Publications by authors named "John A Detre"

222 Publications

Blood flow response to orthostatic challenge identifies signatures of the failure of static cerebral autoregulation in patients with cerebrovascular disease.

BMC Neurol 2021 Apr 9;21(1):154. Epub 2021 Apr 9.

Department of Neurology (Stroke Unit). Hospital de la Santa Creu i Sant Pau, Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain.

Background: The cortical microvascular cerebral blood flow response (CBF) to different changes in head-of-bed (HOB) position has been shown to be altered in acute ischemic stroke (AIS) by diffuse correlation spectroscopy (DCS) technique. However, the relationship between these relative ΔCBF changes and associated systemic blood pressure changes has not been studied, even though blood pressure is a major driver of cerebral blood flow.

Methods: Transcranial DCS data from four studies measuring bilateral frontal microvascular cerebral blood flow in healthy controls (n = 15), patients with asymptomatic severe internal carotid artery stenosis (ICA, n = 27), and patients with acute ischemic stroke (AIS, n = 72) were aggregated. DCS-measured CBF was measured in response to a short head-of-bed (HOB) position manipulation protocol (supine/elevated/supine, 5 min at each position). In a sub-group (AIS, n = 26; ICA, n = 14; control, n = 15), mean arterial pressure (MAP) was measured dynamically during the protocol.

Results: After elevated positioning, DCS CBF returned to baseline supine values in controls (p = 0.890) but not in patients with AIS (9.6% [6.0,13.3], mean 95% CI, p < 0.001) or ICA stenosis (8.6% [3.1,14.0], p = 0.003)). MAP in AIS patients did not return to baseline values (2.6 mmHg [0.5, 4.7], p = 0.018), but in ICA stenosis patients and controls did. Instead ipsilesional but not contralesional CBF was correlated with MAP (AIS 6.0%/mmHg [- 2.4,14.3], p = 0.038; ICA stenosis 11.0%/mmHg [2.4,19.5], p < 0.001).

Conclusions: The observed associations between ipsilateral CBF and MAP suggest that short HOB position changes may elicit deficits in cerebral autoregulation in cerebrovascular disorders. Additional research is required to further characterize this phenomenon.
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http://dx.doi.org/10.1186/s12883-021-02179-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033703PMC
April 2021

A perfusion phantom for ASL MRI based on impinging jets.

Magn Reson Med 2021 Aug 27;86(2):1145-1158. Epub 2021 Mar 27.

Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Purpose: We present a novel perfusion phantom for validation of arterial spin labeled (ASL) perfusion MRI methods and protocols.

Methods: Impinging jets, driven by a peristaltic pump, were used to achieve perfusion-like mixing of magnetically labeled inflowing fluid within a perfusion compartment. The phantom was validated by varying pump rates and obtaining ASL-MRI data at multiple postlabeling delays using a pseudo-continuous ASL sequence with a 3D stack-of-spirals readout. An additional data set was acquired using a pseudo-continuous ASL sequence with a 2D EPI readout. Phantom sensitivity to pseudo-continuous ASL labeling efficiency was also tested.

Results: Fluid dynamics simulations predicted that maximum mixing would occur near the central axis of the perfusion compartment. Experimentally observed signal changes within this region were reproducible and well fit by the standard Buxton general kinetic model. Simulations and experimental data showed no label outflow from the perfusion chamber and calculated perfusion rates, averaged over the entire phantom volume, agreed with the expected volumetric flow rates provided by the flow pump. Phantom sensitivity to pseudo-continuous ASL labeling parameters was also demonstrated.

Conclusion: Perfusion-like signal can be simulated using impinging jets to create a well-mixed compartment. Observed perfusion and transit time values were reproducible and within the physiological range for brain perfusion. This phantom design has a broad range of potential applications in both basic and clinical research involving ASL MRI.
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http://dx.doi.org/10.1002/mrm.28697DOI Listing
August 2021

Association of Intensive vs Standard Blood Pressure Control With Magnetic Resonance Imaging Biomarkers of Alzheimer Disease: Secondary Analysis of the SPRINT MIND Randomized Trial.

JAMA Neurol 2021 May;78(5):568-577

Department of Diagnostic Medicine, Dell Medical School, University of Texas at Austin, Austin.

Importance: Meta-analyses of randomized clinical trials have indicated that improved hypertension control reduces the risk for cognitive impairment and dementia. However, it is unclear to what extent pathways reflective of Alzheimer disease (AD) pathology are affected by hypertension control.

Objective: To evaluate the association of intensive blood pressure control on AD-related brain biomarkers.

Design, Setting, And Participants: This is a substudy of the Systolic Blood Pressure Intervention Trial (SPRINT MIND), a multicenter randomized clinical trial that compared the efficacy of 2 different blood pressure-lowering strategies. Potential participants (n = 1267) 50 years or older with hypertension and without a history of diabetes or stroke were approached for a brain magnetic resonance imaging (MRI) study. Of these, 205 participants were deemed ineligible and 269 did not agree to participate; 673 and 454 participants completed brain MRI at baseline and at 4-year follow-up, respectively; the final follow-up date was July 1, 2016. Analysis began September 2019 and ended November 2020.

Interventions: Participants were randomized to either a systolic blood pressure goal of less than 120 mm Hg (intensive treatment: n = 356) or less than 140 mm Hg (standard treatment: n = 317).

Main Outcomes And Measures: Changes in hippocampal volume, measures of AD regional atrophy, posterior cingulate cerebral blood flow, and mean fractional anisotropy in the cingulum bundle.

Results: Among 673 recruited patients who had baseline MRI (mean [SD] age, 67.3 [8.2] years; 271 women [40.3%]), 454 completed the follow-up MRI at a median (interquartile range) of 3.98 (3.7-4.1) years after randomization. In the intensive treatment group, mean hippocampal volume decreased from 7.45 cm3 to 7.39 cm3 (difference, -0.06 cm3; 95% CI, -0.08 to -0.04) vs a decrease from 7.48 cm3 to 7.46 cm3 (difference, -0.02 cm3; 95% CI, -0.05 to -0.003) in the standard treatment group (between-group difference in change, -0.033 cm3; 95% CI, -0.062 to -0.003; P = .03). There were no significant treatment group differences for measures of AD regional atrophy, cerebral blood flow, or mean fractional anisotropy.

Conclusions And Relevance: Intensive treatment was associated with a small but statistically significant greater decrease in hippocampal volume compared with standard treatment, consistent with the observation that intensive treatment is associated with greater decreases in total brain volume. However, intensive treatment was not associated with changes in any of the other MRI biomarkers of AD compared with standard treatment.

Trial Registration: ClinicalTrials.gov Identifier: NCT01206062.
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http://dx.doi.org/10.1001/jamaneurol.2021.0178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941253PMC
May 2021

An MRI protocol for anatomical and functional evaluation of the California sea lion brain.

J Neurosci Methods 2021 Apr 10;353:109097. Epub 2021 Feb 10.

Henry H. Wheeler, Jr. Brain Imaging Center, 188 Li Ka Shing Center for Biomedical and Health Sciences, University of California, Berkeley, CA, 94720, USA. Electronic address:

Background: Domoic acid (DOM) is a neurotoxin produced by some harmful algae blooms in coastal waters. California sea lions (Zalophus californianus) exposed to DOM often strand on beaches where they exhibit a variety of symptoms, including seizures. These animals typically show hippocampal atrophy on MRI scans.

New Method: We describe an MRI protocol for comprehensive evaluation of DOM toxicosis in the sea lion brain. We intend to study brain development in pups exposed in utero. The protocol depicts the hippocampal formation as the primary region of interest. We include scans for quantitative morphometry, functional and structural connectivity, and a cerebral blood flow map.

Results: High-resolution 3D anatomical scans facilitate post hoc slicing in arbitrary planes and accurate morphometry. We demonstrate the first cerebral blood flow map using MRI, and the first structural tractography from a live sea lion brain.

Comparison With Existing Methods: Scans were compared to prior anatomical and functional studies in live sea lions, and structural connectivity in post mortem specimens. Hippocampal volumes were broadly in line with prior studies, with differences likely attributable to the 3D approach used here. Functional connectivity of the dorsal left hippocampus matched that found in a prior study conducted at a lower magnetic field, while structural connectivity in the live brain agreed with findings observed in post mortem studies.

Conclusions: Our protocol provides a comprehensive, longitudinal view of the functional and anatomical changes expected to result from DOM toxicosis. It can also screen for other common neurological pathologies and is suitable for any pinniped that can fit inside an MRI scanner.
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http://dx.doi.org/10.1016/j.jneumeth.2021.109097DOI Listing
April 2021

Structural and Functional Brain Parameters Related to Cognitive Performance Across Development: Replication and Extension of the Parieto-Frontal Integration Theory in a Single Sample.

Cereb Cortex 2021 Feb;31(3):1444-1463

Brain Behavior Laboratory and the Neurodevelopment and Psychosis Section, Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.

The parieto-frontal integration theory (PFIT) identified a fronto-parietal network of regions where individual differences in brain parameters most strongly relate to cognitive performance. PFIT was supported and extended in adult samples, but not in youths or within single-scanner well-powered multimodal studies. We performed multimodal neuroimaging in 1601 youths age 8-22 on the same 3-Tesla scanner with contemporaneous neurocognitive assessment, measuring volume, gray matter density (GMD), mean diffusivity (MD), cerebral blood flow (CBF), resting-state functional magnetic resonance imaging measures of the amplitude of low frequency fluctuations (ALFFs) and regional homogeneity (ReHo), and activation to a working memory and a social cognition task. Across age and sex groups, better performance was associated with higher volumes, greater GMD, lower MD, lower CBF, higher ALFF and ReHo, and greater activation for the working memory task in PFIT regions. However, additional cortical, striatal, limbic, and cerebellar regions showed comparable effects, hence PFIT needs expansion into an extended PFIT (ExtPFIT) network incorporating nodes that support motivation and affect. Associations of brain parameters became stronger with advancing age group from childhood to adolescence to young adulthood, effects occurring earlier in females. This ExtPFIT network is developmentally fine-tuned, optimizing abundance and integrity of neural tissue while maintaining a low resting energy state.
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http://dx.doi.org/10.1093/cercor/bhaa282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7869090PMC
February 2021

Cerebral Pulsed Arterial Spin Labeling Perfusion Weighted Imaging Predicts Language and Motor Outcomes in Neonatal Hypoxic-Ischemic Encephalopathy.

Front Pediatr 2020 25;8:576489. Epub 2020 Sep 25.

Children's Hospital of Philadelphia, Philadelphia, PA, United States.

To compare cerebral pulsed arterial spin labeling (PASL) perfusion among controls, hypoxic ischemic encephalopathy (HIE) neonates with normal conventional MRI(HIE/MRI⊕), and HIE neonates with abnormal conventional MRI(HIE/MRI⊖). To create a predictive machine learning model of neurodevelopmental outcomes using cerebral PASL perfusion. A total of 73 full-term neonates were evaluated. The cerebral perfusion values were compared by permutation test to identify brain regions with significant perfusion changes among 18 controls, 40 HIE/MRI⊖ patients, and 15 HIE/MRI⊕ patients. A machine learning model was developed to predict neurodevelopmental outcomes using the averaged perfusion in those identified brain regions. Significantly decreased PASL perfusion in HIE/MRI⊖ group, when compared with controls, were found in the anterior corona radiata, caudate, superior frontal gyrus, precentral gyrus. Both significantly increased and decreased cerebral perfusion changes were detected in HIE/MRI⊕ group, when compared with HIE/MRI⊖ group. There were no significant perfusion differences in the cerebellum, brainstem and deep structures of thalamus, putamen, and globus pallidus among the three groups. The machine learning model demonstrated significant correlation ( < 0.05) in predicting language( = 0.48) and motor( = 0.57) outcomes in HIE/MRI⊖ patients, and predicting language( = 0.76), and motor( = 0.53) outcomes in an additional group combining HIE/MRI⊖ and HIE/MRI⊕. Perfusion MRI can play an essential role in detecting HIE regardless of findings on conventional MRI and predicting language and motor outcomes in HIE survivors. The perfusion changes may also reveal important insights into the reperfusion response and intrinsic autoregulatory mechanisms. Our results suggest that perfusion imaging may be a useful adjunct to conventional MRI in the evaluation of HIE in clinical practice.
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http://dx.doi.org/10.3389/fped.2020.576489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546822PMC
September 2020

Rotated spiral RARE for high spatial and temporal resolution volumetric arterial spin labeling acquisition.

Neuroimage 2020 12 12;223:117371. Epub 2020 Sep 12.

Division of MRI Research, Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA.

Background: Arterial Spin Labeling (ASL) MRI can provide quantitative images that are sensitive to both time averaged blood flow and its temporal fluctuations. 3D image acquisitions for ASL are desirable because they are more readily compatible with background suppression to reduce noise, can reduce signal loss and distortion, and provide uniform flow sensitivity across the brain. However, single-shot 3D acquisition for maximal temporal resolution typically involves degradation of image quality through blurring or noise amplification by parallel imaging. Here, we report a new approach to accelerate a common stack of spirals 3D image acquisition by pseudo golden-angle rotation and compressed sensing reconstruction without any degradation of time averaged blood flow images.

Methods: 28 healthy volunteers were imaged at 3T with background-suppressed unbalanced pseudo-continuous ASL combined with a pseudo golden-angle Stack-of-Spirals 3D RARE readout. A fully-sampled perfusion-weighted volume was reconstructed by 3D non-uniform Fast Fourier Transform (nuFFT) followed by sum-of-squares combination of the 32 individual channels. Coil sensitivities were estimated followed by reconstruction of the 39 single-shot volumes using an L-wavelet Compressed-Sensing reconstruction. Finally, brain connectivity analyses were performed in regions where BOLD signal suffers from low signal-to-noise ratio and susceptibility artifacts.

Results: Image quality, assessed with a non-reference 3D blurring metric, of full time averaged blood flow was comparable to a conventional interleaved acquisition. The temporal resolution provided by the acceleration enabled identification and quantification of resting-state networks even in inferior regions such as the amygdala and inferior frontal lobes, where susceptibility artifacts can degrade conventional resting-state fMRI acquisitions.

Conclusion: This approach can provide measures of blood flow modulations and resting-state networks for free within any research or clinical protocol employing ASL for resting blood flow.
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http://dx.doi.org/10.1016/j.neuroimage.2020.117371DOI Listing
December 2020

Cerebral metabolic rate of oxygen during transition from wakefulness to sleep measured with high temporal resolution OxFlow MRI with concurrent EEG.

J Cereb Blood Flow Metab 2021 Apr 14;41(4):780-792. Epub 2020 Jun 14.

Laboratory for Structural Physiologic and Functional Imaging, Department of Radiology, University of Pennsylvania Perelman School of Medicine, PA, USA.

During slow-wave sleep, synaptic transmissions are reduced with a concomitant reduction in brain energy consumption. We used 3 Tesla MRI to noninvasively quantify changes in the cerebral metabolic rate of O (CMRO) during wakefulness and sleep, leveraging the 'OxFlow' method, which provides venous O saturation (SvO) along with cerebral blood flow (CBF). Twelve healthy subjects (31.3 ± 5.6 years, eight males) underwent 45-60 min of continuous scanning during wakefulness and sleep, yielding one image set every 3.4 s. Concurrent electroencephalography (EEG) data were available in eight subjects. Mean values of the metabolic parameters measured during wakefulness were stable, with coefficients of variation below 7% (average values: CMRO = 118 ± 12 µmol O/min/100 g, SvO = 67.0 ± 3.7% HbO, CBF = 50.6 ±4.3 ml/min/100 g). During sleep, on average, CMRO decreased 21% (range: 14%-32%; average nadir = 98 ± 16 µmol O/min/100 g), while EEG slow-wave activity, expressed in terms of -power, increased commensurately. Following sleep onset, CMRO was found to correlate negatively with relative -power (r = -0.6 to -0.8,  < 0.005), and positively with heart rate (r = 0.5 to 0.8,  < 0.0005). The data demonstrate that OxFlow MRI can noninvasively measure dynamic changes in cerebral metabolism associated with sleep, which should open new opportunities to study sleep physiology in health and disease.
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http://dx.doi.org/10.1177/0271678X20919287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983504PMC
April 2021

Two nights of recovery sleep restores hippocampal connectivity but not episodic memory after total sleep deprivation.

Sci Rep 2020 05 29;10(1):8774. Epub 2020 May 29.

Center for Functional Neuroimaging, Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA.

Sleep deprivation significantly impairs a range of cognitive and brain function, particularly episodic memory and the underlying hippocampal function. However, it remains controversial whether one or two nights of recovery sleep following sleep deprivation fully restores brain and cognitive function. In this study, we used functional magnetic resonance imaging (fMRI) and examined the effects of two consecutive nights (20-hour time-in-bed) of recovery sleep on resting-state hippocampal connectivity and episodic memory deficits following one night of total sleep deprivation (TSD) in 39 healthy adults in a controlled in-laboratory protocol. TSD significantly reduced memory performance in a scene recognition task, impaired hippocampal connectivity to multiple prefrontal and default mode network regions, and disrupted the relationships between memory performance and hippocampal connectivity. Following TSD, two nights of recovery sleep restored hippocampal connectivity to baseline levels, but did not fully restore memory performance nor its associations with hippocampal connectivity. These findings suggest that more than two nights of recovery sleep are needed to fully restore memory function and hippocampal-memory associations after one night of total sleep loss.
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http://dx.doi.org/10.1038/s41598-020-65086-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260173PMC
May 2020

Accelerating GluCEST imaging using deep learning for B correction.

Magn Reson Med 2020 10 17;84(4):1724-1733. Epub 2020 Apr 17.

Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA.

Purpose: Glutamate weighted Chemical Exchange Saturation Transfer (GluCEST) MRI is a noninvasive technique for mapping parenchymal glutamate in the brain. Because of the sensitivity to field (B ) inhomogeneity, the total acquisition time is prolonged due to the repeated image acquisitions at several saturation offset frequencies, which can cause practical issues such as increased sensitivity to patient motions. Because GluCEST signal is derived from the small z-spectrum difference, it often has a low signal-to-noise-ratio (SNR). We proposed a novel deep learning (DL)-based algorithm armed with wide activation neural network blocks to address both issues.

Methods: B correction based on reduced saturation offset acquisitions was performed for the positive and negative sides of the z-spectrum separately. For each side, a separate deep residual network was trained to learn the nonlinear mapping from few CEST-weighted images acquired at different ppm values to the one at 3 ppm (where GluCEST peaks) in the same side of the z-spectrum.

Results: All DL-based methods outperformed the "traditional" method visually and quantitatively. The wide activation blocks-based method showed the highest performance in terms of Structural Similarity Index (SSIM) and peak signal-to-noise ratio (PSNR), which were 0.84 and 25dB respectively. SNR increases in regions of interest were over 8dB.

Conclusion: We demonstrated that the new DL-based method can reduce the entire GluCEST imaging time by ˜50% and yield higher SNR than current state-of-the-art.
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http://dx.doi.org/10.1002/mrm.28289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082274PMC
October 2020

H magnetic resonance spectroscopy of H-to-H exchange quantifies the dynamics of cellular metabolism in vivo.

Nat Biomed Eng 2020 03 27;4(3):335-342. Epub 2020 Jan 27.

Center for Magnetic Resonance and Optical Imaging, Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Quantitative mapping of the in vivo dynamics of cellular metabolism via non-invasive imaging contributes to our understanding of the initiation and progression of diseases associated with dysregulated metabolic processes. Current methods for imaging cellular metabolism are limited by low sensitivities, costs or the use of specialized hardware. Here, we introduce a method that captures the turnover of cellular metabolites by quantifying signal reductions in proton magnetic resonance spectroscopy (MRS) resulting from the replacement of H with H. The method, which we termed quantitative exchanged-label turnover MRS, only requires deuterium-labelled glucose and standard magnetic resonance imaging scanners, and with a single acquisition provides steady-state information and metabolic rates for several metabolites. We used the method to monitor glutamate, glutamine, γ-aminobutyric acid and lactate in the brains of unaffected and glioma-bearing rats following the administration of H-labelled glucose and H-labelled acetate. Quantitative exchanged-label turnover MRS should broaden the applications of routine H MRS.
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http://dx.doi.org/10.1038/s41551-019-0499-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7071956PMC
March 2020

Arterial spin labeling versus F-FDG-PET to identify mild cognitive impairment.

Neuroimage Clin 2020 23;25:102146. Epub 2019 Dec 23.

Department of Neurology, University of Pennsylvania, Philadelphia, PA, United States. Electronic address:

Neurodegenerative biomarkers support diagnosis and measurement of disease progression in the Alzheimer's disease (AD) continuum. F-Fluorodeoxyglucose Positron Emission Tomography (F-FDG-PET), which measures glucose metabolism, is one of the most commonly used biomarkers of neurodegeneration, but is expensive and requires exposure to ionizing radiation. Arterial Spin Labeled (ASL) perfusion Magnetic Resonance Imaging (MRI) provides non invasive quantification of cerebral blood flow (CBF), which is believed to be tightly coupled to glucose metabolism. Here we aimed to compare the performances of ASL derived CBF and F-FDG-PET derived standardized uptake value ratio (SUVR) in discriminating patients with mild cognitive impairment (MCI) from older Controls. 2D pseudo continuous ASL and F-FDG-PET data with adequate scan quality from 50 MCI study participants (age=73.0 ± 7.0 years, 16 female) and 35 older controls (age=70.2 ± 6.9 years, 20 female), acquired in close temporal proximity, usually on the same day, were considered for this study. We assessed Control-patient group differences both at voxel level and within a priori regions of interest (ROIs). We also compared their area under receiver operating characteristic curves (AUC) with mean CBF or SUVR in a priori selected posterior cingulate cortex (PCC). CBF and F-FDG-PET showed abnormalities in similar areas, particularly in medial temporoparietal regions, consistent with the typically observed pattern of prodromal AD. The hypoperfusion pattern with relative CBF (obtained by normalizing voxel CBF values with mean CBF in putamen) was more localized than with absolute CBF. Pearson's correlation coefficients between the T-scores corresponding to the group-differences obtained with F-FDG-PET SUVR and absolute and relative ASL CBF were 0.46 and 0.43 (p<0.001), respectively. ROI analyses were also consistent, with the strongest differences observed in PCC (p<0.01). F-FDG-PET SUVR, absolute and relative CBF in the PCC ROI demonstrated moderate and similar discriminatory power in predicting MCI status with AUC of 0.71 ± 0.12, 0.77 ± 0.12 and 0.74 ± 0.13, respectively. In conclusion, ASL CBF may be a reasonable, less expensive and safer substitute for F-FDG-PET in clinical research.
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http://dx.doi.org/10.1016/j.nicl.2019.102146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957781PMC
December 2020

Estimating regional cerebral blood flow using resting-state functional MRI via machine learning.

J Neurosci Methods 2020 02 19;331:108528. Epub 2019 Nov 19.

Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA; Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. Electronic address:

Background: Perfusion MRI is an important modality in many brain imaging protocols, since it probes cerebrovascular changes in aging and many diseases; however, it may not be always available.

New Method: We introduce a new method that seeks to estimate regional perfusion properties using spectral information of resting-state functional MRI (rsfMRI) via machine learning. We used pairs of rsfMRI and arterial spin labeling (ASL) images from the same individuals with normal cognition and mild cognitive impairment (MCI), and built support vector machine models aiming to estimate regional cerebral blood flow (CBF) from the rsfMRI signal alone.

Results: This method demonstrated higher associations between the estimated CBF and actual CBF (ASL-CBF) at the total lobar gray matter (r = 0.40; FDR-p = 1.9e-03), parietal lobe (r = 0.46, FDR-p = 8e-04), and occipital lobe (r = 0.35; FDR-p = 0.01) using rsfMRI signals of frequencies [0.01-0.15] Hertz compared to frequencies [0.01-0.10] Hertz and [0.01-0.20] Hertz. We further observed significant associations between the estimated CBF and actual CBF in 24 regions of interest (p < 0.05), with the highest association observed in the superior parietal lobule (r = 0.50, FDR-p = 0.002). Moreover, the estimated CBF at superior parietal lobule showed significant correlation with the mini-mental state exam (MMSE) score (r = 0.27; FDR-p = 0.04) and decreased in MCI with lower MMSE score compared to NC group (FDR-p = 0.04).

Comparison With Existing Methods: Consistent with previous findings, this new method also suggests that rsfMRI signals contain perfusion information.

Conclusion: The proposed framework can obtain estimates of regional perfusion from rsfMRI, which can serve as surrogate perfusion measures in the absence of ASL.
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http://dx.doi.org/10.1016/j.jneumeth.2019.108528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216635PMC
February 2020

Metabolic and vascular risk factors are associated with reduced cerebral blood flow and poorer midlife memory performance.

Hum Brain Mapp 2020 03 25;41(4):855-864. Epub 2019 Oct 25.

Heart and Stroke Foundation, Canadian Partnership for Stroke Recovery, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada.

Midlife metabolic and vascular risk factors (MVRFs) predict cognitive decline and dementia; however, these risk factors tend to overlap, and the mechanisms underlying their effects on cognitive performance are not well understood. This cross-sectional study investigates the contributions of MVRFs to regional cerebral blood flow (CBF) and verbal learning & memory among middle-aged adults. We used partial least squares (PLS) analysis to create latent risk factor profiles and examine their associations to CBF in 93 regions of interest among 451 participants (age 50.3 ± 3.5 years) of the Coronary Artery Risk Development in Young Adults. This multivariate analysis revealed regional CBF was lower in relation to obesity (higher body mass index and waist circumference), dysregulated glucose homeostasis (higher fasting glucose, oral glucose tolerance, and higher fasting insulin), and adverse fasting lipid profile (lower high-density lipoprotein cholesterol and higher triglycerides). In a sensitivity analysis, we found that significant associations between MVRFs and CBF were prominent in the hypertension-medicated subgroup. In a mediation model, the PLS-based MVRFs profile was associated with memory performance (rey auditory verbal learning test); however, CBF was not a significant mediator of this association. The results describe an adverse midlife metabolic profile that might set the stage for incipient dementia and contribute to widespread changes in CBF.
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http://dx.doi.org/10.1002/hbm.24844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7267901PMC
March 2020

Single-Voxel H MR spectroscopy of cerebral nicotinamide adenine dinucleotide (NAD ) in humans at 7T using a 32-channel volume coil.

Magn Reson Med 2020 03 10;83(3):806-814. Epub 2019 Sep 10.

Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania.

Purpose: Reliable monitoring of tissue nicotinamide adenine dinucleotide (NAD ) concentration may provide insights on its roles in normal and pathological aging. In the present study, we report a H MRS pulse sequence for the in vivo, localized H MRS detection of NAD from the human brain.

Methods: Studies were carried out on a 7T Siemens MRI scanner using a 32-channel product volume coil. The pulse sequence consisted of a spectrally selective low bandwidth E-BURP-1 90° pulse. PRESS localization was achieved using optimized Shinnar-Le Roux 180° pulses and overlapping gradients were used to minimize the TE. The reproducibility of NAD quantification was measured in 11 healthy volunteers. The association of cerebral NAD with age was assessed in 16 healthy subjects 26-78 years old.

Results: Spectra acquired from a voxel placed in subjects' occipital lobe consisted of downfield peaks from the H , H , and H protons of the nicotinamide moiety of NAD between 8.9-9.35 ppm. The mean ± SD within-session and between-session coefficients of variation were found to be 6.14 ± 2.03% and 6.09 ± 3.20%, respectively. In healthy volunteers, an age-dependent decline of the NAD levels in the brain was also observed (β = -1.24 μM/y, SE = 0.21, P < 0.001).

Conclusion: We demonstrated the feasibility and robustness of a newly developed H MRS technique to measure localized cerebral NAD at 7T MRI using a commercially available RF head coil. This technique may be further applied to detect and quantify NAD from different regions of the brain as well as from other tissues.
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http://dx.doi.org/10.1002/mrm.27971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879788PMC
March 2020

Quantification of cerebral blood flow in adults by contrast-enhanced near-infrared spectroscopy: Validation against MRI.

J Cereb Blood Flow Metab 2020 08 9;40(8):1672-1684. Epub 2019 Sep 9.

Department of Medical Biophysics, Western University, London, ON, Canada.

The purpose of this study was to assess the accuracy of absolute cerebral blood flow (CBF) measurements obtained by dynamic contrast-enhanced (DCE) near-infrared spectroscopy (NIRS) using indocyanine green as a perfusion contrast agent. For validation, CBF was measured independently using the MRI perfusion method arterial spin labeling (ASL). Data were acquired at two sites and under two flow conditions (normocapnia and hypercapnia). Depth sensitivity was enhanced using time-resolved detection, which was demonstrated in a separate set of experiments using a tourniquet to temporally impede scalp blood flow. A strong correlation between CBF measurements from ASL and DCE-NIRS was observed (slope = 0.99 ± 0.08, y-intercept = -1.7 ± 7.4 mL/100 g/min, and  = 0.88). Mean difference between the two techniques was 1.9 mL/100 g/min (95% confidence interval ranged from -15 to 19 mL/100g/min and the mean ASL CBF was 75.4 mL/100 g/min). Error analysis showed that structural information and baseline absorption coefficient were needed for optimal CBF reconstruction with DCE-NIRS. This study demonstrated that DCE-NIRS is sensitive to blood flow in the adult brain and can provide accurate CBF measurements with the appropriate modeling techniques.
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http://dx.doi.org/10.1177/0271678X19872564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370369PMC
August 2020

Cerebral Blood Flow Response During Bolus Normal Saline Infusion After Ischemic Stroke.

J Stroke Cerebrovasc Dis 2019 Nov 13;28(11):104294. Epub 2019 Aug 13.

Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania.

Goals: We quantified cerebral blood flow response to a 500 cc bolus of 0.9%% normal saline (NS) within 96 hours of acute ischemic stroke (AIS) using diffuse correlation spectroscopy (DCS).

Materials And Methods: Subjects with AIS in the anterior, middle, or posterior cerebral artery territory were enrolled within 96 hours of symptom onset. DCS measured relative cerebral blood flow (rCBF) in the bilateral frontal lobes for 15 minutes at rest (baseline), during a 30-minute infusion of 500 cc NS (bolus), and for 15 minutes after completion (post-bolus). Mean rCBF for each time period was calculated for individual subjects and median rCBF for the population was compared between time periods. Linear regression was used to evaluate for associations between rCBF and clinical features.

Results: Among 57 subjects, median rCBF (IQR) increased relative to baseline in the ipsilesional hemisphere by 17% (-2.0%, 43.1%), P< 0.001, and in the contralesional hemisphere by 13.3% (-4.3%, 36.0%), P < .004. No significant associations were found between ipsilesional changes in rCBF and age, race, infarct size, infarct location, presence of large vessel stenosis, NIH stroke scale, or symptom duration.

Conclusion: A 500 cc bolus of .9% NS produced a measurable increase in rCBF in both the affected and nonaffected hemispheres. Clinical features did not predict rCBF response.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2019.07.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823150PMC
November 2019

Calibrated fMRI for dynamic mapping of CMRO responses using MR-based measurements of whole-brain venous oxygen saturation.

J Cereb Blood Flow Metab 2020 07 8;40(7):1501-1516. Epub 2019 Aug 8.

Laboratory for Structural, Physiologic and Functional Imaging (LSPFI), Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA.

Functional MRI (fMRI) can identify active foci in response to stimuli through BOLD signal fluctuations, which represent a complex interplay between blood flow and cerebral metabolic rate of oxygen (CMRO) changes. Calibrated fMRI can disentangle the underlying contributions, allowing quantification of the CMRO response. Here, whole-brain venous oxygen saturation () was computed alongside ASL-measured CBF and BOLD-weighted data to derive the calibration constant, , using the proposed -based calibration. Data were collected from 10 subjects at 3T with a three-part interleaved sequence comprising background-suppressed 3D-pCASL, 2D BOLD-weighted, and single-slice dual-echo GRE (to measure via susceptometry-based oximetry) acquisitions while subjects breathed normocapnic/normoxic, hyperoxic, and hypercapnic gases, and during a motor task. was computed via -based calibration from both hypercapnia and hyperoxia stimulus data, and results were compared to conventional hypercapnia or hyperoxia calibration methods. Mean in gray matter did not significantly differ between calibration methods, ranging from 8.5 ± 2.8% (conventional hyperoxia calibration) to 11.7 ± 4.5% (Y-based calibration in response to hyperoxia), with hypercapnia-based values between ( = 0.56). Relative CMRO changes from finger tapping were computed from each map. CMRO increased by ∼20% in the motor cortex, and good agreement was observed between the conventional and proposed calibration methods.
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http://dx.doi.org/10.1177/0271678X19867276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308517PMC
July 2020

MRI evaluation of cerebrovascular reactivity in obstructive sleep apnea.

J Cereb Blood Flow Metab 2020 06 15;40(6):1328-1337. Epub 2019 Jul 15.

Department of Radiology, University of Pennsylvania Health System, Philadelphia, PA, USA.

Obstructive sleep apnea (OSA) is characterized by intermittent obstruction of the airways during sleep. Cerebrovascular reactivity (CVR) is an index of cerebral vessels' ability to respond to a vasoactive stimulus, such as increased CO. We hypothesized that OSA alters CVR, expressed as a breath-hold index (BHI) defined as the rate of change in CBF or BOLD signal during a controlled breath-hold stimulus mimicking spontaneous apneas by being both hypercapnic and hypoxic. In 37 OSA and 23 matched non sleep apnea (NSA) subjects, we obtained high temporal resolution CBF and BOLD MRI data before, during, and between five consecutive BH stimuli of 24 s, each averaged to yield a single BHI value. Greater BHI was observed in OSA relative to NSA as derived from whole-brain CBF (78.6 ± 29.6 vs. 60.0 ± 20.0 mL/min/100 g,  = 0.010) as well as from flow velocity in the superior sagittal sinus (0.48 ± 0.18 vs. 0.36 ± 0.10 cm/s,  = 0.014). Similarly, BOLD-based BHI was greater in OSA in whole brain (0.19 ± 0.08 vs. 0.15 ± 0.03%/s,  = 0.009), gray matter (0.22 ± 0.09 vs. 0.17 ± 0.03%/s,  = 0.011), and white matter (0.14 ± 0.06 vs. 0.10 ± 0.02%/s,  = 0.010). The greater CVR is not currently understood but may represent a compensatory mechanism of the brain to maintain oxygen supply during intermittent apneas.
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http://dx.doi.org/10.1177/0271678X19862182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7238371PMC
June 2020

Characterizing a perfusion-based periventricular small vessel region of interest.

Neuroimage Clin 2019 12;23:101897. Epub 2019 Jun 12.

Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA; Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA. Electronic address:

The periventricular white matter (PVWM) is supplied by terminal distributions of small vessels and is particularly susceptible to developing white matter lesions (WML) associated with cerebral small vessel disease (CSVD). We obtained group-averaged cerebral blood flow (CBF) maps from Arterial Spin Labeled (ASL) perfusion MRI data obtained in 436 middle-aged (50.4 ± 3.5 years) subjects in the NHLBI CARDIA study and in 61 elderly (73.3 ± 6.9 years) cognitively normal subjects recruited from the Penn Alzheimer's Disease Center (ADC) and found that the lowest perfused brain voxels are located within the PVWM. We constructed a white matter periventricular small vessel (PSV) region of interest (ROI) by empirically thresholding the group averaged CARDIA CBF map at CBF < 15 ml/100 g/min. Thereafter we compared CBF in the PSV ROI and in the remaining white matter (RWM) with the location and volume of WML measured with Fluid Attenuated Inversion Recovery (FLAIR) MRI. WM CBF was lower within WML than outside WML voxels (p < <0.0001) in both the PSV and RWM ROIs, however this difference was much smaller (p < <0.0001) in the PSV ROI than in the RWM suggesting a more homogenous reduction of CBF in the PSV region. Normalized WML volumes were significantly higher in the PSV ROI than in the RWM and in the elderly cohort as compared to the middle-aged cohort (p < <0.0001). Additionally, the PSV ROI showed a significantly (p = .001) greater increase in lesion volume than the RWM in the elderly ADC cohort than the younger CARDIA cohort. Considerable intersubject variability in PSV CBF observed in both study cohorts likely represents biological variability that may be predictive of future WML and/or cognitive decline. In conclusion, a data-driven PSV ROI defined by voxels with low perfusion in middle age defines a region with homogeneously reduced CBF that is particularly susceptible to progressive ischemic injury in elderly controls. PSV CBF may provide a mechanistically specific biomarker of CSVD.
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http://dx.doi.org/10.1016/j.nicl.2019.101897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6595083PMC
June 2020

Perfusion Enhancement with Respiratory Impedance After Stroke (PERI-Stroke).

Neurotherapeutics 2019 10;16(4):1296-1303

Department of Neurology, University of Pennsylvania, Philadelphia, USA.

Intrathoracic pressure influences cardiac output and may affect cerebral blood flow (CBF). We aimed to quantify the cerebral hemodynamic response to intrathoracic pressure reduction in patients with acute ischemic stroke using a noninvasive respiratory impedance (RI) device. We assessed low-level (6 cm HO) and high-level (12 cm HO) RI in 17 spontaneously breathing patients within 72 h of anterior circulation acute ischemic stroke. Average age was 65 years, and 35% were female. Frontal lobe tissue perfusion and middle cerebral artery velocity (MCAv) were continuously monitored with optical diffuse correlation spectroscopy (DCS) and transcranial Doppler ultrasound, respectively. High-level RI resulted in a 7% increase in MCAv (p = 0.004). MCAv varied across all studied levels (baseline vs low-level vs high-level, p = 0.006), with a significant test of trend (p = 0.002). Changes were not seen in DCS measured tissue perfusion by nonparametric pairwise comparison. Mixed effects regression analysis identified a small increase in both MCAv (low-level RI: β 2.1, p < 0.001; high-level RI: β 5.0, p < 0.001) and tissue-level flow (low-level RI: β 5.4, p < 0.001; high-level RI: β 5.9, p < 0.001). There was a small increase in mean arterial pressure during low-level and high-level RI, 4% (p = 0.013) and 4% (p = 0.017), respectively. End-tidal CO remained stable throughout the protocol. RI was well tolerated. Manipulating intrathoracic pressure via noninvasive RI was safe and produced a small but measurable increase in cerebral perfusion in acute ischemic stroke patients. Future studies are warranted to assess whether RI is feasible and tolerable for prolonged use in hyperacute stroke management.
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http://dx.doi.org/10.1007/s13311-019-00744-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6985403PMC
October 2019

Transcranial Optical Monitoring of Cerebral Hemodynamics in Acute Stroke Patients during Mechanical Thrombectomy.

J Stroke Cerebrovasc Dis 2019 Jun 8;28(6):1483-1494. Epub 2019 Apr 8.

Department of Physics & Astronomy, University of Pennsylvania, Philadelphia, Pennsylvania.

Introduction: Mechanical thrombectomy is revolutionizing treatment of acute stroke due to large vessel occlusion (LVO). Unfortunately, use of the modified Thrombolysis in Cerebral Infarction score (mTICI) to characterize recanalization of the cerebral vasculature does not address microvascular perfusion of the distal parenchyma, nor provide more than a vascular "snapshot." Thus, little is known about tissue-level hemodynamic consequences of LVO recanalization. Diffuse correlation spectroscopy (DCS) and diffuse optical spectroscopy (DOS) are promising methods for continuous, noninvasive, contrast-free transcranial monitoring of cerebral microvasculature.

Methods: Here, we use a combined DCS/DOS system to monitor frontal lobe hemodynamic changes during endovascular treatment of 2 patients with ischemic stroke due to internal carotid artery (ICA) occlusions.

Results And Discussion: The monitoring instrument identified a recanalization-induced increase in ipsilateral cerebral blood flow (CBF) with little or no concurrent change in contralateral CBF and extracerebral blood flow. The results suggest that diffuse optical monitoring is sensitive to intracerebral hemodynamics in patients with ICA occlusion and can measure microvascular responses to mechanical thrombectomy.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2019.03.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686873PMC
June 2019

Variability in the Analgesic Response to Ibuprofen Is Associated With Cyclooxygenase Activation in Inflammatory Pain.

Clin Pharmacol Ther 2019 09 29;106(3):632-641. Epub 2019 Apr 29.

Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.

The mechanisms underlying interindividual variability in analgesic efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) are not well understood. Therefore, we performed pain phenotyping, functional neuroimaging, pharmacokinetic/pharmacodynamic assessments, inflammation biomarkers, and gene expression profiling in healthy subjects who underwent surgical extraction of bony impacted third molars and were treated with ibuprofen (400 mg; N = 19) or placebo (N = 10). Analgesic efficacy was not associated with demographic or clinical characteristics, ibuprofen pharmacokinetics, or the degree of cyclooxygenase inhibition by ibuprofen. Compared with partial responders to ibuprofen (N = 9, required rescue medication within the dosing interval), complete responders (N = 10, no rescue medication) exhibited greater induction of urinary prostaglandin metabolites and serum tumor necrosis factor-α and interleukin 8. Differentially expressed genes in peripheral blood mononuclear cells were enriched for inflammation-related pathways. These findings suggest that a less pronounced activation of the inflammatory prostanoid system is associated with insufficient pain relief on ibuprofen alone and the need for additional therapeutic intervention.
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http://dx.doi.org/10.1002/cpt.1446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6753944PMC
September 2019

Test-retest reliability of cerebral blood flow for assessing brain function at rest and during a vigilance task.

Neuroimage 2019 06 17;193:157-166. Epub 2019 Mar 17.

Laboratory of Applied Brain and Cognitive Sciences, Shanghai International Studies University, Shanghai, China; Center for Functional Neuroimaging, Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Division of Sleep and Chronobiology, Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. Electronic address:

Arterial spin labeled (ASL) perfusion magnetic resonance imaging (MRI) is increasingly used to assess regional brain activity and cerebrovascular function in both healthy and clinical populations. ASL perfusion imaging provides a quantitative measure of regional brain activity by determining absolute cerebral blood flow (CBF) values at a resting state or during task performance. However, the comparative reliability of these ASL measures is not well characterized. It is also unclear whether the test-retest reliability of absolute CBF or task-induced CBF change measures would be comparable to the reliability of task performance. In this study, fifteen healthy participants were scanned three times in a strictly controlled in-laboratory study while at rest and during performing a simple and reliable psychomotor vigilance test (PVT). The reliability of absolute CBF and task-induced CBF changes was evaluated using the intraclass correlation coefficient (ICC) and compared to that of task performance. Absolute CBF showed excellent test-retest reliability across the three scans for both resting and PVT scans. The reliability of regional absolute CBF was comparable to that of behavioral measures of PVT performance, and was slightly higher during PVT scans as compared with resting scans. Task-induced regional CBF changes demonstrated only poor to moderate reliability across three scans. These findings suggest that absolute CBF measures are more reliable than task-induced CBF changes for characterizing regional brain function, especially for longitudinal and clinical studies.
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http://dx.doi.org/10.1016/j.neuroimage.2019.03.016DOI Listing
June 2019

Structural and functional asymmetry of medial temporal subregions in unilateral temporal lobe epilepsy: A 7T MRI study.

Hum Brain Mapp 2019 06 21;40(8):2390-2398. Epub 2019 Jan 21.

Center for Neuroengineering and Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania.

Mesial temporal lobe epilepsy (TLE) is a common neurological disorder affecting the hippocampus and surrounding medial temporal lobe (MTL). Although prior studies have analyzed whole-brain network distortions in TLE patients, the functional network architecture of the MTL at the subregion level has not been examined. In this study, we utilized high-resolution 7T T2-weighted magnetic resonance imaging (MRI) and resting-state BOLD-fMRI to characterize volumetric asymmetry and functional network asymmetry of MTL subregions in unilateral medically refractory TLE patients and healthy controls. We subdivided the TLE group into mesial temporal sclerosis patients (TLE-MTS) and MRI-negative nonlesional patients (TLE-NL). Using an automated multi-atlas segmentation pipeline, we delineated 10 MTL subregions per hemisphere for each subject. We found significantly different patterns of volumetric asymmetry between the two groups, with TLE-MTS exhibiting volumetric asymmetry corresponding to decreased volumes ipsilaterally in all hippocampal subfields, and TLE-NL exhibiting no significant volumetric asymmetries other than a mild decrease in whole-hippocampal volume ipsilaterally. We also found significantly different patterns of functional network asymmetry in the CA1 subfield and whole hippocampus, with TLE-NL patients exhibiting asymmetry corresponding to increased connectivity ipsilaterally and TLE-MTS patients exhibiting asymmetry corresponding to decreased connectivity ipsilaterally. Our findings provide initial evidence that functional neuroimaging-based network properties within the MTL can distinguish between TLE subtypes. High-resolution MRI has potential to improve localization of underlying brain network disruptions in TLE patients who are candidates for surgical resection.
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http://dx.doi.org/10.1002/hbm.24530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6497534PMC
June 2019

Arterial spin labeling provides a reliable neurobiological marker of autism spectrum disorder.

J Neurodev Disord 2018 12 13;10(1):32. Epub 2018 Dec 13.

Center for Autism Research, The Children's Hospital of Philadelphia, Roberts Center for Pediatric Research, 2716 South Street, 5th floor, Philadelphia, PA, 19146-2305, USA.

Background: Research on neurobiological markers of autism spectrum disorder (ASD) has been elusive. However, radionuclide studies of cerebral blood flow (CBF) have shown decreased blood flow (hypoperfusion) in the temporal lobes of individuals with ASD across ages and intelligence. This observation fits with current neuroscientific models that implicate temporal regions in social perception and social cognition. Arterial spin labeled perfusion MRI allows noninvasive quantification of regional CBF as part of a multimodal MRI protocol. This method is almost entirely absent from ASD research to date. Our a priori hypothesis was that children with ASD would present with hypoperfusion in the temporal lobes-most notably the fusiform gyrus (given its prominent role in ASD social perception deficits). We also sought to examine the reproducibility of CBF measures, and their relationship to individual differences in facial recognition and ASD symptoms.

Methods: A total of 58 males (33 with ASD) between the ages of 12 and 17 years participated in the study. All children completed two arterial spin labeling and structural (T1) scans using a 3 T Siemens Verio scanner approximately 8 weeks apart, as well as behavioral testing at time 1 that included diagnostic measures and the Benton Facial Recognition Test. CBF was the key dependent variable, as was facial recognition performance, and ASD symptoms. The two scans were used for reliability analyses.

Results: The ASD group showed hypoperfusion in the bilateral fusiform gyrus and in right inferior temporal gyrus. Intra-class correlations showed moderate to good reliability across time within both groups, and no diagnostic group × time interactions. CBF in the left fusiform gyrus was significantly positively correlated with facial recognition. No significant correlations were observed with core ASD symptoms.

Conclusions: Arterial spin labeling revealed hypoperfusion in children with ASD in regions critical to social perception and cognition. The left fusiform gyrus plays an important role in facial recognition, and greater CBF in this region was correlated with more normative facial recognition performance in children with ASD. This study takes an important first step in establishing CBF of the temporal lobes as a reliable marker of ASD.
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http://dx.doi.org/10.1186/s11689-018-9250-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6292037PMC
December 2018

Assessment of uterine artery geometry and hemodynamics in human pregnancy with 4d flow mri and its correlation with doppler ultrasound.

J Magn Reson Imaging 2019 01 3;49(1):59-68. Epub 2018 Nov 3.

Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Background: Uterine artery (UtA) hemodynamics might be used to predict risk of hypertensive pregnancy disorders, including preeclampsia and intrauterine growth restriction.

Purpose Or Hypothesis: To determine the feasibility of 4D flow MRI in pregnant subjects by characterizing UtA anatomy, computing UtA flow, and comparing UtA velocity, and pulsatility and resistivity indices (PI, RI) with transabdominal Doppler ultrasound (US).

Study Type: Prospective cross-sectional study from June 6, 2016, to May 2, 2018.

Population Or Subjects Or Phantom Or Specimen Or Animal Model: Forty-one singleton pregnant subjects (age [range] = 27.0 ± 5.9 [18-41] years) in their second or third trimester. We additionally scanned three subjects who had prepregnancy diabetes or chronic hypertension.

Field Strength/sequence: The subjects underwent UtA and placenta MRI using noncontrast angiography and 4D flow at 1.5T.

Assessment: UtA anatomy was described based on 4D flow-derived noncontrast angiography, while UtA flow properties were characterized by net flow, systolic/mean/diastolic velocity, PI and RI through examination of 4D flow data. PI and RI are standard hemodynamic parameters routinely reported on Doppler US.

Statistical Tests: Spearman's rank correlation, Wilcoxon signed rank tests, and Bland-Altman plots were used to preliminarily investigate the relationships between flow parameters, gestational age, and Doppler US. or RESULTS: 4D flow MRI and UtA flow quantification was feasible in all subjects. There was considerable heterogeneity in UtA geometry in each subject between left and right UtAs and between subjects. Mean 4D flow-based parameters were: mean bilateral flow rate = 605.6 ± 220.5 mL/min, PI = 0.72 ± 0.2, and RI = 0.47 ± 0.1. Bilateral flow did not change with gestational age. We found that MRI differed from US in terms of lower PI (mean difference -0.1) and RI (mean difference < -0.1) with Wilcoxon signed rank test P = 0.05 and P = 0.13, respectively.

Data Conclusion: 4D flow MRI is a feasible approach for describing UtA anatomy and flow in pregnant subjects.

Level Of Evidence: Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2019;49:59-68.
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http://dx.doi.org/10.1002/jmri.26229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6298841PMC
January 2019

Task-enhanced arterial spin labeled perfusion MRI predicts longitudinal neurodegeneration in mild cognitive impairment.

Hippocampus 2019 01 6;29(1):26-36. Epub 2018 Nov 6.

Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Mild cognitive impairment (MCI) is considered a prodromal stage of Alzheimer's disease (AD), but is also recognized to be a heterogeneous condition. Biomarkers that predict AD progression in MCI are of clinical significance because they can be used to better identify appropriate candidates for therapeutic intervention studies. It has been hypothesized that comparing to structural measurements, functional ones may be more sensitive to early disease abnormalities and the sensitivity could be further enhanced when combined with cognitive task, a "brain stress test." In this study, we investigated the value of regional cerebral blood flow (CBF), measured by arterial spin labeled perfusion MRI (ASL MRI) during a memory-encoding task, in predicting the estimated rate of hippocampal atrophy, an established marker of AD progression. Thirty-one amnestic MCI patients (20 male and 11 female; age: 70.9 ± 6.5 years, range from 56 to 83 years; mini mental status examination: 27.8 ± 1.8) and 42 normal control subjects (13 male and 29 female; age: 70.6 ± 8.8 years, range from 55 to 88 years; mini mental status examination: 29.1 ± 1.2) were included in this study. We compared the predictive value of CBF during task to CBF during rest and structural volumetry. Both region-of-interest and voxelwise analyses showed that baseline CBF measurements during task (strongest effect in fusiform gyrus, region-of-interest analysis statistics: r = 0.56, p = .003), but not resting ASL MRI or structural volumetry, were correlated with the estimated rate of hippocampal atrophy in amnestic MCI patients. Further, stepwise linear regression demonstrated that resting ASL MRI and volumetry did not provide complementary information in prediction. These results support the notion that physiologic measures during a cognitive challenge may increase the ability to detect subtle functional changes that predict progression. As such, ASL MRI could have important utility in stratifying candidates for AD treatment trials.
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http://dx.doi.org/10.1002/hipo.23026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309706PMC
January 2019

Regional Cerebral Blood Flow in Children and Young Adults with Chronic Kidney Disease.

Radiology 2018 09 12;288(3):849-858. Epub 2018 Jun 12.

From the School of Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei, Taiwan; Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pa; International Ph.D. Program in Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei, Taiwan; Research Center of Translational Imaging, College of Medicine, Taipei Medical University, Taipei, Taiwan (H.S.L.); Division of Nephrology, Department of Pediatrics, Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pa (E.A.H.); Department of Pediatrics, Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pa (A.F.J.); Department of Radiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pa (J.B.W.); Division of Nephrology, Children's Hospital of Philadelphia, Philadelphia, Pa (N.L.); Brain Behavior Laboratory, Department of Psychiatry, University of Pennsylvania, Philadelphia, Pa (A.M.P.); Brain Behavior Laboratory, Department of Psychiatry, University of Pennsylvania, Philadelphia, Pa (R.C.G.); Department of Allied Health Sciences, University of North Carolina School of Medicine, Chapel Hill, NC (S.R.H.); Division of Developmental and Behavioral Pediatrics, Department of Pediatrics, Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pa (J.R.); Division of Nephrology, Departments of Pediatrics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania; Division of Nephrology, Children's Hospital of Philadelphia, Philadelphia, Pa (S.L.F.); and Departments of Neurology and Radiology, Perelman School of Medicine at the University of Pennsylvania, 3W Gates Pavilion, 3400 Spruce St, Philadelphia, PA 19104 (J.A.D.).

Purpose To investigate the pathophysiologic effects of chronic kidney disease (CKD) on brain function in children with CKD by correlating cerebral blood flow (CBF) with clinical and behavioral indexes. Materials and Methods In this prospective study, 73 pediatric patients with CKD (mean age, 15.80 years ± 3.63; range, 9-25 years) and 57 control subjects (mean age, 15.65 years ± 3.76; range, 9-25 years) were recruited. CBF measurements were acquired with an MRI arterial spin labeling scheme. Neurocognitive measurements were performed with traditional and computerized neurocognitive batteries. Clinical data were also collected. Group-level global and regional CBF differences between patients with CKD and control subjects were assessed. Regression analyses were conducted to evaluate the associations among regional CBF, clinical variables, and cognitive performance. Results Patients with CKD showed higher global CBF compared with control subjects that was attributable to reduced hematocrit level (mean, 60.2 mL/100 g/min ± 9.0 vs 56.5 mL/100 g/min ± 8.0, respectively). White matter CBF showed correlation with blood pressure (r = 0.244, P = .039), a finding suggestive of altered cerebrovascular autoregulation. Regional CBF differences between patients and control subjects included regions in the "default mode" network. In patients with CKD, positive extrema in the precuneus showed a strong correlation with executive function (ρ = 0.608, P = .001). Conclusion Systemic effects of estimated glomerular filtration rate, hematocrit level, and blood pressure on CBF and alterations in regional CBF may reflect impaired brain function underlying neurocognitive symptoms in CKD. These findings further characterize the nature of alterations in brain physiologic features in children, adolescents, and young adults with CKD.
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http://dx.doi.org/10.1148/radiol.2018171339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6102080PMC
September 2018

Reproducibility of 2D GluCEST in healthy human volunteers at 7 T.

Magn Reson Med 2018 11 25;80(5):2033-2039. Epub 2018 May 25.

Department of Radiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.

Purpose: To investigate the reproducibility of gray and white matter glutamate contrast of a brain slice among a small group of healthy volunteers by using the 2D single-slice glutamate CEST (GluCEST) imaging technique.

Methods: Six healthy volunteers were scanned multiple times for within-day and between-day reproducibility. One more volunteer was scanned for within-day reproducibility at 7T MRI. Glutamate CEST contrast measurements were calculated for within subjects and among the subjects and the coefficient of variations are reported.

Results: The GluCEST measurements were highly reproducible in the gray and white matter area of the brain slice, whether it was within-day or between-day with a coefficient of variation of less than 5%.

Conclusion: This preliminary study in a small group of healthy volunteers shows a high degree of reproducibility of GluCEST MRI in brain and holds promise for implementation in studying age-dependent changes in the brain.
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http://dx.doi.org/10.1002/mrm.27362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6107408PMC
November 2018