or without HIF inhibitor 2-methoxyestradiol (2ME2) (10mg/kg) administered intraperitoneally. Neurobehavioral function was assessed daily by neurological scores and open field testing. DCI was defined 3days later by detecting a new infarction on MRI. Global CBF depression was notable early after SAH, but dobutamine showed significant improvement in CBF, lower incidence of DCI, and better recovery of neuroscores and open field test variables compared with isoflurane postconditioning (P<0.05). CBF over the entire brain on day 1 predicted DCI with a cut-off of 36.5ml/100g/min (80% specificity and 67% sensitivity), with a better area under the curve (0.83 versus 0.75) than the hemispheric CBF measured on the perforated side. The dobutamine-mediated outcomes were attenuated (P<0.05) by 2ME2 pretreatment. The data suggest that cardiac support with dobutamine improves global CBF depression induced by early brain injury, leading to reduced prevalence of DCI and better functional outcomes after experimental SAH, in which HIF may be acting as a critical mediator.

Neurocardiac protection with milrinone for restoring acute cerebral hypoperfusion and delayed ischemic injury after experimental subarachnoid hemorrhage

BACKGROUND AND PURPOSE Acute cerebral hypoperfusion following subarachnoid hemorrhage (SAH) is highly related to the pathogenesis of delayed cerebral ischemia (DCI), but the therapeutic option is poorly available. This study aimed to clarify the effect of milrinone (MIL) on cerebral blood flow (CBF) and related outcomes after experimental SAH. METHODS Twenty-seven male C57BL/6 mice were assigned to either sham surgery (SAH-sham; n=6), SAH induced by endovascular perforation (control; n=10), or SAH followed by cardiac support with intravenous MIL (n=11) performed 1.5-h after SAH induction. CBF, neurobehavioral function, occurrence of DCI were assessed by MR-continuous arterial spin labeling, daily neurological score testing, and diffusion- and T2-weighted MR images on days 1 and 3, respectively. RESULTS Initial global CBF depression was notable in mice of control and MIL groups as compared to the SAH-sham group (P<0.05). MIL raised CBF in a dose-dependent manner (P<0.001), resulted in lower incidence of DCI (P=0.008) and better recovery from neurobehavioral decline than control (P<0.001). The CBF values on day 1 predicted DCI with a cut-off of 42.5ml/100g/min (82% specificity and 83% sensitivity), which was greater in mice treated with MIL than those of control (51.7 versus 37.6ml/100g/min; P<0.001). CONCLUSION MIL improves post-SAH acute hypoperfusion that can lead to the prevention of DCI and functional worsening, acting as a neurocardiac protective agent against EBI.

Regional reliability of quantitative signal targeting with alternating radiofrequency (STAR) labeling of arterial regions (QUASAR).

Quantitative signal targeting with alternating radiofrequency labeling of arterial regions (QUASAR) is a recent spin labeling technique that could improve the reliability of brain perfusion measurements. Although it is considered reliable for measuring gray matter as a whole, it has never been evaluated regionally. Here we assessed this regional reliability.

Comorbid masticatory impairment delays recovery from acute cerebral ischemia and locomotor hypoactivity after subarachnoid hemorrhage in mice

Tooth loss and related changes in the functionality may lead to worse outcome of stroke patients, but the effect on hemorrhagic stroke remains unclear. This study aimed to determine the impact of impaired masticatory function on acute cerebral oxygenation and locomotor activity after experimental subarachnoid haemorrhage (SAH). Twenty C57BL/6 mice with (MC‐treated group) or without (control group) prior treatment of cutting off the upper molars were subjected to SAH by endovascular perforation. Grading of SAH and acute cerebral infarction were assessed by MR images. Brain tissue oxygen saturation (SbtO2) by photoacoustic imaging and parameters related to locomotor activity by open‐field test were analyzed serially after SAH. In all mice, global SbtO2 depression was notable immediately after SAH induction (P <.001), which recovered close to the baseline levels until day 3. However, MC‐treated mice demonstrated a prolonged relative cerebral hypoxia (<40% of the baseline SbtO2) as compared to the control (3 ± 1 vs 1 ± 1 days; P <.05). The average distance travelled on day 7 and the ratio of central‐area distance/total travelled distance by open‐field test between days 7 and 14 were significantly lower in MC‐treated mice than in the control mice (P <.05), although the occurrences of new infarction were not statistically different (P >.05). These data suggest a possible link between preceding masticatory impairment and early brain injury to deteriorate neurobehavioural function in patients after SAH.This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/1440-1681.12874 This article is protected by copyright. All rights reserved. PROF. TATSUSHI MUTOH (Orcid ID : 0000-0001-7770-379X)

Reduced CBF recovery detected by longitudinal 3D-SSP SPECT analyses predicts outcome of postoperative patients after subarachnoid haemorrhage

The aim of this study was to evaluate the impact of cerebral blood flow (CBF) recovery obtained from brain single‐photon emission computed tomography (SPECT) images on postoperative outcome after aneurysmal subarachnoid haemorrhage (SAH). Twenty‐nine patients who had undergone surgical clipping for ruptured anterior communicating artery aneurysms were analyzed prospectively. Routine measurements of CBF were performed using technetium‐99 m hexamethyl propyleneamine oxine SPECT on days 4 and 14 after SAH. Regional voxel data analyzed by three dimensional stereotactic surface projection (3D‐SSP) were compared between patients and age‐matched normal database (NDB). In 3D‐SSP analysis of all patients, cortical hypoperfusion around the surgical site in bilateral frontal lobes was evident on day 4 (P < .05 vs NDB), which was improved significantly on day 14. However, the recovery was less complete in patients with poor clinical grades (P < .05) and presenting symptoms attributable to delayed cerebral ischaemia (DCI) (P < .05) than those without. Multivariate analysis showed that patients with mild to moderate CBF recovery (relative Z‐score differences of <4) (P = .014; odds ratio, 2.5; 95% confidence interval, 1.93–3.31) was independently associated with poor functional outcome at 3 months. We conclude that reduced CBF recovery detected by serial 3D‐SSP SPECT image analyses can be a potential predictor of poor prognosis in postoperative patients after SAH.

Phase Difference-Enhanced Magnetic Resonance (MR) Imaging (PADRE) Technique for the Detection of Age-Related Microstructural Changes in Optic Radiation: Comparison with Diffusion Tensor Imaging (DTI)

Background The optic radiation (OR) is a white-matter bundle connecting the lateral geniculate body and the visual cortex. Phase difference-enhanced imaging (PADRE) is a new MRI technique that is able to achieve precise delineation of the OR. The aim of this study was to investigate the effect of age on the volume and signal intensity of the OR using PADRE, and to establish a volumetric reference of the OR from a healthy population, compared with diffusion tensor imaging (DTI). Material/Methods Thirty-nine healthy volunteers underwent MR imaging with PADRE and DTI sequences on a 3.0-T scanner. For the volumetric analysis with PADRE, the OR corresponding to the external sagittal stratum was manually traced, while an automated thresholding method was used for the DTI-based volumetric analysis of the OR. Results The mean right and left OR volumes measured from the PADRE images were 1469.0±242.4 mm3 and 1372.6±310.2 mm3, respectively. Although OR volume showed no significant correlation with age, the normalized OR signal intensity showed a linear correlation with increasing age (r2=0.50–0.53; P<0.01). The OR signal intensity on PADRE and DTI-related quantitative parameters for the OR showed significant correlations (r2=0.46–0.49; P<0.01). Conclusions The PADRE technique revealed exceptional preservation of OR volume, even in later life. Moreover, PADRE was able to detect age-related changes in signal intensity of the OR and may contribute to future analyses of pathological neurodegeneration in patients with glaucoma and multiple sclerosis.

Utility of diffusion tensor imaging parameters for diagnosis of hemimegalencephaly.

Background Hemimegalencephaly is a rare hamartomatous entity characterised by enlargement of all or part of the cerebral hemisphere ipsilaterally with cortical dysgenesis, large lateral ventricle and white matter hypertrophy with or without advanced myelination. Although conventional magnetic resonance imaging (MRI) is useful for detecting these diagnostic features, hemimegalencephaly is not always easily distinguished from other entities, especially when hemimegalencephaly shows blurring between the grey and white matter. Diffusion tensor imaging (DTI) is a functional MRI technique commonly used to assess the integrity of white matter. The usefulness of DTI in assessing hemimegalencephaly has not been fully elucidated. In this study, we clarified the characteristics of hemimegalencephaly with regard to DTI and its parameters including fractional anisotropy and apparent diffusion coefficient. Methods Three patients with hemimegalencephaly underwent MRI including DTI. We first visually compared fractional anisotropy mapping and conventional MRI. Next, we quantitatively measured the fractional anisotropy and apparent diffusion coefficient values in the subcortical white matter of the hemisphere with hemimegalencephaly and corresponding normal-appearing contralateral regions and analysed the values using the Mann–Whitney U test. Results On fractional anisotropy mapping, we could clearly distinguish the junction of grey and white matter and observed thicker white matter in the hemisphere with hemimegalencephaly, which was unclear on conventional MRI. The white matter in the hemisphere with hemimegalencephaly showed significantly higher fractional anisotropy (P < 0.0001) and lower apparent diffusion coefficient (P = 0.0022) values than the normal contralateral side. Conclusion DTI parameters showed salient hemimegalencephaly features and could be useful in its assessment.

Quantitative MRI evaluation of glaucomatous changes in the visual pathway

Background The aims of this study were to investigate glaucomatous morphological changes quantitatively in the visual cortex of the brain with voxel-based morphometry (VBM), a normalizing MRI technique, and to clarify the relationship between glaucomatous damage and regional changes in the visual cortex of patients with open-angle glaucoma (OAG). Methods Thirty-one patients with OAG (age: 55.9 ± 10.7, male: female = 9: 22) and 20 age-matched controls (age: 54.9 ± 9.8, male: female = 10: 10) were included in this study. The cross-sectional area (CSA) of the optic nerve was manually measured with T2-weighed MRI. Images of the visual cortex were acquired with T1-weighed 3D magnetization-prepared rapid acquisition with gradient echo (MPRAGE) sequencing, and the normalized regional visual cortex volume, i.e., gray matter density (GMD), in Brodmann areas (BA) 17, 18, and 19, was calculated with a normalizing technique based on statistic parametric mapping 8 (SPM8) analysis. We compared the regional GMD of the visual cortex in the control subjects and OAG patients. Spearman’s rank correlation analysis was used to determine the relationship between optic nerve CSA and GMD in BA 17, 18, and 19. Results We found that the normal and OAG patients differed significantly in optic nerve CSA (p < 0.001) and visual cortex GMD in BA 17 (p = 0.030), BA 18 (p = 0.003), and BA 19 (p = 0.005). In addition, we found a significant correlation between optic nerve CSA and visual cortex GMD in BA 19 (r = 0.33, p = 0.023), but not in BA 17 (r = 0.17, p = 0.237) or BA 18 (r = 0.24, p = 0.099). Conclusion Quantitative MRI parametric evaluation of GMD can detect glaucoma-associated anatomical atrophy of the visual cortex in BA 17, 18, and 19. Furthermore, GMD in BA 19 was significantly correlated to the damage level of the optic nerve, as well as the retina, in patients with OAG. This is the first demonstration of an association between the cortex of the brain responsible for higher-order visual function and glaucoma severity. Evaluation of the visual cortex with MRI is thus a very promising potential method for objective examination in OAG.

Noninvasive three-dimensional power Doppler imaging for the assessment of acute cerebral blood flow alteration in a mouse model of subarachnoid haemorrhage

We aimed to evaluate the feasibility of a non‐invasive method of cerebral blood flow (CBF) measurement using high‐frequency power Doppler ultrasound imaging in a mouse model of subarachnoid haemorrhage (SAH). The 3‐dimensionally (3D) reconstructed blood flow signals (%vascularity) within the brain volume of the middle cerebral artery territory correlated well with reference parameters, baseline carotid artery blood flow (r2 = 0.52, P < 0.0001) and normalized CBF changes (r2 = 0.74 P < 0.0001). These data suggest that the 3D power Doppler analysis may have the potential for reflecting real‐time CBF changes during the acute phase of experimental SAH, which may be applicable to preclinical studies on early brain injury.