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Brain vascular health worsens with age, as is made evident by resting grey matter cerebral blood flow (CBF GM ) reductions and lengthening arterial transit time (ATT GM ). Exercise training can improve aspects of brain health in older adults, yet its effects on CBF GM and ATT GM remain unclear. This randomised controlled trial assessed responses of CBF GM and ATT GM to a 26 week exercise intervention in 65 healthy older adults (control: n = 33, exercise: n = 32, aged 60-81 years), including whether changes in CBF GM or ATT GM were associated with changes in cognitive functions. Multiple-delay pseudo-continuous arterial spin labelling data were used to estimate resting global and regional CBF GM and ATT GM . Results showed no between-group differences in CBF GM or ATT GM following the intervention. However, exercise participants with the greatest cardiorespiratory gains (n = 17; ∆V̇O 2peak >2 mL/kg/min) experienced global CBF GM reductions (-4.0 [-7.3, -0.8] mL/100 g/min). Cognitive functions did not change in either group and changes were not associated with changes in CBF GM or ATT GM . Our findings indicate that exercise training in older adults may induce global CBF GM reductions when high cardiorespiratory fitness gains are induced, but this does not appear to affect cognitive functions., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Katrien Segaert reports financial support was provided by the Research Council of Norway. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: One possible contributing factor for cerebral blood flow (CBF) decline in normal aging is the increase in partial volume effects due to brain atrophy, as cortical thinning can exacerbate the contamination of gray-matter (GM) voxels by other tissue types. This work investigates CBF changes in normal aging of a large elderly cohort aged 54 to 84 and how correction for partial volume effects that would accommodate potential changes in GM might affect this., Methods: The study cohort consisted of 474 participants aged 54 to 84 years using pseudo-continuous arterial spin labeling MRI. A volumetric pipeline and a surface-based pipeline were applied to measure global and regional perfusion. Volumetric regions of interest (ROIs) included GM, cerebral white matter, vascular territories, and the brain atlas from the UK Biobank. The cortical parcellation was using Desikan-Killiany atlas. Non-partial volume effect correction (PVEc) and PVEc GM-CBF changes with aging were modeled using linear regressions., Results: Global GM CBF decreased by 0.17 mL/100 g/min per year with aging before PVEc (p < 0.05) and was 0.18 mL/100 g/min after PVEc (p < 0.05). All cortical parcels exhibited CBF decreases with age before PVEc. After PVEc, seven parcels retained decreasing trends. However, GM CBF demonstrated increase with age after PVEc in three parcels., Conclusion: Although decreases in global perfusion are observed with aging before PVEc, perfusion variations appear to be more regionally selective after PVEc. This supports the understanding that variation in cerebral perfusion with age observed with imaging is influenced by regional changes in anatomy that can be accommodated with PVEc, but perfusion variation is still observable even after PVE is accounted for., (© 2024 The Author(s). Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Background: Vascular degeneration is an important cause of brain damage in aging. Assessing the functional properties of the cerebral vascular system may aid early diagnosis and prevention., Purpose: To investigate the relationships between potential vascular functional markers and vascular risks, brain parenchymal damage, and cognition., Study Type: Retrospective., Subjects: Two hundred two general community subjects (42-80 years, males/females: 127/75)., Field Strength/sequence: 3 T, spin echo T1W/T2W/FLAIR, resting-state functional MRI with an echo-planar sequence (rsfMRI), pseudo-continuous arterial spin labeling (pCASL) with a three-dimensional gradient-spin echo sequence., Assessment: Cerebral blood flow (CBF) in gray matter calculated using pCASL, blood transit times calculated using rsfMRI, and the SD of internal carotid arteries signal (ICA std ) calculated using rsfMRI; visual assessment for lacunes; quantification of white matter hyperintensity volume; permutation test for quality control; collection of demographic and clinical data, Montreal Cognitive Assessment, Mini-Mental State Examination., Statistical Tests: Kolmogorov-Smirnov test; Spearman rank correlation analysis; Multivariable linear regression analysis controlling for covariates; The level of statistical significance was set at P < 0.05., Results: Age was negatively associated with ICA std (β = -0.180). Diabetes was associated with longer blood transit time from large arteries to capillary bed (β = 0.185, adjusted for age, sex, and intracranial volume). Larger ICA std was associated with less presence of lacunes (odds ratio: 0.418, adjusted for age and sex). Higher gray matter CBF (β = 0.154) and larger ICA std (β = 0.136) were associated with better MoCA scores (adjusted for age, sex, and education)., Data Conclusion: Prolonged blood transit time, decreased ICA std , and diminished CBF were associated with vascular dysfunction and cognitive impairment. They may serve as vascular functional markers in future studies., Evidence Level: 3 TECHNICAL EFFICACY: Stage 3., (© 2024 International Society for Magnetic Resonance in Medicine.)

Cerebrovascular and neurological diseases exhibit sex-specific patterns in prevalence, severity, and regional specificity, some of which are associated with altered cerebral blood flow (CBF). Females often exhibit higher resting CBF, but understanding the impact of sex per se on CBF is hampered by study variability in age, comorbidities, medications, and control for menstrual cycle or hormone therapies. A majority of studies report whole brain CBF without differentiating between gray and white matter or without assessing regional CBF. Thus fundamental sex differences in regional or whole brain CBF remain unclarified. While controlling for the above confounders, we tested the hypothesis that females will exhibit higher total gray and white matter perfusion as well as regional gray matter perfusion. Adults 18-30 yr old (females = 22 and males = 26) were studied using arterial spin labeling (ASL) magnetic resonance imaging (MRI) scans followed by computational anatomy toolbox (CAT12) analysis in statistical parametric mapping (SPM12) to quantify CBF relative to brain volume. Females displayed 40% higher perfusion globally (females = 62 ± 9 and males = 45 ± 10 mL/100 g/min, P < 0.001), gray matter (females = 75 ± 11 and males = 54 ± 12 mL/100 g/min, P < 0.001), and white matter (females = 44 ± 6 and males = 32 ± 7 mL/100 g/min, P < 0.001). Females exhibited greater perfusion than males in 67 of the 68 regions tested, ranging from 14% to 66% higher. A second MRI approach (4-dimensional flow) focused on large arteries confirmed the sex difference in global CBF. These data indicate strikingly higher basal CBF in females at global, gray, and white matter levels and across dozens of brain regions and offer new clarity into fundamental sex differences in global and regional CBF regulation before aging or pathology. NEW & NOTEWORTHY MRI used to measure cerebral blood flow (CBF) in gray matter, white matter, and 68 regions in healthy men and women. This study demonstrated that CBF is 40% higher in women, the highest sex difference reported, when controlling for numerous important clinical confounders like age, smoking, menstrual cycle, comorbidities, and medications.

How do regional brain volume ratios and cerebral blood flow (CBF, mL/min) change with aging, and are there sex differences? This study aimed to comprehensively evaluate the relationships between regional brain volume ratios and CBF in healthy brains. The study participants were healthy volunteers who underwent three-dimensional T1-weighted MRI, time-of-flight MR angiography, and four-dimensional (4D) flow MRI between 2020 and 2022. The brain was automatically segmented into 21 brain subregions from 3D T1-weighted MRI, and CBF in 16 major intracranial arteries were measured by 4D flow MRI. The relationships between segmented brain volume ratios and CBFs around the circle of Willis were comprehensively investigated in each decade and sex. This study included 129 healthy volunteers (mean age ± SD, 48.2 ± 16.8; range, 22-92 years; 43 males and 86 females). The association was strongest between the cortical gray matter volume ratio and total outflow of the intracranial major arteries distal to the circle of Willis (Pearson's correlation coefficient, r: 0.425). In addition, the mean flow of the total inflow and outflow around the circle of Willis were significantly greater in women than men, and significant left-right differences were observed in CBFs even on the peripheral side of the circle of Willis. Moreover, the correlation was strongest between the left cortical gray matter volume ratio and the combined flows of the left anterior and posterior cerebral arteries distal to the circle of Willis (r: 0.486). There was a trend toward greater total intracranial CBF, especially among women in their 40s and younger, who had a larger cortical gray matter volume. This finding may be one of the reasons for the approximately twofold higher incidence of cerebral aneurysms and subarachnoid hemorrhage, and a threefold higher incidence of migraine headaches.

Cerebral blood flow (CBF) and arterial transit time (ATT), markers of brain vascular health, worsen with age. The primary aim of this cross-sectional study was to identify modifiable determinants of CBF and ATT in healthy older adults ( n = 78, aged 60-81 years). Associations between cardiorespiratory fitness and CBF or ATT were of particular interest because the impact of cardiorespiratory fitness is not clear within existing literature. Secondly, this study assessed whether CBF or ATT relate to cognitive function in older adults. Multiple post-labelling delay pseudo-continuous arterial spin labelling estimated resting CBF and ATT in grey matter. Results from multiple linear regressions found higher BMI was associated with lower global CBF (β = -0.35, P = 0.008) and a longer global ATT (β = 0.30, P = 0.017), global ATT lengthened with increasing age (β = 0.43, P = 0.004), and higher cardiorespiratory fitness was associated with longer ATT in parietal (β = 0.44, P = 0.004) and occipital (β = 0.45, P = 0.003) regions. Global or regional CBF or ATT were not associated with processing speed, working memory, or attention. In conclusion, preventing excessive weight gain may help attenuate age-related declines in brain vascular health. ATT may be more sensitive to age-related decline than CBF, and therefore useful for early detection and management of cerebrovascular impairment. Finally, cardiorespiratory fitness appears to have little effect on CBF but may induce longer ATT in specific regions.

Background and Objectives: Neuroimaging studies in patients with temporal lobe epilepsy (TLE) show widespread brain network alterations beyond the mesiotemporal lobe. Despite the critical role of the cerebrovascular system in maintaining whole-brain structure and function, changes in cerebral blood flow (CBF) remain incompletely understood in the disease. Here, we studied whole-brain perfusion and vascular network alterations in TLE and assessed its associations with gray and white matter compromises and various clinical variables., Methods: We included individuals with and without pharmaco-resistant TLE who underwent multimodal 3T MRI, including arterial spin labelling, structural, and diffusion-weighted imaging. Using surface-based MRI mapping, we generated individualized cortico-subcortical profiles of perfusion, morphology, and microstructure. Linear models compared regional CBF in patients with controls and related alterations to morphological and microstructural metrics. We further probed interregional vascular networks in TLE, using graph theoretical CBF covariance analysis. The effects of disease duration were explored to better understand the progressive changes in perfusion. We assessed the utility of perfusion in separating patients with TLE from controls using supervised machine learning., Results: Compared with control participants (n = 38; mean ± SD age 34.8 ± 9.3 years; 20 females), patients with TLE (n = 24; mean ± SD age 35.8 ± 10.6 years; 12 females) showed widespread CBF reductions predominantly in fronto-temporal regions (Cohen d -0.69, 95% CI -1.21 to -0.16), consistent in a subgroup of patients who remained seizure-free after surgical resection of the seizure focus. Parallel structural profiling and network-based models showed that cerebral hypoperfusion may be partially constrained by gray and white matter changes (8.11% reduction in Cohen d ) and topologically segregated from whole-brain perfusion networks (area under the curve -0.17, p < 0.05). Negative effects of progressive disease duration further targeted regional CBF profiles in patients ( r = -0.54, 95% CI -0.77 to -0.16). Perfusion-derived classifiers discriminated patients from controls with high accuracy (71% [70%-82%]). Findings were robust when controlling for several methodological confounds., Discussion: Our multimodal findings provide insights into vascular contributions to TLE pathophysiology affecting and extending beyond mesiotemporal structures and highlight their clinical potential in epilepsy diagnosis. As our work was cross-sectional and based on a single site, it motivates future longitudinal studies to confirm progressive effects, ideally in a multicentric setting.

Reduced cerebral blood flow (CBF) in the temporoparietal region and gray matter volumes (GMVs) in the temporal lobe were previously reported in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). However, the temporal relationship between reductions in CBF and GMVs requires further investigation. This study sought to determine if reduced CBF is associated with reduced GMVs, or vice versa. Data came from 148 volunteers of the Cardiovascular Health Study Cognition Study (CHS-CS), including 58 normal controls (NC), 50 MCI, and 40 AD who had perfusion and structural MRIs during 2002-2003 (Time 2). Sixty-three of the 148 volunteers had follow-up perfusion and structural MRIs (Time 3). Forty out of the 63 volunteers received prior structural MRIs during 1997-1999 (Time 1). The relationships between GMVs and subsequent CBF changes, and between CBF and subsequent GMV changes were investigated. At Time 2, we observed smaller GMVs (p<0.05) in the temporal pole region in AD compared to NC and MCI. We also found associations between: (1) temporal pole GMVs at Time 2 and subsequent declines in CBF in this region (p=0.0014) and in the temporoparietal region (p=0.0032); (2) hippocampal GMVs at Time 2 and subsequent declines in CBF in the temporoparietal region (p=0.012); and (3) temporal pole CBF at Time 2 and subsequent changes in GMV in this region (p = 0.011). Therefore, hypoperfusion in the temporal pole may be an early event driving its atrophy. Perfusion declines in the temporoparietal and temporal pole follow atrophy in this temporal pole region.

We investigated the reduction in regional brain volume and cerebral blood flow (CBF) with aging and explored potential sex differences in healthy brains. Three-dimensional (3D) T1-weighted magnetic resonance imaging (MRI), time-of-flight magnetic resonance angiography, and four-dimensional (4D) flow MRI were performed on 129 healthy volunteers aged 22-92 years. The brains of healthy volunteers were segmented into 21 subregions using 3D T1-weighted MRI and CBFs in 16 major intracranial arteries were measured using 4D flow MRI. The cortical gray matter volume decreased linearly with aging, whereas the cerebral white matter volume increased until the 40s and then decreased, and the subcortical gray matter volume changed little with aging. The cortical gray matter volume was significantly associated with the total CBF of the major intracranial arteries distal to the circle of Willis; however, the cerebral white matter and subcortical gray matter volumes were not. Generally, women have higher total CBF than men, particularly in their 40s and younger, despite the smaller intracranial volume and smaller diameters of intracranial arteries than men. This may contribute to the higher incidence of subarachnoid hemorrhage due to cerebral aneurysms and migraine in women., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: A contrast agent-free approach would be preferable to the frequently used invasive approaches for evaluating cerebral perfusion in chronic migraineurs (CM). In this work, non-invasive quantitative volumetric perfusion imaging was used to evaluate alterations in cerebral perfusion in CM., Methods: We used conventional brain structural imaging sequences and 3D pseudo-continuous arterial spin labeling (3D PCASL) to examine thirteen CM patients and fifteen normal controls (NCs). The entire brain gray matter underwent voxel-based analysis, and the cerebral blood flow (CBF) values of the altered positive areas were retrieved to look into the clinical variables' significant correlation., Results: Brain regions with the decreased perfusion were located in the left postcentral gyrus, bilateral middle frontal gyrus, left middle occipital gyrus, left superior parietal lobule, left medial segment of superior frontal gyrus, and right orbital part of the inferior frontal gyrus. White matter fibers with decreased perfusion were located in bilateral superior longitudinal tracts, superior corona radiata, external capsules, anterior and posterior limbs of the internal capsule, anterior corona radiata, inferior longitudinal fasciculus, and right corticospinal tract. However, the correlation analysis showed no significant correlation between the CBF value of the above positive brain regions with clinical variables (p > 0.05)., Conclusion: The current study provided more useful information to comprehend the pathophysiology of CM and revealed a new insight into the neural mechanism of CM from the pattern of cerebral hypoperfusion., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objectives: To determine the relationship between systemic arterial blood flow (SABF) and cerebral perfusion measures in multiple sclerosis (MS) patients., Methods: Cerebral perfusion and SABF were assessed in 118 patients (75 clinically isolated syndrome (CIS)/relapsing-remitting MS and 43 progressive MS) through MRI examination with dynamic susceptibility contrast perfusion-weighted imaging (DSC-PWI) and Doppler ultrasound, respectively. Measures of mean transit time (MTT) and time-to-peak (TTP), measured in seconds, of the normal-appearing whole brain (NAWB) and gray matter (GM) were calculated. Blood flow through the bilateral common carotid and vertebral arteries (in mL/min) represents the SABF. Whole brain volume (WBV) and body mass index (BMI) were used as additional covariates., Results: Higher systolic blood pressure was associated with lower SABF (-0.256, p = 0.006). In the total MS sample, higher SABF was associated with shorter MTT and TTP of the NAWB (r = -0.256, p = 0.007 and r = -0.307, p = 0.001) and GM (r = -0.239, p = 0.012 and r = -0.3, p = 0.001). The SABF and TTP associations were driven by the PMS patients (r = -0.451, p = 0.004 and r = -0.451, p = 0.011). Only in PMS, SABF remained a significant predictor of NAWB (standardized β = -0.394, p = 0.022) and GM TTP (standardized β = -0.351, p = 0.037). MTT and TTP were significantly lower in patients within lower SABF quartiles when compared to the higher quartiles (age-, sex-, BMI-, and WBV-adjusted ANCOVA p < 0.025)., Conclusions: The direct relationship between systemic and cerebral blood flow seen in PMS patients may suggest failure in cerebrovascular reactivity mechanisms and insufficient perfusion control. Cerebral blood flow in PMS may be increasingly dependent on the SABF., Key Points: • In progressive multiple sclerosis (MS) patients, the systemic arterial blood flow (SABF) is associated with perfusion-based measure of time-to-peak (TTP) of the normal-appearing whole brain (r = -0.451, p = 0.004) and gray matter (r = -0.451, p = 0.004). • Cerebral blood flow in progressive MS is directly dependent on systemic arterial blood flow and may be influenced by blood pressure changes. • Neurovascular unit impairment may play an important role in MS pathophysiology and contribute towards greater clinical disability., (© 2022. The Author(s), under exclusive licence to European Society of Radiology.)

This study examined the associations of body mass index (BMI), waist-to-hip ratio (WHR), waist circumference (WC), and physical activity (PA) with gray matter cerebral blood flow (CBF GM ) in older adults. Cross-sectional data was used from the Irish Longitudinal Study on Ageing (n = 495, age 69.0 ±7.4 years, 52.1% female). Whole-brain CBF GM was quantified using arterial spin labeling MRI. Results from multivariable regression analysis revealed that an increase in BMI of 0.43 kg/m 2 , WHR of 0.01, or WC of 1.3 cm were associated with the same reduction in CBF GM as 1 year of advancing age. Participants overweight by BMI or with high WHR/WC reporting low/moderate PA had up to 3 ml/100g/min lower CBF GM (p ≤ .011); there was no significant reduction for those reporting high PA. Since PA could potentially moderate obesity/CBF associations, this may be a cost-effective and relatively easy way to help mitigate the negative impact of obesity in an older population, such as cerebral hypoperfusion, which is an early mechanism in vascular dementia and Alzheimer's disease., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

VO 2 max (maximal oxygen consumption), a validated measure of aerobic fitness, has been associated with better cerebral artery compliance and measures of brain morphology, such as higher cortical thickness (CT) in frontal, temporal and cingular cortices, and larger grey matter volume (GMV) of the middle temporal gyrus, hippocampus, orbitofrontal cortex and cingulate cortex. Single sessions of physical exercise can promptly enhance cognitive performance and brain activity during executive tasks. However, the immediate effects of exercise on macro-scale properties of the brain's grey matter remain unclear. We investigated the impact of one session of moderate-intensity physical exercise, compared with rest, on grey matter volume, cortical thickness, working memory performance, and task-related brain activity in older adults. Cross-sectional associations between brain measures and VO 2 max were also tested. Exercise did not induce statistically significant changes in brain activity, grey matter volume, or cortical thickness. Cardiovascular fitness, measured by VO 2 max, was associated with lower grey matter blood flow in the left hippocampus and thicker cortex in the left superior temporal gyrus. Cortical thickness was reduced at post-test independent of exercise/rest. Our findings support that (1) fitter individuals may need lower grey matter blood flow to meet metabolic oxygen demand, and (2) have thicker cortex., (© 2021. The Author(s).)

Objective: To establish normative reference values for total grey matter cerebral blood flow (CBF GM ) measured using pseudo-continuous arterial spin labelling (pCASL) MRI in a large cohort of community-dwelling adults aged 54 years and older., Background: Quantitative assessment of CBF GM may provide an imaging biomarker for the early detection of those at risk of neurodegenerative diseases, such as Alzheimer's and dementia. However, the use of this method to differentiate normal age-related decline in CBF GM from pathological reduction has been hampered by the lack of reference values for cerebral perfusion., Methods: The study cohort comprised a subset of wave 3 (2014-2015) participants from The Irish Longitudinal Study on Ageing (TILDA), a large-scale prospective cohort study of individuals aged 50 and over. Of 4309 participants attending for health centre assessment, 578 individuals returned for 3T multi-parametric MRI brain examinations. In total, CBF GM data acquired from 468 subjects using pCASL-MRI were included in this analysis. Normative values were estimated using Generalised Additive Models for Location Shape and Scale (GAMLSS) and are presented as percentiles, means and standard deviations., Results: The mean age of the cohort was 68.2 ± 6.9 years and 51.7% were female. Mean CBF GM for the cohort was 36.5 ± 8.2 ml/100 g/min. CBF GM decreased by 0.2 ml/100 g/min for each year increase in age (95% CI = -0.3, -0.1; p ≤ 0.001) and was 3.1 ml/100 g/min higher in females (95% CI = 1.6, 4.5; p ≤ 0.001)., Conclusions: This study is by far the largest single-site study focused on an elderly community-dwelling cohort to present normative reference values for CBF GM measured at 3T using pCASL-MRI. Significant age- and sex-related differences exist in CBF GM ., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021. Published by Elsevier Inc.)

The human blood-brain barrier (BBB) transporter P-gp can efflux amyloid-β (Aβ) out of the central nervous system (CNS). Aβ is thought to be the causative agent for Alzheimer's disease (AD). Using positron emission tomography imaging, we have shown that BBB P-gp activity is reduced in AD, as quantified by the in vivo brain distribution of the P-gp probe [ 11 C]-verapamil. Therefore, the aim of this study was to determine whether this reduced BBB P-gp activity in AD was due to decreased P-gp abundance at the BBB. Using targeted proteomics, we quantified the abundance of P-gp and other drug transporters in gray matter brain microvessels isolated from 43 subjects with AD and 38 age-matched controls (AMCs) from regions affected by AD (hippocampus and the parietal lobe of the brain cortex) and not affected by AD (cerebellum). First, P-gp abundance was decreased in the BBB of the hippocampus vs. the cerebellum in both subjects with AD and AMCs, and therefore was not AD-related. In addition, gray matter BBB abundance of P-gp (and of other transporters) in the hippocampus and the parietal lobe was not different between AD and AMC. The gray matter BBB abundance of all drug transporters decreased with age, likely due to age-dependent decrease in the density of brain microvessels. Collectively, the observed reduced in vivo cerebral BBB P-gp activity in AD cannot be explained by reduced abundance of P-gp at the BBB. Nevertheless, the drug transporter abundance at the human gray matter BBB data provided here can be used to predict brain distribution of drugs targeted to treat CNS diseases, including AD., (© 2020 The Authors Clinical Pharmacology & Therapeutics © 2020 American Society for Clinical Pharmacology and Therapeutics.)

Purpose: The long-term impact of low-grade germinal matrix-intraventricular hemorrhage (GMH-IVH) on brain perfusion has not been fully investigated. We aimed to compare cortical and deep gray matter (GM) cerebral blood flow (CBF) obtained with pseudo-continuous arterial spin labeling (pCASL), among preterm neonates with and without low-grade GMH-IVH and full-term controls., Methods: 3T-pCASL examinations of 9 healthy full-term neonates (mean gestational age 38.5 weeks, range 38-39) and 28 preterm neonates studied at term-equivalent age were analyzed. Eighteen preterm neonates presented normal brain MRI (mean gestational age 30.50 weeks, range 29-31) and 10 low-grade GMH-IVH according to Volpe's grading system (mean gestational age 32 weeks, range 28-34). A ROI-based mean CBF quantification was performed in 5 cortical (frontal, parietal, temporal, insula, occipital), and 4 subcortical GM regions (caudate, putamen, pallidum, thalamus) for each cerebral hemisphere. CBF differences were explored using a nonparametric analysis of covariance., Results: Low-grade GMH-IVH hemispheres showed consistently lower CBF in all GM regions when compared with healthy preterm neonates, after controlling the confounding effect of gestational age, postmenstrual age, and birth weight P < .001, η 2  = .394. No significant differences were observed between neonates with low-grade GMH and full-term controls. Healthy preterm neonates showed significantly higher CBF than full-term controls in parietal (P = .032), temporal (P = .016), and occipital cortex (P = .024), and at level of thalamus (P = .023) and caudate nucleus (P = .014)., Conclusion: Low-grade GMH-IVH is associated with lower CBF in posterior cortical and subcortical gray matter regions in preterm neonates, suggesting regional vulnerability of these developing brain structures.

Much attention has been paid to the effects of mild traumatic brain injury (mTBI) on cerebrovascular reactivity in adult populations, yet it remains understudied in pediatric injury. In this study, 30 adolescents (12-18 years old) with pediatric mTBI (pmTBI) and 35 age- and sex-matched healthy controls (HC) underwent clinical and neuroimaging assessments during sub-acute (6.9 ± 2.2 days) and early chronic (120.4 ± 11.7 days) phases of injury. Relative to controls, pmTBI reported greater initial post-concussion symptoms, headache, pain, and anxiety, resolving by four months post-injury. Patients reported increased sleep issues and exhibited deficits in processing speed and attention across both visits. In grey-white matter interface areas throughout the brain, pmTBI displayed increased maximal fit/amplitude of a time-shifted end-tidal CO 2 regressor to blood oxygen-level dependent response relative to HC, as well as increased latency to maximal fit. The alterations persisted through the early chronic phase of injury, with maximal fit being associated with complaints of ongoing sleep disturbances during post hoc analyses but not cognitive measures of processing speed or attention. Collectively, these findings suggest that deficits in the speed and degree of cerebrovascular reactivity may persist longer than current conceptualizations about clinical recovery within 30 days.

Herein, we report abdominal aortic thrombosis as a rare cause of acute spinal cord infarction. A 78-year-old man with multiple vascular risk factors developed acute paraplegia with sensory and urinary disturbances and signs of ischemia in both lower limbs. The post-mortem study done 3 days after the onset of symptoms revealed a large coagulum in the abdominal aorta, distal to the renal arteries and extending to bilateral common iliac arteries; in addition, marked atherosclerosis was present in most large blood vessels. Premature incomplete necrotic foci were seen in the ventral gray matter of the spinal cord from T6 through S5; the surrounding white matter and dorsal gray matter were spared. Considering our autopsy case, spinal cord gray matter may be more vulnerable to ischemia than the white matter., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Multi-post-labeling-delay pseudo-continuous arterial spin labeling (multi-PLD PCASL) allows for absolute quantification of the cerebral blood flow (CBF) as well as the arterial transit time (ATT). Estimating these perfusion parameters from multi-PLD PCASL data is a non-linear inverse problem, which is commonly tackled by fitting the single-compartment model (SCM) for PCASL, with CBF and ATT as free parameters. The longitudinal relaxation time of tissue T 1t is an important parameter in this model, as it governs the decay of the perfusion signal entirely upon entry in the imaging voxel. Conventionally, T 1t is fixed to a population average. This approach can cause CBF quantification errors, as T 1t can vary significantly inter- and intra-subject. This study compares the impact on CBF quantification, in terms of accuracy and precision, of either fixing T 1t , the conventional approach, or estimating it alongside CBF and ATT. It is shown that the conventional approach can cause a significant bias in CBF. Indeed, simulation experiments reveal that if T 1t is fixed to a value that is 10% off its true value, this may already result in a bias of 15% in CBF. On the other hand, as is shown by both simulation and real data experiments, estimating T 1t along with CBF and ATT results in a loss of CBF precision of the same order, even if the experiment design is optimized for the latter estimation problem. Simulation experiments suggest that an optimal balance between accuracy and precision of CBF estimation from multi-PLD PCASL data can be expected when using the two-parameter estimator with a fixed T 1t value between population averages of T 1t and the longitudinal relaxation time of blood T 1b ., (© 2019 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.)

Vessel loss in the aging brain is commonly reported, yet important questions remain concerning whether there are regional vulnerabilities and what mechanisms could account for these regional differences, if they exist. Here we imaged and quantified vessel length, tortuosity and width in 15 brain regions in young adult and aged mice. Our data indicate that vessel loss was most pronounced in white matter followed by cortical, then subcortical grey matter regions, while some regions (visual cortex, amygdala, thalamus) showed no decline with aging. Regions supplied by the anterior cerebral artery were more vulnerable to loss than those supplied by middle or posterior cerebral arteries. Vessel width and tortuosity generally increased with age but neither reliably predicted regional vessel loss. Since capillaries are naturally prone to plugging and prolonged obstructions often lead to vessel pruning, we hypothesized that regional susceptibilities to plugging could help predict vessel loss. By mapping the distribution of microsphere-induced capillary obstructions, we discovered that regions with a higher density of persistent obstructions were more likely to show vessel loss with aging and vice versa. These findings indicate that age-related vessel loss is region specific and can be explained, at least partially, by regional susceptibilities to capillary plugging.

The blood oxygen-level dependent (BOLD) functional magnetic resonance imaging (fMRI) signal depends on an interplay of cerebral blood flow (CBF), oxygen metabolism, and cerebral blood volume. Despite wide usage of BOLD fMRI, it is not clear how these physiological components create the BOLD signal. Here, baseline CBF and its dynamics evoked by a brief stimulus (2 s) in human visual cortex were measured at 3T. We found a stereotypical CBF response: immediate increase, rising to a peak a few second after the stimulus, followed by a significant undershoot. The BOLD hemodynamic response function (HRF) was also measured in the same session. Strong correlations between HRF and CBF peak responses indicate that the flow responses evoked by neural activation in nearby gray matter drive the early HRF. Remarkably, peak CBF and HRF were also strongly modulated by baseline perfusion. The CBF undershoot was reliable and significantly correlated with the HRF undershoot. However, late-time dynamics of the HRF and CBF suggest that oxygen metabolism can also contribute to the HRF undershoot. Combined measurement of the CBF and HRF for brief neural activation is a useful tool to understand the temporal dynamics of neurovascular and neurometabolic coupling.

Cardiorespiratory fitness is thought to have beneficial effects on systemic vascular health, in part, by decreasing arterial stiffness. However, in the absence of non-invasive methods, it remains unknown whether this effect extends to the cerebrovasculature. The present study uses a novel pulsed arterial spin labelling (pASL) technique to explore the relationship between cardiorespiratory fitness and arterial compliance of the middle cerebral arteries (MCAC). Other markers of cerebrovascular health, including resting cerebral blood flow (CBF) and cerebrovascular reactivity to CO 2 (CVR CO2 ) were also investigated. Eleven healthy males aged 21 ± 2 years with varying levels of cardiorespiratory fitness (maximal oxygen uptake ( V · O 2MAX ) 38-76 ml/min/kg) underwent MRI scanning at 3 Tesla. Higher V · O 2MAX was associated with greater MCAC (R 2  = 0.64, p  < 0.01) and lower resting grey matter CBF (R 2  = 0.75, p  < 0.01). However, V · O 2MAX was not predictive of global grey matter BOLD-based CVR (R 2  = 0.47, p  = 0.17) or CBF-based CVR (R 2  = 0.19, p  = 0.21). The current experiment builds upon the established benefits of exercise on arterial compliance in the systemic vasculature, by showing that increased cardiorespiratory fitness is associated with greater cerebral arterial compliance in early adulthood.

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 2 ) changes. Calibrated fMRI can disentangle the underlying contributions, allowing quantification of the CMRO 2 response. Here, whole-brain venous oxygen saturation ( Y v ) was computed alongside ASL-measured CBF and BOLD-weighted data to derive the calibration constant, M , using the proposed Y v -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 Y v via susceptometry-based oximetry) acquisitions while subjects breathed normocapnic/normoxic, hyperoxic, and hypercapnic gases, and during a motor task. M was computed via Y v -based calibration from both hypercapnia and hyperoxia stimulus data, and results were compared to conventional hypercapnia or hyperoxia calibration methods. Mean M 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 v -based calibration in response to hyperoxia), with hypercapnia-based M values between ( p  = 0.56). Relative CMRO 2 changes from finger tapping were computed from each M map. CMRO 2 increased by ∼20% in the motor cortex, and good agreement was observed between the conventional and proposed calibration methods.

Long-term exercise interventions have been shown to be a potent trigger for both neurogenesis and vascular plasticity. However, little is known about the underlying temporal dynamics and specifically when exercise-induced vascular adaptations first occur, which is vital for therapeutic applications. In this study, we investigated whether a single session of moderate-intensity exercise was sufficient to induce changes in the cerebral vasculature. We employed arterial spin labeling magnetic resonance imaging to measure global and regional cerebral blood flow (CBF) before and after 20 min of cycling. The blood vessels' ability to dilate, measured by cerebrovascular reactivity (CVR) to CO2 inhalation, was measured at baseline and 25-min postexercise. Our data showed that CBF was selectively increased by 10-12% in the hippocampus 15, 40, and 60 min after exercise cessation, whereas CVR to CO2 was unchanged in all regions. The absence of a corresponding change in hippocampal CVR suggests that the immediate and transient hippocampal adaptations observed after exercise are not driven by a mechanical vascular change and more likely represents an adaptive metabolic change, providing a framework for exploring the therapeutic potential of exercise-induced plasticity (neural, vascular, or both) in clinical and aged populations., (© The Author(s) 2019. Published by Oxford University Press.)

Medial temporal lobe dependent cognitive functions are highly vulnerable to hypoxia in the hippocampal region, yet little is known about the relationship between the richness of hippocampal vascular supply and cognition. Hippocampal vascularization patterns have been categorized into a mixed supply from both the posterior cerebral artery and the anterior choroidal artery or a single supply by the posterior cerebral artery only. Hippocampal arteries are small and affected by pathological changes when cerebral small vessel disease is present. We hypothesized, that hippocampal vascularization patterns may be important trait markers for vascular reserve and modulate (i) cognitive performance; (ii) structural hippocampal integrity; and (iii) the effect of cerebral small vessel disease on cognition. Using high-resolution 7 T time-of-flight angiography we manually classified hippocampal vascularization patterns in older adults with and without cerebral small vessel disease in vivo. The presence of a mixed supplied hippocampus was an advantage in several cognitive domains, including verbal list learning and global cognition. A mixed supplied hippocampus also was an advantage for verbal memory performance in cerebral small vessel disease. Voxel-based morphometry showed higher anterior hippocampal grey matter volume in mixed, compared to single supply. We discuss that a mixed hippocampal supply, as opposed to a single one, may increase the reliability of hippocampal blood supply and thereby provide a hippocampal vascular reserve that protects against cognitive impairment., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Neuropsychological tests, structural neuroimaging, and functional neuroimaging are employed as diagnostic and monitoring biomarkers of patients with Alzheimer's disease (AD)Objective:We aimed to elucidate the similarities and differences in neuropsychological tests and neuroimaging with the use of the Mini-Mental State Examination (MMSE), Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-cog), structural magnetic resonance image (MRI), and perfusion single photon emission computed tomography (SPECT), and parametric image analyses to understand its role in AD., Methods: Clinically-diagnosed AD patients (n = 155) were scanned with three-dimensional T1-weighted MRI and N-isopropyl-p-[123I] iodoamphetamine SPECT. Statistical parametric mapping 12 was used for preprocessing images, statistical analyses, and voxel-based morphometry for gray matter volume analyses. Group comparison (AD versus healthy controls), multiple regression analyses with MMSE, ADAS-cog total score, and ADAS-cog subscores as variables, were performed., Results: The AD group showed bilateral hippocampal volume reduction and hypoperfusion in the bilateral temporo-parietal lobe and posterior midline structures. Worse MMSE and ADAS-cog total score were associated with bilateral temporo-parietal volume loss and hypoperfusion. MMSE, but not ADAS-cog, was associated with the posterior midline structures. The ADAS-cog subscores were associated with the temporal volume, while perfusion analyses were linked to the left temporo-parietal region with the language function and right analogous region with the constructional praxis subscore., Conclusion: MMSE and ADAS-cog are associated with temporo-parietal regions, both in volume and perfusion. The MMSE score is associated with posterior midline structures and linked to an abnormal diagnostic AD pattern. Perfusion image analyses better represents the cognitive function in AD patients.

At very low diffusion weighting the diffusion MRI signal is affected by intravoxel incoherent motion (IVIM) caused by dephasing of magnetization due to incoherent blood flow in capillaries or other sources of microcirculation. While IVIM measurements at low diffusion weightings have been frequently used to investigate perfusion in the body as well as in malignant tissue, the effect and origin of IVIM in normal brain tissue is not completely established. We investigated the IVIM effect on the brain diffusion MRI signal in a cohort of 137 radiologically-normal patients (62 male; mean age = 50.2 ± 17.8, range = 18 to 94). We compared the diffusion tensor parameters estimated from a mono-exponential fit at b = 0 and 1000 s/mm 2 versus at b = 250 and 1000 s/mm 2 . The asymptotic fitting method allowed for quantitative assessment of the IVIM signal fraction f* in specific brain tissue and regions. Our results show a mean (median) percent difference in the mean diffusivity of about 4.5 (4.9)% in white matter (WM), about 7.8 (8.7)% in cortical gray matter (GM), and 4.3 (4.2)% in thalamus. Corresponding perfusion fraction f* was estimated to be 0.033 (0.032) in WM, 0.066 (0.065) in cortical GM, and 0.033 (0.030) in the thalamus. The effect of f* with respect to age was found to be significant in cortical GM (Pearson correlation ρ ​= ​0.35, p ​= ​3*10 -5 ) and the thalamus (Pearson correlation ρ = 0.20, p = 0.022) with an average increase in f* of 5.17*10 -4 /year and 3.61*10 -4 /year, respectively. Significant correlations between f* and age were not observed for WM, and corollary analysis revealed no effect of gender on f*. Possible origins of the IVIM effect in normal brain tissue are discussed., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Brain function, the brain's metabolic activity, cerebral blood flow (CBF), and intracranial pressure are intimately linked within the tightly autoregulated regime of intracranial physiology in which the role of tissue viscoelasticity remains elusive. We applied multifrequency magnetic resonance elastography (MRE) paired with CBF measurements in 14 healthy subjects exposed to 5-min carbon dioxide-enriched breathing air to induce cerebral vasodilatation by hypercapnia. Stiffness and viscosity as quantified by the magnitude and phase angle of the complex shear modulus, | G *| and ϕ , as well as CBF of the whole brain and 25 gray matter sub-regions were analyzed prior to, during, and after hypercapnia. In all subjects, whole-brain stiffness and viscosity increased due to hypercapnia by 3.3 ± 1.9% and 2.0 ± 1.1% which was accompanied by a CBF increase of 36 ± 15%. Post-hypercapnia, | G *| and ϕ reduced to normal values while CBF decreased by 13 ± 15% below baseline. Hypercapnia-induced viscosity changes correlated with CBF changes, whereas stiffness changes did not. The MRE-measured viscosity changes correlated with blood viscosity changes predicted by the Fåhræus-Lindqvist model and microvessel diameter changes from the literature. Our results suggest that brain viscoelastic properties are influenced by microvessel blood flow and blood viscosity: vasodilatation and increased blood viscosity due to hypercapnia result in an increase in MRE values related to viscosity.

The antiepileptic effect of ketogenic diets is acknowledged but its mechanism of action is poorly understood. The present work aimed to evaluate possible effects of a calorie-restricted ketogenic diet (CRKD) on brain growth and angiogenesis in normal prepubertal rats. Two groups of prepubertal rats were fed with a standard diet (group 1) or a CRKD (group 2) for ten weeks. Then, rats were sacrificed and the thickness for the following structures was evaluated by histology: (1) cerebral cortex, (2) deep cerebral white matter, and (3) substantia nigra. The capillary density was also evaluated within: (1) cerebral cortex, (2) dentate gyrus of the hippocampus, (3) periaqueductal grey matter, and (4) substantia nigra. The results showed a smaller thickness of all the areas examined and a reduced capillary density within the cerebral cortex in the CRKD-treated group compared to the control group. These findings suggest an association between reduced angiogenesis within the cerebral cortex and the antiepileptic effects of CRKD., Competing Interests: The authors declare no conflict of interest.

Functional magnetic resonance imaging (fMRI) is now capable of sub-millimetre scale measurements over the entire human brain, however with such high resolutions each voxel is influenced by the local fine-scale details of the cerebral cortical vascular anatomy. The cortical vasculature is structured with the pial vessels lying tangentially along the grey matter surface, intracortical diving arterioles and ascending venules running perpendicularly to the surface, and a randomly oriented capillary network within the parenchyma. It is well-known that the amplitude of the blood-oxygenation level dependent (BOLD) signal emanating from a vessel depends on its orientation relative to the B 0 -field. Thus the vascular geometric hierarchy will impart an orientation dependence to the BOLD signal amplitudes and amplitude differences due to orientation differences constitute a bias for interpreting neuronal activity. Here, we demonstrate a clear effect of cortical orientation to B 0 in the resting-state BOLD-fMRI amplitude (quantified as the coefficient of temporal signal variation) for 1.1 mm isotropic data at 7T and 2 mm isotropic at 3T. The maximum bias, i.e. the fluctuation amplitude difference between regions where cortex is perpendicular to vs. parallel to B 0 , is about +70% at the pial surface at 7T and +11% at 3T. The B 0 orientation bias declines with cortical depth, becomes progressively smaller closer to the white matter surface, but then increases again to a local maximum within the white matter just beneath the cortical grey matter, suggesting a distinct tangential network of white matter vessels that also generate a BOLD orientation effect. We further found significant (negative) biases with the cortex orientation to the anterior-posterior anatomical axis of the head: a maximum negative bias of about -30% at the pial surface at 7T and about -13% at 3T. The amount of signal variance explained by the low frequency drift, motion and the respiratory cycle also showed a cortical orientation dependence; only the cardiac cycle induced signal variance was independent of cortical orientation, suggesting that the cardiac induced component of the image time-series fluctuations is not related to a significant change in susceptibility. Although these orientation effects represent a signal bias, and are likely to be a nuisance in high-resolution analyses, they may help characterize the vascular influences on candidate fMRI acquisitions and, thereby, may be exploited to improve the neuronal specificity of fMRI., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background and Purpose- Hematoma location within the cerebellum may help identify the dominant small vessel disease type (cerebral amyloid angiopathy [CAA] versus nonamyloid small vessel disease). However, it is unknown whether this holds true for cerebral microbleeds (CMBs) within the cerebellum. We tested the hypothesis that cerebellar CMBs restricted to the cortex and vermis (defined as superficial regions) are associated with clinically diagnosed and pathology-verified CAA. Methods- Three hundred and seven consecutive spontaneous intracerebral hemorrhage (ICH) patients with a baseline magnetic resonance imaging that included susceptibility-weighted imaging or angiography were enrolled. Using a topographical template, cerebellar CMB patterns were defined as strictly superficial versus deep (cerebellar gray nuclei and white matter) or mixed (both regions involved). Thirty-six ICH patients with cerebellar CMBs and neuropathology data available were evaluated for the presence of CAA. Results- One hundred and thirty-five (44%) ICH patients had CMBs in the cerebellum. In the patient group with cerebellar CMBs, 85 (63%) showed a superficial pattern, and 50 (37%) had a deep/mixed pattern. Strictly superficial cerebellar CMBs were independently associated with a supratentorial pattern of probable CAA-ICH according to the Boston criteria (odds ratio, 1.6; CI, 1.03-2.5) and deep/mixed cerebellar CMBs with a pattern of deep/mixed ICH (odds ratio, 1.8; CI, 1.2-2.7). Pathologically verified CAA was present in 23 of 24 (96%) patients with superficial cerebellar CMBs versus 3 of 12 (25%) patients with deep/mixed cerebellar CMBs ( P<0.001). Conclusions- In ICH patients, cerebellar CMBs are relatively common and often restricted to superficial regions. A strictly superficial distribution of cerebellar CMBs is associated with clinically diagnosed and pathologically verified CAA.

Spreading depolarization (SD) is a self-propagating wave of near-complete neuronal depolarization that is abundant in a wide range of neurological conditions, including stroke. SD was only recently documented in humans and is now considered a therapeutic target for brain injury, but the mechanisms related to SD in complex brains are not well understood. While there are numerous approaches to interventional imaging of SD on the exposed brain surface, measuring SD deep in brain is so far only possible with low spatiotemporal resolution and poor contrast. Here, we show that photoacoustic imaging enables the study of SD and its hemodynamics deep in the gyrencephalic brain with high spatiotemporal resolution. As rapid neuronal depolarization causes tissue hypoxia, we achieve this by continuously estimating blood oxygenation with an intraoperative hybrid photoacoustic and ultrasonic imaging system. Due to its high resolution, promising imaging depth and high contrast, this novel approach to SD imaging can yield new insights into SD and thereby lead to advances in stroke, and brain injury research.

Background: Autonomic nervous system dysfunction has been previously observed in multiple sclerosis (MS) patients., Objective: To assess associations between magnetic resonance imaging-detected neuroinflammatory and neurodegenerative pathology and postural venous flow changes indicative of autonomic nervous system function., Methods: We used a standardized 3T magnetic resonance imaging protocol to scan 138 patients with MS and 49 healthy controls. Lesion volume and brain volumes were assessed. The cerebral venous flow (CVF) was examined by color-Doppler sonography in supine and upright positions and the difference was calculated as ΔCVF. Based on ΔCVF, subjects were split into absolute or quartile groups. Student's t test, χ 2 -test, and analysis of covariance adjusted for age and sex were used accordingly. Benjamini-Hochberg procedure corrected the p-values for multiple comparisons., Results: No differences were found between healthy controls and patients with MS in both supine and upright Doppler-derived CVF, nor in prevalence of abnormal postural venous control. Patients with absolute negative ΔCVF had higher disability scores (p = 0.013), lower gray matter (p = 0.039) and cortical (p = 0.044) volumes. The negative ΔCVF MS group also showed numerically worse bladder/bowel function when compared to the positive ΔCVF (2.3 vs. 1.5, p = 0.052). Similarly, the lowest quartile ΔCVF MS group had higher T1-lesion volumes (p = 0.033), T2-lesion volumes (p = 0.032), and lower deep gray matter (p = 0.043) and thalamus (p = 0.033) volumes when compared to those with higher ΔCVF quartiles., Conclusion: No difference in postural venous outflow between patients with MS and healthy controls was found. However, when the abnormal ΔCVF is present within the MS population, it may be associated with more inflammatory and neurodegenerative pathology. Further studies should explore whether the orthostatic venous changes are an aging or an MS-related phenomenon and if the etiology is due to impaired autonomic nervous system functioning.

The 18 kDa translocator protein (TSPO) is a marker of microglia activation and the main target of positron emission tomography (PET) ligands for neuroinflammation. Previous works showed that accounting for TSPO endothelial binding improves PET quantification for [ 11 C]PBR28, [ 18 F]DPA714 and [ 11 C]-R-PK11195. It is still unclear, however, whether the vascular signal is tracer-dependent. This work aims to explore the relationship between the TSPO vascular and tissue components for PET tracers with varying affinity, also assessing the impact of affinity towards the differentiability amongst kinetics and the ensuing ligand amenability to cluster analysis for the extraction of a reference region. First, we applied the compartmental model accounting for vascular binding to [ 11 C]-R-PK11195 data from six healthy subjects. Then, we compared the [ 11 C]-R-PK11195 vascular binding estimates with previously published values for [ 18 F]DPA714 and [ 11 C]PBR28. Finally, we determined the suitability for reference region extraction by calculating the angle between grey and white matter kinetics. Our results showed that endothelial binding is common to all TSPO tracers and proportional to their affinity. By consequence, grey and white matter kinetics were most similar for the radioligand with the highest affinity (i.e. [ 11 C]PBR28), hence poorly suited for the extraction of a reference region using supervised clustering.

Objective: The gold standard for the diagnosis of idiopathic normal pressure hydrocephalus (iNPH) is the CSF removal test. For elderly patients, however, a less invasive diagnostic method is required. On MRI, high-convexity tightness was reported to be an important finding for the diagnosis of iNPH. On SPECT, patients with iNPH often show hyperperfusion of the high-convexity area. The authors tested 2 hypotheses regarding the SPECT finding: 1) it is relative hyperperfusion reflecting the increased gray matter density of the convexity, and 2) it is useful for the diagnosis of iNPH. The authors termed the SPECT finding the convexity apparent hyperperfusion (CAPPAH) sign., Methods: Two clinical studies were conducted. In study 1, SPECT was performed for 20 patients suspected of having iNPH, and regional cerebral blood flow (rCBF) of the high-convexity area was examined using quantitative analysis. Clinical differences between patients with the CAPPAH sign (CAP) and those without it (NCAP) were also compared. In study 2, the CAPPAH sign was retrospectively assessed in 30 patients with iNPH and 19 healthy controls using SPECT images and 3D stereotactic surface projection., Results: In study 1, rCBF of the high-convexity area of the CAP group was calculated as 35.2–43.7 ml/min/100 g, which is not higher than normal values of rCBF determined by SPECT. The NCAP group showed lower cognitive function and weaker responses to the removal of CSF than the CAP group. In study 2, the CAPPAH sign was positive only in patients with iNPH (24/30) and not in controls (sensitivity 80%, specificity 100%). The coincidence rate between tight high convexity on MRI and the CAPPAH sign was very high (28/30)., Conclusions: Patients with iNPH showed hyperperfusion of the high-convexity area on SPECT; however, the presence of the CAPPAH sign did not indicate real hyperperfusion of rCBF in the high-convexity area. The authors speculated that patients with iNPH without the CAPPAH sign, despite showing tight high convexity on MRI, might have comorbidities such as Alzheimer’s disease.

Quantification of regional cerebral blood flow (CBF) using [ 15 O]H 2 O positron emission tomography (PET) requires the use of an arterial input function. Arterial sampling, however, is not always possible, for example in ill-conditioned or paediatric patients. Therefore, it is of interest to explore the use of non-invasive methods for the quantification of CBF. For validation of non-invasive methods, test-retest normal and hypercapnia data from 15 healthy volunteers were used. For each subject, the data consisted of up to five dynamic [ 15 O]H 2 O brain PET studies of 10 min and including arterial sampling. A measure of CBF was estimated using several non-invasive methods earlier reported in literature. In addition, various parameters were derived from the time-activity curve (TAC). Performance of these methods was assessed by comparison with full kinetic analysis using correlation and agreement analysis. The analysis was repeated with normalization to the whole brain grey matter value, providing relative CBF distributions. A reliable, absolute quantitative estimate of CBF could not be obtained with the reported non-invasive methods. Relative (normalized) CBF was best estimated using the double integration method.

Background: Reports on the relative importance of the diastolic and systolic blood pressures (DBP and SBP) in age-related cognitive decline are mixed. Investigating the relation between DBP/SBP and functional and structural brain changes could elucidate which of the 2 measures is more critically important for brain function and, consequently, cognitive impairment., Methods: We investigated the association of SBP and DBP with cortical volume, cerebral blood flow (CBF), and white matter lesions (WML), in nondemented older adults with and without mild cognitive impairment (MCI; N = 265, 185 MCI, mean age = 64 years). Brachial blood pressure was measured twice while seated, and the average of the 2 measures was used. Cortical volume, gray matter (GM) CBF, and WML were estimated using T1-weighted imaging, arterial spin labeling, and fluid attenuation inversion recovery, respectively., Results: Reduced cortical volume was associated with elevated DBP (β= -0.18, P = 0.034) but not with SBP (β = -0.10, P = 0.206). GM CBF was associated with DBP (β = -0.13, P = 0.048) but not with SBP (β = -0.07, P = 0.275). Likewise, CBF within brain regions where MCI patients showed hypoperfusion were only associated with DBP (DBP: β = -0.17, P = 0.005; SBP: β = -0.09, P = 0.120). WML volume was associated with both DBP (β = 0.20, P = 0.005) and SBP (β = 0.30, P < 0.001). For all measures, there was no interaction between DBP/SBP and cognitive status, indicating that these associations were independent of the cognitive status., Conclusions: Independently of the cognitive status, DBP is more critically important for GM volume and perfusion, whereas WML is associated with both blood pressures, likely reflecting long-term effect of hypertension and autoregulation dysfunction.

Objective: Studies have identified longitudinally that there exists an association between depression, cerebral blood flow (CBF), and white matter hyperintensities that are thought to be due to vascular pathologies in the brain. However, the changes in CBF, a measure that reflects cerebrovascular integrity, following pharmacotherapy are not well understood. In this study, we investigated the dynamic CBF changes over the course of antidepressant treatment and the association of these changes with depressive symptoms., Methods: We used pseudocontinuous arterial spin labeling to investigate CBF changes in a sample of older patients (≥ 50 years of age; N = 46; 29 female) with a DSM-IV diagnosis of major depressive disorder. Participants had 5 magnetic resonance imaging scans (at baseline, the day after receiving a placebo, the day after receiving a first dose of venlafaxine, a week after starting venlafaxine treatment, and at the end of trial [12 weeks]). Montgomery-Asberg Depression Rating Scale (MADRS) was used to evaluate depression severity and treatment outcome. We investigated the association between changes in depression severity with changes in voxel-wise CBF while adjusting for potential confounding factors., Results: Increased CBF in the middle and posterior cingulate between baseline and end of treatment was significantly associated with percent decrease in MADRS score, independent of sex and Mini-Mental State Examination score (5,000 permutations, cluster forming threshold P < .005, family-wise error P < .05). No significant effects were detected between baseline and other scans (ie, placebo, acute [single dose], or subacute [after a week])., Conclusions: Regional CBF increases were associated with decreases in depressive symptoms. This observation is consistent with the vascular depression hypothesis in late-life depression., Trial Registration: ClinicalTrials.gov identifiers: NCT00892047 and NCT01124188., (© Copyright 2018 Physicians Postgraduate Press, Inc.)

Type 1 diabetes is associated with slower psychomotor speed, but the neural basis of this relationship is not yet understood. The basal ganglia are a set of structures that are vulnerable to small vessel disease, particularly in individuals with type 1 diabetes. Thus, we examined the relationship between psychomotor speed and resting state resting cerebral blood flow in a sample of adults with diabetes onset during childhood (≤ 17 years of age). The sample included 77 patients (39 M, 38 F) with a mean age of 47.43 ± 5.72 years, age of onset at 8.50 ± 4.26 years, and duration of disease of 38.92 ± 4.18 years. Resting cerebral blood flow was quantified using arterial spin labeling. After covarying for sex, years of education and normalized gray matter volume, slower psychomotor speed was associated with lower cerebral blood flow in bilateral caudate nucleus-thalamus and a region in the superior frontal gyrus. These results suggest that the basal ganglia and frontal cortex may underlie slower psychomotor speed in individuals with type 1 diabetes.

Objectives: To assess observer variability of different reference tissues used for relative CBV (rCBV) measurements in DSC-MRI of glioma patients., Methods: In this retrospective study, three observers measured rCBV in DSC-MR images of 44 glioma patients on two occasions. rCBV is calculated by the CBV in the tumour hotspot/the CBV of a reference tissue at the contralateral side for normalization. One observer annotated the tumour hotspot that was kept constant for all measurements. All observers annotated eight reference tissues of normal white and grey matter. Observer variability was evaluated using the intraclass correlation coefficient (ICC), coefficient of variation (CV) and Bland-Altman analyses., Results: For intra-observer, the ICC ranged from 0.50-0.97 (fair-excellent) for all reference tissues. The CV ranged from 5.1-22.1 % for all reference tissues and observers. For inter-observer, the ICC for all pairwise observer combinations ranged from 0.44-0.92 (poor-excellent). The CV ranged from 8.1-31.1 %. Centrum semiovale was the only reference tissue that showed excellent intra- and inter-observer agreement (ICC>0.85) and lowest CVs (<12.5 %). Bland-Altman analyses showed that mean differences for centrum semiovale were close to zero., Conclusion: Selecting contralateral centrum semiovale as reference tissue for rCBV provides the lowest observer variability., Key Points: • Reference tissue selection for rCBV measurements adds variability to rCBV measurements. • rCBV measurements vary depending on the choice of reference tissue. • Observer variability of reference tissue selection varies between poor and excellent. • Centrum semiovale as reference tissue for rCBV provides the lowest observer variability.

Background: Understanding how vascular and metabolic factors impact on cognitive function is essential to develop efficient therapies to prevent and treat cognitive losses in older age. Cerebral metabolic rate of oxygen (CMRO2), cerebral blood flow (CBF) and venous oxygenation (Yv) comprise key physiologic processes that maintain optimum functioning of neural activity. Changes to these parameters across the lifespan may precede neurodegeneration and contribute to age-related cognitive decline. This study examined differences in blood flow and metabolism between 31 healthy younger (<50 years) and 29 healthy older (>50 years) adults; and investigated whether these parameters contribute to cognitive performance., Method: Participants underwent a cognitive assessment and MRI scan. Grey matter CMRO2 was calculated from measures of CBF (phase contrast MRI), arterial and venous oxygenation (TRUST MRI) to assess group differences in physiological function and the contribution of these parameters to cognition., Results: Performance on memory (p<0.001) and attention tasks (p<0.001) and total CBF were reduced (p<0.05), and Yv trended toward a decrease (p = .06) in the older group, while grey matter CBF and CMRO2 did not differ between the age groups. Attention was negatively associated with CBF when adjusted (p<0.05) in the older adults, but not in the younger group. There was no such relationship with memory. Neither cognitive measure was associated with oxygen metabolism or venous oxygenation in either age group., Conclusion: Findings indicated an age-related imbalance between oxygen delivery, consumption and demand, evidenced by a decreased supply of oxygen with unchanged metabolism resulting in increased oxygen extraction. CBF predicted attention when the age-effect was controlled, suggesting a task- specific CBF- cognition relationship., Competing Interests: The authors have declared that no competing interests exist.

Background: Cerebrospinal fluid (CSF) is thought to flow into the brain via perivascular spaces around arteries, where it mixes with interstitial fluid. The precise details concerning fluid outflow remain controversial. Although fluid dynamics have been studied in the brain, little is known about spinal cord fluid inflow and outflow. Understanding the normal fluid physiology of the spinal cord may give insight into the pathogenesis of spinal cord oedema and CSF disorders such as syringomyelia. We therefore aimed to determine the fluid outflow pathways in the rat spinal cord., Methods: A fluorescent tracer, Alexa-Fluor ® -647 Ovalbumin, was injected into the extracellular space of either the cervicothoracic lateral white matter or the grey matter in twenty-two Sprague-Dawley rats over 250 s. The rats were sacrificed at 20 or 60 min post injection. Spinal cord segments were sectioned and labelled with vascular antibodies for immunohistochemistry., Results: Fluorescent tracer was distributed over two to three spinal levels adjacent to the injection site. In grey matter injections, tracer spread radially into the white matter. In white matter injections, tracer was confined to and redistributed along the longitudinal axonal fibres. Tracer was conducted towards the pial and ependymal surfaces along vascular structures. There was accumulation of tracer around the adventitia of the intramedullary arteries, veins and capillaries, as well as the extramedullary vessels. A distinct layer of tracer was deposited in the internal basement membrane of the tunica media of arteries. In half the grey matter injections, tracer was detected in the central canal., Conclusions: These results suggest that in the spinal cord interstitial fluid movement is modulated by tissue diffusivity of grey and white matter. The central canal, and the compartments around or within blood vessels appear to be dominant pathways for fluid drainage in these experiments. There may be regional variations in fluid outflow capacity due to vascular and other anatomical differences between the grey and white matter.

The vertebrate blood-brain barrier (BBB) is composed of cerebral microvascular endothelial cells (CEC). The BBB acts as a semi-permeable cellular interface that tightly regulates bidirectional molecular transport between blood and the brain parenchyma in order to maintain cerebral homeostasis. The CEC phenotype is regulated by a variety of factors, including cells in its immediate environment and within functional neurovascular units. The cellular composition of the brain parenchyma surrounding the CEC varies between different brain regions; this difference is clearly visible in grey versus white matter. In this review, we discuss evidence for the existence of brain vascular heterogeneity, focusing on differences between the vessels of the grey and white matter. The region-specific differences in the vasculature of the brain are reflective of specific functions of those particular brain areas. This BBB-endothelial heterogeneity may have implications for the course of pathogenesis of cerebrovascular diseases and neurological disorders involving vascular activation and dysfunction. This heterogeneity should be taken into account when developing BBB-neuro-disease models representative of specific brain areas.

Calibrated functional magnetic resonance imaging (fMRI) is a method to independently measure the metabolic and hemodynamic contributions to the blood oxygenation level dependent (BOLD) signal. This technique typically requires the use of a respiratory challenge, such as hypercapnia or hyperoxia, to estimate the calibration constant, M. There has been a recent push to eliminate the gas challenge from the calibration procedure using asymmetric spin echo (ASE) based techniques. This study uses simulations to better understand spin echo (SE) and ASE signals, analytical modelling to characterize the signal evolution, and in vivo imaging to validate the modelling. Using simulations, it is shown how ASE imaging generally underestimates M and how this depends on several parameters of the acquisition, including echo time and ASE offset, as well as the vessel size. This underestimation is the result of imperfect SE refocusing due to diffusion of water through the extravascular environment surrounding the microvasculature. By empirically characterizing this SE attenuation as an exponential decay that increases with echo time, we have proposed a quadratic ASE biophysical signal model. This model allows for the characterization and compensation of the SE attenuation if SE and ASE signals are acquired at multiple echo times. This was tested in healthy subjects and was found to significantly increase the estimates of M across grey matter. These findings show promise for improved gas-free calibration and can be extended to other relaxation-based imaging studies of brain physiology., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: To investigate changes in cerebral blood flow (CBF) in gray matter (GM) between 6 months and 15 years of age and to provide CBF values for the brain, GM, white matter (WM), hemispheres and lobes., Methods: Between 2013 and 2016, we retrospectively included all clinical MRI examinations with arterial spin labeling (ASL). We excluded subjects with a condition potentially affecting brain perfusion. For each subject, mean values of CBF in the brain, GM, WM, hemispheres and lobes were calculated. GM CBF was fitted using linear, quadratic and cubic polynomial regression against age. Regression models were compared with Akaike's information criterion (AIC), and Likelihood Ratio tests., Results: 84 children were included (44 females/40 males). Mean CBF values were 64.2 ± 13.8 mL/100 g/min in GM, and 29.3 ± 10.0 mL/100 g/min in WM. The best-fit model of brain perfusion was the cubic polynomial function (AIC = 672.7, versus respectively AIC = 673.9 and AIC = 674.1 with the linear negative function and the quadratic polynomial function). A statistically significant difference between the tested models demonstrating the superiority of the quadratic (p = 0.18) or cubic polynomial model (p = 0.06), over the negative linear regression model was not found. No effect of general anesthesia (p = 0.34) or of gender (p = 0.16) was found., Conclusion: we provided values for ASL CBF in the brain, GM, WM, hemispheres, and lobes over a wide pediatric age range, approximately showing inverted U-shaped changes in GM perfusion over the course of childhood., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background Impaired autoregulation may contribute to the pathogenesis of cerebral small vessel disease. Reliable protocols for measuring microvascular reactivity are required to test this hypothesis and for providing secondary endpoints in clinical trials. Aims To develop and assess a protocol for acquisition and processing of cerebrovascular reactivity by MRI, in subcortical tissue of patients with small vessel disease and minor stroke. Methods We recruited 15 healthy volunteers, testing paradigms using 1- and 3-min 6% CO 2 challenges with repeat scanning, and 15 patients with history of minor stroke. We developed a protocol to measure cerebrovascular reactivity and delay times, assessing tolerability and reproducibility in grey and white matter areas. Results The 3-min paradigm yielded more reproducible data than the 1-min paradigm (CV respectively: 7.9-15.4% and 11.7-70.2% for cerebrovascular reactivity in grey matter), and was less reproducible in white matter (16.1-24.4% and 27.5-141.0%). Tolerability was similar for the two paradigms, but mean cerebrovascular reactivity and cerebrovascular reactivity delay were significantly higher for the 3-min paradigm in most regions. Patient tolerability was high with no evidence of greater failure rate (1/15 patients vs. 2/15 volunteers withdrew at the first visit). Grey matter cerebrovascular reactivity was lower in patients than in volunteers (0.110-0.234 vs. 0.172-0.313%/mmHg; p < 0.05 in 6/8 regions), as was the white matter cerebrovascular reactivity delay (16.2-43.9 vs. 31.1-47.9 s; p < 0.05 in 4/8 regions). Conclusions An effective and well-tolerated protocol for measurement of cerebrovascular reactivity was developed for use in ongoing and future trials to investigate small vessel disease pathophysiology and to measure treatment effects.

Background: Abnormal cortical cerebral blood flow and gray matter volume have been frequently reported in patients with major depressive disorder (MDD). In contrast, although the role of the cerebellum in MDD pathophysiology has attracted considerable interest more recently, studies investigating both functional and structural aspects of cerebellar integrity are scarce., Methods: In this study, we used structural and functional magnetic resonance imaging (MRI) to investigate cerebellar volume and regional cerebellar blood flow (rCBF) at rest in clinically acute MDD patients (n = 22) and healthy controls (n = 18). We acquired high-resolution structural images at 3 T together with perfusion images obtained with continuous arterial spin labeling. Cerebellar structure and function were investigated using cerebellum-optimized analysis techniques., Results: Markedly increased rCBF was found in bilateral cerebellar areas VIIa and VIIIb (p < 0.05 family-wise-error [FWE] corrected). Significant differences in cerebellar volume between patients and controls were not found (p < 0.05, FWE-corrected). Left cerebellar area VIIa perfusion was significantly associated with depressive symptoms, as measured by the Hamilton Depression Rating Scale., Limitations: Potential limitations of this study include the modest sample size, the cross-sectional design, the lack of task-related imaging and the heterogeneity of drug treatment., Conclusions: The data suggest contributions of "affective" cerebellar regions to MDD pathophysiology and symptom expression. While cerebellar perfusion at rest is compromised in MDD, cerebellar volume seems to be less affected., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background and Purpose: The spatial correlation between WM and cortical GM disease in multiple sclerosis is controversial and has not been previously assessed with perfusion MR imaging. We sought to determine the nature of association between lobar WM, cortical GM, volume and perfusion., Materials and Methods: Nineteen individuals with secondary-progressive multiple sclerosis, 19 with relapsing-remitting multiple sclerosis, and 19 age-matched healthy controls were recruited. Quantitative MR perfusion imaging was used to derive CBF, CBV, and MTT within cortical GM, WM, and T2-hyperintense lesions. A 2-step multivariate linear regression (corrected for age, disease duration, and Expanded Disability Status Scale) was used to assess correlations between perfusion and volume measures in global and lobar normal-appearing WM, cortical GM, and T2-hyperintense lesions. The Bonferroni adjustment was applied as appropriate., Results: Global cortical GM and WM volume was significantly reduced for each group comparison, except cortical GM volume of those with relapsing-remitting multiple sclerosis versus controls. Global and lobar cortical GM CBF and CBV were reduced in secondary-progressive multiple sclerosis compared with other groups but not for relapsing-remitting multiple sclerosis versus controls. Global and lobar WM CBF and CBV were not significantly different across groups. The distribution of lobar cortical GM and WM volume reduction was disparate, except for the occipital lobes in patients with secondary-progressive multiple sclerosis versus those with relapsing-remitting multiple sclerosis. Moderate associations were identified between lobar cortical GM and lobar normal-appearing WM volume in controls and in the left temporal lobe in relapsing-remitting multiple sclerosis. No significant associations occurred between cortical GM and WM perfusion or volume. Strong correlations were observed between cortical-GM perfusion, normal appearing WM and lesional perfusion, with respect to each global and lobar region within HC, and RRMS and SPMS patients ( R 2 ≤ 0.96, P < .006 and R 2 ≤ 0.738, P < .006)., Conclusions: The weak correlation between lobar WM and cortical GM volume loss and perfusion reduction suggests the independent pathophysiology of WM and cortical GM disease., (© 2018 by American Journal of Neuroradiology.)

Objective: We determined if transcranial color-coded Doppler derived hemodynamics are associated with MRI-based cerebral blood flow (CBF) in regions clinically important to dementia in healthy middle-aged adults., Approach: In 30 subjects (18m/12f; age  =  52  ±  1 years), blood flow velocity (BFV) and cerebrovascular conductance (CVC) were measured with transcranial color-coded Doppler (TCCD) at the middle cerebral artery (MCA) and cerebral blood flow (CBF) was assessed with arterial spin labeled perfusion MRI., Main Results: BFV and CVC were associated with hippocampus (r  =  0.58 and r  =  0.61, both p  <  0.01) and occipitoparietal (r  =  0.50 and r  =  0.58, both p  <  0.01) CBF. CVC was further associated with posterior cingulate CBF (r  =  0.58 p  <  0.01). Independent of age and sex, BFV and CVC were associated with hippocampus (r  =  0.59 and r  =  0.55, both p  <  0.003) and occipitoparietal (r  =  0.50 and r  =  0.57, both p  <  0.01) CBF. CVC was independently associated with posterior cingulate CBF (r  =  0.38, p  =  0.049)., Significance: TCCD-measured BFV and CVC of the MCA are indicators of cerebral perfusion to clinically valuable brain regions in healthy middle-aged adults. TCCD may not be a good indicator of blood flow to cerebral white matter.

Using a systematic investigation of brain blood volume, in high-resolution synchrotron 3D images of microvascular structures within cortical regions of a primate brain, we challenge several basic questions regarding possible vascular bias in high-resolution functional neuroimaging. We present a bilateral comparison of cortical regions, where we analyze relative vascular volume in voxels from 150 to 1000 μm side lengths in the white and grey matter. We show that, if voxel size reaches a scale smaller than 300 µm, the vascular volume can no longer be considered homogeneous, either within one hemisphere or in bilateral comparison between samples. We demonstrate that voxel size influences the comparison between vessel-relative volume distributions depending on the scale considered (i.e., hemisphere, lobe, or sample). Furthermore, we also investigate how voxel anisotropy and orientation can affect the apparent vascular volume, in accordance with actual fMRI voxel sizes. These findings are discussed from the various perspectives of high-resolution brain functional imaging. Hum Brain Mapp 38:5756-5777, 2017. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)