D namic State of Water Molecular Dis lacement of the Brain durin the Cardiac Cycle in Idiopathic Normal Pressure Hydrocephalus

13301甲第4200号博士(保健学)金沢大学博士論文要旨Abstract 要約Outlin

A method for assessing metabolic information on liver and bone marrow by use of double gradient-echo with spectral fat suppression

Our aim in this study was to create a noninvasive and practical method for evaluating metabolic information on the liver (iron content and lipid infiltration) and spine (bone mineral density and marrow fat degeneration) using double gradient-echo with and without the spectral fat suppression technique (double-GRE-FS). We arranged phantoms made of various concentrations of superparamagnetic iron oxide solution adjacent to neutral fat to obtain slice planes with various fat fractions using the partial volume effect. We obtained double-GRE-FS images and calculated the T2* values. The fat fraction was calculated from signal intensities of double-GRE-FS images after T2* decay, baseline, and slope corrections. We assessed the fat fraction and the relationship between R2* of the water component and the iron concentration. In addition, we evaluated those values in human bone marrow and liver, including a patient with liver steatosis. The actual fat fraction value was consistent with the fat fraction obtained with the double-GRE-FS method, and the calculated fat fraction was unaffected by the iron concentration. There was a strong positive correlation between R 2* of the water component and the iron concentration. There was a negative correlation between the fat fraction and the bone mineral density, and the R2* was correlated with the bone mineral density. The calculated fat fraction in the liver steatosis patient was significantly higher than that in healthy volunteers. The double-GRE-FS makes it possible to assess the fat fraction and R2* simultaneously, and to obtain metabolic information on the liver and bone marrow. © 2014 Japanese Society of Radiological Technology and Japan Society of Medical Physics

Time-resolved magnetic resonance angiography as a follow-up method for visceral artery aneurysm treated with coil-embolisation

Purpose: The purpose of this study is to assess the feasibility and usefulness of time-resolved magnetic resonance angiography (TR-MRA) for follow-up of visceral artery aneurysms (VAAs) after embolotherapy. Material and methods: Twenty-one VAAs (11 splenic, six renal, three internal iliac, and one superior pancreaticoduodenal artery aneurysms) in 18 patients (median age, 64 years; range, 36-88 years) previously treated by embolisation with platinum coils, were evaluated. The mean size of the aneurysm was 10.5 cm3 (range, 0.3-132 cm3). Among them, 19 lesions were treated by aneurysmal packing with or without distal-to-proximal embolisation. For the remaining two lesions, distal-to-proximal embolization alone was performed. The mean observation period after embolotherapy was 35 weeks (range, 4-216). All patients underwent TR-MRA following an intravenous bolus injection of gadolinium chelate. Recanalisation was diagnosed when any portion of the aneurysmal sac was enhanced in the arterial phase. Results: On TR-MRA, two lesions were diagnosed as recanalised. They were confirmed by transcatheter arteriography and re-treated by embolotherapy. For the remaining 19 lesions, there were no findings of recanalisation on TR-MRA. Conclusions: TR-MRA appears to be a feasible method for follow-up examination of VAAs treated by embolotherapy

Assessing white matter microstructural changes in idiopathic normal pressure hydrocephalus using voxel-based R2* relaxometry analysis

BackgroundR2* relaxometry and quantitative susceptibility mapping can be combined to distinguish between microstructural changes and iron deposition in white matter. Here, we aimed to explore microstructural changes in the white matter associated with clinical presentations such as cognitive impairment in patients with idiopathic normal-pressure hydrocephalus (iNPH) using R2* relaxometry analysis in combination with quantitative susceptibility mapping.MethodsWe evaluated 16 patients clinically diagnosed with possible or probable iNPH and 18 matched healthy controls (HC) who were chosen based on similarity in age and sex. R2* and quantitative susceptibility mapping were compared using voxel-wise and atlas-based one-way analysis of covariance (ANCOVA). Finally, partial correlation analyses were performed to assess the relationship between R2* and clinical presentations.ResultsR2* was lower in some white matter regions, including the bilateral superior longitudinal fascicle and sagittal stratum, in the iNPH group compared to the HC group. The voxel-based quantitative susceptibility mapping results did not differ between the groups. The atlas-based group comparisons yielded negative mean susceptibility values in almost all brain regions, indicating no clear paramagnetic iron deposition in the white matter of any subject. R2* and cognitive performance scores between the left superior longitudinal fasciculus (SLF) and right sagittal stratum (SS) were positively correlated. In addition to that, R2* and gait disturbance scores between left SS were negatively correlated.ConclusionOur analysis highlights the microstructural changes without iron deposition in the SLF and SS, and their association with cognitive impairment and gait disturbance in patients with iNPH

Idiopathic Normal-Pressure Hydrocephalus: Temporal Changes in ADC during Cardiac Cycle

Normal-pressure hydrocephalus (NPH) is characterized by a clinical triad of ataxia, incontinence, and dementia, as well as dilated ventricles but normal cerebrospinal fluid (CSF) pressures. In patients with NPH, CSF shunt placement is effective for improving these symptoms (1). NPH has attracted attention as one of the few treatable causes of dementia. Diagnosis of idiopathic NPH (INPH) without a known cause of communicating hydrocephalus, including subarachnoid hemorrhage or meningitis, is particularly difficult (2). Moreover, to clarify the cause of NPH, accurately diagnose NPH, and identify appropriate patients for shunt surgery, several tests have been proposed, including cisternography, the CSF tap test, resistance measures, external lumbar drainage, and intracranial pressure recording, in addition to clinical findings and conventional imaging diagnosis with x-ray computed tomography or magnetic resonance (MR) imaging (3–6). It has also been reported (7) that a single standard for the prognostic evaluation of patients with INPH was lacking and that supplemental tests could increase the predictive accuracy of the prognosis. The CSF tap test is a particularly reliable examination, but it is invasive and has low sensitivity. It has been proposed that MR imaging CSF flow studies can be used to noninvasively obtain information about intracranial mechanical properties in INPH (eg, intracranial compliance) (2,8–12). However, the diagnostic utility of this latter method is still not established.Arterial inflow into the cranium induces venous and CSF outflow and displacement of the intracranial spinal cord during the cardiac cycle, resulting in pulsatile brain motion (12–14). Brain pulsation (ie, bulk motion) reportedly can give rise to artifactual phase dispersion and may lead to overestimation of the apparent diffusion coefficient (ADC) (15,16). Brockstedt et al (17) reported that ADC was not changed significantly during the cardiac cycle with the single-shot echo-planar imaging (EPI) sequence widely used in diffusion MR imaging. However, they analyzed only two delay times (100 and 400 msec) between the R peaks in the cardiac cycle. To more completely analyze ADC changes during the cardiac cycle, our own group has previously evaluated the temporal change in ADC during the entire cardiac cycle by using an electrocardiographically (ECG)-triggered single-shot diffusion EPI sequence to minimize bulk motion effect. As a result, we revealed in a previous study that white matter ADC changed significantly over the cardiac cycle and that such changes were synchronized with the arterial inflow (volume loading) at systole (18). We further hypothesize that changes in ADC during the cardiac cycle are related to the biomechanical properties of intracranial tissues; hence, observed temporal changes in ADC in diseases such as INPH that are characterized by low intracranial compliance (12) may well be different than those in other diseases. Therefore, the purpose of our study was to determine whether temporal changes in ADC over the cardiac cycle were different in patients with INPH as compared with patients with ex vacuo ventricular dilatation and healthy control subjects

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target