Functional magnetic particle imaging (fMPI) of cerebrovascular changes in the rat brain during hypercapnia.

Objective.Non-invasive functional brain imaging modalities are limited in number, each with its own complex trade-offs between sensitivity, spatial and temporal resolution, and the directness with which the measured signals reflect neuronal activation. Magnetic particle imaging (MPI) directly maps the cerebral blood volume (CBV), and its high sensitivity derives from the nonlinear magnetization of the superparamagnetic iron oxide nanoparticle (SPION) tracer confined to the blood pool. Our work evaluates functional MPI (fMPI) as a new hemodynamic functional imaging modality by mapping the CBV response in a rodent model where CBV is modulated by hypercapnic breathing manipulation.Approach.The rodent fMPI time-series data were acquired with a mechanically rotating field-free line MPI scanner capable of 5 s temporal resolution and 3 mm spatial resolution. The rat's CBV was modulated for 30 min with alternating 5 min hyper-/hypocapnic states, and processed using conventional fMRI tools. We compare our results to fMRI responses undergoing similar hypercapnia protocols found in the literature, and reinforce this comparison in a study of one rat with 9.4T BOLD fMRI using the identical protocol.Main results.The initial image in the time-series showed mean resting brain voxel SNR values, averaged across rats, of 99.9 following the first 10 mg kg-1SPION injection and 134 following the second. The time-series fit a conventional General Linear Model with a 15%-40% CBV change and a peak pixel CNR between 12 and 29, 2-6× higher than found in fMRI.Significance.This work introduces a functional modality with high sensitivity, although currently limited spatial and temporal resolution. With future clinical-scale development, a large increase in sensitivity could supplement other modalities and help transition functional brain imaging from a neuroscience tool focusing on population averages to a clinically relevant modality capable of detecting differences in individual patients.

The utility of arterial spin labelled perfusion-weighted magnetic resonance imaging in measuring the vascularity of high grade gliomas - A prospective study.

Background: Dynamic susceptibility contrast (DSC) perfusion weighted imaging (PWI) currently remains the gold standard technique for measuring cerebral perfusion in glioma diagnosis and surveillance. Arterial spin labelling (ASL) PWI is a non-invasive alternative that does not require gadolinium contrast administration, although it is yet to be applied in widespread clinical practice. This study aims to assess the utility of measuring signal intensity in ASL PWI in predicting glioma vascularity by measuring maximal tumour signal intensity in patients based on pre-operative imaging and comparing this to maximal vessel density on histopathology. Methods: Pseudocontinuous ASL (pCASL) and DSC images were acquired pre-operatively in 21 patients with high grade gliomas. The maximal signal intensity within the gliomas over a region of interest of 100 mm2 was measured and also normalised to the contralateral cerebral cortex (nTBF-C), and cerebellum (nTBF-Cb). Maximal vessel density per 1 mm2 was determined on histopathology using CD31 and CD34 immunostaining on all participants. Results: Using ASL, statistically significant correlation was observed between maximal signal intensity (p < 0.05) and nTBF-C (p < 0.05) to maximal vessel density based on histopathology. Although a positive trend was also observed nTBF-Cb, this did not reach statistical significance. Using DSC, no statistically significant correlation was found between signal intensity, nTBF-C and nTBF-Cb. There was no correlation between maximal signal intensity between ASL and DSC. Average vessel density did not correlate with age, sex, previous treatment, or IDH status. Conclusions: ASL PWI imaging is a reliable marker of evaluating the vascularity of high grade gliomas and may be used as an adjunct to DSC PWI.

Visible CCD Camera-Guided Photoacoustic Imaging System for Precise Navigation during Functional Rat Brain Imaging.

In photoacoustic (PA) imaging, tissue absorbs specific wavelengths of light. The absorbed energy results in thermal expansion that generates ultrasound waves that are reconstructed into images. Existing commercial PA imaging systems for preclinical brain imaging are limited by imprecise positioning capabilities and inflexible user interfaces. We introduce a new visible charge-coupled device (CCD) camera-guided photoacoustic imaging (ViCPAI) system that integrates an ultrasound (US) transducer and a data acquisition platform with a CCD camera for positioning. The CCD camera accurately positions the US probe at the measurement location. The programmable MATLAB-based platform has an intuitive user interface. In vitro carbon fiber and in vivo animal experiments were performed to investigate the precise positioning and imaging capabilities of the ViCPAI system. We demonstrated real-time capturing of bilateral cerebral hemodynamic changes during (1) forelimb electrical stimulation under normal conditions, (2) forelimb stimulation after right brain focal photothrombotic ischemia (PTI) stroke, and (3) progression of KCl-induced cortical spreading depression (CSD). The ViCPAI system accurately located target areas and achieved reproducible positioning, which is crucial in animal and clinical experiments. In animal experiments, the ViCPAI system was used to investigate bilateral cerebral cortex responses to left forelimb electrical stimulation before and after stroke, showing that the CBV and SO2 in the right primary somatosensory cortex of the forelimb (S1FL) region were significantly changed by left forelimb electrical stimulation before stroke. No CBV or SO2 changes were observed in the bilateral cortex in the S1FL area in response to left forelimb electrical stimulation after stroke. While monitoring CSD progression, the ViCPAI system accurately locates the S1FL area and returns to the same position after the probe moves, demonstrating reproducible positioning and reducing positioning errors. The ViCPAI system utilizes the real-time precise positioning capability of CCD cameras to overcome various challenges in preclinical and clinical studies.

Vascular responses of penetrating vessels during cortical spreading depolarization with ultrasound dynamic ultrafast Doppler imaging.

The dynamic vascular responses during cortical spreading depolarization (CSD) are causally related to pathophysiological consequences in numerous neurovascular conditions, including ischemia, traumatic brain injury, cerebral hemorrhage, and migraine. Monitoring of the hemodynamic responses of cerebral penetrating vessels during CSD is motivated to understand the mechanism of CSD and related neurological disorders. Six SD rats were used, and craniotomy surgery was performed before imaging. CSDs were induced by topical KCl application. Ultrasound dynamic ultrafast Doppler was used to access hemodynamic changes, including cerebral blood volume (CBV) and flow velocity during CSD, and further analyzed those in a single penetrating arteriole or venule. The CSD-induced hemodynamic changes with typical duration and propagation speed were detected by ultrafast Doppler in the cerebral cortex ipsilateral to the induction site. The hemodynamics typically showed triphasic changes, including initial hypoperfusion and prominent hyperperfusion peak, followed by a long-period depression in CBV. Moreover, different hemodynamics between individual penetrating arterioles and venules were proposed by quantification of CBV and flow velocity. The negative correlation between the basal CBV and CSD-induced change was also reported in penetrating vessels. These results indicate specific vascular dynamics of cerebral penetrating vessels and possibly different contributions of penetrating arterioles and venules to the CSD-related pathological vascular consequences. We proposed using ultrasound dynamic ultrafast Doppler imaging to investigate CSD-induced cerebral vascular responses. With this imaging platform, it has the potential to monitor the hemodynamics of cortical penetrating vessels during brain injuries to understand the mechanism of CSD in advance.

Evaluation of collateral status and outcome in patients with middle cerebral artery stenosis in late time window by CT perfusion imaging.

Objectives: Collateral status (CS) is a crucial determinant of outcome in patients with ischemic stroke. We aimed to test whether the cerebral blood volume (CBV) and cerebral blood flow (CBF) based on computed tomography perfusion (CTP) measurements can quantitatively evaluate CS and explore the predictive ability of CTP parameters in determining clinical outcomes in patients with MCA severe stenosis or occlusion presenting beyond 24 h. Materials and methods: In this retrospective study, data obtained from September 2018 to March 2022 in consecutive stroke patients caused by isolated middle cerebral artery severe stenosis or occlusion were reviewed within 24-72 h after onset. Correlation between the collateral score systems assessed with CT angiography (CTA) and CTP parameters was calculated using the Spearman correlation. The optimal threshold of the CBV ratio for predicting a good outcome was determined using receiver operating characteristic curve (ROC) analysis. Results: A total of 69 patients met inclusion criteria. Both the CBV ratio and the CBF ratio had significant correlation with collateral score systems assessed with CTA [CBV ratio and Tan score: rs = 0.702, P < 0.0001; CBV ratio and regional leptomeningeal collateral (rLMC) score: rs = 0.705, P < 0.0001; CBV ratio and Miteff score: rs = 0.625, P < 0.0001. CBF ratio and Tan score: rs= 0.671, P < 0.0001; CBF ratio and rLMC score: rs = 0.715, P < 0.0001; CBF ratio and Miteff score: rs = 0.535, P < 0.0001]. ROC analysis revealed the CBV ratio performed better than the qualitative collateral assessments and the CBF ratio in the prediction of a favorable 90-day modified Rankin scale score. The CBV ratio was a useful parameter that predicted a good functional outcome [area under the curve (AUC), 0.922; 95% CI, 0.862 ± 0.982]. Conclusions: In late time window stroke patients, the CBV and CBF ratio on CTP may be valuable parameters for quantitatively revealing the collateral status after stroke. In addition, the CBV ratio was the predictor of clinical outcomes in patients with MCA severe stenosis or occlusion.

Quantitative Hemodynamic Measurements in Cortical Vessels Using Functional Ultrasound Imaging.

Red blood cell velocity (RBCv), cerebral blood flow (CBF), and volume (CBV) are three key parameters when describing brain hemodynamics. Functional ultrasound imaging is a Doppler-based method allowing for real-time measurement of relative CBV at high spatiotemporal resolution (100 × 110 × 300 µm3, up to 10 Hz) and large scale. Nevertheless, the measure of RBCv and CBF in small cortical vessels with functional ultrasound imaging remains challenging because of their orientation and size, which impairs the ability to perform precise measurements. We designed a directional flow filter to overpass these limitations allowing us to measure RBCv in single vessels using a standard functional ultrasound imaging system without contrast agents (e.g., microbubbles). This method allows to quickly extract the number of vessels in the cortex that was estimated to be approximately 650/cm3 in adult rats, with a 55-45% ratio for penetrating arterioles versus ascending venules. Then, we analyzed the changes in RBCv in these vessels during forepaw stimulation. We observed that ∼40 vessels located in the primary somatosensory forelimb cortex display a significant increase of the RBCv (median ΔRBCv ∼15%, maximal ΔRBCv ∼60%). As expected, we show that RBCv was higher for penetrating arterioles located in the center than in the periphery of the activated area. The proposed approach extends the capabilities of functional ultrasound imaging, which may contribute to a better understanding of the neurovascular coupling at the brain-wide scale.

Estimation of Cerebral Hemodynamics and Oxygenation During Various Intensities of Rowing Exercise: An NIRS Study.

Purpose: This study aimed to investigate changes in cerebral hemodynamics and oxygenation at moderate, heavy, maximal and supramaximal intensities of rowing exercise. It also examined whether these changes reflect alterations in sensation of effort and mood. We also aimed to examine the effects of peak pulmonary oxygen consumption ( V . O2peak ) on cerebral oxygenation. Methods: Eleven rowers, consisting out of six athletes and five recreational rowers [two female; age, 27 ± 9 years; height, 171 ± 7 cm, body mass, 67 ± 9 kg; V . O2peak , 53.5 ± 6.5 mL min-1 kg-1] rowed a 13-min session separated by 10 and 3 min, at 70 (Ex70%) and 80% of V . O2peak (Ex80%), respectively, on a rowing ergometer, followed by three sessions of 1-min supramaximal exercise (ExSp). After a warm-up at 60% of V . O2peak (ExM), seven male rowers performed a 2,000 m all-out test (Ex2000). Cardiovascular and respiratory variables were measured. Cerebral oxygenation was investigated by near-infrared time-resolved spectroscopy (TRS) to measure cerebral hemoglobin oxygen saturation (ScO2) and total hemoglobin concentration ([HbT]) in the prefrontal cortex (PFC) quantitatively. We estimated the relative changes from rest in cerebral metabolic rate for oxygen (rCMRO2) using TRS at all intensities. During Ex70% and Ex80%, ratings of perceived exertion (RPE) were monitored, and alteration of the subject's mood was evaluated using a questionnaire of Positive-and-Negative-Affect-Schedule after Ex70% and Ex80%. Results: When exercise intensity changed from Ex70% to Ex80%, the sense of effort increased while ScO2 decreased. [HbT] remained unchanged. After Ex70% and Ex80%, a negative mood state was less prominent compared to rest and was accompanied by increases in both ScO2 and [HbT]. At termination of Ex2000, ScO2 decreased by 23% compared to rest. Changes in ScO2 correlated with V . O2peak only during Ex2000 (r = -0.86; p = 0.01). rCMRO2 did not decrease at any intensities. Conclusion: Our results suggest that alterations in the sense of effort are associated with oxygenation in the PFC, while positive changes in mood status are associated with cerebral perfusion and oxygen metabolism estimated by TRS. At exhaustion, the cerebral metabolic rate for oxygen is maintained despite a decrease in ScO2.

The cholinergic system modulates negative BOLD responses in the prefrontal cortex once electrical perforant pathway stimulation triggers neuronal afterdischarges in the hippocampus.

Repeated high-frequency pulse-burst stimulations of the rat perforant pathway elicited positive BOLD responses in the right hippocampus, septum and prefrontal cortex. However, when the first stimulation period also triggered neuronal afterdischarges in the hippocampus, then a delayed negative BOLD response in the prefrontal cortex was generated. While neuronal activity and cerebral blood volume (CBV) increased in the hippocampus during the period of hippocampal neuronal afterdischarges (h-nAD), CBV decreased in the prefrontal cortex, although neuronal activity did not decrease. Only after termination of h-nAD did CBV in the prefrontal cortex increase again. Thus, h-nAD triggered neuronal activity in the prefrontal cortex that counteracted the usual neuronal activity-related functional hyperemia. This process was significantly enhanced by pilocarpine, a mACh receptor agonist, and completely blocked when pilocarpine was co-administered with scopolamine, a mACh receptor antagonist. Scopolamine did not prevent the formation of the negative BOLD response, thus mACh receptors modulate the strength of the negative BOLD response.

Does physiological-based cord clamping improve cerebral tissue oxygenation and perfusion in healthy term neonates? - A randomized controlled trial.

Objectives: To evaluate cerebral tissue oxygenation index (cTOI) during neonatal transition in a group of healthy full-term neonates receiving either a physiological-based approach of deferred cord clamping (CC) after the onset of stable regular breathing (PBCC group) or a standard approach of time-based CC < 1 min (control group). Secondary aim was to evaluate changes in cerebral blood volume (ΔCBV), peripheral arterial oxygen saturation (SpO2) and heart rate (HR) in those neonates. Materials and Methods: We conducted a randomized controlled trial (clinicaltrials.gov: NCT02763436) including vaginally delivered healthy full-term neonates. Continuous measurements of cTOI and ΔCBV using near-infrared spectroscopy, and of SpO2 and HR using pulse oximetry were performed within the first 15 min after birth. Data of each minute of the PBCC group were compared to those of the control group. Results: A total of 71 full-term neonates (PBCC: n = 35, control: n = 36) with a mean (SD) gestational age of 40.0 (1.0) weeks and a birth weight of 3,479 (424) grams were included. Median (IQR) time of CC was 275 (197-345) seconds and 58 (35-86) seconds in the PBCC and control group, respectively (p < 0.001). There were no significant differences between the two groups regarding cTOI (p = 0.319), ΔCBV (p = 0.814), SpO2 (p = 0.322) and HR (p = 0.878) during the first 15 min after birth. Conclusion: There were no significant differences in the course of cTOI as well as ΔCBV, SpO2 and HR during the first 15 min after birth in a group of healthy full-term neonates, who received either deferred CC after the onset of stable regular breathing or standard CC < 1 min. Thus, deferring CC ≥ 1 min following a physiological-based approach offers no benefits regarding cerebral tissue oxygenation and perfusion after uncomplicated vaginal delivery compared to a time-based CC approach.

Prediction of IDH Mutation Status in High-grade Gliomas Using DWI and High T1-weight DSC-MRI.

RATIONALE AND OBJECTIVES: We aimed to evaluate the diagnostic performance of diffusion-weighted imaging (DWI) and dynamic susceptibility contrast-enhanced (DSC) magnetic resonance imaging (MRI) parameters in the noninvasive prediction of the isocitrate dehydrogenase (IDH) mutation status in high-grade gliomas (HGGs). MATERIALS AND METHODS: A total of 58 patients with histopathologically proved HGGs were included in this retrospective study. All patients underwent multiparametric MRI on 3-T, including DSC-MRI and DWI before surgery. The mean apparent diffusion coefficient (ADC), relative maximum cerebral blood volume (rCBV), and percentage signal recovery (PSR) of the tumor core were measured and compared depending on the IDH mutation status and tumor grade. The Mann-Whitney U test was used to detect statistically significant differences in parameters between IDH-mutant-type (IDH-m-type) and IDH-wild-type (IDH-w-type) HGGs. Receiver operating characteristic curve (ROC) analysis was performed to evaluate the diagnostic performance. RESULTS: The rCBV was significantly higher, and the PSR value was significantly lower in IDH-w-type tumors than in the IDH-m group (p = 0.002 and <0.001, respectively).The ADC value in IDH-w-type tumors was significantly lower compared with the one in IDH-m types (p = 0.023), but remarkable overlaps were found between the groups. The PSR showed the best diagnostic performance with an AUC of 0.938 and with an accuracy rate of 0.87 at the optimal cutoff value of 86.85. The combination of the PSR and the rCBV for the identification of the IDH mutation status increased the discrimination ability at the AUC level of 0.955. In terms of each tumor grade, the PSR and rCBV showed significant differences between the IDH-m and IDH-w groups (p ≤0.001). CONCLUSION: The rCBV and PSR from DSC-MRI may be feasible noninvasive imaging parameters for predicting the IDH mutation status in HGGs. The standardization of the imaging protocol is indispensable to the utility of DSC perfusion MRI in wider clinical usage.

Cerebral hemodynamics and capillary dysfunction in late-onset major depressive disorder.

In major depressive disorder (MDD), perfusion changes in cortico-limbic pathways are interpreted as altered neuronal activity, but they could also signify changes in neurovascular coupling due to altered capillary function. To examine capillary function in late-onset MDD, 22 patients and 22 age- and gender-matched controls underwent perfusion MRI. We measured normalized cerebral blood flow (nCBF), cerebral blood volume (nCBV), and relative transit-time heterogeneity (RTH). Resulting brain oxygenation was estimated in terms of oxygen tension and normalized metabolic rate of oxygen (nCMRO2). Patients revealed signs of capillary dysfunction (elevated RTH) in the anterior prefrontal cortex and ventral anterior cingulate cortex bilaterally and in the left insulate cortex compared to controls, bilateral hypometabolism (parallel reductions of nCBV, nCBF, and CMRO2) but preserved capillary function in the subthalamic nucleus and globus pallidus bilaterally, and hyperactivity with preserved capillary function (increased nCBF) in the cerebellum and brainstem. Our data support that perfusion changes in deep nuclei and cerebellum reflect abnormally low and high activity, respectively, in MDD patients, but suggest that microvascular pathology affects neurovascular coupling in ventral circuits. We speculate that microvascular pathology is important for our understanding of etiology of late-onset MDD as well as infererences about resulting brain activity changes.

Impaired cerebral vascular and metabolic responses to parametric N-back tasks in subjective cognitive decline.

Previous studies reported abnormally increased and/or decreased blood oxygen level-dependent (BOLD) activations during functional tasks in subjective cognitive decline (SCD). The neurophysiological basis underlying these functional aberrations remains debated. This study aims to investigate vascular and metabolic responses and their dependence on cognitive processing loads during functional tasks in SCD. Twenty-one SCD and 18 control subjects performed parametric N-back working-memory tasks during MRI scans. Task-evoked percentage changes (denoted as δ) in cerebral blood volume (δCBV), cerebral blood flow (δCBF), BOLD signal (δBOLD) and cerebral metabolic rate of oxygen (δCMRO2) were evaluated. In the frontal lobe, trends of decreased δCBV, δCBF and δCMRO2 and increased δBOLD were observed in SCD compared with control subjects under lower loads, and these trends increased to significant differences under the 3-back load. δCBF was significantly correlated with δCMRO2 in controls, but not in SCD subjects. As N-back loads increased, the differences between SCD and control subjects in δCBF and δCMRO2 tended to enlarge. In the parietal lobe, no significant between-group difference was observed. Our findings suggested that impaired vascular and metabolic responses to functional tasks occurred in the frontal lobe of SCD, which contributed to unusual BOLD hyperactivation and was modulated by cognitive processing loads.

A Novel Proposal for an Index for Regional Cerebral Perfusion Pressure - A Theoretical Approach Using Fluid Dynamics.

Cerebral blood flow (CBF) / cerebral blood volume (CBV) ratio derived by [15O] H2O/ CO2 and CO positron emission tomography (PET) examination has been used as an index for cerebral perfusion pressure (CPP). CBF/CBV was demonstrated to be related mean arterial pressure (MAP) in baboons. However, this formula has not been confirmed to be proportionate to CPP. We have developed a new index for CPP using the Poiseuille equation based on a simple model. Our model suggests that CBF/CBV2 is proportionate to CPP and that it is mathematically a more accurate index than CBF/CBV. This new index needs experimental validation in the future.

Detection of Cerebrovascular Loss in the Normal Aging C57BL/6 Mouse Brain Using in vivo Contrast-Enhanced Magnetic Resonance Angiography.

Microvascular rarefaction, or the decrease in vascular density, has been described in the cerebrovasculature of aging humans, rats, and, more recently, mice in the presence and absence of age-dependent diseases. Given the wide use of mice in modeling age-dependent human diseases of the cerebrovasculature, visualization, and quantification of the global murine cerebrovasculature is necessary for establishing the baseline changes that occur with aging. To provide in vivo whole-brain imaging of the cerebrovasculature in aging C57BL/6 mice longitudinally, contrast-enhanced magnetic resonance angiography (CE-MRA) was employed using a house-made gadolinium-bearing micellar blood pool agent. Enhancement in the vascular space permitted quantification of the detectable, or apparent, cerebral blood volume (aCBV), which was analyzed over 2 years of aging and compared to histological analysis of the cerebrovascular density. A significant loss in the aCBV was detected by CE-MRA over the aging period. Histological analysis via vessel-probing immunohistochemistry confirmed a significant loss in the cerebrovascular density over the same 2-year aging period, validating the CE-MRA findings. While these techniques use widely different methods of assessment and spatial resolutions, their comparable findings in detected vascular loss corroborate the growing body of literature describing vascular rarefaction aging. These findings suggest that such age-dependent changes can contribute to cerebrovascular and neurodegenerative diseases, which are modeled using wild-type and transgenic laboratory rodents.

Imaging glioma biology: spatial comparison of amino acid PET, amide proton transfer, and perfusion-weighted MRI in newly diagnosed gliomas.

PURPOSE: Imaging glioma biology holds great promise to unravel the complex nature of these tumors. Besides well-established imaging techniques such O-(2-[18F]fluoroethyl)-L-tyrosine (FET)-PET and dynamic susceptibility contrast (DSC) perfusion imaging, amide proton transfer-weighted (APTw) imaging has emerged as a promising novel MR technique. In this study, we aimed to better understand the relation between these imaging biomarkers and how well they capture cellularity and vascularity in newly diagnosed gliomas. METHODS: Preoperative MRI and FET-PET data of 46 patients (31 glioblastoma and 15 lower-grade glioma) were segmented into contrast-enhancing and FLAIR-hyperintense areas. Using established cutoffs, we calculated hot-spot volumes (HSV) and their spatial overlap. We further investigated APTw and CBV values in FET-HSV. In a subset of 10 glioblastoma patients, we compared cellularity and vascularization in 34 stereotactically targeted biopsies with imaging. RESULTS: In glioblastomas, the largest HSV was found for APTw, followed by PET and CBV (p < 0.05). In lower-grade gliomas, APTw-HSV was clearly lower than in glioblastomas. The spatial overlap of HSV was highest between APTw and FET in both tumor entities and regions. APTw correlated significantly with cellularity, similar to FET, while the association with vascularity was more pronounced in CBV and FET. CONCLUSIONS: We found a relevant spatial overlap in glioblastomas between hotspots of APTw and FET both in contrast-enhancing and FLAIR-hyperintense tumor. As suggested by earlier studies, APTw was lower in lower-grade gliomas compared with glioblastomas. APTw meaningfully contributes to biological imaging of gliomas.

Quantitative vascular neuroimaging of the rat brain using superparamagnetic nanoparticles: New insights on vascular organization and brain function.

A method called Quantitative Ultra-Short Time-to-Echo Contrast Enhanced (QUTE-CE) Magnetic Resonance Imaging (MRI) which utilizes superparamagnetic iron oxide nanoparticles (SPIONs) as a contrast agent to yield positive contrast angiograms with high clarity and definition is applied to the whole live rat brain. QUTE-CE MRI intensity data are particularly well suited for measuring quantitative cerebral blood volume (qCBV). A global map of qCBV in the awake resting-state with unprecedented detail was created via application of a 3D MRI rat brain atlas with 173 segmented and annotated brain areas. From this map we identified two distributed, integrated neural circuits showing the highest capillary densities in the brain. One is the neural circuitry involved with the primary senses of smell, hearing and vision and the other is the neural circuitry of memory. Under isoflurane anesthesia, these same circuits showed significant decreases in qCBV suggesting a role in consciousness. Neural circuits in the brainstem associated with the reticular activating system and the maintenance of respiration, body temperature and cardiovascular function showed an increase in qCBV with anesthesia. During awake CO2 challenge, 84 regions showed significant increases relative to an awake baseline state. This CO2 response provides a measure of cerebral vascular reactivity and regional perfusion reserve with the highest response measured in the somatosensory cortex. These results demonstrate the utility of QUTE-CE MRI for qCBV analysis and offer a new perspective on brain function and vascular organization.

Capillary dysfunction is associated with symptom severity and neurodegeneration in Alzheimer's disease.

INTRODUCTION: We examined whether cortical microvascular blood volume and hemodynamics in Alzheimer's disease (AD) are consistent with tissue hypoxia and whether they correlate with cognitive performance and the degree of cortical thinning. METHODS: Thirty-two AD patients underwent cognitive testing, structural magnetic resonance imaging (MRI), and perfusion MRI at baseline and after 6 months. We measured cortical thickness, microvascular cerebral blood volume (CBV), cerebral blood flow (CBF), mean transit time (MTT), and capillary transit time heterogeneity (CTH) and estimated tissue oxygen tension (PtO2). RESULTS: At baseline, poor cognitive performance and regional cortical thinning correlated with lower CBF and CBV, with higher MTT and CTH and with low PtO2 across the cortex. Cognitive decline over time was associated with increasing whole brain relative transit time heterogeneity (RTH = CTH/MTT). DISCUSSION: Our results confirm the importance of microvascular pathology in AD. Deteriorating microvascular hemodynamics may cause hypoxia, which is known to precipitate amyloid retention.

Dynamic Susceptibility Contrast MR Imaging in Glioma: Review of Current Clinical Practice.

Dynamic susceptibility contrast (DSC) MR imaging, a perfusion-weighted MR imaging technique typically used in neuro-oncologic applications for estimating the relative cerebral blood volume within brain tumors, has demonstrated much potential for determining prognosis, predicting therapeutic response, and assessing early treatment response of gliomas. This review highlights recent developments using DSC-MR imaging and emphasizes the need for technical standardization and validation in prospective studies in order for this technique to become incorporated into standard-of-care imaging for patients with brain tumors.

Arterial input function and gray matter cerebral blood volume measurements in children.

PURPOSE: To investigate how arterial input functions (AIFs) vary with age in children and compare the use of individual and population AIFs for calculating gray matter CBV values. Quantitative measures of cerebral blood volume (CBV) using dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI) require measurement of an AIF. AIFs are affected by numerous factors including patient age. Few data presenting AIFs in the pediatric population exists. MATERIALS AND METHODS: Twenty-two previously treated pediatric brain tumor patients (mean age, 6.3 years; range, 2.0-15.3 years) underwent DSC-MRI scans on a 3T MRI scanner over 36 visits. AIFs were measured in the middle cerebral artery. A functional form of an adult population AIF was fitted to each AIF to obtain parameters reflecting AIF shape. The relationship between parameters and age was assessed. Correlations between gray matter CBV values calculated using the resulting population and individual patient AIFs were explored. RESULTS: There was a large variation in individual patient AIFs but correlations between AIF shape and age were observed. The center (r = 0.596, P < 0.001) and width of the first-pass peak (r = 0.441, P = 0.007) were found to correlate significantly with age. Intrapatient coefficients of variation were significantly lower than interpatient values for all parameters (P < 0.001). Differences in CBV values calculated with an overall population and age-specific population AIF compared to those calculated with individual AIFs were 31.3% and 31.0%, respectively. CONCLUSION: Parameters describing AIF shape correlate with patient age in line with expected changes in cardiac output. In pediatric DSC-MRI studies individual patient AIFs are recommended.

Analysis of three leakage-correction methods for DSC-based measurement of relative cerebral blood volume with respect to heterogeneity in human gliomas.

PURPOSE: Aim of this study was to investigate the influence of contrast agent leakage on relative cerebral blood volume (rCBV), using clinical dynamic susceptibility contrast (DSC) protocols. Different correction methods were compared, in order to identify a clinically reliable method. MATERIALS AND METHODS: DSC perfusion data from patients with glioma were acquired with a single-shot EPI technique at 3.0T using a pre-dose. Three different post-processing methods for leakage correction were compared, concerning rCBV, the permeability related parameter K2 and the predominant leakage effect in tumor regions (T1 effect: K2>0; T2* effect: K2<0). Additionally, simulations were performed, to investigate the influence of noise and input curve modifications on correction results. RESULTS: Our results indicate several differences between post-processing methods with regard to rCBV values, reflected by the fact that the distribution of detected leakage effects and the correction strength differed between methods. Leakage was heterogeneous within tumorous tissue and between patients, with a general predominance of T2* effects but an increased amount of T1 effects in low grade glioma. Simulations confirmed differential dependencies on signal-to-noise ratios, mean transit times and input curves as possible reasons. CONCLUSION: The impact of leakage is complex, thus adequate correction necessitates care. Standardized input parameters are one important factor for comparability of rCBV and K2 values among patients. The extension of DSC analysis with K2 maps could potentially allow improved differentiation between tumor grades. Further methods need to integrate special advantages of existing approaches to achieve more reliable rCBV estimates within clinically reasonable calculation times.