Decreased diffusivity along the perivascular space and cerebral hemodynamic disturbance in adult moyamoya disease.

Moyamoya disease (MMD) causes cerebral arterial stenosis and hemodynamic disturbance, the latter of which may disrupt glymphatic system activity, the waste clearance system. We evaluated 46 adult patients with MMD and 33 age- and sex-matched controls using diffusivity along the perivascular space (ALPS) measured with diffusion tensor imaging (ALPS index), which may partly reflect glymphatic system activity, and multishell diffusion MRI to generate freewater maps. Twenty-three patients were also evaluated via 15O-gas positron emission tomography (PET), and all patients underwent cognitive tests. Compared to controls, patients (38.4 (13.2) years old, 35 females) had lower ALPS indices in the left and right hemispheres (1.94 (0.27) vs. 1.65 (0.25) and 1.94 (0.22) vs. 1.65 (0.19), P < 0.001). While the right ALPS index showed no correlation, the left ALPS index was correlated with parenchymal freewater (ρ = -0.47, P < 0.001); perfusion measured with PET (cerebral blood flow, ρ = 0.70, P < 0.001; mean transit time, ρ = -0.60, P = 0.003; and oxygen extraction fraction, ρ = -0.52, P = 0.003); and cognitive tests (trail making test part B for executive function; ρ = -0.37, P = 0.01). Adult patients with MMD may exhibit decreased glymphatic system activity, which is correlated with the degree of hemodynamic disturbance, increased interstitial freewater, and cognitive dysfunction, but further investigation is needed.

Spatial coefficient of variation of arterial spin labeling MRI for detecting hemodynamic disturbances measured with 15O-gas PET in patients with moyamoya disease.

PURPOSE: The aim of this study was to investigate whether the spatial coefficient of variation of arterial spin labeling (ASL-CoV) acquired in clinical settings can be used to estimate the hemodynamic disturbances measured with 15O-gas positron emission tomography (PET), especially an increased oxygen extraction fraction (OEF), in patients with moyamoya disease. METHODS: We evaluated 68 adult patients with moyamoya disease who underwent ASL (postlabeling delay (PLD) = 1525 ms and 2525 ms) and PET. Regional values were measured using the middle cerebral artery territorial atlas divided into proximal, middle, and distal regions based on the arterial transit time, and correlations of ASL-CoV with cerebral blood flow, cerebral blood volume, mean transit time, and OEF, as well as the relationship between increased OEF and ASL-CoV, were evaluated. RESULTS: Regardless of the choice of region and PLD, ASL-CoV was significantly correlated with PET-measured parameters, including OEF (|ρ|= 0.30-0.80, P < 0.001). Regions with an increased OEF showed a significantly higher ASL-CoV than regions with a nonincreased OEF (P ≤ 0.03) regardless of the choice of region and PLD. The accuracy of identification of an increased OEF was highest when using a PLD of 1525 ms and the middle region (area under the curve = 0.750; using a cutoff value of 31.27, sensitivity = 97.4%, specificity = 41.7%, negative predictive value = 92.6%, and positive predictive value = 67.9%). CONCLUSION: ASL-CoV may help identify patients with increased OEF.

Improvement in cognitive decline after indirect bypass surgery in adult moyamoya disease: implication of 15O-gas positron emission tomography.

PURPOSE: To investigate the characteristics of patients with moyamoya disease (MMD) who show improvement in their cognitive decline after bypass surgery by analyzing the hemodynamic and metabolic parameters of 15O-gas positron emission tomography (PET). MATERIALS AND METHODS: We retrospectively analyzed adult patients with MMD who were evaluated with PET and cognitive tests before and approximately one year after indirect bypass surgery. The PET parameters of the left Rolandic area were compared between patients who did and did not show improvement in their cognitive decline. RESULTS: Of the 19 patients analyzed, fourteen (74%) showed improvement in either the verbal or performance intelligence quotient (VIQ or PIQ). Three out of four patients with perioperative infarction experienced significant cognitive decline. The preoperative oxygen extraction fraction (OEF) was significantly higher in patients who showed improvement in their cognitive decline in terms of the PIQ than in those patients who did not (P = 0.03). The postoperative increase in the cerebral metabolic rate of oxygen (CMRO2) was significantly higher in patients who showed improvement in their cognitive decline in terms of the VIQ than in those who did not (P = 0.02). CONCLUSION: Adult patients with MMD might show improvement in their cognitive decline after successful indirect bypass surgery if they have a severely increased regional OEF before the surgery and an increased regional CMRO2 after the surgery. CLINICAL TRIAL REGISTRATION: URL: https://www.umin.ac.jp/ctr/. Unique identifier: UMIN000027949.

Detection of hemodynamic impairment on 15O gas PET using visual assessment of arterial spin-labeling MR imaging in patients with moyamoya disease.

It is unclear whether the visual assessment of noninvasive arterial spin labeling magnetic resonance imaging (ASL) can identify instances of hemodynamic compromise including an elevated oxygen extraction fraction (OEF) measured by 15O-gas positron emission tomography (PET). Here we evaluated the relationship between a four-point visual assessment system referred to as 'ASL scores' using ASL with two postlabeling delays (PLDs; 1525 ms and 2525 ms) and some quantitative hemodynamic parameters measured by PET. We retrospectively evaluated the cases of 18 Japanese patients with moyamoya disease who underwent ASL and PET. We compared the patients' regional ASL scores on two ASL images to the regional values of PET parameters, and we observed a significant trend in accord with the presumed clinical severity among all PET parameters and ASL scores (p < .003). The ASL score of the long PLD (2525 ms) showed the highest specificity (98.5%) for elevated OEF. Our results suggest that hemodynamic impairment (including elevated OEF) in patients with moyamoya disease may be grossly assessed by a visual assessment of noninvasive ASL images, which can be easily obtained in clinical settings.

Intravoxel incoherent motion perfusion in patients with Moyamoya disease: comparison with 15O-gas positron emission tomography.

BACKGROUND: Intravoxel incoherent motion magnetic resonance imaging (IVIM) enables non-invasive measurement of brain perfusion. PURPOSE: To investigate whether IVIM could be used to evaluate the hemodynamic disturbance of Moyamoya disease (MMD) by comparison with the gold-standard 15O-gas positron emission tomography (PET) method. MATERIAL AND METHODS: Ten consecutive patients with MMD (six women; mean age = 42.8 years) and 10 age-matched healthy controls were evaluated by diffusion-weighted images with 12 different b values in the range of 0-900 s/mm2 and 15O-gas PET. Tomographic maps of IVIM parameters, perfusion fraction (f ), pseudo-diffusion coefficient (D*), and f・D*, as well as cerebral blood volume (CBV), cerebral blood flow (CBF), and mean transit time (MTT) maps obtained with PET, were normalized and hemispheric gray and white matter values were calculated. IVIM parametric values were compared with PET parameters and with clinically assessed disease severity. RESULTS: There was significant correlation between D* and MTT (r = -0.74, P < 0.001) and between f・D* and CBF (r = 0.52, P = 0.02) in the cortical areas. The f values in the white matter were significantly higher in symptomatic MMD patients than in healthy controls (P = 0.01). CONCLUSION: IVIM may be used to non-invasively investigate cerebral hemodynamic impairment in patients with MMD. Further evaluation is needed to establish IVIM usage in clinical settings.

Unraveling Specific Brain Microstructural Damage in Moyamoya Disease Using Diffusion Magnetic Resonance Imaging and Positron Emission Tomography.

BACKGROUND AND PURPOSE: Chronic ischemia may induce brain microstructural damage and lead to neurocognitive dysfunction in patients with Moyamoya disease (MMD). We applied neurite orientation dispersion and density imaging (NODDI) and 15O-gas positron emission tomography (PET) to elucidate the specific ischemic brain microstructural damage of MMD in the cortex and the white matter. MATERIALS AND METHODS: Thirty-one patients (16-63years old, 9 males) and 20 age- and sex-matched normal controls were enrolled in this study. NODDI evaluates quantitative parameters reflecting neurite and axonal density, network complexity and the interstitial fluid in all participants. Of 31 patients, 12 newly diagnosed patients were evaluated with PET, also. We evaluated correlations between the microstructural parameters of NODDI and the hemodynamic and metabolic parameters of PET, the relationship between NODDI and clinical severity of each hemisphere (Normal, Asymtpomatic, Symptomatic, and Infarcted) as well as neurocognitive performance. RESULTS: All NODDI parameters significantly correlated with PET parameters (absolute r = 0.46-0.83, P ≤ .048) and clinical severity (P < .001), suggesting that neurite and axonal density and network complexity decreased, and the interstitial fluid increased, as the ischemic burden became severe. NODDI parameters reflecting neurite and axonal density and network complexity significantly correlated with neurocognitive profiles (r = 0.36-0.64, P ≤ .048), but the interstitial fluid component did not. CONCLUSIONS: Chronic ischemia in patients with MMD may induce decreased neurite and axonal density, simplified network complexity, and may lead to neurocognitive dysfunction. The increased interstitial fluid accompanying hemodynamic impairment may not be identical to the decreased neurite density and might be driven by another mechanism.

Usefulness of 11C-Methionine Positron Emission Tomography for Monitoring of Treatment Response and Recurrence in a Glioblastoma Patient on Bevacizumab Therapy: A Case Report.

Recently developed molecular targeted therapies such as bevacizumab (BEV; Avastin) therapy have therapeutic efficacy for glioblastoma. However, it is difficult to distinguish between a tumor response and nonenhancing tumor progression with conventional magnetic resonance imaging (MRI) after BEV administration. Here we present a recurrent glioblastoma case in which 11C-methionine positron emission tomography (MET-PET) provided useful information for detecting tumor recurrence after complete remission, as assessed by the Response Assessment in Neuro-Oncology criteria. A 47-year-old male with a left frontal lobe glioblastoma experienced recurrence 6 months postoperatively. We administered BEV concomitantly with temozolomide, subsequent to gamma knife surgery. Two months after starting BEV, complete remission was obtained. MET uptake on PET gradually decreased and had nearly disappeared 4 months after initiating BEV. No enhanced area was seen on MRI for 17 months after BEV initiation. Nevertheless, MET-PET revealed recurrence, visualized as nonenhancing tumor progression. MET-PET provides useful information for detecting glioblastoma recurrence, which lacks contrast enhancement on MRI after BEV therapy.

Unique Angiographic Appearances of Moyamoya Disease Detected with 3-Dimensional Rotational Digital Subtraction Angiography Imaging Showing the Hemodynamic Status.

BACKGROUND: The aim of this study was to identify the unique morphological arterial features in patients with moyamoya disease on 3-dimensional rotational digital subtraction angiography. MATERIALS AND METHODS: One hundred seven hemispheres of 58 consecutive patients with moyamoya disease that were analyzed with fused 3-dimensional images of internal carotid angiograms and vertebral angiograms that were marked with different colors were reviewed. Angiographic findings in the posterior watershed area were classified, and the utility of the classification was analyzed by comparing it with clinical presentations and quantitative hemodynamic parameters obtained with positron emission tomography. RESULTS: Two unique angiographic appearances were identified. A vacant vessel appearance (no arterial inflow despite absence of cortical infarction) was observed mostly in transient ischemic attack hemispheres. In hemispheres with a vacant vessel appearance, cerebral blood flow was decreased, cerebral blood volume was increased, and mean transit time was prolonged significantly (P = .00017, P = .0061, and P = .00026, respectively). A cocktail vessel appearance (mixture of carotid and vertebral arterial flow) was most commonly observed in asymptomatic cases, as well as in ischemic hemispheres. Cerebral blood volume increased and mean transit time was prolonged significantly (P = .036 and P = .014, respectively) in hemispheres with a cocktail vessel appearance. The trend of progression in hemodynamic severity in the order of normal appearance, cocktail vessel appearance, and vacant vessel appearance in the watershed area was statistically significant. CONCLUSION: Fused 3-dimensional digital subtraction angiography demonstrated unique angiographic features in the watershed area, and this represented the degree of cerebral hemodynamic impairment in moyamoya disease.

Increased Binding Potential of Brain Adenosine A1 Receptor in Chronic Stages of Patients with Diffuse Axonal Injury Measured with [1-methyl-11C] 8-dicyclopropylmethyl-1-methyl-3-propylxanthine Positron Emission Tomography Imaging.

The positron emission tomography (PET) radioligand for adenosine A1 receptor (A1R) [1-methyl-11C] 8-dicyclopropylmethyl-1-methyl-3-propylxanthine (MPDX) has recently been developed for human brain imaging. In the present study, we evaluated the alteration of the A1R in patients with diffuse axonal injury (DAI) in chronic stage in vivo. Ten patients with DAI (7 men and 3 women) were included in this study. Three PET examinations were sequentially performed to measure A1R binding with 11C-MPDX, glucose metabolism with 18F-fluorodeoxyglucose (FDG), and central benzodiazepine receptor binding with 11C-flumazenil (FMZ), and decreases of 11C-FMZ uptake indicate neuronal loss. 11C- MPDX did not depict any lesion with significantly decreased nondisplaceable binding potential (BPND) in comparison to healthy controls (14 men) in region of interest (ROI) analysis. Instead, it showed a significant increase of BPND in the lower frontal and posterior cingulate cortexes and rolandic area (p < 0.05) in ROI analysis. In 18F-FDG PET, the standardized uptake values (SUVs) ratio to the whole brain were decreased in anterior and posterior cingulate gyrus compared to controls (14 men and 9 women; p < 0.01). In 11C-FMZ PET, the SUV ratio to the cerebellum was decreased in anterior cingulate gyrus in ROI analysis (controls, 9 men and 6 women; p < 0.01). The area with significantly increased 11C-MPDX binding, lower frontal cortex, rolandic area, and posterior cingulate gyrus, did not overlap with the areas of neuronal loss detected by decreased 11C-FMZ binding and did not completely overlap with area of reduced18F-FDG uptake. We obtained the first 11C-MPDX PET images reflecting the A1R BPND in human DAI brain in vivo. 11C-MPDX depicted increased A1R BPND in the areas surrounding the injured brain, whereas 18F-FDG demonstrated reduction throughout the brain. The results suggested that A1R might continuously confer neuroprotective or neuromodulatory effects in DAI even in the chronic stage.

ATRX status correlates with 11 C-methionine uptake in WHO grade II and III gliomas with IDH1 mutations.

Recent studies on gliomas have shown frequent alterations in the alpha-thalassemia/mental retardation syndrome X-linked gene (ATRX). This study was designed to determine whether ATRX status correlates with uptake of 11C-methionine in WHO grades II and III gliomas. Sixty-two patients underwent 11C-methionine positron emission tomography scans prior to histological diagnosis. The tumor-to-normal ratio (T/N) of 11C-methionine uptake was calculated by dividing the maximum standardized uptake value (SUV) for the tumor by the mean SUV of the normal brain. After surgery, tumor samples were subjected to immunohistochemistry for ATRX and IDH1-R132H followed by IDH1/2 sequencing. Twenty-seven of the sixty-two patients were found to have the IDH mutation. Nine of the twenty-seven gliomas harboring IDH mutations exhibited loss of nuclear ATRX expression, which is accompanied with an astrocytic tumor lineage and a poor prognosis. The mean T/N ratio in tumors with loss of nuclear ATRX expression was 2.20 ± 0.53, i.e., significantly lower than that of tumors with ATRX retention (3.28 ± 1.32, p = 0.0171, U test). Our study showed ATRX status to correlate with the T/N ratio and the outcomes of WHO grade II and III glioma patients with the IDH1 mutation. Our data provide new information on the biology and imaging characteristics of gliomas.

Oscillations in the embryonic chick olfactory bulb: initial expression and development revealed by optical imaging with a voltage-sensitive dye.

In a previous study, we applied a multiple-site optical recording technique with a voltage-sensitive dye to the embryonic chick olfactory system and showed that functional synaptic transmission in the olfactory bulb was expressed at embryonic 6-7-day stages. It is known that oscillations, i.e. stereotyped sinusoidal neural activity, appear in the olfactory system of various species. The focus of the present study is to determine whether the oscillation is also generated in the embryonic chick olfactory bulb and, if this is the case, when the oscillation appears and how its profiles change during embryogenesis. At the early stages of development (embryonic 6- to 8-day stages), postsynaptic response-related optical signals evoked by olfactory nerve stimulation exhibited a simple monophasic waveform that lasted for a few seconds. At embryonic 9-day stage, the optical signal became multi-phasic, and the oscillatory event was detected in some preparations. The oscillation was restricted to the distal half of the olfactory bulb. As development proceeded, the incidence and duration of the oscillation gradually increased, and the waveform became complicated. In some cases at embryonic 12-day stage, the oscillation lasted for nearly a minute. The frequency of the oscillation increased slightly with development, but it remained in the range of theta oscillation during the 9- to 12-day stages. We discuss the ontogenetic dynamics of the oscillation and the significance of this activity in the developing olfactory bulb.

Successful coil embolization of a ruptured basilar artery aneurysm in a child with leukemia: a case report.

Ruptured intracranial aneurysms are rare in the pediatric population compared to adults. This has incited considerable discussion on how to treat children with this condition. Here, we report a child with a ruptured saccular basilar artery aneurysm that was successfully treated with coil embolization. A 12-year-old boy with acute lymphoblastic leukemia and accompanying abdominal candidiasis after chemotherapy suddenly complained of a severe headache and suffered consciousness disturbance moments later. Computed tomography scans and cerebral angiography demonstrated acute hydrocephalus and subarachnoid hemorrhage caused by saccular basilar artery aneurysm rupture. External ventricular drainage was performed immediately. Because the patient was in severe condition and did not show remarkable signs of central nervous system infection in cerebrospinal fluid studies, we applied endovascular treatment for the ruptured saccular basilar artery aneurysm, which was successfully occluded with coils. The patient recovered without new neurological deficits after ventriculoperitoneal shunting. Recent reports indicate that both endovascular and microsurgical techniques can be used to effectively treat ruptured cerebral aneurysms in pediatric patients. A minimally invasive endovascular treatment was effective in the present case, but long-term follow-up will be necessary to confirm the efficiency of endovascular treatment for children with ruptured saccular basilar artery aneurysms.

Evaluation of voltage-sensitive fluorescence dyes for monitoring neuronal activity in the embryonic central nervous system.

Using an optical imaging technique with voltage-sensitive dyes (VSDs), we investigated the functional organization and architecture of the central nervous system (CNS) during embryogenesis. In the embryonic nervous system, a merocyanine-rhodanine dye, NK2761, has proved to be the most useful absorption dye for detecting neuronal activity because of its high signal-to-noise ratio (S/N), low toxicity and small dye bleaching. In the present study, we evaluated the suitability of fluorescence VSDs for optical recording in the embryonic CNS. We screened eight styryl (hemicyanine) dyes in isolated brainstem-spinal cord preparations from 7-day-old chick embryos. Measurements of voltage-related optical signals were made using a multiple-site optical recording system. The signal size, S/N, photobleaching, effects of perfusion and recovery of neural responses after staining were compared. We also evaluated optical responses with various magnifications. Although the S/N was lower than with the absorption dye, clear optical responses were detected with several fluorescence dyes, including di-2-ANEPEQ, di-4-ANEPPS, di-3-ANEPPDHQ, di-4-AN(F)EPPTEA, di-2-AN(F)EPPTEA and di-2-ANEPPTEA. Di-2-ANEPEQ showed the largest S/N, whereas its photobleaching was faster and the recovery of neural responses after staining was slower. Di-4-ANEPPS and di-3-ANEPPDHQ also exhibited a large S/N but required a relatively long time for recovery of neural activity. Di-4-AN(F)EPPTEA, di-2-AN(F)EPPTEA and di-2-ANEPPTEA showed smaller S/Ns than di-2-ANEPEQ, di-4-ANEPPS and di-3-ANEPPDHQ; but the recovery of neural responses after staining was faster. This study demonstrates the potential utility of these styryl dyes in optical monitoring of voltage changes in the embryonic CNS.