Global CBF Research Articles

444 Quantitative Mapping of Cerebral Blood Flow and Blood-Brain Barrier Water Exchange Rate (Kw) Reveals the Mechanobiological Impact of Cranioplasty: A Magnetic Resonance Imaging Study of Patients With Cranial Defects

INTRODUCTION: Large cranial defects may cause neurological decline due to brain shift, while cranioplasty may improve cognitive function, although the underlying mechanisms remain poorly understood. Blood-brain barrier (BBB) water exchange rate (Kw) is a novel magnetic resonance imaging (MRI) method which provides insights into the processes underlying the effects of cranioplasty. METHODS: Adult patients with cranial defects who were candidates for elective cranioplasty were consented and enrolled. Using a 3T MRI, we conducted baseline imaging on all patients, and repeated the imaging during the early post-cranioplasty period. The Kw and CBF were quantified, and asymmetry was calculated as the difference between the values on the ipsilateral and contralateral hemispheres relative to the cranial defect, divided by the sum of those values. Pairwise comparisons of the changes from baseline to post-cranioplasty period were performed using Wilcoxon signed-rank test. RESULTS: A total of 10 patients were enrolled (mean age: 35.4 ± 9.49, 9/10 men). The global CBF showed significant improvements after cranioplasty. There was a remarkable Kw asymmetry in the caudate area at baseline (low on defect side), which significantly improved post-operatively (median: -0.077 vs. 0.021, p = 0.049), while the changes in CBF in this area were not significant (median: -0.002 vs. 0.014, p = 0.160). Other brain regions yielded no significant changes in Kw asymmetry. CONCLUSIONS: Reduced Kw has been reported in cognitive decline and cerebral small vessel diseases, and may be related to impaired water circulation in the brain. We observed increased global CBF and Kw asymmetry in caudate which may reflect improved brain physiology and water circulation following cranioplasty. Kw is a non-invasive and non-contrast method that offers an opportunity to understand the intricate changes in brain homeostasis following reconstruction surgery.

Range and variability of CBF in young adults: PC‐MRI and ASL studies

AbstractSeveral studies have compared phase contrast magnetic resonance imaging (PC‐MRI) with arterial spin labeling (ASL) in the same cohort of subjects. However, these earlier comparisons included subjects across a wide age range, which can contribute to increased intersubject variability. We compared the range and variability of CBF based on PC‐MRI and ASL in a group of young subjects. We also explored whether the comparison between PC‐MRI and ASL was dependent on sex. Thirty young subjects (17 females) were recruited in this study. The CBF from PC‐MRI (CBFPC) was calculated as the total blood flow normalized to brain parenchyma mass. The CBF from ASL (CBFASL) was quantified based on the perfusion kinetic model. The ratio between CBFASL and CBFPC was calculated. Females exhibited significantly higher CBF using both PC‐MRI (p < 0.05) and ASL (p < 0.005) compared with males. The disparity in CBF between sexes was more prominent in ASL measurements. A significant correlation was observed between CBFPC and CBFASL values (r = 0.47, p < 0.01), and CBFASL tended to be lower than CBFPC values (p < 0.001). This difference between CBFASL and CBFPC was more pronounced in males, as evidenced by the smaller CBFASL/CBFPC ratio in males (p < 0.05). The measurement of global CBF with PC‐MRI and ASL are correlated, but CBFASL exhibits lower values than CBFPC. As the underestimation of CBFASL is prominent in males, ASL amplifies the sexual dimorphism in CBF compared with PC‐MRI.

Cerebral Hemodynamic and Metabolic Abnormalities in Neonatal Hypocalcemia: Findings from Advanced MRI.

Neonatal hypocalcemia is the most common metabolic disorder, and whether asymptomatic disease should be treated with calcium supplements remains controversial. We aimed to quantify neonatal hypocalcemia's global CBF and cerebral metabolic rate of oxygen (CMRO2) using physiologic MR imaging and elucidate the pathophysiologic vulnerabilities of neonatal hypocalcemia. A total of 37 consecutive patients with neonatal hypocalcemia were enrolled. They were further divided into subgroups with and without structural MR imaging abnormalities, denoted as neonatal hypocalcemia-a (n = 24) and neonatal hypocalcemia-n (n = 13). Nineteen healthy neonates were enrolled as a control group. Brain physiologic parameters determined using phase-contrast MR imaging, T2-relaxation-under-spin-tagging MR imaging, and brain volume were compared between patients with neonatal hypocalcemia (their subgroups) and controls. Predictors for neonatal hypocalcemia-related brain injuries were identified using multivariate logistic regression analysis and expressed as ORs with 95% CIs. Patients with neonatal hypocalcemia showed significantly lower CBF and CMRO2 compared with controls. Furthermore, the neonatal hypocalcemia-a subset (versus controls or neonatal hypocalcemia-n) had significantly lower CBF and CMRO2. There was no obvious difference in CBF and CMRO2 between the neonatal hypocalcemia-n subset and controls. CBF and CMRO2 were independently associated with neonatal hypocalcemia. The ORs were 0.80 (95% CI, 0.65-0.99) and 0.97 (95% CI, 0.89-1.05) for CBF and CMRO2, respectively. Neonatal hypocalcemia with structural damage may exhibit lower hemodynamics and cerebral metabolism. CBF may be useful in assessing the need for calcium supplementation in asymptomatic neonatal hypocalcemia to prevent brain injury.

Sex modifies the association between hippocampal blood flow and episodic memory in cognitively unimpaired individuals

AbstractBackgroundCerebral blood flow (CBF) is disrupted in Alzheimer’s disease (AD) and associated with worse cognition, including episodic memory performance. Sex differences have been noted in both CBF and memory performance in AD; women demonstrate higher global CBF and memory performance than men. However, the effect of sex on the association between CBF and memory performance has not been explored. This study examined whether there were sex differences in the association between memory performance and CBF in AD‐related regions in typically aging older adults.MethodThe study included 119 functionally intact (CDR=0) older adults from the UCSF Hillblom Aging Network (mean age 74.9 (5.7), 51.2% females) who completed a cognitive assessment with brain MRI including T1‐weighted and arterial spin labeling (ASL) in hippocampal and precentral gyrus (as control) regions. Episodic memory was assessed by the California Verbal Learning Test and Benson figure delayed recall. Mean Z‐scores estimated a memory composite score. Memory composites were the dependent variable in regression models testing the interaction between regional ASL and sex as predictors, and age, education, APOE‐ε4, hippocampal volume, and vascular burden composite as covariates.ResultThere were no significant sex differences in levels of hippocampal CBF, but females performed better on the memory composite (p<0.001) than males after adjustment for age and education. We found that sex modified the association between hippocampal CBF and memory performance (figure 1) (p=0.04). Specifically, the positive association between hippocampal CBF and memory performances was stronger in men compared to women. This interaction remained significant after further adjusting for APOE‐ε4, hippocampal volume, and vascular burden. There was no significant sex by CBF interaction on memory performance when examining precentral CBF (p=0.79).ConclusionOur result suggests that sex modifies the association between memory performance and perfusion in brain regions vulnerable to pathological changes in preclinical AD. Specifically, greater hippocampal CBF is positively associated with memory performance in men but not women. Men may benefit more from increased blood flow, possibly reflecting vascular integrity, in hippocampal regions in memory performance than women. This work highlights mechanisms that may be differentially vulnerable by sex differences and inform risk for neurodegenerative diseases.

Associations between cortical microinfarcts, hippocampal atrophy, and cerebral small vessel disease

AbstractBackgroundBrain cortical microinfarcts (CMI) are negatively correlated with cognitive function in both normal aging and Alzheimer’s disease (AD). High‐field structural magnetic resonance imaging (MRI) has facilitated in vivo detection of CMIs but their significance and underlying pathological mechanism remain uncertain. Here we assessed correlations between CMIs and medial temporal lobe (MTL) cortical thickness, white matter hyperintensity (WMH) volume, and relative periventricular white matter cerebral blood flow (PVWM CBF) in healthy individuals. PVWM CBF is thought to provide a measure of cerebral small vessel function.Method76 cognitively intact subjects age 65 ± 15 years were scanned using a hybrid 7T/3T protocol. CMIs were counted by visual inspection on T1‐weighted MP2RAGE (0.7mm3) and FLAIR (0.8mm3) scans obtained at 7T. T1‐weighted MPRAGE, FLAIR and 3D arterial spin labeling (ASL) data were also acquired at 3T and were used to calculate cortical thickness, WMH volume, and regional CBF. Spearman and Pearson bivariate tests were used for statistical analyses.Result185 CMIs were detected in 63 of 76 (83%) 7T scans (range:0‐8, 66% multiple CMIs). Age and sex were not significantly correlated with CMI number.A significant positive Pearson correlation was seen between the number of CMIs and log‐transformed WMH volume (r(74)= 0.23, p=0.04) and a more significant negative correlation between the number of CMIs and PVWM CBF normalized to global CBF was also observed (r(74)= ‐0.37, p=0.003).Significant negative correlations between CMI number and mean cortical thickness in Brodmann area 35 (BA35) (r(73)= ‐0.24, p=0.04) and parahippocampal cortex (r(73)= ‐0.26, p=0.03) was observed with nonsignificant trends in BA36 and entorhinal cortex.ConclusionSignificant correlations between the CMI number and both relative PVWM CBF and WMH volume suggests a contribution of small vessel ischemic disease in the development of CMIs. The negative correlation between CMIs and MTL cortical thickness supports the possibility of a mutual underlying pathway for CMIs and Alzheimer’s disease that may be mediated by cerebral amyloid angiopathy.

Comparison of test\u2013retest reliability of BOLD and pCASL fMRI in a two-center study

BackgroundThe establishment of test–retest reliability and reproducibility (TRR) is an important part of validating any research tool, including functional magnetic resonance imaging (fMRI). The primary objective of this study is to investigate the reliability of pseudo-Continuous Arterial Spin Labeling (pCASL) and Blood Oxygen Level Dependent (BOLD) fMRI data acquired across two different scanners in a sample of healthy adults. While single site/single scanner studies have shown acceptable repeatability, TRR of both in a practical multisite study occurring in two facilities spread out across the country with weeks to months between scans is critically needed.MethodsTen subjects were imaged with similar 3 T MRI scanners at the University of Pittsburgh and Massachusetts General Hospital. Finger-tapping and Resting-state data were acquired for both techniques. Analysis of the resting state data for functional connectivity was performed with the Functional Connectivity Toolbox, while analysis of the finger tapping data was accomplished with FSL. pCASL Blood flow data was generated using AST Toolbox. Activated areas and networks were identified via pre-defined atlases and dual-regression techniques. Analysis for TRR was conducted by comparing pCASL and BOLD images in terms of Intraclass correlation coefficients, Dice Similarity Coefficients, and repeated measures ANOVA.ResultsBoth BOLD and pCASL scans showed strong activation and correlation between the two locations for the finger tapping tasks. Functional connectivity analyses identified elements of the default mode network in all resting scans at both locations. Multivariate repeated measures ANOVA showed significant variability between subjects, but no significant variability for location. Global CBF was very similar between the two scanning locations, and repeated measures ANOVA showed no significant differences between the two scanning locations.ConclusionsThe results of this study show that when similar scanner hardware and software is coupled with identical data analysis protocols, consistent and reproducible functional brain images can be acquired across sites. The variability seen in the activation maps is greater for pCASL versus BOLD images, as expected, however groups maps are remarkably similar despite the low number of subjects. This demonstrates that multi-site fMRI studies of task-based and resting state brain activity is feasible.

Impact of hydroxytyrosol on stroke: tracking therapy response on neuroinflammation and cerebrovascular parameters using PET-MR imaging and on functional outcomes.

Immune cells have been implicated in influencing stroke outcomes depending on their temporal dynamics, number, and spatial distribution after ischemia. Depending on their activation status, immune cells can have detrimental and beneficial properties on tissue outcome after stroke, highlighting the need to modulate inflammation towards beneficial and restorative immune responses. Novel dietary therapies may promote modulation of pro- and anti-inflammatory immune cell functions.Among the dietary interventions inspired by the Mediterranean diet, hydroxytyrosol (HT), the main phenolic component of the extra virgin olive oil (EVOO), has been suggested to have antioxidant and anti-inflammatory properties in vitro. However, immunomodulatory effects of HT have not yet been studied in vivo after stroke.The aim of this project is therefore to monitor the therapeutic effect of a HT-enriched diet in an experimental stroke model using non-invasive in vivo multimodal imaging, behavioural phenotyping and cross-correlation with ex vivo parameters.Methods: A total of N = 22 male C57BL/6 mice were fed with either a standard chow (n = 11) or a HT enriched diet (n = 11) for 35 days, following a 30 min transient middle cerebral artery occlusion (tMCAo). T2-weighted (lesion) and perfusion (cerebral blood flow)-/diffusion (cellular density)-weighted MR images were acquired at days 1, 3, 7, 14, 21 and 30 post ischemia. [18F]DPA-714 (TSPO, neuroinflammation marker) PET-CT scans were acquired at days 7, 14, 21 and 30 post ischemia. Infarct volume (mm3), cerebral blood flow (mL/100g/min), apparent diffusion coefficient (10-4·mm2/s) and percentage of injected tracer dose (%ID/mL) were assessed.Behavioural tests (grip test, rotarod, open field, pole test) were performed prior and after ischemia to access therapy effects on sensorimotor functions.Ex vivo analyses (IHC, IF, WB) were performed to quantify TSPO expression, immune cells including microglia/macrophages (Iba-1, F4/80), astrocytes (GFAP) and peripheral markers in serum such as thiobarbituric acid reactive substances (TBARS) and nitric oxide (NO) 35 days post ischemia. Additionally, gene expression of pro- and anti-inflammatory markers were assessed by rt-qPCR, including tspo, cd163, arg1, tnf and Il-1β.Results: No treatment effect was observed on temporal [18F]DPA-714 uptake within the ischemic and contralateral region (two-way RM ANOVA, p = 0.71). Quantification of the percentage of TSPO+ area by immunoreactivity indicated a slight 2-fold increase in TSPO expression within the infarct region in HT-fed mice at day 35 post ischemia (p = 0.011) correlating with a 2-3 fold increase in Iba-1+ cell population expressing CD163 as anti-inflammatory marker (R2 = 0.80). Most of the GFAP+ cells were TSPO-. Only few F4/80+ cells were observed at day 35 post ischemia in both groups.No significant treatment effect was observed on global ADC and CBF within the infarct and the contralateral region over time. Behavioural tests indicated improved strength of the forepaws at day 14 post ischemia (p = 0.031).Conclusion: An HT-enriched diet significantly increased the number of Iba-1+ microglia/macrophages in the post-ischemic area, inducing higher expression of anti-inflammatory markers while no clear-cut effect was observed. Also, HT did not affect recovery of the cerebrovascular parameters, including ADC and CBF.Altogether, our data indicated that a prolonged dietary intervention with HT, as a single component of the Mediterranean diet, induces molecular changes that may improve stroke outcomes. Therefore, we support the use of the Mediterranean diet as a multicomponent therapy approach after stroke.

Single and repeated ketamine treatment induces perfusion changes in sensory and limbic networks in major depressive disorder

Ketamine infusion therapy can produce fast-acting antidepressant effects in patients with major depressive disorder (MDD). Yet, how single and repeated ketamine treatment induces brain systems-level neuroplasticity underlying symptom improvement is unknown. Advanced multiband imaging (MB) pseudo-continuous arterial spin labeling (pCASL) perfusion MRI data was acquired from patients with treatment resistant depression (TRD) (N = 22, mean age=35.2 ± 9.95 SD, 27% female) at baseline, and 24 h after receiving single, and four subanesthetic (0.5 mg/kg) intravenous ketamine infusions. Changes in global and regional CBF were compared across time points, and relationships with overall mood, anhedonia and apathy were examined. Comparisons between patients at baseline and controls (N = 18, mean age=36.11 ± 14.5 SD, 57% female) established normalization of treatment effects. Results showed increased regional CBF in the cingulate and primary and higher-order visual association regions after first ketamine treatment. Baseline CBF in the fusiform, and acute changes in CBF in visual areas were related to symptom improvement after single and repeated ketamine treatment, respectively. In contrast, after serial infusion therapy, decreases in regional CBF were observed in the bilateral hippocampus and right insula with ketamine treatment. Findings demonstrate that neurophysiological changes occurring with single and repeated ketamine treatment follow both a regional and temporal pattern including sensory and limbic regions. Initial changes are observed in the posterior cingulate and precuneus and primary and higher-order visual areas, which relate to clinical responses. However, repeated exposure to ketamine, though not relating to clinical outcome, appears to engage deeper limbic structures and insula.ClinicalTrials.gov: Biomarkers of Fast Acting Therapies in Major Depression, https://clinicaltrials.gov/ct2/show/NCT02165449, NCT02165449

Comparison of simultaneous arterial spin labeling MRI and 15O-H2O PET measurements of regional cerebral blood flow in rest and altered perfusion states

Arterial spin labelling (ASL) is a non-invasive magnetic resonance imaging (MRI) technique that may provide fully quantitative regional cerebral blood flow (rCBF) images. However, before its application in clinical routine, ASL needs to be validated against the clinical gold standard, 15O-H2O positron emission tomography (PET). We aimed to compare the two techniques by performing simultaneous quantitative ASL-MRI and 15O-H2O-PET examinations in a hybrid PET/MRI scanner. Duplicate rCBF measurements were performed in healthy young subjects (n = 14) in rest, during hyperventilation, and after acetazolamide (post-ACZ), yielding 63 combined PET/MRI datasets in total. Average global CBF by ASL-MRI and 15O-H2O-PET was not significantly different in any state (40.0 ± 6.5 and 40.6 ± 4.1 mL/100 g/min, respectively in rest, 24.5 ± 5.1 and 23.4 ± 4.8 mL/100 g/min, respectively, during hyperventilation, and 59.1 ± 10.4 and 64.7 ± 10.0 mL/100 g/min, respectively, post-ACZ). Overall, strong correlation between the two methods was found across all states (slope = 1.01, R2 = 0.82), while the correlations within individual states and of reactivity measures were weaker, in particular in rest (R2 = 0.05, p = 0.03). Regional distribution was similar, although ASL yielded higher perfusion and absolute reactivity in highly vascularized areas. In conclusion, ASL-MRI and 15O-H2O-PET measurements of rCBF are highly correlated across different perfusion states, but with variable correlation within and between hemodynamic states, and systematic differences in regional distribution.

Intensive Hypoglycemia Avoidance and Improved Awareness of Hypoglycemia Associated with Partial Recovery Activation Lost in Hypoglycemia Unaware Patients with Type 1 Diabetes

Aim: The brain senses hypoglycemia and governs symptomatic, hormonal and behavioral responses to it. This study aimed to understand the differences in regional brain responses to experimental hypoglycemia between adults with type 1 diabetes (T1D) with intact hypoglycemia awareness [HA] and impaired awareness of hypoglycemia [IAH] and evaluate the impact of intensive hypoglycemia avoidance on these responses. Methods: We performed ASL fMRI scans to measure global and regional cerebral blood flow [CBF and rCBF] and measured symptomatic and hormonal responses to experimental hypoglycemia [47 mg/dl] in 15 HA T1D subjects and 22 subjects with IAH matched for age, HbA1c and duration of diabetes. Those with IAH underwent a hypoglycemia avoidance program including education, frequent contact and additional technology where required, including sensor augmented pump therapy with predictive low glucose suspend before being restudied with ASL FMRI at hypoglycemia. Results: Baseline scans: Global CBF increased in response to hypoglycemia in HA and IAH [HA 6.3% p=0.01; IAH 8.0%, p=0.03; HA vs. IAH p=NS]. There was greater increase in rCBF in thalamus, prefrontal cortex and orbitofrontal cortex in HA vs. IAH and greater reduction in rCBF in the hippocampus. Repeat scans: The hypoglycemia avoidance program improved subjective awareness [Gold score 6 ±1 vs. 4.2±1.9; p = 0.001] in the 12 completers. Compared to baseline scans, there was a trend to greater increase in rCBF in the anterior cingulate cortex in response to hypoglycemia [p=0.058], but no changes in the thalamus, prefrontal or orbitofrontal cortices. Conclusion: Intensive education and support can improve hypoglycemia awareness with some restoration of activation in the anterior cingulate cortex, but frontal changes are not restored suggesting cognitive responses to hypoglycemia may not be changed by these interventions. Disclosure P. Choudhary: Speaker's Bureau; Self; Medtronic MiniMed, Inc., Novo Nordisk Inc.. Advisory Panel; Self; Becton, Dickinson and Company, Sanofi-Aventis, Roche Diabetes Care Health and Digital Solutions, Lilly. M. Nwokolo: None. O. O'Daly: None. S.A. Amiel: Advisory Panel; Self; Medtronic MiniMed, Inc., Novo Nordisk A/S, Roche Diabetes Care Health and Digital Solutions. F.O. Zelaya: None.

Components of day-to-day variability of cerebral perfusion measurements - Analysis of phase contrast mapping magnetic resonance imaging measurements in healthy volunteers.

PurposeThe aim of the study was to investigate the components of day-to-day variability of repeated phase contrast mapping (PCM) magnetic resonance imaging measurements of global cerebral blood flow (gCBF).Materials and methodsTwo dataset were analyzed. In Dataset 1 duplicated PCM measurements of total brain flow were performed in 11 healthy young volunteers on two separate days applying a strictly standardized setup. For comparison PCM measurements obtained from a previously published study (Dataset 2) were analyzed in order to assess long-term variability in an aged population in a less strictly controlled setup. Global CBF was calculated by normalizing total brain flow to brain volume. On each day measurements of hemoglobin, caffeine and glucose were obtained. Linear mixed models were applied to estimate coefficients of variation (CV) of total (CVt), between-subject (CVb), within-subject day-to-day (CVw), and intra-session residual variability (CVr).ResultsIn Dataset 1 CVt, CVb, CVw and CVr were estimated to be 11%, 9.4%, 4% and 4.2%, respectively, and to 8.8%, 7.2%, 2.7% and 4.3%, respectively, when adjusting for hemoglobin and plasma caffeine. In Dataset 2 CVt, CVb and CVw were estimated to be 25.4%, 19.2%, and 15.0%, respectively, and decreased to 16.6%, 8.2% and 12.5%, respectively, when adjusting for the same covariates.DiscussionOur results suggest that short-term day-to-day variability of gCBF is relatively low compared to between-subject variability when studied in standardized conditions, whereas long-term variability in an aged population appears to be much larger when studied in less a standardized setup. The results further showed that from 20% to 35% of the total variability in gCBF can be attributed to the effects of hemoglobin and caffeine.

Cerebral Perfusion Is Perturbed by Preterm Birth and Brain Injury.

Early disturbances in systemic and cerebral hemodynamics are thought to mediate prematurity-related brain injury. However, the extent to which CBF is perturbed by preterm birth is unknown. Our aim was to compare global and regional CBF in preterm infants with and without brain injury on conventional MR imaging using arterial spin-labeling during the third trimester of ex utero life and to examine the relationship between clinical risk factors and CBF. We prospectively enrolled preterm infants younger than 32 weeks' gestational age and <1500 g and performed arterial spin-labeling MR imaging studies. Global and regional CBF in the cerebral cortex, thalami, pons, and cerebellum was quantified. Preterm infants were stratified into those with and without structural brain injury. We further categorized preterm infants by brain injury severity: moderate-severe and mild. We studied 78 preterm infants: 31 without brain injury and 47 with brain injury (29 with mild and 18 with moderate-severe injury). Global CBF showed a borderline significant increase with increasing gestational age at birth (P = .05) and trended lower in preterm infants with brain injury (P = .07). Similarly, regional CBF was significantly lower in the right thalamus and midpons (P < .05) and trended lower in the midtemporal, left thalamus, and anterior vermis regions (P < .1) in preterm infants with brain injury. Regional CBF in preterm infants with moderate-severe brain injury trended lower in the midpons, right cerebellar hemisphere, and dentate nuclei compared with mild brain injury (P < .1). In addition, a significant, lower regional CBF was associated with ventilation, sepsis, and cesarean delivery (P < .05). We report early disturbances in global and regional CBF in preterm infants following brain injury. Regional cerebral perfusion alterations were evident in the thalamus and pons, suggesting regional vulnerability of the developing cerebro-cerebellar circuitry.

Task related cerebral blood flow changes of patients with chronic fatigue syndrome: an arterial spin labeling study

ABSTRACT Purpose: One hallmark of chronic fatigue syndrome (ME/CFS) is task related worsening of fatigue. Global brain hypoperfusion, abnormal regional activation, and altered functional connectivity of brain areas associated with cognition and memory have been reported but remain controversial. Methods: We enrolled 17 female participants fulfilling the CDC Criteria for ME/CFS and 16 matched healthy controls (HC). Using a 3T-Phillips Achieva MRI-scanner, pseudo-continuous arterial spin-labeling (pCASL), was used to study the dynamics of regional cerebral blood flow (rCBF) and their relationship to mental fatigue in ME/CFS patients and HC during a demanding cognitive task, i.e. modified Paced-Auditory-Serial-Addition-Testing (PASAT). Results: ME/CFS subjects reported more fatigue than HC at baseline (p < .01). Global brain perfusion of ME/CFS and HC subjects was similar at rest. The PASAT resulted in significantly increased fatigue in ME/CFS participants and HC. Although not different between groups, overall CBF significantly increased over the first 3 min of the PASAT and then decreased thereafter. Regional CBF (rCBF) changes were significantly different between groups during the post-task recovery period. Whereas improvement of fatigue of ME/CFS subjects was associated with decreased rCBF in both superior temporal gyri (STG), precuneus, and fusiform gyrus, it was associated with increased rCBF in the same areas in HC. Conclusions: Our results suggest that ME/CFS is associated with normal global CBF at rest and during a strenuous task (PASAT); however rCBF of several brain regions associated with memory, goal-oriented attention, and visual function was differentially associated with recovery from fatigue in ME/CFS patients and HC.

UBC-Nepal expedition: The use of oral antioxidants does not alter cerebrovascular function at sea level or high altitude.

What is the central question of the study? Does the use of antioxidants alter cerebrovascular function and blood flow at sea level (344m) and/or high altitude (5050m)? What is the main finding and its importance? This is the first study to investigate whether antioxidant administration alters cerebrovascular regulation and blood flow in response to hypercapnia, acute hypoxia and chronic hypoxia in healthy humans. We demonstrate that an acute dose of antioxidants does not alter cerebrovascular function and blood flow at sea level (344m) or after 12days at high altitude (5050m). Hypoxia is associated with an increase in systemic and cerebral formation of free radicals and associated reactants that may be linked to impaired cerebral vascular function and neurological sequelae. To what extent oral antioxidant prophylaxis impacts cerebrovascular function in humans throughout the course of acclimatization to the hypoxia of terrestrial high altitude has not been examined. Thus, the purpose of the present study was to examine the influence of orally ingested antioxidants at clinically relevant doses (vitamins C and E and α-lipoic acid) on cerebrovascular regulation at sea level (344m; n=12; female n=2 participants) and at high altitude (5050m; n=9; female n=2) in a randomized, placebo-controlled and double-blinded crossover design. Hypercapnic and hypoxic cerebrovascular reactivity tests of the internal carotid artery (ICA) were conducted at sea level, and global and regional cerebral blood flow (CBF; i.e. ICA and vertebral artery) were assessed 10-12days after arrival at 5050m. At sea level, acute administration of antioxidants did not alter cerebral hypoxic cerebrovascular reactivity (pre versus post: 1.5±0.7 versus 1.2±0.8%∆CBF/-%∆SpO2; P=0.96) or cerebral hypercapnic cerebrovascular reactivity (pre versus post: 5.7±2.0 versus 5.8±1.9%∆CBF/∆mmHg; P=0.33). Furthermore, global CBF (P=0.43) and cerebral vascular conductance (ICA P=0.08; vertebral artery P=0.32) were unaltered at 5050m after antioxidant administration. In conclusion, these data show that an oral antioxidant cocktail known to attenuate systemic oxidative stress failed to alter cerebrovascular function at sea level and CBF during acclimatization to high altitude.

Hybrid PET/MRI imaging in healthy unsedated newborn infants with quantitative rCBF measurements using 15O-water PET

In this study, a new hybrid PET/MRI method for quantitative regional cerebral blood flow (rCBF) measurements in healthy newborn infants was assessed and the low values of rCBF in white matter previously obtained by arterial spin labeling (ASL) were tested. Four healthy full-term newborn subjects were scanned in a PET/MRI scanner during natural sleep after median intravenous injection of 14 MBq 15O-water. Regional CBF was quantified using a one-tissue-compartment model employing an image-derived input function (IDIF) from the left ventricle. PET rCBF showed the highest values in the thalami, mesencephalon and brain stem and the lowest in cortex and unmyelinated white matter. The average global CBF was 17.8 ml/100 g/min. The average frontal and occipital unmyelinated white matter CBF was 10.3 ml/100 g/min and average thalamic CBF 31.3 ml/100 g/min. The average white matter/thalamic ratio CBF was 0.36, significantly higher than previous ASL data. The rCBF ASL measurements were all unsuccessful primarily owing to subject movement. In this study, we demonstrated for the first time, a minimally invasive PET/MRI method using low activity 15O-water PET for quantitative rCBF assessment in unsedated healthy newborn infants and found a white/grey matter CBF ratio similar to that of the adult human brain.

Spatial Correlation of Pathology and Perfusion Changes within the Cortex and White Matter in Multiple Sclerosis.

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. 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. 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 (R2 ≤ 0.96, P < .006 and R2 ≤ 0.738, P < .006). The weak correlation between lobar WM and cortical GM volume loss and perfusion reduction suggests the independent pathophysiology of WM and cortical GM disease.

Short-term apparent brain tissue changes are contributed by cerebral blood flow alterations.

Structural MRI (sMRI)-identified tissue “growth” after neuropsychological training has been reported in many studies but the origins of those apparent tissue changes (ATC) still remain elusive. One possible contributor to ATC is brain perfusion since T1-weighted MRI, the tool used to identify ATC, is sensitive to perfusion-change induced tissue T1 alterations. To test the hypothetical perfusion contribution to ATC, sMRI data were acquired before and after short-term global and regional perfusion manipulations via intaking a 200 mg caffeine pill and performing a sensorimotor task. Caffeine intake caused a global CBF reduction and apparent tissue density reduction in temporal cortex, anterior cingulate cortex, and the limbic area; sensorimotor task induced CBF increase and apparent tissue increase in spatially overlapped brain regions. After compensating CBF alterations through a voxel-wise regression, the ATC patterns demonstrated in both experiments were substantially suppressed. These data clearly proved existence of the perfusion contribution to short-term ATC, and suggested a need for correcting perfusion changes in longitudinal T1-weighted structural MRI analysis if a short-term design is used.

Non-Ischemic Cerebral Energy Dysfunction at the Early Brain Injury Phase following Aneurysmal Subarachnoid Hemorrhage.

The pathophysiology of early brain injury following aneurysmal subarachnoid hemorrhage (SAH) is still not completely understood. Using brain perfusion CT (PCT) and cerebral microdialysis (CMD), we examined whether non-ischemic cerebral energy dysfunction may be a pathogenic determinant of EBI. A total of 21 PCTs were performed (a median of 41 h from ictus onset) among a cohort of 18 comatose mechanically ventilated SAH patients (mean age 58 years, median admission WFNS score 4) who underwent CMD and brain tissue PO2 (PbtO2) monitoring. Cerebral energy dysfunction was defined as CMD episodes with lactate/pyruvate ratio (LPR) >40 and/or lactate >4 mmol/L. PCT-derived global CBF was categorized as oligemic (CBF < 28 mL/100 g/min), normal (CBF 28-65 mL/100 g/min), or hyperemic (CBF 69-85 mL/100 g/min), and was matched to CMD/PbtO2 data. Global CBF (57 ± 14 mL/100 g/min) and PbtO2 (25 ± 9 mm Hg) were within normal ranges. Episodes with cerebral energy dysfunction (n = 103 h of CMD samples, average duration 7.4 h) were frequent (66% of CMD samples) and were associated with normal or hyperemic CBF. CMD abnormalities were more pronounced in conditions of hyperemic vs. normal CBF (LPR 54 ± 12 vs. 42 ± 7, glycerol 157 ± 76 vs. 95 ± 41 µmol/L; both p < 0.01). Elevated brain LPR correlated with higher CBF (r = 0.47, p < 0.0001). Cerebral energy dysfunction is frequent at the early phase following poor-grade SAH and is associated with normal or hyperemic brain perfusion. Our data support the notion that mechanisms alternative to ischemia/hypoxia are implicated in the pathogenesis of early brain injury after SAH.

ARTERIAL STIFFNESS IS ASSOCIATED WITH LOWER CEREBRAL BLOOD PERFUSION IN OLDER ADULTS

Arterial stiffness is an emerging risk factor for Alzheimer's disease and related dementias, partly through its novel associations with both cerebrovascular disease and β-amyloid deposition. Initial reports suggest that greater aortic stiffness may be related to lower cerebral perfusion in the brain. This study included participants from a randomized controlled clinical trial of exercise who received brain MRIs and cognitive testing before and after 6 months of aerobic training or stretching exercise. MRI included multi-phase pseudo-continuous arterial spin labeling to define cerebral blood flow in the whole brain gray matter (CBFgm). A subset of participants received baseline (n=17) and/or post-intervention (n=22) measures of central arterial stiffness using the AtCor SphygmoCor XCEL to obtain carotid-femoral pulse wave velocity (cfPWV). General linear models were used to assess associations between cfPWV and (global and voxel wise) cerebral blood flow with and without adjustment for age, gender, education, intracranial volume and APOE-4 status. Participants in this sample had a mean(SD) age of 67(9) years [range 51–89], 60% women, 19% were APOE-ε4 positive and all had at least an 12th grade education. Baseline cfPWV was negatively correlated with CBFgm (figure), showed regional specificity, and remained significant adjustment for covariates (beta = -4.3(1.8), p=0.04). Baseline and post intervention measures of cfPWV were highly correlated (rho=0.62, P<0.01) and showed similar negative associations with global CBFgm; however, change in cfPWV was not associated with changes global CBFgm (p=0.35). Correlations between global CBF and arterial stiffness by gender.

Hemodynamic Disturbances in the Early Phase After Subarachnoid Hemorrhage: Regional Cerebral Blood Flow Studied by Bedside Xenon-enhanced CT.

The mechanisms leading to neurological deterioration and the devastating course of delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH) are still not well understood. Bedside xenon-enhanced computerized tomography (XeCT) enables measurements of regional cerebral blood flow (rCBF) during neurosurgical intensive care. In the present study, CBF characteristics in the early phase after severe SAH were explored and related to clinical characteristics and early clinical course outcome. Patients diagnosed with SAH and requiring mechanical ventilation were prospectively enrolled in the study. Bedside XeCT was performed within day 0 to 3. Data from 64 patients were obtained. Median global CBF was 34.9 mL/100 g/min (interquartile range [IQR], 26.7 to 41.6). There was a difference in CBF related to age with higher global CBF in the younger patients (30 to 49 y). CBF was also related to the severity of SAH with lower CBF in Fisher grade 4 compared with grade 3. rCBF disturbances and hypoperfusion were common; in 43 of the 64 patients rCBF<20 mL/100 g/min was detected in more than 10% of the region-of-interest (ROI) area and in 17 patients such low-flow area exceeded 30%. rCBF was not related to the localization of the aneurysm; there was no difference in rCBF of ipsilateral compared with contralateral vascular territories. In patients who initially were in Hunt & Hess grade I to III, median global CBF day 0 to 3 was significantly lower for patients who were in poor neurological state at discharge compared with patients in good neurological state, 25.5 mL/100 g/min (IQR, 21.3 to 28.3) versus 37.8 mL/100 g/min (IQR, 30.5 to 47.6). CBF disturbances are common in the early phase after SAH. In many patients, CBF was heterogenic and substantial areas with low rCBF were detected. Age and CT Fisher grade were factors influencing global cortical CBF. Bedside XeCT may be a tool to identify patients at risk of deteriorating so they can receive intensified management, but this needs further exploration.