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For better quantification of perfusion with arterial spin labeling (ASL), partial volume correction (PVC) is used to disentangle the signals from gray matter (GM) and white matter within any voxel. Based on physiological considerations, PVC algorithms typically assume zero signal in the cerebrospinal fluid (CSF). Recent measurements, however, have shown that CSF-ASL signal can exceed 10% of GM signal, even when using recommended ASL labeling parameters. CSF signal is expected to particularly affect PVC results in the choroid plexus. This study aims to measure the impact of CSF signal on PVC perfusion measurements, and to investigate the potential use of PVC to retrieve pure CSF-ASL signal for blood-CSF barrier characterization. In vivo imaging included six pCASL sequences with variable label duration and post-labeling delay (PLD), and an eight-echo 3D-GRASE readout. A dataset was simulated to estimate the effect of CSF-PVC with known ground-truth parameters. Differences between the results of CSF-PVC and non-CSF-PVC were estimated for regions of interest (ROls) based on GM probability, and a separate ROI isolating the choroid plexus. In vivo, the suitability of PVC-CSF signal as an estimate of pure CSF was investigated by comparing its time course with the long-TE CSF signal. Results from both simulation and in vivo data indicated that including the CSF signal in PVC improves quantification of GM CBF by approximately 10%. In simulated data, this improvement was greater for multi-PLD (model fitting) quantification than for single PLD (similar to 1-5% difference). In the choroid plexus, the difference between CSF-PVC and non-CSF-PVC was much larger, averaging around 30%. Long-TE (pure) CSF signal could not be estimated from PVC CSF signal as it followed a different time course, indicating the presence of residual macrovascular signal in the PVC. The inclusion of CSF adds value to PVC for more accurate measurements of GM perfusion, and especially for quantification of perfusion in the choroid plexus and study of the glymphatic system.

Introduction: Low cerebral blood flow can affect cognition in patients with high-grade asymptomatic internal carotid artery stenosis. Current clinical algorithms use stroke risk to determine which patients should undergo revascularization without considering cognitive decline. Although correlations between low-flow and cognitive impairment have been reported, it is not known whether a threshold exists below which such a correlation expresses itself. Such information would be critical in treatment decisions about whether to intervene in patients with high-grade carotid artery stenosis who are at risk for cognitive decline. Objective: To determine how reduced blood flow correlates with lower cognitive scores. Methods: Patients with ≥80% unilateral internal carotid artery stenosis with no history of stroke were recruited from inpatient and outpatient practices at a single, large, comprehensive stroke center. Patients underwent bilateral insonation of middle cerebral arteries with standard 2-Hz probes over the temporal windows with transcranial Doppler. Cognitive assessments were performed by an experienced neuropsychologist using a cognitive battery comprising 14 standardized tests with normative samples grouped by age. Z-scores were generated for each test and averaged to obtain a composite Z-score for each patient. Multivariable linear regression examined associations between mean flow velocity (MFV) and composite Z-score, adjusting for age, education, and depression. The Davies test was used to determine if there was a breakpoint for a non-zero difference in slope of a segmented relationship over the range of composite Z-score values. Results: Forty-two patients with unilateral high-grade internal carotid artery stenosis without stroke were enrolled (26 males, age = 74 ± 9 years, education = 16 ± 3 years). Average composite Z-score was –0.31 SD below the age-specific normative mean (range –2.8 to +1.2 SD). In linear regression adjusted for age, education, and depression, MFV correlated with cognitive Z-score (β = 0.308, p = 0.043). A single breakpoint in the range of composite Z-scores was identified at 45 cm/s. For MFV 45 cm/s, Z-score change was nonsignificant (95% CI: –0.07 to 0.05). Conclusions: In high-grade, asymptomatic carotid artery stenosis, cognitive impairment correlated linearly with lower flow in the hemisphere fed by the occluded internal carotid artery, but only below a threshold of MFV = 45 cm/s. Identifying a hemodynamic threshold for cognitive decline using a simple, noninvasive method may influence revascularization decision-making in otherwise “asymptomatic” carotid disease.

Background\ud Low-dose lipopolysaccharide (LPS) is a well-established experimental method for inducing systemic inflammation and shown by microscopy to activate microglia in rodents. Currently, techniques for in-vivo imaging of glia in humans are limited to TSPO (Translocator protein) PET, which is expensive, methodologically challenging, and has poor cellular specificity. Diffusion-weighted magnetic resonance spectroscopy (DW-MRS) sensitizes MR spectra to diffusion of intracellular metabolites, potentially providing cell-specific information about cellular morphology. In this preliminary study, we applied DW-MRS to measure changes in the apparent diffusion coefficients (ADC) of glial and neuronal metabolites to healthy participants who underwent an LPS administration protocol. We hypothesized that the ADC of glial metabolites will be selectively modulated by LPS-induced glial activation.\ud \ud Methods\ud Seven healthy male volunteers, (mean 25.3 ± 5.9 years) were each tested in two separate sessions once after LPS (1 ng/Kg intravenously) and once after placebo (saline). Physiological responses were monitored during each session and serial blood samples and Profile of Mood States (POMS) completed to quantify white blood cell (WBC), cytokine and mood responses. DW-MRS data were acquired 5-5½ hours after injection from two brain regions: grey matter in the left thalamus, and frontal white matter.\ud \ud Results\ud Body temperature, heart rate, WBC and inflammatory cytokines were significantly higher in the LPS compared to the placebo condition (p < 0.001). The ADC of the glial metabolite choline (tCho) was also significantly increased after LPS administration compared to placebo (p = 0.008) in the thalamus which scaled with LPS-induced changes in POMS total and negative mood (Adj R2 = 0.83; p = 0.004).\ud \ud Conclusions\ud DW-MRS may be a powerful new tool sensitive to glial cytomorphological changes in grey matter induced by systemic inflammation.

The mismatch in the spatial resolution of Arterial Spin Labeling (ASL) MRI perfusion images and the anatomy of functionally distinct tissues in the brain leads to a partial volume effect (PVE), which in turn confounds the estimation of perfusion into a specific tissue of interest such as gray or white matter. This confound occurs because the image voxels contain a mixture of tissues with disparate perfusion properties, leading to estimated perfusion values that reflect primarily the volume proportions of tissues in the voxel rather than the perfusion of any particular tissue of interest within that volume. It is already recognized that PVE influences studies of brain perfusion, and that its effect might be even more evident in studies where changes in perfusion are co-incident with alterations in brain structure, such as studies involving a comparison between an atrophic patient population vs control subjects, or studies comparing subjects over a wide range of ages. However, the application of PVE correction (PVEc) is currently limited and the employed methodologies remain inconsistent. In this article, we outline the influence of PVE in ASL measurements of perfusion, explain the main principles of PVEc, and provide a critique of the current state of the art for the use of such methods. Furthermore, we examine the current use of PVEc in perfusion studies and whether there is evidence to support its wider adoption. We conclude that there is sound theoretical motivation for the use of PVEc alongside conventional, ‘uncorrected’, images, and encourage such combined reporting. Methods for PVEc are now available within standard neuroimaging toolboxes, which makes our recommendation straightforward to implement. However, there is still more work to be done to establish the value of PVEc as well as the efficacy and robustness of existing PVEc methods.

Arterial spin labeling (ASL) has undergone significant development since its inception, with a focus on improving standardization and reproducibility of its acquisition and quantification. In a community-wide effort towards robust and reproducible clinical ASL image processing, we developed the software package ExploreASL, allowing standardized analyses across centers and scanners.The procedures used in ExploreASL capitalize on published image processing advancements and address the challenges of multi-center datasets with scanner-specific processing and artifact reduction to limit patient exclusion. ExploreASL is self-contained, written in MATLAB and based on Statistical Parameter Mapping (SPM) and runs on multiple operating systems. To facilitate collaboration and data-exchange, the toolbox follows several standards and recommendations for data structure, provenance, and best analysis practice.ExploreASL was iteratively refined and tested in the analysis of >10,000 ASL scans using different pulse-sequences in a variety of clinical populations, resulting in four processing modules: Import, Structural, ASL, and Population that perform tasks, respectively, for data curation, structural and ASL image processing and quality control, and finally preparing the results for statistical analyses on both single-subject and group level. We illustrate ExploreASL processing results from three cohorts: perinatally HIV-infected children, healthy adults, and elderly at risk for neurodegenerative disease. We show the reproducibility for each cohort when processed at different centers with different operating systems and MATLAB versions, and its effects on the quantification of gray matter cerebral blood flow.ExploreASL facilitates the standardization of image processing and quality control, allowing the pooling of cohorts which may increase statistical power and discover between-group perfusion differences. Ultimately, this workflow may advance ASL for wider adoption in clinical studies, trials, and practice.

Arterial spin labeling (ASL) has undergone significant development since its inception, with a focus on improving standardization and reproducibility of its acquisition and quantification. In a community-wide effort towards robust and reproducible clinical ASL image processing, we developed the software package ExploreASL, allowing standardized analyses across centers and scanners.The procedures used in ExploreASL capitalize on published image processing advancements and address the challenges of multi-center datasets with scanner-specific processing and artifact reduction to limit patient exclusion. ExploreASL is self-contained, written in MATLAB and based on Statistical Parameter Mapping (SPM) and runs on multiple operating systems. The toolbox adheres to previously defined international standards for data structure, provenance, and best analysis practice.ExploreASL was iteratively refined and tested in the analysis of >10,000 ASL scans using different pulse-sequences in a variety of clinical populations, resulting in four processing modules: Import, Structural, ASL, and Population that perform tasks, respectively, for data curation, structural and ASL image processing and quality control, and finally preparing the results for statistical analyses on both single-subject and group level. We illustrate ExploreASL processing results from three cohorts: perinatally HIV-infected children, healthy adults, and elderly at risk for neurodegenerative disease. We show the reproducibility for each cohort when processed at different centers with different operating systems and MATLAB versions, and its effects on the quantification of gray matter cerebral blood flow.ExploreASL facilitates the standardization of image processing and quality control, allowing the pooling of cohorts to increase statistical power and discover between-group perfusion differences. Ultimately, this workflow may advance ASL for wider adoption in clinical studies, trials, and practice.

Early nutritional deprivation may cause irreversible damage to the brain and seems to affect cognitive function in older age. We investigated whether prenatal undernutrition was associated with brain perfusion differences in older age. We acquired Arterial spin labeling scans in 118 Dutch famine birth cohort members. Using linear regression analyses, cerebral blood flow was compared between exposed and unexposed groups in gray matter (GM) and white matter (WM), perfusion territories, the neurodegeneration-related regions anterior and posterior cingulate cortex and precuneus. Furthermore, we compared the GM/WM ratio and the spatial coefficient of variation as a proxy of overall cerebrovascular health. The WM arterial spin labeling signal and the GM/WM ratio were significantly lower and higher, respectively, among exposed participants (−2.5 mL/100 g/min [95% CI: −4.3 to −0.8; p = 0.01] and 0.48 [0.19 to 0.76; p = 0.002], respectively). Exposed men had lower cerebral blood flow in anterior and posterior cingulate cortices (−8.0 mL/100 g/min [−15.1 to −0.9; p = 0.03]; −11.4 mL/100 g/min [−19.6 to −3.2; p = 0.02]) and higher spatial coefficient of variation (0.05 [0.00 to 0.09; p = 0.05]). The latter seemed largely mediated by higher 2h-glucose levels at age 50. Our findings suggest that prenatal undernutrition affects brain perfusion parameters providing further evidence for life-long effects of undernutrition during early brain development.

The development of brain circuits is coupled with changes in neurovascular coupling, which refers to the close relationship between neural activity and cerebral blood flow (CBF). Studying the characteristics of CBF during resting state in developing brain can be a complementary way to understand the functional connectivity of the developing brain. Arterial spin labeling (ASL), as a noninvasive MR technique, is particularly attractive for studying cerebral perfusion in children and even newborns. We have collected pulsed ASL data in resting state for 47 healthy subjects from young children to adolescence (aged from 6 to 20 years old). In addition to studying the developmental change of static CBF maps during resting state, we also analyzed the CBF time series to reveal the dynamic characteristics of CBF in differing age groups. We used the seed-based correlation analysis to examine the temporal relationship of CBF time series between the selected ROIs and other brain regions. We have shown the developmental patterns in both static CBF maps and dynamic characteristics of CBF. While higher CBF of default mode network (DMN) in all age groups supports that DMN is the prominent active network during the resting state, the CBF connectivity patterns of some typical resting state networks show distinct patterns of metabolic activity during the resting state in the developing brains.

OBJECTIVE: Partial volume (PV) correction is an important step in arterial spin labeling (ASL) MRI that is used to separate perfusion from structural effects when computing the mean gray matter (GM) perfusion. There are three main methods for performing this correction: (1) GM-threshold, which includes only voxels with GM volume above a preset threshold; (2) GM-weighted, which uses voxel-wise GM contribution combined with thresholding; and (3) PVC, which applies a spatial linear regression algorithm to estimate the flow contribution of each tissue at a given voxel. In all cases, GM volume is obtained using PV maps extracted from the segmentation of the T1-weighted (T1w) image. As such, PV maps contain errors due to the difference in readout type and spatial resolution between ASL and T1w images. Here, we estimated these errors and evaluated their effect on the performance of each PV correction method in computing GM cerebral blood flow (CBF).MATERIALS AND METHODS: Twenty-two volunteers underwent scanning using 2D echo planar imaging (EPI) and 3D spiral ASL. For each PV correction method, GM CBF was computed using PV maps simulated to contain estimated errors due to spatial resolution mismatch and geometric distortions which are caused by the mismatch in readout between ASL and T1w images. Results were analyzed to assess the effect of each error on the estimation of GM CBF from ASL data.RESULTS: Geometric distortion had the largest effect on the 2D EPI data, whereas the 3D spiral was most affected by the resolution mismatch. The PVC method outperformed the GM-threshold even in the presence of combined errors from resolution mismatch and geometric distortions. The quantitative advantage of PVC was 16% without and 10% with the combined errors for both 2D and 3D ASL. Consistent with theoretical expectations, for error-free PV maps, the PVC method extracted the true GM CBF. In contrast, GM-weighted overestimated GM CBF by 5%, while GM-threshold underestimated it by 16%. The presence of PV map errors decreased the calculated GM CBF for all methods.CONCLUSION: The quality of PV maps presents no argument for the preferential use of the GM-threshold method over PVC in the clinical application of ASL.

Background and purpose To compare the structural and hemodynamic changes of healthy brain tissue in the cerebral hemisphere contralateral to the tumor following photon and proton radiochemotherapy. Materials and methods Sixty-seven patients (54.9 ±14.0 years) diagnosed with glioblastoma undergoing adjuvant photon (n = 47) or proton (n = 19) radiochemotherapy with temozolomide after tumor resection underwent T1-weighted and arterial spin labeling MRI. Changes in volume and perfusion before and 3 to 6 months after were compared between therapies. Results A decrease in gray matter (GM) (−2.2%, P 0.001 ) and white matter (WM) (−1.2%, P 0.001 ) volume was observed in photon-therapy patients compared to the pre-radiotherapy baseline. In contrast, for the proton-therapy group, no significant differences in GM (0.3%, P = 0.64) or WM (−0.4%, P = 0.58) volume were observed. GM volume decreased with 0.9% per 10 Gy dose increase ( P 0.001 ) and differed between the radiation modalities ( P 0.001 ) . Perfusion decreased in photon-therapy patients (−10.1%, P = 0.002), whereas the decrease in proton-therapy patients, while comparable in magnitude, did not reach statistical significance (−9.1%, P = 0.12). There was no correlation between perfusion decrease and either dose (P = 0.64) or radiation modality (P = 0.94). Conclusions Our results show that the tissue volume decrease depends on radiation dose delivered to the healthy hemisphere and differs between treatment modalities. In contrast, the decrease in perfusion was comparable for both irradiation modalities. We conclude that proton therapy may reduce brain-volume loss when compared to photon therapy.

Cortical thinning is a potentially important biomarker, but the pathophysiology in cerebrovascular disease is unknown. We investigated the association between regional cortical blood flow and regional cortical thickness in patients with asymptomatic unilateral high-grade internal carotid artery disease without stroke. Twenty-nine patients underwent high resolution anatomical and single-delay, pseudocontinuous arterial spin labeling magnetic resonance imaging with partial volume correction to assess gray matter baseline flow. Cortical thickness was estimated using Freesurfer software, followed by co-registration onto each patient’s cerebral blood flow image space. Paired t-tests assessed regional cerebral blood flow in motor cortex (supplied by the carotid artery) and visual cortex (indirectly supplied by the carotid) on the occluded and unoccluded side. Pearson correlations were calculated between cortical thickness and regional cerebral blood flow, along with age, hypertension, diabetes and white matter hyperintensity volume. Multiple regression and generalized estimating equation were used to predict cortical thickness bilaterally and in each hemisphere separately. Cortical blood flow correlated with thickness in motor cortex bilaterally (p = 0.0002), and in the occluded and unoccluded sides individually; age (p = 0.002) was also a predictor of cortical thickness in the motor cortex. None of the variables predicted cortical thickness in visual cortex. Blood flow was significantly lower on the occluded versus unoccluded side in the motor cortex (p

Objective: Cortical thinning has been reported in patients with cerebrovascular disease and degenerative dementia, but the direct impact of regional hypoperfusion on cortical pathology has been difficult to establish. We examined the association between regional cerebral blood flow (rCBF) and regional cortical thickness (rCT) in a cohort of patients with unilateral high-grade internal carotid artery (ICA) disease without history of stroke. Methods: Twenty-seven patients age 73±10yrs, 11F with unilateral ICA stenosis ≥80% or occlusion but no stroke underwent MRI, including high resolution T1 (MPRAGE) and tissue specific pseudocontinuous arterial spin labeling (ts-pCASL) to assess cortical thickness and gray matter resting CBF. Cortical thickness was measured in each hemisphere in the primary motor cortex (M1--Brodmann Area 4) by a blinded investigator using Freesurfer software ( http://surfer.nmr.mgh.harvard.edu/ ), and in visual cortex (V1, Brodmann area 17) as a control for nonspecific effects in the posterior circulation. Paired t-tests were used to assess hemispheral asymmetry for rCBF and for rCT in M1 on the occluded vs unoccluded side. Linear regression was used to predict the effect of rCBF on rCT in M1 on the occluded side. Results: Cortex was 0.08mm thinner on the side of ICA occlusion in M1 (95%CI=0.04-0.11, p=0.0003). There was no rCT asymmetry in V1 (p=.276). rCBF was 9.3 ml/100gm*min -1 lower in M1 of the occluded hemisphere (95%CI=5.1-13.5, p2 =.128, p=.038). Conclusion: Cortical thinning occurred in M1 on the side of carotid occlusion in the absence of stroke, and correlated with lower rCBF. Brodmann area 4 was chosen to represent the distal field of the carotid artery. Our finding demonstrates an important effect of chronically reduced blood flow on brain pathology, and suggests that a broader definition of “symptomatic” carotid artery disease may be needed.

Cerebral blood flow (CBF) regulation is a critical element in cerebrovascular pathophysiology, particularly in large vessel disease, but the best method to use for hemodynamic assessment is not clear. We examined 4 different blood-flow related measures in patients with unilateral high-grade carotid artery disease, assessing asymmetry between the occluded vs non-occluded side, and the correlations among the measures.Thirty-three patients (age 50-93, 19 M) with unilateral 80-100% ICA occlusion but no stroke underwent: 1) mean flow velocity (MFV) in both middle cerebral arteries by transcranial Doppler (TCD), 2) quantitative resting CBF using pseudo-continuous arterial spin labeling (pCASL) MRI, 3) vasomotor reactivity (VMR) in response to 5% CO2 inhalation, and 4) dynamic cerebral autoregulation (DCA) assessing the counter-regulation of blood flow to spontaneous changes in blood pressure using TCD monitoring and finger photoplethysmography. Paired t-tests and Pearson correlations assessed side-to-side differences within each measure, and correlations between measures.CBF (p=0.001), MFV (p0.001), VMR (p=0.008), and DCA (p=0.047) all showed significantly lower values on the occluded side. The 4 measures were independent of each other on correlation analysis, even when controlling for age and anterior circle of Willis collateral (all partial correlations0.233 and p-values0.468).These 4 measures showed high sensitivity to the occluded carotid artery, but their dissociation suggests that any given measure only partially characterizes the hemodynamic state. Additional research is needed to explore the multifaceted biology of cerebral blood flow regulation.

Duchenne muscular dystrophy is caused by dystrophin gene mutations which lead to the absence of the protein dystrophin. A significant proportion of patients suffer from learning and behavioural disabilities, in addition to muscle weakness. We have previously shown that these patients have a smaller total brain and grey matter volume, and altered white matter microstructure compared to healthy controls. Patients with more distal gene mutations, predicted to affect dystrophin isoforms Dp140 and Dp427, showed greater grey matter reduction. Now, we studied if cerebral blood flow in Duchenne muscular dystrophy patients is altered, since cerebral expression of dystrophin also occurs in vascular endothelial cells and astrocytes associated with cerebral vasculature. T1-weighted anatomical and pseudo-continuous arterial spin labeling cerebral blood flow images were obtained from 26 patients and 19 age-matched controls (ages 8-18 years) on a 3 tesla MRI scanner. Group comparisons of cerebral blood flow were made with and without correcting for grey matter volume using partial volume correction. Results showed that patients had a lower cerebral blood flow than controls (40.0 +/- 6.4 and 47.8 +/- 6.3 mL/100 g/min respectively, p = 0.0002). This reduction was independent of grey matter volume, suggesting that they are two different aspects of the pathophysiology. Cerebral blood flow was lowest in patients lacking Dp140. There was no difference in CBF between ambulant and non-ambulant patients. Only three patients showed a reduced left ventricular ejection fraction. No correlation between cerebral blood flow and age was found. Our results indicate that cerebral perfusion is reduced in Duchenne muscular dystrophy patients independent of the reduced grey matter volume.(c) 2016 Elsevier B.V. All rights reserved.

Background: Cerebral blood flow (CBF) regulation is a critical element in cerebrovascular pathophysiology, particularly in large vessel disease. Different methods to assess hemodynamics may represent different aspects of blood flow regulation, however, uniquely affecting outcomes and management. We examined 4 different blood-flow related measures in patients with high-grade unilateral carotid disease, assessing asymmetry between the occluded vs non-occluded side, and the correlations among the measures. Methods: Thirty-three patients (age 50-93, 19M) with unilateral 80-100% ICA occlusion but no stroke underwent: 1) quantitative resting CBF using continuous arterial spin labeling (CASL) MRI, 2) mean flow velocity (MFV) in both middle cerebral arteries (MCAs) by transcranial Doppler, 3). Vasomotor reactivity (VMR) in response to 2 minutes of 5% CO2 inhalation, and 4) Dynamic cerebral autoregulation (DCA) using continuous insonation of both MCAs for 10 minutes at depth 56mm with a standard head frame. Phase shift (PS) between spontaneous oscillations in blood pressure (measured with finger photoplethysmography) and MCA MFV at frequencies .06-.12 Hz was calculated for each hemisphere using transfer function analysis. Lower PS indicated worse autoregulation. Paired T-tests and Pearson correlations were used to look for side-to-side differences within each measure, and correlations between measures (SPSS v.22). Results: CASL CBF (p=.001), MFV (p0.09). Conclusions: These 4 measures showed high sensitivity to the occluded carotid artery, but appear to represent independent aspects of cerebral blood flow (CASL: resting gray matter CBF; MFV: whole-hemisphere CBF; VMR: cerebrovascular reserve, and DCA: homeostatic blood flow regulation) suggesting that any given measure only partially characterizes hemodynamic state. Further investigation will use these 4 measures to predict outcomes including vascular cognitive impairment.

The insight provided by fMRI, particularly BOLD fMRI, has been critical to the understanding of human brain function. Unfortunately, the application of fMRI techniques in clinical research has been held back by several factors. In order for the clinical field to successfully apply fMRI, two main challenges posed by aging and diseased brains need to be overcome: (1) difficulties in signal measurement and interpretation, and (2) partial voluming effects (PVE). Recent work has addressed the first challenge by developing fMRI methods that, in contrast to BOLD, provide a direct measurement of a physiological correlate of function. One such method is Arterial Spin Labeling (ASL) fMRI, which provides images of cerebral blood flow (CBF) in physiologically meaningful units. Although the problems caused by PVE can be mitigated to some degree through the acquisition of high spatial resolution fMRI data, both hardware and experimental design considerations limit this solution. Our team has developed a PVE correction (PVEc) algorithm that produces CBF images that are theoretically independent of tissue content and the associated PVE. The main drawback of the current PVEc method is that it introduces an inherent smoothing of the functional data. This smoothing effect can reduce the sensitivity of the method, complicating the detection of local changes in CBF, such as those due to stroke or activation. Here, we present results from an improved PVEc algorithm (ssPVEc), which uses high-resolution structural space information to correct for the tissue-driven heterogeneity in the ASL signal. We tested the ssPVEc method on ASL images obtained on patients with asymptomatic carotid occlusive disease during rest and motor activation. Our results showed that the sensitivity of the ssPVEc method (defined as the average T-value in the activated region) was at least 1.5 times greater than that of the original, functional space, fsPVEc, for all patients.

By comparing hemodynamic signals acquired immediately before and during activation, functional magnetic resonance imaging (fMRI) is well suited for mapping acute changes in brain function. However, it remains unclear whether fMRI can map functional changes over longer periods. Here, we address this issue by empirically testing the feasibility of arterial spin labeling (ASL) fMRI to detect changes in cerebral blood flow (CBF) with baseline and task separated by 1 month. To increase the sensitivity of the method, we applied an algorithm that yielded flow density (CBFd) images that were independent of tissue content. To increase the accuracy, we developed a technique that generated arterial transit time at each voxel, independently. Results showed that activation changes in CBFd during the same session were statistically the same as across 30 days. The activation CBFd on day-30 was 34% (motor) and 25% (visual) higher than the respective baselines of 83 and 107 mL/100 g/min obtained on day-1. Furthermore, the signal-to-noise ratio of the CBFd measurement was 2.1 and 2.9 times higher than that of the conventional CBF for within-subject and across-subjects comparisons, respectively ( n=9 healthy young subjects). Taken together, these results indicate that CBFd measure could be better suited than net CBF to map long-term changes in brain function.

The purpose of this preliminary study was to examine cerebral blood flow (CBF) as measured by arterial spin labeling (ASL) in tissue classified as white matter hyperintensities (WMH), normal appearing white matter, and grey matter. Seventeen healthy older adults received structural and ASL MRI. Cerebral blood flow was derived for three tissue types: WMH, normal appearing white matter, and grey matter. Cerebral blood flow was lower in WMH areas relative to normal appearing white matter, which in turn, was lower than grey matter. Regions with consistently lower CBF across individuals were more likely to appear as WMH. Results are consistent with an emerging literature linking diminished regional perfusion with the risk of developing WMH.

Partial volume effects (PVE) are a consequence of limited spatial resolution in brain imaging. In arterial spin labeling (ASL) MRI, the problem is exacerbated by the nonlinear dependency of the ASL signal on magnetization contributions from each tissue within an imaged voxel. We have developed an algorithm that corrects for PVE in ASL imaging. The algorithm is based on a model that represents the voxel intensity as a weighted sum of pure tissue contribution, where the weighting coefficients are the tissue's fractional volume in the voxel. Using this algorithm, we were able to estimate cerebral blood flow (CBF) for gray matter (GM) and white matter (WM) independently. The average voxelwise ratio of GM to WM CBF was approximately 3.2, in good agreement with reports in the literature. As proof of concept, data from PVE-corrected method were compared with those from the conventional, PVE-uncorrected method. As hypothesized, the two yielded similar CBF values for voxels containing >95% GM and differed in proportion with the voxels' heterogeneity. More importantly, the GM CBF assessed with the PVE-corrected method was independent of the voxels' heterogeneity, implying that estimation of flow was unaffected by PVE. An example of application of this algorithm in motor-activation data is also given.

Variance estimates can be used in conjunction with scientifically meaningful effect sizes to design experiments with type II error control. Here we present estimates of intra- and inter-subject variances for region of interest (ROI) from resting cerebral blood flow (CBF) maps obtained using whole brain, spin echo echoplanar (SE-EPI) continuous arterial spin labeling (CASL) imaging on 52 elderly subjects (age=70.5+/-7.9 years, 29 males). There was substantial intrasubject systematic variability in CBF of gray matter ROIs corresponding to a range of standard deviations=[39-168] (ml/(100 g min)). This variability was mainly due to two factors: (1) an expected inverse relationship between ROI volume and intrasubject variance and (2) an increased effective post-labeling delay for more superior slices acquired later in the sequence. For example, intrasubject variance in Brodmann area 4 (BA 4) was approximately 8 times larger than in hippocampus, despite their similar gray matter volumes. Estimated ROI-wise power was computed for various numbers of acquired CBF images, numbers of subjects, and CBF effect sizes for two experimental designs: independent sample t-test and paired t-test. The theoretical effects of pulse sequence and field strength on general applicability of these results are discussed.

Background: High grade internal carotid artery (ICA) disease can alter cerebral autoregulation and thus increase risk for ischemia. We aimed to differentiate two types of autoregulation - dynamic cerebral autoregulation (DCA), thought to be a homeostatic process, and vasomotor reactivity (VMR), which determines cerebrovascular reserve - in patients with asymptomatic ICA stenosis. Methods: Twenty-two patients (age 50-93, 16M) with unilateral 80-100% ICA occlusion but no stroke underwent quantitative CBF measurements using continuous arterial spin labeling (CASL) MRI. DCA was performed by continuous insonation of both middle cerebral arteries with transcranial Doppler for 10 minutes at depth 56mm using a standard head frame. Phase shift (PS) between spontaneous oscillations in blood pressure (measured with finger photoplethysmography (Finapres)) and MCA mean flow velocities (MFV) at frequencies .06-.12 Hz was calculated for each hemisphere using transfer function analysis. Lower degree of PS indicated worse autoregulation (abnormal Results: MCA MFV (p Conclusions: DCA but not VMR correlated with a low flow state produced by high grade ICA disease in asymptomatic patients. Our results suggest that in ICA stenosis dynamic/homeostatic mechanisms may be affected without substantially altering the static/protective mechanism of cerebrovascular reserve. Ongoing studies will investigate the effect of these two autoregulatory mechanisms on vascular cognitive impairment. 1 Ortega-Gutierrez S, et al. J Neuroimaging. 2014 24:379-86

Cerebral blood flow (CBF) is a physiological correlate of brain function and metabolism and as such an essential parameter for investigating how aging and disease affect the brain. Arterial spin labeling (ASL) is an fMRI method that provides absolute measurement of CBF non-invasively and with higher spatial resolution than non-MRI methods. However, application of ASL in older populations is hampered by partial volume effects (PVE) and tissue dependent changes in CBF. We have developed a tissue-specific ASL method (ts-ASL) that provides `flow density' measures by quantifying CBF for each tissue separately and independently of tissue content. Using simulated functional and structural images, we investigated the effects of brain atrophy and random noise on the SNR of GM CBF measured with conventional and ts-ASL. Results showed that: (1) For all noise levels, the SNR of ts-ASL was higher. For example, for a random Gaussian noise with standard deviation σ = 4, the SNR of GM CBF obtained with ts-ASL was ~3 times higher than the SNR of the conventional method. (2) In contrast to conventional ASL, which was substantially affected by brain atrophy, ts-ASL was virtually independent of it. (3) The sensitivity of ts-ASL for detecting focal changes in CBF (ΔCBF) in the presence of atrophy and noise was also higher compared to the conventional method. In hippocampus, for 15% atrophy and Gaussian noise with σ = 4, conventional and ts-ASL retrieved 73% and 90% of the modeled ΔCBF, respectively. Taken together, these results indicate that ts-ASL may be better suited for measuring CBF in the presence of atrophy and random noise, both of which are expected to increase with aging and disease.

Background: High grade carotid stenosis produces hemodynamic effects on the brain, but the relationship between cerebral autoregulation, absolute CBF and neurovascular coupling has not been well-delineated. Methods: Twelve subjects (age 74±9, 3F) with unilateral ICA stenosis (80-100% occluded) but no infarct (asymptomatic or TIA only) underwent dynamic cerebral autoregulation (DCA) testing with transcranial Doppler by comparing phase shift (PS) of spontaneous oscillations in blood pressure (measured with finger photoplethysmography (Finapres)) versus MCA flow velocities at frequencies .06-.12 Hz using transfer function analysis, lower degree of PS indicating worse autoregulation.Neurovascular coupling was assessed by amplitude of absolute increase in CBF in bilateral Brodman area (BA) 4 during a bilateral repetitive hand closure task using continuous arterial spin labeling (CASL) MRI. Four activation (ON) periods were averaged and subtracted from 4 rest (OFF) periods. Resting CBF for each hemisphere’s motor cortex was determined by averaging the OFF periods. Results: All subjects showed: 1) hemispheric asymmetry in baseline CBF with the occluded side being on average 25mL/100g*min (+/- 14 mL/100g*min) lower than the unoccluded hemisphere. 2) hemispheric asymmetry in motor activation: unoccluded hemisphere average activation (mean_CBF_ON - mean_CBF_OFF) in BA4 was 23.7mL/100g*min, representing a 21% increase in local CBF due to activation; occluded hemisphere mean activation was 14 mL/100g*min, representing 18% percent increase in local CBF. 3) Hemispheric asymmetry in DCA, PS=33.1 deg ± 31 on the occluded side vs. 43.5 deg±23 on the non-occluded side. Both the hemispheral difference in baseline CBF (impaired flow) and the difference in DCA measurement (impaired autoregulation) were good predictors of the lower activation (neurovascular coupling) on the occluded hemisphere: R 2 = 0.85 and 0.80, respectively. Conclusion: Both impaired resting CBF and impaired cerebral autoregulation appear to contribute to decreased neurovascular coupling in carotid artery occlusive disease, representing a potential mechanism for occult neuronal dysfunction such as mild cognitive impairment in this patient population.

Most analysis of multi-subject fMRI data is concerned with determining whether there exists a significant population-wide ‘activation’ in a comparison between two or more conditions. This is typically assessed by testing the average value of a contrast of parameter estimates (COPE) against zero in a general linear model (GLM) analysis. However, important information can also be obtained by testing whether there exist significant individual differences in effect magnitude between subjects, i.e. whether the variance of a COPE is significantly different from zero. Intuitively, such a test amounts to testing whether inter-individual differences are larger than would be expected given the within-subject error variance. We compare several methods for estimating variance components, including a) a naive estimate using ordinary least squares (OLS); b) linear mixed effects in R (LMER); c) a novel Matlab implementation of iterative generalized least squares (IGLS) and its restricted maximum likelihood variant (RIGLS). All methods produced reasonable estimates of within- and between-subject variance components, with IGLS providing an attractive balance between sensitivity and appropriate control of false positives. Finally, we use the IGLS method to estimate inter-subject variance in a perfusion fMRI study (N = 18) of social evaluative threat, and show evidence for significant inter-individual differences in ventromedial prefrontal cortex (VMPFC), amygdala, hippocampus and medial temporal lobes, insula, and brainstem, with predicted inverse coupling between VMPFC and the midbrain periaqueductal gray only when high inter-individual variance was used to define the seed for functional connectivity analyses. In sum, tests of variance provides a way of selecting regions that show significant inter-individual variability for subsequent analyses that attempt to explain those individual differences.

Cerebral blood flow (CBF) is a well-established correlate of brain function and therefore an essential parameter for studying the brain at both normal and diseased states. Arterial spin labeling (ASL) is a noninvasive fMRI technique that uses arterial water as an endogenous tracer to measure CBF. ASL provides reliable absolute quantification of CBF with higher spatial and temporal resolution than other techniques. And yet, the routine application of ASL has been somewhat limited. In this review, we start by highlighting theoretical complexities and technical challenges of ASL fMRI for basic and clinical research. While underscoring the main advantages of ASL versus other techniques such as BOLD, we also expound on inherent challenges and confounds in ASL perfusion imaging. In closing, we expound on several exciting developments in the field that we believe will make ASL reach its full potential in neuroscience research.

The accuracy of cerebral blood flow (CBF) imaging in humans has been impeded by the par- tial volume effects (PVE), which are a consequence of the limited spatial resolution. Because of brain atrophy, PVE can be particularly problematic in imaging the elderly and can considerably overestimate the CBF difference with the young. The primary goal of this study was to separate the structural decline from the true CBF reduction in elderly. To this end, a PVE-correction algorithm was applied on the CBF images acquired with spin-echo EPI continuous arterial spin labeling MRI (voxel size 5 3.4 3 3.4 3 8 mm 3 ). Tissue-specific CBF images that were independent of voxels' tissue fractional volume were obtained in elderly (N 5 30) and young (N 5 26); mean age difference was 43 years. Globally, PVE-corrected gray matter CBF was 88.2 6 16.1 and 107.3 6 17.5 mL/100 g min 21 in elderly and young, respectively. The largest PVE contribution was found in the frontal lobe and accounted for an additional 10% and 12% increase in the age-related CBF difference between men and women, respec- tively. The GM-to-WM CBF ratios were found to be on average 3.5 in elderly and 3.9 in young. Whole brain voxelwise comparisons showed marked CBF decrease in anterior cingulate (bilateral), caudate (bilateral), cingulate gyrus (bilateral), cuneus (left), inferior frontal gyrus (left), insula (left), middle frontal gyrus (left), precuneus (bilateral), prefrontal cortex (bilateral), and superior frontal gyrus (bilat- eral) in men and amygdala (bilateral), hypothalamus (left), hippocampus (bilateral), and middle frontal gyrus (right) in women. Hum Brain Mapp 00:000-000, 2009. V V C 2009 Wiley-Liss, Inc.

Background: Partial volume effects (PVE) due to limited spatial resolution in brain imaging can be quite substantial, particularly in studies of Alzherimer’s Disease (AD). In arterial spin labeling (ASL) MRI, PVE are exacerbated by the nonlinear dependency of the signal on voxel tissue-heterogeneity. We have developed an algorithm that corrects for PVE in ASL and applied it to ASL data from AD and healthy controls (HC) in order to separate the true, disease-related, hypoperfusion from that due to brain atrophy. Methods: 1) The algorithm is based on linear regression and estimates the pure tissue signals by modeling the voxel magnetization as a weighted sum of MGM, MWM, and MCSF contributions and the ASL difference signal as a weighted sum of MGM and MWM contributions. The weighting coefficients in both cases are the tissue’s fractional volume, which are obtained from high-resolution structural MRIs. The algorithm is based on the assumption that local magnetization and CBF are constant over a small region surrounding the voxel. 2) Subjects & Imaging ASL perfusion images were acquired on 10 patients with moderate-to-severe probable AD and 19 age-matched HC as described in a previous study (Asllani et al, JCBFM Oct24(2007)). For each subject, linear regression was performed on control and difference ASL images in subject’s native space using a 11x11x1 regression-kernel. Images were then transformed into Talairach standard space. Results: PVE correction algorithm enables the extraction of pure GM CBF that is, theoretically, uncontaminated by contribution from WM. Global GM CBF was 57 18 and 96 21 (ml/100g*min) for AD and controls, respectively. This corresponded to 63% and 55% increases in estimation of GM CBF for AD and HC, respectively, as compared to the uncorrected method (Fig.1) Voxelwise t-statistic for between-group comparisons showed 30% more voxels surviving the statistical threshold (cluster-level corrected, P 0.001) when pure GM CBF images were used as compared to the PVEuncorrected data. These additional areas were mainly in the cingulate, inferior frontal, and superior occipital gyri (Fig.2). Conclusions: Extraction of pure tissue CBF by correcting for PVE shows great promise for providing a sensitive biomarker of early detection of AD. IC-P3-167 THE DEVELOPMENT OF SMART CONTRAST AGENTS FOR MRI IMAGING OF ALZHEIMER’S DISEASE

Continuous arterial spin labeling (CASL) magnetic resonance imaging (MRI) was combined with multivariate analysis for detection of an Alzheimer's disease (AD)-related cerebral blood flow (CBF) covariance pattern. Whole-brain resting CBF maps were obtained using spin echo, echo planar imaging (SE-EPI) CASL in patients with mild AD ( n=12, age=70.7±8.7 years, 7 males, modified Mini-Mental State Examination (mMMS)=38.7/57±11.1) and age-matched healthy controls (HC) ( n=20; age=72.1±6.5 years, 8 males). A covariance pattern for which the mean expression was significantly higher ( Pcorrected=0.05). The area under the ROC curve for discriminating AD versus HC was 0.97 and 0.94 for covariance pattern and gray matter ROI, respectively. Fewer areas of depressed CBF in AD were detected using voxelwise analysis (corrected, P

Cerebral blood flow (CBF) is a well-established correlate of brain function and therefore an essential parameter for studying the brain at both normal and diseased states. Arterial spin labeling (ASL) is a noninvasive fMRI technique that uses arterial water as an endogenous tracer to measure CBF. ASL provides reliable absolute quantification of CBF with higher spatial and temporal resolution than other techniques. And yet, the routine application of ASL has been somewhat limited. In this review, we start by highlighting theoretical complexities and technical challenges of ASL fMRI for basic and clinical research. While underscoring the main advantages of ASL versus other techniques such as BOLD, we also expound on inherent challenges and confounds in ASL perfusion imaging. In closing, we expound on several exciting developments in the field that we believe will make ASL reach its full potential in neuroscience research.