A non-invasive reference-based method for imaging the cerebral metabolic rate of oxygen by PET/MR: theory and error analysis

Positron emission tomography (PET) remains the gold standard for quantitative imaging of the cerebral metabolic rate of oxygen (CMRO2); however, it is an invasive and complex procedure that requires accounting for recirculating [O-15]H2O (RW) and the cerebral blood volume (CBV). This study presents a non-invasive reference-based technique for imaging CMRO2 that was developed for PET/magnetic resonance imaging (MRI) with the goal of simplifying the PET procedure while maintaining its ability to quantify metabolism. The approach is to use whole-brain (WB) measurements of oxygen extraction fraction (OEF) and cerebral blood flow (CBF) to calibrate [O-15]O-2-PET data, thereby avoiding the need for invasive arterial sampling. Here we present the theoretical framework, along with error analyses, sensitivity to PET noise and inaccuracies in input parameters, and initial assessment on PET data acquired from healthy participants. Simulations showed that neglecting RW and CBV corrections caused errors in CMRO2 of less than 10% for changes in regional OEF of 25%. These predictions were supported by applying the reference-based approach to PET data, which resulted in remarkably similar CMRO2 images to those generated by analyzing the same data using a modeling approach that incorporated the arterial input functions and corrected for CBV contributions. Significant correlations were observed between regional CMRO2 values from the two techniques (slope = 1.00 0.04, R-2 > 0.98) with no significant differences found for integration times of 3 and 5 min. In summary, results demonstrate the feasibility of producing quantitative CMRO2 images by PET/MRI without the need for invasive blood sampling

気分状態に依存しない双極性障害と大うつ病性障害における脳梁の白質微細構造の差異

OBJECTIVE: It is difficult to distinguish between bipolar disorder and major depressive disorder (MDD) in patients lacking a clear history of mania. There is an urgent need for an objective biomarker for differential diagnosis. Using diffusion tensor imaging, this study investigated the differences in the brain white matter microstructure between patients with bipolar disorder and MDD. METHODS: Participants included 16 patients with bipolar disorder and 23 patients with MDD having depressed or euthymic states based on DSM-IV-TR criteria and 23 healthy volunteers. Whole-brain voxel-based morphometric analysis was used to detect any significant differences in fractional anisotropy between patients with bipolar disorder and MDD. The study was conducted between August 2011 and July 2015. RESULTS: We found a significant decrease in fractional anisotropy values in the anterior part of the corpus callosum in patients with bipolar disorder compared with MDD (P < .001), which did not depend on the patients' affective state. This decrease was associated with increased radial diffusivity values (P < .05), which was also found in patients with bipolar disorder when compared with healthy volunteers (P < .05). We predicted bipolar disorder and MDD in all patients using the fractional anisotropy values, with a correct classification rate of 76.9%. CONCLUSIONS: The present study revealed that patients with bipolar disorder have microstructural abnormalities in the corpus callosum during depressed or euthymic states, which may deteriorate the exchange of emotional information between the cerebral hemispheres, resulting in emotional dysregulation. Our results indicate the possible use of diffusion tensor imaging as a differential diagnostic tool.博士（医学）・甲第662号・平成29年3月15日© Copyright 2017 Physicians Postgraduate Press, Inc.発行元の規定により、本文の登録不可。本文は以下のURLを参照 "http://dx.doi.org/10.4088/JCP.15m09851" （※全文閲覧は学内限定

Imaging of the appearance time of cerebral blood using [15O]H2O PET for the computation of correct CBF

BACKGROUND: Quantification of cerebral blood flow (CBF) is important for the understanding of normal and pathologic brain physiology. Positron emission tomography (PET) with H(2)(15)O (or C(15)O(2)) can quantify CBF and apply kinetic analyses, including autoradiography (ARG) and the basis function methods (BFM). These approaches, however, are sensitive to input function errors such as the appearance time of cerebral blood (ATB), known as the delay time. We estimated brain ATB in an image-based fashion to correct CBF by accounting for differences in computed CBF values using three different analyses: ARG and BFM with and without fixing the partition coefficient. METHODS: Subject groups included those with no significant disorders, those with elevated cerebral blood volume, and those with reduced CBF. All subjects underwent PET examination, and CBF was estimated using the three analyses. The ATB was then computed from the differences of the obtained CBF values, and ATB-corrected CBF values were computed. ATB was also estimated for regions of interest (ROIs) of multiple cortical regions. The feasibility of the present method was tested in a simulation study. RESULTS: There were no significant differences in the obtained ATB between the image- and ROI-based methods. Significantly later appearance was found in the cerebellum compared to other brain regions for all groups. In cortical regions where CBF was reduced due to occlusive lesions, the ATB was 0.2 ± 1.2 s, which was significantly delayed relative to the contralateral regions. A simulation study showed that the ATB-corrected CBF was less sensitive to errors in input function, and noise on the tissue curve did not enhance the degree of noise on ATB-corrected CBF image. CONCLUSIONS: This study demonstrates the potential utility of visualizing the ATB in the brain, enabling the determination of CBF with less sensitivity to error in input function

Lack of partial renal response by 12 weeks after induction therapy predicts poor renal response and systemic damage accrual in lupus nephritis class III or IV

BACKGROUND: Lupus nephritis class III or IV is associated with a poor prognosis for both patient and renal survival. Recommendations for the management of lupus nephritis have recently been established, and changing therapies is recommended for patients who do not respond adequately to induction therapy. However, it remains a major challenge to determine when to switch the treatment. In this study, we identified early prognostic factors capable of predicting poor renal outcome as well as overall damage accrual in patients with lupus nephritis class III or IV. METHODS: Eighty patients with biopsy-proven lupus nephritis class III or IV were retrospectively recruited and divided into two groups: those with complete renal response (CR) or non-CR at 3 years after induction therapy. We investigated when clinical responses were obtained at each observational period from baseline to year 3. Clinical responses were divided into three groups: CR, partial renal response (PR), and non-PR. Furthermore, patients were assessed using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) and cumulative dose of corticosteroid for 3 years. RESULTS: Forty-four patients with CR and thirty-six with non-CR were enrolled. The cumulative CR rate was 85.0%. PR rates of patients with CR were significantly higher than those with non-CR from week 12 (p < 0.01). We identified the achievement of PR at 12 weeks as an independent predictor (OR 3.57, p = 0.03) by multivariate analysis. We next divided all patients into two groups according to PR achievement at week 12. The cumulative CR rate of the patients who achieved PR at week 12 was significantly higher than that of those who did not (96.5% vs 69.2%, p < 0.001). Furthermore, a significantly higher SDI and cumulative dose of corticosteroid were seen in the patients who did not achieve PR at week 12 than in those who did, regardless of their CR status, at year 3. CONCLUSIONS: Lack of PR at week 12 predicts a lower likelihood of achieving CR at 3 years and a higher SDI

F-18 fluorodeoxyglucose uptake and water-perfusable tissue fraction in assessment of myocardial viability

OBJECTIVES: (15)O-water-perfusable tissue fraction (PTF) has been shown to be a potential index for assessing myocardial viability in PET, an alternative to (18)F-fluorodeoxyglucose (FDG). This study aimed to directly compare these two independent methods in assessing myocardial viability in patients with abnormal wall motion. METHODS: PET study was performed on 16 patients with previous myocardial infarction, before coronary artery bypass graft operation (CABG). The protocol included a (15)O-carbonmonoxide static, a (15)O-water dynamic and an (18)F-FDG dynamic scan, during the euglycemic hyperinsulinemic clamp. Echocardiography was performed at the time of PET and 5–12 months after the CABG, and the wall motion recovery was evaluated on segmental and global bases. Consistency between PTF and (18)F-FDG was evaluated visually and also in a quantitative manner. Predictive values for the wall motion recovery were also compared between the two approaches. RESULTS: The image quality of (18)F-FDG was superior to that of (15)O-water. The qualitative PTF showed significantly smaller defects than (18)F-FDG, and the quantitative PTF showed slightly greater values than (18)F-FDG in the infarcted region. The two methods were, however, consistent visually and also quantitatively. The predictive values of the wall motion recovery were almost equal between the two approaches. The absolute (18)F-FDG uptake was varied in normal segments, and predictive values for the wall motion recovery by the absolute (18)F-FDG was less (accuracy: 80 %) compared with those by the relative (18)F-FDG (accuracy: 87 %) and the quantitative PTF (accuracy: 89 %). CONCLUSION: Despite the small sample size, PTF appears to give consistent results with the (18)F-FDG approach, and might be an alternative viability assessment

Renal vascular resistance is increased in patients with kidney transplant

Background Despite improvement in short-term outcome of kidney transplants, the long-term survival of kidney transplants has not changed over past decades. Kidney biopsy is the gold standard of transplant pathology but it's invasive. Quantification of transplant blood flow could provide a novel non-invasive method to evaluate transplant pathology. The aim of this retrospective cross-sectional pilot study was to evaluate positron emission tomography (PET) as a method to measure kidney transplant perfusion and find out if there is correlation between transplant perfusion and histopathology. Methods Renal cortical perfusion of 19 kidney transplantation patients [average time from transplantation 33 (17-54) months; eGFR 55 (47-69) ml/min] and 10 healthy controls were studied by [(15) O]H2O PET. Perfusion and Doppler resistance index (RI) of transplants were compared with histology of one-year protocol transplant biopsy. Results Renal cortical perfusion of healthy control subjects and transplant patients were 2.7 (2.4-4.0) ml min(- 1) g(- 1) and 2.2 (2.0-3.0) ml min(- 1) g(- 1), respectively (p = 0.1). Renal vascular resistance (RVR) of the patients was 47.0 (36.7-51.4) mmHg mL(- 1)min(- 1)g(- 1) and that of the healthy 32.4 (24.6-39.6) mmHg mL(- 1)min(-1)g(-1) (p = 0.01). There was a statistically significant correlation between Doppler RI and perfusion of transplants (r = - 0.51, p = 0.026). Transplant Doppler RI of the group of mild fibrotic changes [0.73 (0.70-0.76)] and the group of no fibrotic changes [0.66 (0.61-0.72)] differed statistically significantly (p = 0.03). No statistically significant correlation was found between cortical perfusion and fibrosis of transplants (p = 0.56). Conclusions [(15) O]H2O PET showed its capability as a method in measuring perfusion of kidney transplants. RVR of transplant patients with stage 2-3 chronic kidney disease was higher than that of the healthy, although kidney perfusion values didn't differ between the groups. Doppler based RI correlated with perfusion and fibrosis of transplants.Peer reviewe

Assessment of a digital and an analog PET/CT system for accurate myocardial perfusion imaging with a flow phantom

In Myocardial Perfusion Imaging (MPI) with Positron Emission Tomography/Computed Tomography (PET/CT) systems, accurate quantification is essential. We assessed flow quantification accuracy over various injected activities using a flow phantom.Methods The study was performed on the digital 4-ring Discovery MI (DMI-20) and analog Discovery 690 (D690) PET/CT systems, using 325-1257 MBq of [O-15]H2O. PET performance and flow quantification accuracy were assessed in terms of count-rates, dead-time factors (DTF), scatter fractions (SF), time-activity curves (TACs), areas-under-the-curves (AUCs) and flow values.Results On DMI-20, prompts of 12.8 Mcps, DTF of 2.06 and SF of 46.1% were measured with 1257 MBq of activity. On the D690, prompts of 6.85 Mcps, DTF of 1.57 and SF of 32.5% were measured with 1230 MBq of activity. AUC values were linear over all activities. Mean wash-in flow error was - 9% for both systems whereas wash-out flow error was - 5% and - 6% for DMI-20 and D690. With the highest activity, wash-out flow error was - 12% and - 7% for the DMI-20 and D690.Conclusion DMI-20 and D690 preserved accurate flow quantification over all injected activities, with maximum error of - 12%. In the future, flow quantification accuracy over the activities and count-rates evaluated in this study should be assessed

Evaluation of [F-18]F-DPA PET for Detecting Microglial Activation in the Spinal Cord of a Rat Model of Neuropathic Pain

Purpose Recent studies have linked activated spinal glia to neuropathic pain. Here, using a positron emission tomography (PET) scanner with high spatial resolution and sensitivity, we evaluated the feasibility and sensitivity of N,N-diethyl-2-(2-(4-([18F]fluoro)phenyl)-5,7-dimethylpyrazolo[1,5-a] pyrimidin3-yl)acetamide -([F-18]F-DPA) imaging for detecting spinal cord microglial activation after partial sciatic nerve ligation (PSNL) in rats.Procedures Neuropathic pain was induced in rats (n = 20) by PSNL, and pain sensation tests were conducted before surgery and 3 and 7 days post- injury. On day 7, in vivo PET imaging and ex vivo autoradiography were performed using -[F-18]F-DPA or -[C-11]PK11195. Ex vivo biodistribution and PET imaging of the removed spinal cord were carried out with -[F-18]F-DPA. Sham-operated and PK11195pretreated animals were also examined.Results Mechanical allodynia was confirmed in the PSNL rats from day 3 through day 7. Ex vivo autoradiography showed a higher lesion-to-background uptake with -[F-18]F-DPA compared with -[C-11]PK11195. Ex vivo PET imaging of the removed spinal cord showed -[F-18]F-DPA accumulation in the inflammation site, which was immunohistochemically confirmed to coincide with microglia activation. Pretreatment with PK11195 eliminated the uptake. The SUV values of in vivo -[F-18]F-DPA and -[C-11]PK11195 PET were not significantly increased in the lesion compared with the reference region, and were fivefold higher than the values obtained from the ex vivo data. Ex vivo biodistribution revealed a twofold higher -[F-18] F-DPA uptake in the vertebral body compared to that seen in the bone from the skull.Conclusions[F-18]F-DPA aided visualization of the spinal cord inflammation site in PSNL rats on ex vivo autoradiography and was superior to -[C-11]PK11195. In vivo -[F-18]F-DPA PET did not allow for visualization of tracer accumulation even using a high-spatial-resolution PET scanner. The main reason for this result was due to insufficient SUVs in the spinal cord region as compared with the background noise, in addition to a spillover from the vertebral body.</p

System evaluation of automated production and inhalation of O-15-labeled gaseous radiopharmaceuticals for the rapid O-15-oxygen PET examinations

Background(15)O-oxygen inhalation PET is unique in its ability to provide fundamental information regarding cerebral hemodynamics and energy metabolism in man. However, the use of O-15-oxygen has been limited in a clinical environment largely attributed to logistical complexity, in relation to a long study period, and the need to produce and inhale three sets of radiopharmaceuticals. Despite the recent works that enabled shortening of the PET examination period, radiopharmaceutical production has still been a limiting factor. This study was aimed to evaluate a recently developed radiosynthesis/inhalation system that automatically supplies a series of O-15-labeled gaseous radiopharmaceuticals of (CO)-O-15, O-15(2), and (CO2)-O-15 at short intervals.MethodsThe system consists of a radiosynthesizer which produces (CO)-O-15, O-15(2), and (CO2)-O-15; an inhalation controller; and an inhalation/scavenging unit. All three parts are controlled by a common sequencer, enabling automated production and inhalation at intervals less than 4.5min. The gas inhalation/scavenging unit controls to sequentially supply of qualified radiopharmaceuticals at given radioactivity for given periods at given intervals. The unit also scavenges effectively the non-inhaled radioactive gases. Performance and reproducibility are evaluated.ResultsUsing an O-15-dedicated cyclotron with deuteron of 3.5MeV at 40A, (CO)-O-15, O-15(2), and (CO2)-O-15 were sequentially produced at a constant rate of 1400, 2400, and 2000MBq/min, respectively. Each of radiopharmaceuticals were stably inhaled at </p

Dysregulation of RNF213 promotes cerebral hypoperfusion

RNF213 is a susceptibility gene for moyamoya disease, yet its exact functions remain unclear. To evaluate the role of RNF213 in adaptation of cerebral blood flow (CBF) under cerebral hypoperfusion, we performed bilateral common carotid artery stenosis surgery using external microcoils on Rnf213 knockout (KO) and vascular endothelial cell-specific Rnf213 mutant (human p.R4810K orthologue) transgenic (EC-Tg) mice. Temporal CBF changes were measured by arterial spin-labelling magnetic resonance imaging. In the cortical area, no significant difference in CBF was found before surgery between the genotypes. Three of eight (37.5%) KO mice died after surgery but all wild-type and EC-Tg mice survived hypoperfusion. KO mice had a significantly more severe reduction in CBF on day 7 than wild-type mice (KO, 29.7% of baseline level; wild-type, 49.3%; p = 0.038), while CBF restoration on day 28 was significantly impaired in both KO (50.0%) and EC-Tg (56.1%) mice compared with wild-type mice (69.5%; p = 0.031 and 0.037, respectively). Changes in the subcortical area also showed the same tendency as the cortical area. Additionally, histological analysis demonstrated that angiogenesis was impaired in both EC-Tg and KO mice. These results are indicative of the essential role of RNF213 in the maintenance of CBF