rCBV Changes Research Articles

Beyond T2-FLAIR mismatch sign in isocitrate dehydrogenase mutant 1p19q non-codeleted astrocytoma: Analysis of tumor core and evolution with multiparametric magnetic resonance imaging.

The T2-FLAIR mismatch sign is an imaging correlate for isocitrate dehydrogenase (IDH)-mutant 1p19q non-codeleted astrocytomas. However, it is only seen in a part of the cases at certain stages. Many of the tumors likely lose T2 homogeneity as they grow in size, and become heterogenous. The aim of this study was to investigate the timecourse of T2-FLAIR mismatch sign, and assess intratumoral heterogeneity using multiparametric magnetic resonance imaging techniques. A total of 128 IDH-mutant gliomas were retrospectively analyzed. Observers blinded to molecular status used strict criteria to select T2-FLAIR mismatch astrocytomas. Pre-biopsy and follow-up standard structural sequences of T2, FLAIR and apparent diffusion coefficient, MR spectroscopy (both single- and multi-voxel techniques), and DSC perfusion were observed. Nine T2-FLAIR mismatch astrocytomas were identified. 7 had MR spectroscopy and perfusion data. The smallest astrocytomas began as rounded T2 homogeneous lesions without FLAIR suppression, and developed T2-FLAIR mismatch during follow-up with falls in NAA and raised Cho/Cr ratio. Larger tumors at baseline with T2-FLAIR mismatch signs developed intratumoral heterogeneity, and showed elevated Cho/Cr ratio and raised relative cerebral blood volume (rCBV). The highest levels of intratumoral Cho/Cr and rCBV changes were located within the tumor core, and this area signifies the progression of the tumors toward high grade. T2-FLAIR mismatch sign is seen at a specific stage in the development of astrocytoma. By assessing the subsequent heterogeneity, MR spectroscopy and perfusion imaging are able to predict the progression of the tumor towards high grade, thereby can assist targeting for biopsy and selective debulking.

Functional ultrasound reveals effects of MRI acoustic noise on brain function

Loud acoustic noise from the scanner during functional magnetic resonance imaging (fMRI) can affect functional connectivity (FC) observed in the resting state, but the exact effect of the MRI acoustic noise on resting state FC is not well understood. Functional ultrasound (fUS) is a neuroimaging method that visualizes brain activity based on relative cerebral blood volume (rCBV), a similar neurovascular coupling response to that measured by fMRI, but without the audible acoustic noise. In this study, we investigated the effects of different acoustic noise levels (silent, 80 dB, and 110 dB) on FC by measuring resting state fUS (rsfUS) in awake mice in an environment similar to fMRI measurement. Then, we compared the results to those of resting state fMRI (rsfMRI) conducted using an 11.7 Tesla scanner. RsfUS experiments revealed a significant reduction in FC between the retrosplenial dysgranular and auditory cortexes (0.56 ± 0.07 at silence vs 0.05 ± 0.05 at 110 dB, p=.01) and a significant increase in FC anticorrelation between the infralimbic and motor cortexes (−0.21 ± 0.08 at silence vs −0.47 ± 0.04 at 110 dB, p=.017) as acoustic noise increased from silence to 80 dB and 110 dB, with increased consistency of FC patterns between rsfUS and rsfMRI being found with the louder noise conditions. Event-related auditory stimulation experiments using fUS showed strong positive rCBV changes (16.5% ± 2.9% at 110 dB) in the auditory cortex, and negative rCBV changes (−6.7% ± 0.8% at 110 dB) in the motor cortex, both being constituents of the brain network that was altered by the presence of acoustic noise in the resting state experiments. Anticorrelation between constituent brain regions of the default mode network (such as the infralimbic cortex) and those of task-positive sensorimotor networks (such as the motor cortex) is known to be an important feature of brain network antagonism, and has been studied as a biological marker of brain disfunction and disease. This study suggests that attention should be paid to the acoustic noise level when using rsfMRI to evaluate the anticorrelation between the default mode network and task-positive sensorimotor network.

Paradoxical Association Between Relative Cerebral Blood Volume Dynamics Following Chemoradiation and Increased Progression-Free Survival in Newly Diagnosed IDH Wild-Type MGMT Promoter Methylated Glioblastoma With Measurable Disease.

Background and PurposeWhile relative cerebral blood volume (rCBV) may be diagnostic and prognostic for survival in glioblastoma (GBM), changes in rCBV during chemoradiation in the subset of newly diagnosed GBM with subtotal resection and the impact of MGMT promoter methylation status on survival have not been explored. This study aimed to investigate the association between rCBV response, MGMT methylation status, and progression-free (PFS) and overall survival (OS) in newly diagnosed GBM with measurable enhancing lesions.Methods1,153 newly diagnosed IDH wild-type GBM patients were screened and 53 patients (4.6%) had measurable post-surgical tumor (>1mL). rCBV was measured before and after patients underwent chemoradiation. Patients with a decrease in rCBV >10% were considered rCBV Responders, while patients with an increase or a decrease in rCBV <10% were considered rCBV Non-Responders. The association between change in enhancing tumor volume, change in rCBV, MGMT promotor methylation status, and PFS or OS were explored.ResultsA decrease in tumor volume following chemoradiation trended towards longer OS (p=0.12; median OS=26.8 vs. 16.3 months). Paradoxically, rCBV Non-Responders had a significantly improved PFS compared to Responders (p=0.047; median PFS=9.6 vs. 7.2 months). MGMT methylated rCBV Non-Responders exhibited a significantly longer PFS compared to MGMT unmethylated rCBV Non-Responders (p<0.001; median PFS=0.5 vs. 7.1 months), and MGMT methylated rCBV Non-Responders trended towards longer PFS compared to methylated rCBV Responders (p=0.089; median PFS=20.5 vs. 13.8 months).ConclusionsThis preliminary report demonstrates that in newly diagnosed IDH wild-type GBM with measurable enhancing disease after surgery (5% of patients), an enigmatic non-response in rCBV was associated with longer PFS, particularly in MGMT methylated patients.

Influence of regional cerebral blood volume on voxel-based morphometry.

The investigation of structural brain alterations is one focus in research of brain diseases like depression. Voxel-based morphometry (VBM) based on high-resolution 3D MRI images is a widely used non-invasive tool for such investigations. However, the result of VBM might be sensitive to local physiological parameters such as regional cerebral blood volume (rCBV) changes. In order to investigate whether rCBV changes may contribute to variation in VBM, we performed analyses in a study with the congenital learned helplessness (cLH) model for long-term findings. The 3D structural and rCBV data were acquired with T2 -weighted rapid acquisition with relaxation enhancement (RARE) pulse sequences. The group effects were determined by standard statistical parametric mapping (SPM) and biological parametric mapping (BPM) and examined further using atlas-based regions. In our genetic animal model of depression, we found co-occurrence of differences in gray matter volume and rCBV, while there was no evidence of significant interaction between both. However, the multimodal analysis showed similar gray matter differences compared with the standard VBM approach. Our data corroborate the idea that two group VBM differences might not be influenced by rCBV differences in genetically different strains. Copyright © 2016 John Wiley & Sons, Ltd.

NIMG-25IMPROVED LEAKAGE CORRECTION FOR DYNAMIC SUSCEPTIBILITY CONTRAST (DSC) PERFUSION MRI ESTIMATES OF RELATIVE CEREBRAL BLOOD VOLUME (rCBV) IN HIGH-GRADE GLIOMAS BY ACCOUNTING FOR BIDIRECTIONAL CONTRAST AGENT EXCHANGE

BACKGROUND: Contrast agent exchange through a compromised BBB results in imprecise estimates of rCBV using DSC-MRI. The current methods for leakage correction, however, are inaccurate in that they only account for leakage from the vascular to extravascular space. The current study explores a new bidirectional leakage model for DSC-MRI for improved rCBV estimates in high-grade gliomas. METHODS: The traditional model-based post-processing leakage correction algorithm that assumes unidirectional contrast agent extravasation (Boxerman-Weisskoff mode, BW-model) to account for bidirectional contrast eagent exchange between intra- and extravascular spaces (Bidir-model). We compared goodness of fit to raw leakage-contaminated relaxation rate curves and differences between modeld interstitial relaxation rate curves collected using DCE-MRI data from the same patients. We then compared the ability for both models to predict response to bevcizumab in recurrent GBMs. RESULTS: Using a mathematical simplification originally applied to DCE data we were able to obtain comparable computation times between the two techniques. The Bidir-model had significantly improved goodness of fit when compared with the BW-model in terms of both fit to raw, contaminated relaxation rate signals from DSC-MRI (P < 0.0001) as well as relaxation rate estimates in the interstitial space estimated using DCE-MRI (P = 0.0041). On average, enhancing tumor rCBV for the traditional BW-model was higher by 16.6%. Specifically, when the DSC signal is corrupted by T1-leakage the BW-model underestimates rCBV, and when then DSC signal is corrupted by T2*-leakage the traditional model overestimates rCBV. Results also suggests changes in rCBV calculated after bevacizumab using the Bidir-model significantly predicts overall survival (P = 0.03), whereas the traditional estimates of rCBV from the BW-model were not predictive. CONCLUSION: Inclusion of bidirectional exchange in the leakage correction model for DSC-MRI significantly improves the model fit to leakage-contaminated DSC-MRI data, significantly improves estimation of rCBV in gliomas, and improves biomarker accuracy for predicting response to anti-angiogenic therapy.

Early Cerebral Blood Volume Changes Predict Progression After Convection-Enhanced Delivery of Topotecan for Recurrent Malignant Glioma

To assess whether early changes in enhancing tumor volume (eTV) and relative cerebral blood volume (rCBV) 1 month after convection-enhanced delivery of topotecan in patients with recurrent malignant glioma correlated with 6-month disease progression status. Sixteen patients were enrolled in a Phase Ib trial of convection-enhanced delivery of topotecan for recurrent malignant glioma. Each patient was evaluated with serial follow-up magnetic resonance imaging at baseline and at 4- to 8-week intervals. Changes at 1 month compared with baseline in eTV and rCBV were evaluated as potential predictors of 6-month progression status, classified as either progressive disease or nonprogressive disease. Relationships between percent changes in eTV and rCBV at 1 month with the probability of progressive disease at 6 months were estimated by the use of logistic regression analysis. Receiver operating characteristic curves for varying percent change thresholds in eTV and rCBV were evaluated by the use of 6-month progressive disease as the reference. There was a significant difference in the percent change in rCBV at 1 month in patients with progressive disease compared with those with nonprogressive disease at 6 months (+12% vs. -29%, P = 0.02). Logistic regression analysis demonstrated on average that a 10% increase in rCBV at 1 month after convection-enhanced delivery of topotecan was associated with 1.7 times the odds of developing progressive disease at 6 months (95% confidence interval [CI] 1.0-2.9 P = 0.05). Receiver operating characteristic analysis for determining progressive disease at 6 months showed a greater area under the curve with rCBV (0.867; 95% CI 0.66-1.00) than with change in enhancing tumor volume (0.767; 95% CI 0.51-1.00). In this selected population of patients with recurrent malignant glioma treated with convection-enhanced delivery of topotecan, early changes in rCBV at 4 weeks after therapy may help predict progression status at 6 months.

Measurement of choroid plexus perfusion using dynamic susceptibility MR imaging: capillary permeability and age-related changes

The cerebrospinal fluid (CSF) plays a major role in the physiology of the central nervous system. The continuous turnover of CSF is mainly attributed to the highly vascularized choroid plexus (CP) located in the cerebral ventricles which represent a complex interface between blood and CSF. We propose a method for evaluating CP functionality in vivo using perfusion MR imaging and establish the age-related changes of associated parameters. Fifteen patients with small intracranial tumors were retrospectively studied. MR Imaging was performed on a 3T MR Scanner. Gradient-echo echo planar images were acquired after bolus injection of gadolinium-based contrast agent (CA). The software developed used the combined T1- and T2-effects. The decomposition of the relaxivity signals enables the calculation of the CP capillary permeability (K2). The relative cerebral blood volume (rCBV), mean transit time (MTT), and signal slope decrease (SSD) were also calculated. The mean permeability K2 of the extracted CP was 0.033+/-0.18 s(-1). K2 and SSD significantly decreased with subject's age whereas MTT significantly increased with subject's age. No significant correlation was found for age-related changes in rCBV and rCBF. The decrease in CP permeability is in line with the age-related changes in CSF secretion observed in animals. The MTT increase indicates significant structural changes corroborated by microscopy studies in animals or humans. Overall, DSC MR-perfusion enables an in vivo evaluation of the hemodynamic state of CP. Clinical applications such as neurodegenerative diseases could be considered thanks to specific functional studies of CP.

Whole Brain Radiation Therapy With Local Simultaneous Integrated Boost Conformal Radiation Therapy in the Treatment for Patients With 1-3 Brain Metastases

To evaluate the feasibility whole brain radiation therapy (WBRT) with local simultaneous integrated boost conformal radiation therapy (SIB-CR) in the patients with one to three brain metastases. Twenty-one patients with one to three brain metastases confirmed by enhanced MRI/CT were prospectively collected and treated by whole brain radiation therapy with local SIB-CR. The prescribed dose of whole brain was 40 Gy/22 fractions and GTV to 55 Gy/22 fractions simultaneously in about 4.5 weeks. The acute radiation toxicities were recorded from the start of treatment to four weeks after the end of treatment. The late toxicities were evaluated. The tumor response was evaluated at 4 weeks after the end of radiation therapy. The overall survival (OS) and intracranial progression-free survival (PFS) time were calculated from the day of treatment until death, intracranial progression or the last follow-up date. There were 11 male and 10 female patients in this group. The median age was 52 years (range, 39-72 years). Fourteen patients received radiation therapy alone while 7 cases received chemoradiation therapy. There were 2 patients with complete response, 16 patients with partial response and 3 patients with stable disease. The overall tumor response rate was 85.7% (18/21). The median follow-up time was 7 months (range, 1-12.5 months). To the follow-up cut-off time, five patients were dead, including 3 cases died of intracranial lesions and 2 of unknown causes. The rate of overall brain control was 85.7% (18/21), the local control rate 90.5% (19/21). The overall median survival time was 7 months. The 6-month OS and intracranial PFS rates were 76.6% and 61.3%, respectively. The 1-year OS and intracranial PFS rates were 61.3% and 65.6%, respectively. The 1-year survival rate of patients treated with radiation therapy alone and chemoradiation therapy was 69.3% and 85.7%, respectively (p = 0.253). Multivariate analysis showed that the RPA classification was correlated with survival. Survival rates among the patients with different RPA scores showed that the median survival period of RPA 1, 2 and 3 level were 9, 8 and 5 months, respectively (p = 0.021). Whole brain irradiation with SIB-CR technique is effective in patients with one to three brain metastases with a higher tumor response and shorter radiation therapy duration and is well tolerated. SIB-CR technique is an effective option for these patients.

Effects of perfusion on diffusion changes in human brain tumors

To characterize the influence of perfusion on the measurement of diffusion changes over time when ADC is computed using standard two-point methods. Functional diffusion maps (FDMs), which depict changes in diffusion over time, were compared with rCBV changes in patients with brain tumors. The FDMs were created by coregistering and subtracting ADC maps from two time points and categorizing voxels where ADC significantly increased (iADC), decreased (dADC), or did not change (ncADC). Traditional FDMs (tFDMs) were computed using b = 0,1000 s/mm(2). Flow-compensated FDMs (fcFDMs) were calculated using b = 500,1000 s/mm(2). Perfusion's influence on FDMs was determined by evaluating changes in rCBV in areas where the ADC change significantly differed between the two FDMs. The mean ΔrCBV in voxels that changed from iADC (dADC) on the tFDM to ncADC on the fcFDM was significantly greater (less) than zero. In addition, mean ΔrCBV in iADC (dADC) voxels on the tFDM was significantly higher (lower) than in iADC (dADC) voxels on the fcFDM. The ability to accurately identify changes in diffusion on traditional FDMs is confounded in areas where perfusion and diffusion changes are colocalized. Flow-compensated FDMs, which use only non-zero b-values, should therefore be the standard approach.

Microvascular cerebral blood volume changes in aging APPswe/PS1dE9 AD mouse model: a voxel-wise approach

Vascular disorders can either be cause or consequence in the pathophysiology of Alzheimer's disease (AD). To comprehensively characterize the occurrence of vascular impairment in a double transgenic mouse model for AD (APPswe/PS1dE9) during aging, we developed a new method to obtain microvascular relative cerebral blood volume (rCBV(micro)) maps from gradient echo MR imaging by histogram evaluation and we applied a voxel-wise approach to detect rCBV(micro) changes. With this methodology the development of cerebral microvascular impairments can be described in vivo with 0.16 mm isotropic resolution for the whole mouse brain. At 8 months, impaired rCBV(micro) appeared in some cortical regions and in the thalamus, which spreads over several sub-cortical areas and the hippocampus at 13 months. With a ROI-based approach, we further showed that hippocampal rCBV(micro) in 13-month-old wild-type and APP(swe)/PS1(dE9) mice correlates well with capillary density measured with immunohistochemical staining. However, no differences in capillary density were detected between genotypes. The rCBV(micro) values showed no significant correlation with amyloid-β (Aβ) plaque deposition, Aβ at blood vessel walls and biochemically measured levels of Aβ₁₋₄₀, Aβ₁₋₄₂ oligomers and fibrillar forms. These results suggest that rCBV(micro) reduction is caused by an impaired vasoactivity of capillaries and arterioles, which is not directly correlated with the amount of Aβ deposition in parenchyma nor blood vessel walls.

Acute Nicotine-Induced Tachyphylaxis Is Differentially Manifest in the Limbic System

Rapid tolerance develops to many of nicotine's behavioral and autonomic effects. A better understanding of the spatiotemporal patterns in neuronal activity as a consequence of acute nicotine tolerance (tachyphylaxis) may help explain its commonly found inverted 'U'-shaped biphasic dose-effect relationship on various behaviors. To this end, we employed high-resolution functional magnetic resonance imaging and relative cerebral blood volume (rCBV) as a marker of neuronal activity, to characterize the regional development of acute tolerance as a function of nicotine dose in naïve, anesthetized rats. A single intravenous nicotine injection at 0.1 and 0.3, but not 0.03 mg/kg, significantly increased neuronal activity in many neocortical areas. In contrast, dose-dependent increases in rCBV were most pronounced in limbic regions, such that responses seen at 0.1 mg/kg nicotine in accumbens, hippocampus, amygdala, and several other limbic areas were not seen following 0.3 mg/kg nicotine. Finally, whereas profound tolerance was observed in many cortical regions after the second of two paired nicotine injections at either 0.1 or 0.3 mg/kg, subcortical limbic structures showed only a weak trend for tolerance. Lack of rCBV changes in animals receiving nicotine methiodide, a quaternary nicotine analog that does not cross the blood-brain barrier, supports a direct neuronal effect of nicotine rather than an action on the vasculature. These data provide pharmacodynamic insight into the regional heterogeneity of nicotine tachyphylaxis development, which may be relevant to behavioral and neurobiological mechanisms associated with repeated tobacco consumption.

FLAIR, T1 contrast enhancement, MR perfusion, and FDG PET following hypofractionated stereotactic radiotherapy (HFSRT), bevacizumab (BEV), and temozolomide (TMZ) for glioblastoma (GBM).

2048 Background: In GBM, VEGF inhibition decreases vascular permeability and MRI contrast enhancement (CE), which may or may not reflect meaningful anti-tumor activity. We sought to evaluate the relationships between different imaging modalities and anti-tumor activity in a prospective phase II trial of BEV, TMZ and HFSRT in GBM. Methods: Newly diagnosed GBM pts (N=40) received HFSRT with concomitant/ adjuvant BEV and TMZ. All pts underwent dynamic susceptibility contrast MR perfusion (DSC) at baseline, after HFSRT and every 2m. An FDG-PET scan was done at cycle 6. McDonald and RANO response criteria were applied. Results: DSC showed early/progressive decreases in relative cerebral blood volume (rCBV): baseline mean rCBV: 2.77; 6 weeks: 1.65 (p=0.014); 2m: 1.07 (p<0.001); 4m: 0.98 (p<0.001). Conversely, the extent of FLAIR hypersignal progressively increased (mean diameter product: 953, 1165, 1145, 1384 at 6 wks, 2m, 4m and 6m). Response rates per McDonald vs RANO were: complete response (27 vs 10%), partial (63 vs 63%), stable disease (3% vs 20%), progression (7 vs 7%). Because progressive FLAIR occurred within the RT port, time to radiographic progression per McDonald and RANO were identical: median 13m. Residual hypermetabolism seen at the 6m PET (N=6/31) predicted poor survival (p<0.001). Three pts with progressive FLAIR but not CE underwent re-resection; two had true PD and one had mainly radionecrosis. Conclusions: As treatment failure was mostly local, RANO criteria did not shorten time to progression compared to McDonald. DSC depicted early changes in rCBV linked to VEGF modulation, validating DSC as a reliable tool to evaluate anti-VEGF properties of new drugs in vivo. However, VEGF modulation was not predictive of durable anti-tumor activity. A positive PET at 6m predicted poor survival, indicating treatment failure even if other imaging modalities suggested otherwise. However, tumor progression may still be present despite negative PET and DSC, particularly in the setting of increasing non-enhancing FLAIR within the RT port. New imaging tools and improved response criteria are needed to guide management of these pts.

Assessment of perihematomal hypoperfusion injury in subacute and chronic intracerebral hemorrhage by CT perfusion imaging

Objective: To study alterations of perihematomal cerebral perfusion associated to subacute and chronic intracerebral hemorrhage (ICH) by means of computed tomography perfusion (CTP) imaging.Methods: Non-enhanced CT scan and CTP examination were performed in 12 patients with subacute and chronic supratentorial ICH. The hematoma volume was measured, and the regional cerebral blood flow (rCBF), regional cerebral blood volume (rCBV), mean transit time (MTT) and time-to-peak (TTP) adjacent to hematoma were measured in 11 of 12 cases.Results: Eleven patients with mean age of 58·1 years were finally analysed. Mean time interval from symptom onset to initial CTP scanning was 18·4 days; mean hematoma volume was 26·8 ml. The gradient of hypoperfusion around the hematoma was revealed by rCBF maps in 11 cases, and by rCBV maps in ten cases. The areas of delayed TTP and MTT were showed in 11 and ten cases, respectively. The degree of reduction in rCBV correlated strongly with the hematoma volume (rinner=0·764, p=0·006;router=0·703, p=0·016). There was no correlation between the changes in rCBF, rCBV, MTT and TTP and the time interval from symptom onset to initial CTP examination.Conclusion: We have concluded that the gradient of hypoperfusion surrounding the hematoma may still exist during the subacute and chronic phases after ICH. The alterations in rCBV correlate with the hematoma volume. We believe that the reperfusion injury marked by increased rCBV contributes to the perilesional brain injury. The quantitative CT perfusion measurements can provide valuable information in individual management and prognostic evaluation of ICH.

Pharmacologic Neuroimaging of the Ontogeny of Dopamine Receptor Function

Characterization of the ontogeny of the cerebral dopaminergic system is crucial for gaining a greater understanding of normal brain development and its alterations in response to drugs of abuse or conditions such as attention-deficit hyperactivity disorder. Pharmacological MRI (phMRI) was used to determine the response to dopamine transporter (DAT) blockers cocaine and methylphenidate (MPH), the dopamine releaser D-amphetamine (AMPH), the selective D1 agonist dihydrexidine, and the D2/D3 agonist quinpirole in young (<30 days old) and adult (>60 days old) rats. In adult rats, cocaine (0.5 mg/kg i.v.) or MPH (2 mg/kg) induced primarily positive cerebral blood volume (rCBV) changes in the dopaminergic circuitry, but negative rCBV changes in the young animals. Microdialysis measurements in the striatum showed that young rats have a smaller increase in extracellular dopamine in response to cocaine than adults. The young rats showed little rCBV response to the selective D1 agonist dihydrexidine in contrast to robust rCBV increases observed in the adults, whereas there was a similar negative rCBV response in the young and adult rats to the D2 agonist quinpirole. We also performed a meta-analysis of literature data on the development of D1 and D2 receptors and the DAT. These data suggest a predominance of D2-like over D1-like function between 20 and 30 days of age. These combined results suggested that the dopamine D1 receptor is functionally inhibited at young age.

DHA and cholesterol containing diets influence Alzheimer-like pathology, cognition and cerebral vasculature in APP swe/PS1 dE9 mice

Cholesterol and docosahexenoic acid (DHA) may affect degenerative processes in Alzheimer's Disease (AD) by influencing Aβ metabolism indirectly via the vasculature. We investigated whether DHA-enriched diets or cholesterol-containing Typical Western Diets (TWD) alter behavior and cognition, cerebral hemodynamics (relative cerebral blood volume (rCBV)) and Aβ deposition in 8- and 15-month-old APP swe/PS1 dE9 mice. In addition we investigated whether changes in rCBV precede changes in Aβ deposition or vice versa. Mice were fed regular rodent chow, a TWD-, or a DHA-containing diet. Behavior, learning and memory were investigated, and rCBV was measured using contrast-enhanced MRI. The Aβ load was visualized immunohistochemically. We demonstrate that DHA altered rCBV in 8-month-old APP/PS1 and wild type mice[AU1]. In 15-month-old APP/PS1 mice DHA supplementation improved spatial memory, decreased Aβ deposition and slightly increased rCBV, indicating that a DHA-enriched diet can diminish AD-like pathology. In contrast, TWD diets decreased rCBV in 15-month-old mice. The present data indicate that long-term dietary interventions change AD-like pathology in APP/PS1 mice. Additionally, effects of the tested diets on vascular parameters were observed before effects on Aβ load were noted. These data underline the importance of vascular factors in the APP/PS1 mouse model of AD pathology.

Use of dynamic susceptibility-contrast MRI (DSC-MRI) to assess perfusion changes in the ipsilateral brain parenchyma from glioblastoma

We investigated the effect of increased tumor perfusion using dynamic susceptibility-contrast magnetic resonance imaging (DSC-MRI) in glioblastoma (GBM) patients on the surrounding ipsilateral brain tissue with respect to perfusion of the normal, unaffected contralateral brain and of the tumor. DSC-MRI was performed in 11 patients with glioblastoma using a multislice T2*-weighed EPI sequence (TR/TE = 2,000/62 ms; FOV 240 mm; matrix 128 x 128; slice thickness 6 mm) on a standard clinical 1.5 Tesla scanner during intravenous injection of 40 cc Gadolinium-DTPA at a flow rate of 5 cc/s. Maps for relative regional cerebral blood volume (rCBV) and relative regional cerebral blood flow (rCBF) were created and relative values analyzed in relation to the arterial input. Relative CBV and CBF were significantly higher in gray matter than in the respective white matter (paired t-test; P < 0.001) with a high correlation for both perfusion parameters between the gray and the white matter in both ipsilateral and contralateral brain (P < 0.001). The highest values for rCBV and rCBF were found in solid tumor tissue with a significant positive correlation between tumor and the adjacent gray matter (for both rCBV and rCBF; P < 0.001). In GBM patients there is increased metabolism and thus increased rCBV and rCBF within the tumor. This increased perfusion of the tumor is not at the expense of perfusion of the ipsilateral normal brain parenchyma and in fact, the rCBV and rCBF values are linked to tumor-induced changes in rCBV and rCBF.

Pharmacological MRI in awake rats predicts selective binding of α4β2 nicotinic receptors

Neuronal nicotinic receptors are the subject of intensive research focused on developing novel therapies for drug abuse, neurocognitive disorders, neurodegenerative diseases, and pain. In this study, we have applied pharmacological magnetic resonance imaging (phMRI) in awake rats to map functional brain responses to the selective alpha(4)beta(2) nicotinic receptor agonists, A-85380, and ABT-594. Moreover, we have validated our methods by comparison with autoradiography using [(3)H]-A-85380 and [(3)H]-ABT-594. Under awake conditions (no anesthesia during scanning) where rats were habituated to the imaging environment, both compounds increased regional cerebral blood volume (rCBV) across multiple brain regions that closely matched regional brain receptor distribution with the same tritiated compounds. In addition, regional ABT-594-induced rCBV changes under awake conditions were also derived and characterized using a pharmacological model. Area-under-curve and maximum rCBV changes in brain were found to be dose-related and region-specific, and corresponded well with the known preclinical behavioral profile of this drug. In contrast, under conditions of alpha-chloralose anesthesia where physiological variables were maintained within normal ranges, increases in rCBV induced by ABT-594 were primarily restricted to some cortical areas and did not agree well with autoradiography data. Our data demonstrate the utility of using phMRI in awake animals to characterize selective pharmacological action but also highlight an important confound (anesthesia) that is rarely considered in preclinical phMRI studies.

A multimodality investigation of cerebral hemodynamics and autoregulation in pharmacological MRI

Pharmacological MRI (phMRI) methods have been widely applied to assess the central hemodynamic response to pharmacological intervention as a surrogate for changes in the underlying neuronal activity. However, many psychoactive drugs can also affect cardiovascular parameters, including arterial blood pressure (BP). Abrupt changes in BP or the anesthetic agents used in preclinical phMRI may impair cerebral blood flow (CBF) autoregulation mechanisms, potentially introducing confounds in the phMRI response. Moreover, relative cerebral blood volume (rCBV), often measured in small-animal phMRI studies, may be sensitive to BP changes even in the presence of intact autoregulation. We applied laser Doppler flowmetry and MRI to measure changes in CBF and microvascular CBV induced by increasing doses of intravenous norepinephrine (NE) challenge in the halothane-anesthetized rat. NE is a potent vasopressor that does not cross the blood-brain barrier and mimics the rapid BP changes typically observed with acute drug challenges. We found that CBF autoregulation was maintained over a BP range of 60-120 mmHg. Under these conditions, no significant central rCBV responses were observed, suggesting that microvascular rCBV changes in response to abrupt changes in perfusion pressure are negligible within the autoregulatory range. Larger BP responses were accompanied by significant changes in both CBV and CBF that might confound the interpretation of phMRI results.

Time-dependent effects of hyperoxia on the BOLD fMRI signal in primate visual cortex and LGN

Hyperoxia is present in many anaesthesia protocols used in animal blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) studies. However, little data exist on the influence of hyperoxia on the magnitude of stimulus-induced relative changes in BOLD fMRI signal (ΔBOLD%). No study to date has investigated these effects in a time-resolved manner, although cerebral vasoregulation offers sites for a time-dependent interaction of hyperoxia and ΔBOLD%. Here we investigated time-dependent effects of an inspiratory oxygen fraction of 90%. We tightly clamped end tidal CO2 and body temperature and recorded physiological parameters relevant to rCBF in (fentanyl/isoflurane) anaesthetized monkeys while using visual stimulation to elicit ΔBOLD%. To clarify whether changes in ΔBOLD% arose from changes in baseline blood oxygenation or rather altered neuronal or vascular reactivity, we directly measured changes in rCBV using monocrystalline ion oxide nanoparticles (MION) as contrast agent. In visual cortex we found a biphasic modulation of stimulus-induced ΔBOLD% under hyperoxia: We observed first a significant decrease in ΔBOLD% by −24% for data averaged over the time interval of 0–180 min post onset of hyperoxia followed by a subsequent recovery to baseline. rCBV response amplitudes were decreased by 21% in the same time interval (0–180 min). In the LGN, we neither found a significant modulation of ΔBOLD% nor of MION response amplitude. The cerebrovascular effects of hyperoxia may, therefore, be regionally specific and cannot be explained by a deoxyhemoglobin dilution model accounting for plasma oxygenation without assuming altered neuronal activity or altered neurovascular coupling.

Brain hemodynamic changes mediated by dopamine receptors: Role of the cerebral microvasculature in dopamine-mediated neurovascular coupling

The coupling between neurotransmitter-induced changes in neuronal activity and the resultant hemodynamic response is central to the interpretation of neuroimaging techniques. In the present study, MRI experiments showed that dopamine transporter blockers such as cocaine and dopamine releasers such as amphetamine and D1 receptor agonists induced large positive increases in relative cerebral blood volume (rCBV) that were not sensitive to nitric oxide synthase inhibition. However, D1/D5 receptor antagonism with SCH-23390 prevented or blocked the hemodynamic response without any concomitant effect on dopamine release. Dopamine D2/D3 receptor agonists, in contrast, induced negative changes in rCBV in brain regions corresponding largely to those endowed with these receptors. D1 and D5 receptor mRNAs were expressed in microvessels of responsive brain areas, while D2 and D3 receptors were not consistently associated with the microvascular bed. D3 receptors had an astroglial localization. Together, these experiments show that direct effects of dopamine upon the vasculature cannot be ignored in measuring the hemodynamic coupling associated with dopaminergic drugs. These results further suggest that this coupling is partially mediated through D1/D5 receptors on the microvasculature leading to increased rCBV and through astroglial D3 receptors leading to decreased rCBV. These data provide additional support for the role of local post-synaptic events in neurovascular coupling and emphasize that the interpretation of fMRI signals exclusively in terms of neuronal activity may be incomplete.