Arterial Spin Labeling Perfusion MRI Research Articles

Arterial spin-labeling magnetic resonance imagings in the cortical and internal watershed infarctions in patients with ipsilateral internal carotid artery stenosis/occlusion

Objective: To investigate the pathophysiological mechanism for the cortical and internal watershed (WS) infarction in patients with a symptomatic internal carotid artery (ICA) stenosis/occlusion, we assessed the cerebral hemodynamic state using arterial spin-labeling (ASL) perfusion MRI with image acquisition at two post-labeling delay (PLD) times

Global fluctuations of cerebral blood flow indicate a global brain network independent of systemic factors

Global synchronization across specialized brain networks is a common feature of network models and in-vivo electrical measurements. Although the imaging of specialized brain networks with blood oxygenation sensitive resting state functional magnetic resonance imaging (rsfMRI) has enabled detailed study of regional networks, the study of globally correlated fluctuations with rsfMRI is confounded by spurious contributions to the global signal from systemic physiologic factors and other noise sources. Here we use an alternative rsfMRI method, arterial spin labeled perfusion MRI, to characterize global correlations and their relationship to correlations and anti-correlations between regional networks. Global fluctuations that cannot be explained by systemic factors dominate the fluctuations in cerebral blood flow. Power spectra of these fluctuations are band limited to below 0.05 Hz, similar to prior measurements of regional network fluctuations in the brain. Removal of these global fluctuations prior to measurement of regional networks reduces all regional network fluctuation amplitudes to below the global fluctuation amplitude and changes the strength and sign of inter network correlations. Our findings support large amplitude, globally synchronized activity across networks that require a reassessment of regional network amplitude and correlation measures.

Better Correlation of Cognitive Function to White Matter Integrity than to Blood Supply in Subjects with Leukoaraiosis.

Leukoaraiosis is associated with increased risk of cognitive impairment, but its pathophysiological pathway is unclear. The aim of the present study was to determine whether brain structural damage or cerebral blood supply better correlated with the global cognitive outcome in subjects with leukoaraiosis. Seventy-five subjects with leukoaraiosis were included in present study, with age ranged from 43 to 85 years, with mean white matter hyperintensities (WMH) volume 30.69 ± 24.35 mL. Among them, 19(25.33%) subjects presented with cerebral microbleeds (CMB) and 40 (53.33%) subjects presented with lacunes. These participants received arterial spin labeling perfusion MRI, diffusion-tensor imaging (DTI) and diffusion Kurtosis imaging. We analyzed the cerebral blood flow (CBF) by dividing the brain tissue into three regions: WMH, normal appearing white matter (NAWM) and cortex. After adjusting for age and gender, the CBF of NAWM was significantly correlated with fractional anisotropy (FA) (r = 0.336, p = 0.004) and mean diffusion (MD) (r = -0.271, p = 0.020) of NAWM, while there lacked of association between CBF of cortex and mean kurtosis (MK) of cortex (r = -0.015, p = 0.912). Meanwhile, both NAWM-FA (r = -0.443, p < 0.001) and NAWM-MD (r = 0.293, p = 0.012), as well as cortex-MK (r = -0.341, p = 0.012) was significantly correlated with WMH volume. Univariate regression analysis demonstrated that global cognitive function was significantly associated with mean FA or MD of both WMH and NAWM, and cortex-CBF, but neither with the cortex-MK, nor the presences of CMB or lacunes. Finally, multiple linear regression analysis revealed that global cognitive function was independently associated with NAWM-FA (standardized β = 0.403, p < 0.001) and WMH-FA (Standardized β = 0.211, p = 0.017), but not with the cortex-CBF. A model that contained NAWM-FA, WMH-FA and years of education explained 49% of the variance of global cognitive function. Cerebral perfusion status might have a significant impact on the maintenance of white matter integrity in subjects with leukoaraiosis. Global cognitive function was more strongly associated with white matter integrity than with blood supply. DTI parameters, especially FA could serve as a potent imaging indicator for detecting the invisible alteration of white matter integrity and implying its potential cognitive relevance.

Voxel-wise correlations between cognition and cerebral blood flow using arterial spin-labeled perfusion MRI in patients with Alzheimer\u2019s disease: a cross-sectional study

BackgroundTo analyze voxel-wise correlation between cerebral blood flow (CBF) measured using ASL-MRI and cognition in patients with Alzheimer’s disease (AD).MethodsForty-one patients diagnosed with AD or mild cognitive impairment due to AD were recruited for this study. CBF images were obtained using ASL-MRI (n = 41) with a post-labeling delay (PLD) of 1.5 and 2.5 s (PLD1.5 and PLD2.5, respectively) using a 3 T scanner, in addition to brain perfusion SPECT with N-isopropyl-4-[I-123]iodoamphetamine (n = 28). Voxel-based analyses were performed for ASL-MRI and SPECT using Mini-Mental State Examination (MMSE) scores as covariates. Differences in CBF between PLD1.5 and PLD2.5 were assessed using a paired t-test with SPM12.ResultsSignificant positive correlations were observed between MMSE scores and CBF at PLD1.5 in the right posterior cingulate cortex (PCC), and both temporo-parietal association cortexes. At PLD2.5, significant positive correlations were determined for MMSE scores and CBF in the superior parietal lobule and the right temporo-parietal association cortex. SPECT showed significant positive correlations in the PCC and both temporo-parietal association cortexes (right-side dominant). PLD1.5 showed significantly higher CBF than PLD2.5 in the proximal areas of vascular territories of the anterior, middle, and posterior cerebral arteries.ConclusionsSignificant positive correlations in CBF, measured with both ASL-MRI and SPECT, with cognition were found in the PCC and temporo-parietal association cortexes. PLD1.5 and PLD2.5 showed similar correlations with cognition, although the CBF images had significant differences.

Culpable brain lesion causing complex partial status in Wilson’s disease: Deduction by arterial spin labeled perfusion MRI

Culpable brain lesion causing complex partial status in Wilson’s disease: Deduction by arterial spin labeled perfusion MRI

Abstract WP36: Post-ischemic Hyperperfusion After Reperfusion Therapy Predicts Hemorrhagic Transformation

Background and Purpose: Post-ischemic hyperperfusion has been considered as a risk factor of hemorrhagic transformation and poor prognosis. To date, however, there is a lack of data about the pathological significance of hyperperfusion after reperfusion therapy. In this study, we evaluated the relationship between hemorrhagic transformation and post-ischemic hyperperfusion after reperfusion therapy by using arterial spin labeled perfusion MRI (ASL) and 123 I IMP-SPECT. Methods: We retrospectively collected data of acute stroke patients with middle cerebral artery (MCA) occlusion who received intravenous thrombolysis and/or endovascular therapy, and underwent pulsed ASL using Q2TIPS-FAIR with 3D-TGSE readout and 123 I IMP-SPECT using dual-table ARG method within 14 days of stroke onset from November 2015 to June 2016. Ipsilateral-contralateral regional cerebral blood flow ratio (IC ratio) was calculated by using three-dimensional stereotactic ROI template (3DSRT) software. Results: Among 47 consecutive acute stroke patients with the MCA occlusion who received reperfusion therapy, 21 underwent only ASL and 10 underwent both ASL and SPECT after reperfusion therapy. The IC ratio of ASL was well correlated with that of SPECT in the MCA territory (r=0.65, p &lt;0.001). Hemorrhagic transformation was observed in 7 patients. IC ratio was higher in patients with hemorrhagic transformation after reperfusion therapy than those without hemorrhagic transformation (2.19±0.35 vs 0.99±0.19, p=0.005). Focal post-ischemic hyperperfusion (IC ratio &gt;1.5) was detected in 7 of 31 patients (23%). The presence of post-ischemic hyperperfusion was significantly associated with hemorrhagic transformation after reperfusion therapy (odds ratio 9.3, 95% confidence interval 1.4 to 64.0, p=0.03). Conclusions: Post-ischemic hyperperfusion detected by ASL predicts hemorrhagic transformation after reperfusion therapy. ASL hyperperfusion may indicate the disruption of blood brain barrier after reperfusion therapy.

Abstract WP148: Basilar Artery Displacement is Associated with Migraine with Aura

Background: Cerebrovascular dysregulation has long been associated with migraine pathophysiology, possibly mediated by hypoperfusion and/or endothelial dysfunction triggering cortical spreading depression. Vessel tortuosity has also been associated with altered hemodynamics and endothelial function. We sought to examine whether basilar artery (BA) tortuosity was altered in migraine. Methods: We performed the Anatomy and Cerebral Hemodynamic Evaluation of Migraine (ACHE-M) study, a prospective, observational, case-control study including high-resolution MR angiography, arterial spin labeled perfusion MRI, and structural MRI. Migraine with aura (MWA), migraine without aura (MwoA), and control subjects between the age of 25-50 were enrolled in a 1:1:1 ratio. Subjects with manifest vascular disease of any type were excluded. Vertebral and basilar artery diameters and BA total lateral displacement from MRI were correlated with regional perfusion and T2/FLAIR white matter lesions that were assessed using methods similar to the Cerebral Abnormalities in Migraine Epidemiologic Risk Analysis study. Results: 163 subjects were included (52 control/52 MWA/ 58 MwoA). Mean age was 33 ± 6 years, and 78% were female. BA diameter was similar across groups (3.6 ± 0.6 mm in all 3 groups). BA displacement was similar in MwoA (5.1±3.0 mm) and controls (4.9±3.1 mm), but tended to be greater in MWA (6.3±3.8 mm, p=0.055 vs. controls). In multivariate analysis incorporating migraine status, age, and sex, BA displacement was significantly associated with MWA (p=0.019), age (p&lt;0.001), and sex (p=0.046). BA displacement was also significantly greater with increasing migraine frequency (p=0.003). There was no association with displacement and posterior cerebral artery territory cerebral blood flow or overall white matter lesion burden. Conclusions: Basilar artery lateral displacement is associated with MWA as well as headache frequency, but this association does not appear to be mediated by cerebral hypoperfusion. Further investigation of the physiological consequences of basilar artery lateral displacement may lead to new insights into the mechanisms of migraine.

Heterogeneous increases of regional cerebral blood flow during preterm brain development: Preliminary assessment with pseudo-continuous arterial spin labeled perfusion MRI

The human brain develops rapidly during 32-45 postmenstrual weeks (PMW), a critical stage characterized by dramatic increases of metabolic demand. The increasing metabolic demand can be inferred through measurements of regional cerebral blood flow (CBF), which might be coupled to regional metabolism in preterm brains. Arterial spin labeled (ASL) perfusion MRI is one of the few viable approaches for imaging regional CBF of preterm brains, but must be optimized for the extremely slow blood velocity unique in preterm brains. In this study, we explored the spatiotemporal CBF distribution in newborns scanned at the age of 32-45PMW using a pseudo-continuous ASL (pCASL) protocol adapted to slow blood flow in neonates. A total of 89 neonates were recruited. PCASL MRI was acquired from 34 normal newborns and phase contrast (PC) images from 19 newborns. Diffusion tensor images (DTI) were acquired from all 89 neonates for measuring cortical fractional anisotropy (FA), which characterizes cortical microstructure. Reproducible CBF measurements were obtained with the adjusted pCASL sequence. Global CBF measurement based on PC MRI was found to double its value in the 3rd trimester. Regional CBF increases were heterogeneous across the brain with a significantly higher rate of CBF increase in the frontal lobe and a lower rate of CBF increase in the occipital lobe. A significant correlation was found between frontal cortical CBF and cortical FA measurements (p<0.01). Increasing CBF values observed in the frontal lobe corresponded to lower FA values, suggesting that dendritic arborization and synaptic formation might be associated with an elevated local CBF. These results offer a preliminary account of heterogeneous regional CBF increases in a vital early developmental period and may shed the light on underlying metabolic support for cortical microstructural changes during the developmental period of 32-45PMW. Preterm effects and limitations of pCASL techniques in newborns need to be carefully considered for interpretation these results.

3D-accelerated, stack-of-spirals acquisitions and reconstruction of arterial spin labeling MRI.

The goal of this study was to develop a 3D acceleration and reconstruction method to improve image quality and resolution of background-suppressed arterial spin-labeled perfusion MRI. Accelerated acquisition was implemented in all three k-space dimensions in a stack-of-spirals readout using variable density spirals and partition undersampling. A single 3D self-consistent parallel imaging (SPIRiT) kernel was calibrated and iteratively applied to reconstruct each imaging volume. Whole-brain (including cerebellum) perfusion imaging was obtained at 3-mm isotropic resolution (nominal) using single- and 2-shot acquisitions and at 2-mm isotropic resolution (nominal) using four-shot acquisitions, achieving effective acceleration factors between 5.5 and 6.6. The signal-to-noise (SNR) performance of 3D SPIRiT was evaluated. The temporal SNR (tSNR) of the cerebral blood flow (CBF) maps and the gray/white matter CBF ratios were quantified. The readout of the arterial spin labeling (ASL) sequence was significantly shortened with acceleration. The CBF values were consistent between accelerated and fully sampled ASL. With shorter spiral interleaves and shorter echo trains, the accelerated images demonstrated reduced blurring and signal dropout in regions with high susceptibility gradients, resulting in improved image quality and increased gray/white matter CBF ratios. The shortened readout was accompanied by a corresponding decrease in tSNR. The 3D acceleration and reconstruction allow a rapid whole-brain readout that improved the quality of ASL perfusion imaging. Magn Reson Med 78:1405-1419, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Arterial spin labeling perfusion magnetic resonance imaging of non-human primates.

Non-human primates (NHPs) resemble most aspects of humans in brain physiology and anatomy and are excellent animal models for translational research in neuroscience, biomedical research and pharmaceutical development. Cerebral blood flow (CBF) offers essential physiological information of the brain to examine the abnormal functionality in NHP models with cerebral vascular diseases and neurological disorders or dementia. Arterial spin labeling (ASL) perfusion MRI techniques allow for high temporal and spatial CBF measurement and are intensively used in studies of animals and humans. In this article, current high-resolution ASL perfusion MRI techniques for quantitative evaluation of brain physiology and function in NHPs are described and their applications and limitation are discussed as well.

Cerebral blood flow modulation insufficiency in brain networks in multiple sclerosis: A hypercapnia MRI study

Cerebrovascular reactivity measures vascular regulation of cerebral blood flow and is responsible for maintaining healthy neurovascular coupling. Multiple sclerosis exhibits progressive neurodegeneration and global cerebrovascular reactivity deficits. This study investigates varied degrees of cerebrovascular reactivity impairment in different brain networks, which may be an underlying cause for functional changes in the brain, affecting long-distance projection integrity and cognitive function; 28 multiple sclerosis and 28 control subjects underwent pseudocontinuous arterial spin labeling perfusion MRI to measure cerebral blood flow under normocapnia (room air) and hypercapnia (5% carbon dioxide gas mixture) breathing. Cerebrovascular reactivity, measured as normocapnic to hypercapnic cerebral blood flow percent increase normalized by end-tidal carbon dioxide change, was determined from seven functional networks (default mode, frontoparietal, somatomotor, visual, limbic, dorsal, and ventral attention networks). Group analysis showed significantly decreased cerebrovascular reactivity in patients compared to controls within the default mode, frontoparietal, somatomotor, and ventral attention networks after multiple comparison correction. Regression analysis showed a significant correlation of cerebrovascular reactivity with lesion load in the default mode and ventral attention networks and with gray matter atrophy in the default mode network. Functional networks in multiple sclerosis patients exhibit varied amounts of cerebrovascular reactivity deficits. Such blood flow regulation abnormalities may contribute to functional communication disruption in multiple sclerosis.

Aerobic fitness is associated with greater hippocampal cerebral blood flow in children

The present study is the first to investigate whether cerebral blood flow in the hippocampus relates to aerobic fitness in children. In particular, we used arterial spin labeling (ASL) perfusion MRI to provide a quantitative measure of blood flow in the hippocampus in 73 7- to 9-year-old preadolescent children. Indeed, aerobic fitness was found to relate to greater perfusion in the hippocampus, independent of age, sex, and hippocampal volume. Such results suggest improved microcirculation and cerebral vasculature in preadolescent children with higher levels of aerobic fitness. Further, aerobic fitness may influence how the brain regulates its metabolic demands via blood flow in a region of the brain important for learning and memory. To add specificity to the relationship of fitness to the hippocampus, we demonstrate no significant association between aerobic fitness and cerebral blood flow in the brainstem. Our results reinforce the importance of aerobic fitness during a critical period of child development.

Developmental trajectories of cerebral blood flow and oxidative metabolism at baseline and during working memory tasks

The neurobiological interpretation of developmental BOLD fMRI findings remains difficult due to the confounding issues of potentially varied baseline of brain function and varied strength of neurovascular coupling across age groups. The central theme of the present research is to study the development of brain function and neuronal activity through in vivo assessments of cerebral blood flow (CBF), oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2) both at baseline and during the performance of a working memory task in a cohort of typically developing children aged 7 to 18years. Using a suite of 4 emerging MRI technologies including MR blood oximetry, phase-contrast MRI, pseudo-continuous arterial spin labeling (pCASL) perfusion MRI and concurrent CBF/BOLD fMRI, we found: 1) At baseline, both global CBF and CMRO2 showed an age related decline while global OEF was stable across the age group; 2) During the working memory task, neither BOLD nor CBF responses showed significant variations with age in the activated fronto-parietal brain regions. Nevertheless, detailed voxel-wise analyses revealed sub-regions within the activated fronto-parietal regions that show significant decline of fractional CMRO2 responses with age. These findings suggest that the brain may become more “energy efficient” with age during development.

Abstract WP57: ASL MR Perfusion Imaging Detects Collateral Blood Flow Patterns and Dynamic Changes After Treatment in Acute Ischemic Stroke

Introduction: Vessel-encoded arterial spin labeling (ASL) perfusion MRI is a new non-invasive method that is able to assess collateral blood flow and the perfusion territories of the brain feeding arteries. Hypothesis: Collateral blood flow imaging with ASL MRI is feasible in acute stroke patients and can be used to study the relationship between infarct location, perfusion territories and collateral patterns, together with dynamic changes after treatment. Method: Consecutive acute stroke patients were imaged within 24 hours of onset. Follow-up imaging was performed at discharge and/or 30 days to assess changes in vascular distribution and final infarct size. The imaging protocol contained a vessel-encoded pseudo-continuous ASL, DWI and MRA sequence. Results: Twenty stroke patients were included (NIHSS, 10; range, 0-23). Twelve patients were treated with tPA and 3 with additional endovascular therapy. Median time from initial imaging to follow-up was 25 days (range, 3-36). 80% of the exams were interpretable. Thirteen subjects (70%) had an ischemic lesion within the expected perfusion territory; 12 within the internal carotid artery (ICA) territory and 3 from basilar artery. In 5 patients (25%), the infarct zone was fed through collateral pathways. Figure A demonstrates a patient with a left ICA occlusion and collateral flow through the anterior and posterior-communicating artery. In 2 of the 5 patients with collaterals there was a shift in the vascular distribution at FU with decline of collateralisation. Figure B shows a patient with a right-sided ICA dissection directly post endovascular therapy with collateral flow from the basilar artery and normalization of the vascular distribution after 30 days. Conclusion: ASL can access perfusion territories and collateral blood flow in acute stroke. It may potentially be used to identify brain tissue without adequate collateral blood flow and stratify patients suitable for appropriate (endovascular) therapy.

Perfusion magnetic resonance imaging provides additional information as compared to anatomical imaging for decision-making in vestibular schwannoma

ObjectiveThe added value of perfusion MRI for decision-making in vestibular schwannoma (VS) patients is unknown. MRI offers two perfusion methods: the first employing contrast agent (dynamic susceptibility contrast (DSC)-MRI) that provides information on cerebral blood volume (CBV) and cerebral blood flow (CBF), the second by magnetic labeling of blood (arterial spin labeling (ASL)-MRI), providing CBF-images. The goal of the current study is to investigate whether DSC and ASL perfusion MRI provides complimentary information to current anatomical imaging in treatment selection process of VS. MethodsNine patients with growing VS with extrameatal diameter >9mm were included (>2mm/year and 20% volume expansion/year) and one patient with 23mm extrameatal VS without growth. DSC and ASL perfusion MRI were obtained on 3T MRI. Perfusion in VS was scored as hyperintense, hypointense or isointense compared to the contralateral region. ResultsSeven patients showed hyperintense signal on DSC and ASL sequences. Three patients showed iso- or hypointense signal on at least one perfusion map (1 patient hypointense on both DSC-MRI and ASL; 1 patient isointense on DSC-CBF; 1 patient isointense on ASL). All patients showed enhancement on post-contrast T1 anatomical scan. ConclusionPerfusion MR provides additional information compared to anatomical imaging for decision-making in VS.

Quantifying fluctuations of resting state networks using arterial spin labeling perfusion MRI

Blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) has been widely used to investigate spontaneous low-frequency signal fluctuations across brain resting state networks. However, BOLD only provides relative measures of signal fluctuations. Arterial Spin Labeling (ASL) MRI holds great potential for quantitative measurements of resting state network fluctuations. This study systematically quantified signal fluctuations of the large-scale resting state networks using ASL data from 20 healthy volunteers by separating them from global signal fluctuations and fluctuations caused by residual noise. Global ASL signal fluctuation was 7.59% ± 1.47% relative to the ASL baseline perfusion. Fluctuations of seven detected resting state networks vary from 2.96% ± 0.93% to 6.71% ± 2.35%. Fluctuations of networks and residual noise were 6.05% ± 1.18% and 6.78% ± 1.16% using 4-mm resolution ASL data applied with Gaussian smoothing kernel of 6mm. However, network fluctuations were reduced by 7.77% ± 1.56% while residual noise fluctuation was markedly reduced by 39.75% ± 2.90% when smoothing kernel of 12 mm was applied to the ASL data. Therefore, global and network fluctuations are the dominant structured noise sources in ASL data. Quantitative measurements of resting state networks may enable improved noise reduction and provide insights into the function of healthy and diseased brain.

Amygdala on the Lookout.

results present an explanatory challenge: why would the amygdala be hypoactive in paranoid individuals who exhibit heightened threat perception and elevated physiological arousal? To explain this paradoxical finding, some investigators hypothesized that reduced frontal control over the amygdala due to dysconnectivity of frontolimbic circuitry could lead to hypervigilanceand misattribution of fear to incoming signals (3). AnotherpossibilityisthatmethodologicallimitationsofBOLD fMRI have obstructed a more accurate quantification of amygdala activity. In this issue of the Journal, a new study conducted by Pinkham and colleagues (5) offers a methodological explanation for discrepant findings concerning aberrant amygdala activity in paranoid schizophrenia. The authors definitively demonstrate higher baseline amygdala activity in paranoid compared with nonparanoid patients with schizophrenia, by employing arterial spin labeling perfusion MRI. Arterial spin labeling allows for a noninvasive and quantitative measurement of regional cerebral blood flow (CBF) by using magneticallylabeledarterialbloodwaterasanendogenoustracer (asopposedtoexogenousradioactivetracersusedinpositron emission tomography) (6). There are both important methodological and conceptual advances here worthy of note. In addition to arterial spin labeling, the authors acquired BOLD fMRI data while participants rated photographs of faces for trustworthiness. By measuring resting state regional CBF and task-related BOLD activity in the same participants, the authors were able to examine group differences in baseline amygdala activity alongside differences in task-related fluctuations of amygdalaactivity.Suchcomparisonsareparticularlyrelevant to schizophrenia, as prior evidence of amygdala hypoactivation relied on BOLD contrasts blind to potential group differences in baseline activity. Indeed, Pinkham and colleagues found that acutely paranoid patients exhibited higher resting CBF in the bilateral amygdala compared with nonparanoid patients and healthy comparison subjects, who did not differ from each other. On the other hand, the BOLD fMRI task analysis revealed a general trend of amygdala hypoactivation in paranoid compared with nonparanoid participants. Thus, observed taskrelated amygdala hypoactivity likely reflects higher baseline amygdala activity that mitigates the stimulus-driven signal change detected by the BOLD contrast. Additional wholebrain group comparisons found greater CBF in the internal capsule, the corpus callosum, and portions of the inferior temporal and fusiform gyri in paranoid compared with nonparanoid patients. Overall, these results suggest that paranoia

Pharmacologically-induced neurovascular uncoupling is associated with cognitive impairment in mice.

There is increasing evidence that vascular risk factors, including aging, hypertension, diabetes mellitus, and obesity, promote cognitive impairment; however, the underlying mechanisms remain obscure. Cerebral blood flow (CBF) is adjusted to neuronal activity via neurovascular coupling (NVC) and this mechanism is known to be impaired in the aforementioned pathophysiologic conditions. To establish a direct relationship between impaired NVC and cognitive decline, we induced neurovascular uncoupling pharmacologically in mice by inhibiting the synthesis of vasodilator mediators involved in NVC. Treatment of mice with the epoxygenase inhibitor N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (MSPPOH), the NO synthase inhibitor l-NG-Nitroarginine methyl ester (L-NAME), and the COX inhibitor indomethacin decreased NVC by over 60% mimicking the aging phenotype, which was associated with significantly impaired spatial working memory (Y-maze), recognition memory (Novel object recognition), and impairment in motor coordination (Rotarod). Blood pressure (tail cuff) and basal cerebral perfusion (arterial spin labeling perfusion MRI) were unaffected. Thus, selective experimental disruption of NVC is associated with significant impairment of cognitive and sensorimotor function, recapitulating neurologic symptoms and signs observed in brain aging and pathophysiologic conditions associated with accelerated cerebromicrovascular aging.

Experimental Neurovascular Uncoupling Promotes Cognitive Impairment in Mice: Implications for Brain and Cerebromicrovascular Aging

There is increasing evidence that vascular risk factors, including aging, hypertension, diabetes mellitus and obesity, promote cognitive impairment, however, the underlying mechanisms remain obscure. Cerebral blood flow (CBF) is adjusted to neuronal activity via neurovascular coupling (NVC) and this mechanism is known to be impaired in the aforementioned pathophysiological conditions. To establish a direct, causal relation between impaired NVC and cognitive decline, we induced neurovascular uncoupling pharmacologically in mice by inhibiting the synthesis of vasodilator mediators involved in NVC. Treatment of mice with the epoxygenase inhibitor MS-PPOH, the NOS inhibitor L-NAME and the COX inhibitor indomethacin decreased NVC by 75% mimicking the aging phenotype, which was associated with significantly impaired spatial working memory (Y-maze), recognition memory (Novel object recognition) and impairment in motor coordination (Rotarod). Blood pressure (tail cuff), basal cerebral perfusion (arterial spin labeling perfusion MRI) and synaptic activity (evoked field potential) were unaffected. Thus, targeted experimental disruption of NVC per se leads to significant impairment of cortical function, including cognitive decline, recapitulating neurological symptoms and signs observed in brain aging and pathophysiological conditions associated with accelerated cerebromicrovascular aging.

Amygdala Hyperactivity at Rest in Paranoid Individuals With Schizophrenia.

The amygdala's role in threat perception suggests that increased activation of this region may be related to paranoid ideation. However, investigations of amygdala function in paranoid individuals with schizophrenia, compared with both healthy individuals and nonparanoid individuals with schizophrenia, have consistently reported reduced task-related activation. The reliance of blood-oxygen-level-dependent functional MRI on a contrast between events and baseline, and the inability to quantitatively measure this baseline, may account for these counterintuitive findings. The present study tested for differences in baseline levels of amygdala activity in paranoid and nonparanoid individuals with schizophrenia using arterial spin labeling perfusion MRI. Resting cerebral blood flow (CBF) and task-related activation of the amygdala were measured in 25 healthy individuals, 16 individuals with schizophrenia who were actively paranoid at the time of scanning, and 16 individuals with schizophrenia who were not paranoid. Analysis of relative CBF values extracted from the amygdala bilaterally revealed significantly increased activity in the left amygdala in paranoid patient volunteers compared with healthy comparison subjects and nonparanoid patient volunteers. Increased CBF was also evident in the right amygdala but did not reach the level of statistical significance. Paranoid volunteers also showed significantly decreased task-related activation of the amygdala compared with the two other groups. These findings suggest that amygdala hyperactivation may underlie paranoia in schizophrenia. Additionally, the reported differences between paranoid and nonparanoid patient volunteers emphasize the importance of considering symptom-based subgroups and baseline levels of activity in future investigations of neural activation in schizophrenia.