Significant Reduction In Cerebral Blood Flow Research Articles

Optimum duration of hyperventilation during electroencephalography

Hyperventilation (HV) is carried out for 3 minutes as a standard activation procedure in most routine electroencephalographic (EEG) procedures. The cerebral blood flow (CBF) reduction and the accompanying cerebral vasoconstriction caused by HV is believed to be the mechanism of EEG activation during HV. Some advocate for 5 minutes of HV, although the optimum duration is unknown. In this study, we measured the CBF continuously over the anterior temporal lobes using subdural probes, which use thermal diffusion flowmetry to measure CBF directly from the cerebral cortex. We sought to determine the duration of HV that produces the maximum reduction in CBF during routine HV in our epilepsy monitoring unit and prolonged the procedure for an additional 2 minutes for this study. Flowtronics® CBF probes were placed over the anterior temporal lobes in addition to the standard subdural strip placement for localization of their seizure focus in six patients who were candidates for epilepsy surgery. CBF was measured continuously for 2 minutes before and 5 minutes during HV for each patient. Time to reach maximum reduction of CBF for each attempt (11 temporal lobes) was computed. At 3 minutes, CBF reduction ranged from 11.6% to 40.0% from the pre-HV CBF level (mean 23.9%). At 5 minutes, CBF ranged from 14.3% to 42.0% (mean 25.7%). Six of the 11 measurements were steady or decreased slightly, and in the five other measurements, CBF showed a reverse trend after 3 minutes. A significant CBF reduction was attained in 3 minutes of HV in all trials. Continued HV after 3 minutes resulted in only a marginal (mean 1.8%) additional CBF reduction after 3 minutes. Thus, we propose that 3 minutes of HV is sufficient for EEG activation by the CBF criterion.

Altered Prefrontal Blood Flow Related With Mild Cognitive Impairment in Parkinson's Disease: A Longitudinal Study.

Cognitive impairment is a common non-motor symptom in Parkinson's disease (PD), with executive dysfunction being an initial manifestation. We aimed to investigate whether and how longitudinal changes in the prefrontal perfusion correlate with mild cognitive impairment (MCI) in patients with PD. We recruited 49 patients with PD with normal cognition and 37 matched healthy control subjects (HCs). Patients with PD completed arterial spin labeling MRI (ASL–MRI) scans and a comprehensive battery of neuropsychological assessments at baseline (V0) and 2-year follow-up (V1). HCs completed similar ASL–MRI scans and neuropsychological assessments at baseline. At V1, 10 patients with PD progressed to MCI (converters) and 39 patients remained cognitively normal (non-converters). We examined differences in the cerebral blood flow (CBF) derived from ASL–MRI and neuropsychological measures (a) between patients with PD and HCs at V0 (effect of the disease), (b) between V1 and V0 in patients with PD (effect of the disease progression), and (c) between converters and non-converters (effect of the MCI progression) using t-tests or ANOVAs with false discovery rate correction. We further analyzed the relationship between longitudinal CBF and neuropsychological changes using multivariate regression models with false discovery rate correction, focusing on executive functions. At V0, no group difference was found in prefrontal CBF between patients with PD and HCs, although patients with PD showed worse performances on executive function. At V1, patients with PD showed significantly reduced CBF in multiple prefrontal regions, including the bilateral lateral orbitofrontal, medial orbitofrontal, middle frontal, inferior frontal, superior frontal, caudal anterior cingulate, and rostral anterior cingulate. More importantly, converters showed a more significant CBF reduction in the left lateral orbitofrontal cortex than non-converters. From V0 to V1, the prolonged completion time of Trail Making Test-B (TMT-B) negatively correlated with longitudinal CBF reduction in the right caudal anterior cingulate cortex. The decreased accuracy of the Stroop Color-Word Test positively correlated with longitudinal CBF reduction in the left medial orbitofrontal cortex. In addition, at V1, the completion time of TMT-B negatively correlated with CBF in the left caudal anterior cingulate cortex. Our findings suggest that longitudinal CBF reduction in the prefrontal cortex might impact cognitive functions (especially executive functions) at the early stages of PD.

Investigating the association between depressive disorders and cerebral haemodynamics

AimsAlterations in cerebral blood flow (CBF) may contribute to the development of depression, and serve as a novel biomarker. The aim of this review is to summarise and synthesise the available evidence on alterations in cerebral haemodynamics in depressive disorders relative to healthy control populations.MethodMEDLINE (1946- present), EMBASE (1947– present), Web of Science (1970–present), PsycINFO (1984–present), CINAHL (1976–present) and CENTRAL were searched using a predefined search strategy. Studies which compared the cerebral haemodynamics of adult patients (>18 years old) with depressive disorders against healthy controls (HC), by any imagining modality, were included. Studies with varying severity and chronicity of depressive disorder were included. A meta-analysis was conducted in four groups: 1) CBF (ml/min/100g) 2) Cerebral blood flow velocity (CBFv) (cm/s) 3) Combined CBF and CBFv 4) Ratio of uptake of radiotracer. A random effects model was used and heterogeneity and publication bias were assessed. Data are presented as mean difference (MD) or standardised mean difference (SMD) and 95% confidence interval (95% CI). A narrative synthesis of the remaining studies was performed.Result87 studies met the inclusion criteria. CBF (ml/min/100g) was significantly reduced in patients with depression compared to HC (15 studies, 538 patients, 416 HC, MD: −2.24 (95% CI −4.12, −0.36), p = 0.02, I2 = 64%). There were no statistically significant differences between patients and controls in the other three outcomes. CBFv (cm/s): 6 studies, 305 patients, 198 HC, MD: −1.23 (95% CI −6.10, 3.64, p = 0.62, I2 = 65%. Combined CBF and CBFv: 20 studies, 804 patients, 573 HC, SMD: −0.16 (95% CI −0.32, 0.01), p = 0.06 I2 = 51%. Ratio of uptake of radiotracer: 3 studies, 60 patients, 53 HC, MD: −0.11 (95% CI −0.11, 0.11), p = 1.00, I2 = 0%). The narrative synthesis revealed varying results, with many studies identifying a decrease in CBF in depressed patients compared to controls, but other studies identifying an increase, or mixed results. Multiple regions of impairment were identified, including the anterior cingulate cortex and prefrontal cortex.ConclusionThere was a statistically significant reduction in CBF in depressed patients compared to controls. The narrative synthesis revealed varying results, however specific regions of interest have been identified. Further research is needed to explore the effect of antidepressant medication, utilising different imaging modalities, and at different levels of disease severity.

211-OR: Differential Cerebral Blood Flow in Controlled and Uncontrolled Patients with Type 2 Diabetes Mellitus

Introduction: Patients with type 2 diabetes mellitus (T2DM) show variable brain tissue changes and mood and cognitive symptoms, which may result from altered cerebral blood flow (CBF). However, the regional CBF status in controlled and uncontrolled T2DM patients remains unclear, which can be examined with arterial spin labeling (ASL) imaging. Our aim was to examine regional CBF between controlled and uncontrolled T2DM patients using ASL imaging procedures. Methods: We collected hemoglobin A1c (A1C) data and 3D pseudo-continuous ASL data from 32 T2DM patients (16 controlled [A1C < 7%], age, 56.5±6.5 years; BMI, 29.6±6.2 kg/m2; 8 female; 16 uncontrolled [A1C ≥ 7%], age, 57.6±7.5 years; BMI, 30.0±5.1 kg/m2; 11 female) using a 3.0-Tesla MRI. A1C was measured by point-of-care testing. Whole-brain CBF maps were calculated, normalized to a common space, smoothed, and compared between groups (controlled T2DM patients vs. uncontrolled T2DM patients) using analysis of covariance (SPM12; covariates, age and sex; p<0.05). Results: No significant differences in age or sex appeared between groups. Multiple brain areas showed decreased CBF values in the cingulate, caudate, putamen, insula, hippocampus, amygdala, thalamus, hypothalamus, midbrain, cerebellum, prefrontal and frontal, and temporal cortices in uncontrolled T2DM patients over controlled T2DM patients. However, few brain sites in controlled T2DM patients, including the cerebellum, pons, medulla, parahippocampal gyrus, and temporal cortices showed reduced CBF over uncontrolled T2DM patients. Conclusion: Uncontrolled T2DM patients show significant reduction in CBF compared to controlled T2DM in areas that are involved in mood and cognition regulation. The findings suggest that uncontrolled levels may contribute to reduce regional CBF leading to site-specific tissue changes resulting to mood and cognition deficits in the condition. Disclosure S. E. Choi: None. B. Roy: None. M. Freeby: Research Support; Self; Abbott Diabetes, Novo Nordisk Inc. R. Kumar: None. Funding National Institutes of Health (1R01NR017190-03, 3R01NR017190-03S1)

M18. REDUCED CORTICAL CEREBRAL BLOOD FLOW IN FIRST EPISODE PSYCHOSIS PATIENTS

BackgroundAbnormal Cerebral Blood Flow (CBF) has been found in patients with chronic schizophrenia (SCZ), first-episode psychosis patients (FEP) and individuals at clinical high-risk (CHR). In particular, previous studies using Arterial Spin Labelling (ASL) found that SCZ have a global reduction of CBF in the cortex and increased CBF in the basal ganglia, the hippocampus, and the amygdala as compared with controls. To date, only one study investigated CBF using ASL in a small cohort of medicated FEP reporting increased CBF in the striatum and reduced frontal CBF as compared with controls. However, it is still not clear whether these abnormalities are related to antipsychotic treatment or rather they reflect a disease state independent from medication. Critically, clinical and pre-clinical evidence suggests that antipsychotics increase CBF, especially in the basal ganglia through dopamine D2 receptors blockade. Here, we assessed CBF differences between FEP and controls in a larger cohort of unmedicated or minimally treated patients. In addition, we tested the association between CBF abnormalities and clinical features.Methods26 FEP (13 medication-free, 9 antipsychotics naïve, 4 minimally treated) and 22 healthy controls (HC) were recruited. FEP and HC were matched for age and gender. Among FEP, 11 had a diagnosis of affective psychosis and 15 of non-affective psychosis. MRI scans were acquired using a GE MR750 3T scanner and a 12-channel head coil. ASL data was acquired using a pseudo-continuous ASL sequence (pCASL). Four control-label pairs were used. Quantification of the CBF data was made using a coil sensitivity map and a proton density image. CBF maps were normalized using non-linear registration and smoothed using a 6 mm full width at half maximum (FWHM) kernel. Grey matter CBF and regional CBF values in each Region of Interest (ROI) were extracted using individual grey matter images and WFU-Pickatlas ROIs with the MarsBar toolbox. Based on previous studies the following ROIs were selected: right and left hippocampus, right and left striatum, right and left frontal cortex. Whole-brain voxel-wise analysis was performed using a non-parametric independent t-test as implemented in FSL randomize (Threshold Free Cluster Enhancement, TFCE, and 5000 permutations). Bonferroni method was used to correct ROI analysis for multiple comparisons (alpha = 0.05, n = 7).ResultsSignificantly reduced CBF was found in FEP as compared with controls in total grey matter CBF (p = 0.004). Whole-brain voxel-wise analysis FEP-HC comparison revealed a widespread cortical reduction in large cortical clusters that encompass the occipital, parietal and frontal cortices (pFWE TFCE corrected < 0.05). ROI analysis revealed a significant reduction in CBF in the right frontal cortex (p = 0.002). A nominal significant reduction was also detected in the left frontal cortex (p = 0.014). No statistically significant differences were found in the other ROI considered (all p > 0.1). Sub-analysis after removing minimally treated patients did not change the results. Both global grey matter CBF and right frontal CBF were reduced in both affective and non-affective psychosis as compared with controls (p < 0.05), whereas no differences were detected between the two clinical groups.DiscussionOur results confirm earlier evidence on reduction of cortical perfusion in FEP. However, in contrast with previous studies, we did not detect any difference in striatal perfusion in our cohort of unmedicated/minimally treated patients. Hence, our results support the hypothesis that alteration in striatal perfusion are likely due to medication. Finally, our results suggest that CBF alterations might have a trans-diagnostic role in the pathophysiology of psychosis.

Is Hyperoxic Hyperventilation Caused by Reduced Carbon Dioxide Washout or Disturbed Brain Redox Homeostasis?

Under oxygen‐enriched conditions, humans present a biphasic ventilatory response that is initially characterized by reduced ventilation (V̇E) as hyperoxia (HX) inhibits the peripheral chemoreceptors. This short‐lived response precedes a paradoxical increase in V̇E that has been termed hyperoxic hyperventilation. Proposed but untested mechanisms for this paradoxical response include central chemoreceptor stimulation via either an increased cerebral partial pressure of carbon dioxide (CO2), which would result from reductions in cerebral blood flow (CBF) and brain CO2–[H+] washout, or (2) an HX‐induced exaggerated production of reactive oxygen species (ROS). To determine the mechanism behind the paradoxical increase in V̇E during hyperoxemia, we submitted 8 healthy young men (24±1 yrs) to 10‐min trials of poikilocapnic HX under (1) saline or (2) ascorbic acid (AA) infusion. V̇E, arterial (a) and internal right jugular venous (Jv) PO2, PCO2, pH, oxidant (8‐isoprostane), and antioxidant (AA) markers, as well as volumetric CBF (Doppler ultrasound) responses, were quantified at the last minute of each trial. Under saline infusion, HX evoked an increase in PaO2 followed by a hyperventilatory response (+3.0 ± 1.2 L/min, p = 0.003) and arterial hypocapnia (−2.4 ± 0.9 mmHg, p = 0.03). HX also evoked a small but significant reduction in CBF (−219.6 ± 36.8 mL/min, p = 0.001) that was followed by unchanged PjvCO2 (−0.1 ± 0.7 mmHg, p = 0.619) and pH (0.001 ± 0.005, p = 0.957). HX under saline infusion also provoked an increase in arterial 8‐isoprostane (18.6 ± 7.5 pg/mL, p = 0.04). On the other hand, intravenous AA augmented arterial antioxidant markers (+584.1 ± 64.6, p = 0.0001 vs. saline) and blunted not only the increase in arterial 8‐isoprostane (−10.7 ± 9.5 pg/mL, p = 0.204) but also the HX‐induced hyperventilation (+0.87 ± 0.64 L/min, p = 0.232) and the arterial hypocapnia (−1.7 ± 0.5 mmHg, p = 0.04 vs. saline) observed during infusion of saline. HX under AA infusion also blunted CBF hypoperfusion (−41.8 ± 26.3 mL/min, p = 0.001 vs. saline) that, in turn, was followed by increases in PjvO2 (+5.3 ± 0.7 mmHg, p = 0.006 vs. saline), PjvCO2 (+1.1 ± 0.50 mmHg, p = 0.03 vs. saline) and a reduction in pH (−0.012 ± 0.004, p = 0.01) that may be explained by the Haldane effect. These findings suggest that hyperoxic hyperventilation is not a consequence of an increased cerebral CO2 partial pressure and a reduced brain CO2–[H+] washout but mediated by central chemoreceptor stimulation likely evoked by excessive production of ROS.Support or Funding InformationSupport: FaperRJ, CNPq, CAPES

Significant localized reduction in cerebral blood flow (CBF) in regions relevant to cognitive function with enzalutamide (ENZA) compared to darolutamide (DARO) and placebo (PBO) in healthy volunteers.

326 Background: DARO is an oral androgen receptor antagonist with a unique structure and a low blood–brain barrier penetrance noted in rodents. Here we compare CBF following administration of DARO, ENZA, and PBO using arterial spin labelled magnetic resonance imaging (ASL-MRI) in humans. Methods: This phase I, randomized, PBO-controlled, 3-period crossover study investigated drug-induced changes in CBF for brain grey matter and for specific regions related to cognitive function in healthy males (age 19–44). Twenty-three participants received a single oral dose of DARO, ENZA, or PBO at 6-week intervals at similar unbound concentrations . An ASL-MRI scan was performed ~4 hours after each dose. Blood samples for drug analysis and physiological measures were collected prior to drug administration and immediately post-scan. ASL data were preprocessed and statistical parametric modelling was used for treatment comparisons (paired t-tests). Whole-brain results were considered significant after correction for multiple comparisons. A linear mixed effects model was used for predetermined region of interest (ROI) analysis, with physiological parameters as nuisance regressors. Results: Drug-concentration data confirmed similar unbound exposure during MRI scans and a complete washout between treatments. No unexpected safety concerns were noted in the study. Whole-brain analysis showed a significant localized 5.2% reduction in CBF for ENZA in temporo-occipital cortices but no significant CBF reduction with DARO compared to PBO. A significant 5.9% localized reduction in CBF was measured for ENZA vs DARO. ROI analysis showed a significant reduction in CBF for ENZA vs PBO (p = 0.045) and for ENZA vs DARO (p = 0.037) in the left and right dorsolateral prefrontal cortices, respectively. A significant reduction was noted in CBF for ENZA vs PBO in right amygdala (p = 0.047). Conclusions: Compared to PBO and DARO, significant localized reductions in CBF were noted for ENZA. These results may be relevant to cognitive function (executive function, memory, and anxiety) with extended treatment and warrant further investigation. Clinical trial information: NCT03704519.

Misery perfusion and amyloid deposition in atherosclerotic major cerebral artery disease.

Although experimental studies have shown that global cerebral hypoperfusion leads to amyloid deposition in the hemisphere with carotid artery occlusion in rodents, the results of such occurrence are controversial in humans. Hence, we aim to determine whether global cerebral hypoperfusion leading to decreased blood flow relative to metabolic demand [increased oxygen extraction fraction (OEF), misery perfusion] is associated with increases in amyloid deposition in the hemisphere with atherosclerotic major cerebral artery disease in patients. We evaluated the distribution of β-amyloid plaques using positron emission tomography and a [18F]-pyridylbenzofuran derivative (18F-FPYBF-2) in 13 patients with unilateral atherosclerotic disease of the internal carotid artery (ICA) or middle cerebral artery (MCA) disease and no cortical infarction. The distribution volume ratio (DVR) of 18F- FPYBF-2 was calculated using dynamic data and Logan graphical analysis with reference tissue and was correlated with the cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2), and OEF, obtained from 15O-gas PET. The mean cortical value was calculated as the mean value within the frontal, posterior cingulate, precuneus, parietal, and lateral temporal cortical regions. Significant reductions in CBF and CMRO2 and increases in OEF were found in the hemisphere ipsilateral to the arterial lesion compared with the contralateral hemisphere. There was no significant difference for 18F-FPYBF-2 DVR between hemispheres. The ipsilateral to contralateral ratio of the 18F- FPYBF-2 DVR was increased in 3 patients, while the ipsilateral to contralateral OEF ratio was increased in 4 patients. The incidence of an increased hemispheric DVR ratio was significantly higher in patients with an increased hemispheric OEF ratio (3/4) than in patients without (0/9) (p < 0.02). Although the 18F- FPYBF-2 DVR in the ipsilateral hemisphere was positively correlated with OEF after adjustment for the 18F- FPYBF-2 DVR in the contralateral hemisphere using multiple regression analysis (p < 0.05), the contribution rate of OEF was small (R2 = 5.5%). Only one of the 4 patients with an increased hemispheric OEF ratio showed amyloid positivity based on the DVR value. In atherosclerotic major cerebral artery disease, misery perfusion accompanied only small increases of amyloid deposition at best. Misery perfusion was not associated with amyloid positivity.

Sensitivity of Multiphase Pseudocontinuous Arterial Spin Labelling (MP pCASL) Magnetic Resonance Imaging for Measuring Brain and Tumour Blood Flow in Mice.

Brain and tumour blood flow can be measured noninvasively using arterial spin labelling (ASL) magnetic resonance imaging (MRI), but reliable quantification in mouse models remains difficult. Pseudocontinuous ASL (pCASL) is recommended as the clinical standard for ASL and can be improved using multiphase labelling (MP pCASL). The aim of this study was to optimise and validate MP pCASL MRI for cerebral blood flow (CBF) measurement in mice and to assess its sensitivity to tumour perfusion. Following optimization of the MP pCASL sequence, CBF data were compared with gold-standard autoradiography, showing close agreement. Subsequently, MP pCASL data were acquired at weekly intervals in models of primary and secondary brain tumours, and tumour microvessel density was determined histologically. MP pCASL measurements in a secondary brain tumour model revealed a significant reduction in blood flow at day 35 after induction, despite a higher density of blood vessels. Tumour core regions also showed reduced blood flow compared with the tumour rim. Similarly, significant reductions in CBF were found in a model of glioma 28 days after tumour induction, together with an increased density of blood vessels. These findings indicate that MP pCASL MRI provides accurate and robust measurements of cerebral blood flow in naïve mice and is sensitive to changes in tumour perfusion.

5-HT6 receptor agonist and antagonist modulates ICV-STZ-induced memory impairment in rats.

5-HT6 receptors are mainly expressed in brain areas associated with learning and memory. Several studies have reported procognitive effects of both 5-HT6 agonist and antagonists. However, the exact mechanism 5-HT6 receptor modulation has not been properly studied especially in the context of cholinergic functions, cerebral blood flow (CBF), brain-derived neural factor (BDNF), oxidative stress, and behavioral changes. In the present study, memory impairment was induced in albino Wistar rats by two doses of intracerebroventricular (ICV) injection of streptozotocin (STZ, 3mg/kg) on first and third day. These rats were evaluated in a battery of behavioral tasks after 14days from the first day of ICV-STZ. Significant memory impairment was seen when ICV-STZ induced rats are assessed by Morris water maze, novel object recognition, social recognition, and passive avoidance tests. There was a significant reduction in CBF, increased oxidative stress (MDA, GSH, and ROS), acetylcholinesterase (AChE) activity, and a decrease in BDNF. Treatment with selective 5-HT6 agonist EMD-386088 (5mg/kg) and antagonist SB-399885 (10mg/kg) prevented ICV-STZ-induced memory impairment when assessed by behavioral tests. Treatment with 5-HT6 ligands significantly prevented the change in CBF and BDNF. Further, protected from MDA and ROS and decreasing GSH in the brain compared to ICV-STZ rats. The rice in brain AChE activity was normalized by both ligands. The changes in locomotor activity by EMD-386088 and SB-399885 treatment were negligible. Thefindings in this studysupport the therapeutic potential of 5-HT6 receptor ligands in the treatment of cognitive dysfunction.

Cerebral blood flow changes during tilt table testing in healthy volunteers, as assessed by Doppler imaging of the carotid and vertebral arteries

ObjectivesUsing different techniques, reduction of cerebral blood flow (CBF) during orthostatic stress were demonstrated. One study reported flow reduction of the right internal carotid (ICA) and vertebral (VA) artery during orthostatic stress by Doppler imaging, with different effects on the 2 vessels. Global CBF changes, using this technique, have not been reported. Therefore, flow of the ICA, VA and global CBF were measured during head-up tilt testing. Methods33 healthy volunteers underwent tilt testing. At three time points (supine, half way and at the end of the test) Doppler imaging of the ICA and VA was performed, as well as PetCO2 measurements. ResultsGlobal CBF was significantly reduced by 4.5 ± 2.8% halfway the test and by 6.0 ± 3.4% at the end. All 4 artery flows were significantly reduced during the tilt, without differences between them. Despite small changes in PetCO2 there was a significant relation between de CBF decrease and PetCO2 decrease (p < 0.05). ConclusionsOrthostatic stress in HV results in a small but significant reduction of CBF by a homogenous reduction in the four cerebral vessels and is modulated by PetCO2 changes. SignificanceCBF changes can be measured during tilt testing using Doppler VA and ICA imaging.

Homoeopathic medicine Mercurius solubilis treatment improves cerebral blood flow and memory in experimentally induced Dementia in rats

Background: Mercurius solubilis (Merc. sol) is a known, accepted homoeopathic medicine for the treatment of various mouth, throat, eye, and ear infections. Previous studies suggested that Merc. sol has anti-inflammatory properties which could be beneficial in memory impairment. Objective: The present study was designed to investigate the effect of Merc. sol on learning and memory and cerebral blood flow (CBF) in the rat model of impaired learning and memory function induced by intracerebroventricularly (ICV) administered streptozotocin (STZ). Materials and Methods: The different potencies of Merc. sol (6, 30, 200, and 1M) were given for 17 days in memory-impaired rats, induced by ICV administration of STZ (3 mg/kg). The Morris water maze test was used to evaluate the learning and memory function on the 14th, 15th, and 16th day. The laser doppler flow meter was used to measure CBF on the 17th day. Results: There was a significant reduction in CBF along with learning and memory functions in STZ (ICV)-treated rats, which were significantly attenuated by the treatment of Merc. sol at all potencies (6, 30, 200, and 1M). Conclusion: Our results demonstrated the effectiveness of Merc. sol in improving memory function and CBF. Thus, it could be used as a therapeutic agent in dementia.

The reduction of regional cerebral blood flow in normal-appearing white matter is associated with the severity of white matter lesions in elderly: a Xeon-CT study.

White matter lesions (WMLs) in normal elderly are related to chronic ischemia, and progression of WML occurs mostly in moderate to severe disease. However, the mechanism is uncertain. Thus, we enrolled fifty-six normal elderly patients without large artery disease. The severity of WML on MRI was graded as grade 0, I, II and III using the modified Fazekas scale. Cerebral blood flow (CBF) was measured by Xenon-CT. We found that CBF (mL/100 g/min) within periventricular lesions and in the right and left centrum semiovales were 20.33, 21.27 and 21.03, respectively, in group I; 16.33, 15.55 and 15.91, respectively, in group II; and 14.05, 14.46 and 14.23, respectively, in group III. CBF of normal-appearing white matter (NAWM) around periventricular areas and in the right and left centrum semiovales were 20.79, 22.26 and 22.15, respectively, in group 0; 21.12, 22.17 and 22.25, respectively, in group I; 18.02, 19.45 and 19.62, respectively, in group II; and 16.38, 18.18 and 16.74, respectively, in group III. Significant reductions in CBF were observed not only within lesions but also in NAWM surrounding the lesions. In addition, CBF was reduced significantly within lesions compared to NAWM of the same grade. Furthermore, CBF was reduced significantly in NAWM in grades II and III when compared to grades 0 and I. Our finding indicates that ischemia may play a role in the pathogenesis of WML. Additionally, our finding provides an alternative explanation for finding that the progression of WML occurred more commonly in patients with moderate to severe WML.

Cathodal transcranial direct current stimulation induces regional, long-lasting reductions of cortical blood flow in rats

Objective:Transcranial direct current stimulation (tDCS) induces polarity-specific changes of cerebral blood flow (CBF). To determine whether these changes are focally limited or if they incorporate large cortical regions and thus have the potential for a therapeutic application, we investigated the effects of cathodal tDCS on CBF in an established tDCS rat model with particular attention to the spatial extension in CBF changes using laser Doppler blood perfusion imaging (LDI).Methods:Twenty-one Sprague Dawley rats received a single 15-minute session of cathodal tDCS at current intensities of 200, 400, 600, or 700 μA applied over electrode contact areas (ECA) of 3·5, 7·0, 10·5, or 14·0 mm2. One animal died prior to the stimulation. Cerebral blood flow was measured prior and after tDCS with LDI in three defined regions of interest (ROI) over the stimulated left hemisphere (region anterior to ECA – ROI 1, ECA – ROI 2, region posterior to ECA – ROI 3).Results:A regional decrease in CBF was measured after cathodal tDCS, the extent of the decrease depending on the current density applied. The most effective and spatially limited reduction in CBF (up to 50%, lasting as long as 90 minutes) was found after the application of 600 μA over an ECA of 10·5 mm2. This significant reduction in CBF even lasted up to 90 minutes in distant cortical areas (ROI 1 and 3) that were not directly related to the ECA (ROI 2).Discussion:Cathodal tDCS induces a regional, long-lasting, reversible decrease in CBF that is not limited to the region to which tDCS is applied.

Regional Cerebral Perfusion Alterations in Patients with Mild Cognitive Impairment and Alzheimer Disease Using Dynamic Susceptibility Contrast MRI

The purpose of this study was to assess regional cerebral perfusion distribution in patients with Alzheimer disease (AD) or mild cognitive impairment (MCI) using dynamic susceptibility contrast magnetic resonance imaging. Regional changes of perfusion were evaluated in 34 patients with AD, 51 patients with MCI, and 23 healthy controls (HCs). Using region of interest analyses, regional cerebral blood flow (CBF), cerebral blood volume, and mean transit time were measured bilaterally in the hippocampus; the temporal, temporoparietal, frontal, and sensomotoric cortices; the anterior and posterior cingulate gyri; the lentiform nucleus; and the cerebellum. A significant reduction of CBF in patients with AD compared to HCs was shown in the frontal and temporoparietal cortices bilaterally, the lentiform nuclei bilaterally, the left posterior cingulate gyrus, and the cerebellum. Compared with patients with MCI, patients with AD presented a reduction of CBF in the frontal cortices bilaterally, the left temporoparietal cortex, and the left anterior and posterior cingulate gyrus. In both hippocampi and the posterior cingulate gyrus, a trend to a slight increase of CBF in patients with MCI was noticed with a decrease in patients with AD. Using dynamic susceptibility contrast magnetic resonance imaging, pathologic alterations of regional brain perfusion can be demonstrated in patients with AD compared to patients with MCI or HCs.

Preservation of the metabolic rate of oxygen in preterm infants during indomethacin therapy for closure of the ductus arteriosus

The aim of this study was to assess and quantify the effects of indomethacin on cerebral blood flow (CBF), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO2) in preterm infants undergoing treatment for a patent ductus arteriosus (PDA). CBF and CMRO2 were measured before and after the first dose of a 3-d course of indomethacin to close hemodynamically significant PDA in preterm neonates. Indocyanine-green (ICG) concentration curves were acquired before and after indomethacin injection to quantify CBF and CMRO2. Eight preterm neonates (gestational age, 27.6 ± 0.5 wk; birth weight, 992 ± 109 g; 6 males:2 females) were treated at a median age of 4.5 d (range, 4-21 d). Indomethacin resulted in an average CBF decrease of 18% (pre- and post-CBF = 12.9 ± 1.3 and 10.6 ± 0.8 ml/100 g/min, respectively) and an OEF increase of 11% (pre- and post-OEF = 0.38 ± 0.02 and 0.42 ± 0.02, respectively) but no significant change in CMRO2 (pre- and post-CMRO2 = 0.83 ± 0.07 and 0.76 ± 0.07 ml O2/100 g/min, respectively). Corresponding mean blood pressure (BP), arterial oxygen saturation (SaO2), heart rate, and end-tidal carbon dioxide tension levels remained unchanged. Indomethacin resulted in significant reduction in CBF but did not alter CMRO2 because of a compensatory increase in OEF.

Heterogeneity of Cortical Lesions in Multiple Sclerosis: An MRI Perfusion Study

In this study, dynamic susceptibility contrast-magnetic resonance imaging (DSC-MRI) was used to quantify the cerebral blood flow (CBF), the cerebral blood volume (CBV), and the mean transit time (MTT) and to analyze the changes in cerebral perfusion associated with the cortical lesions in 44 patients with relapsing-remitting multiple sclerosis. The cortical lesions showed a statistically significant reduction in CBF and CBV compared with the normal-appearing gray matter, whereas there were no significant changes in the MTT. The reduced perfusion suggests a reduction of metabolism because of the loss of cortical neurons. A small population of outliers showing an increased CBF and/or CBV has also been detected. The presence of hyperperfused outliers may imply that perfusion could evolve during inflammation. These findings show that perfusion is altered in cortical lesions and that DSC-MRI can be a useful tool to investigate more deeply the evolution of cortical lesions in multiple sclerosis.

Effect of angiotensin II on spatial memory, cerebral blood flow, cholinergic neurotransmission, and brain derived neurotrophic factor in rats

Studies have shown the involvement of angiotensin II (Ang II) in neurobehavioral aspects, but the exact role of Ang II in memory is still ambiguous. This study explored the effect of central Ang II on spatial memory along with cholinergic neurotransmission, brain energy metabolism, cerebral blood flow (CBF), and brain-derived neurotrophic factor (BDNF) in rats. Spatial memory was evaluated by Morris water maze (MWM) after Ang II (ICV) administration in male Sprague-Dawley rats. CBF was measured by laser Doppler flowmetry. Oxidative stress adenosine triphosphate (ATP), BDNF, acetylcholinesterase (AChE), and acetylcholine (ACh) were estimated in the cortex and hippocampus at 1, 24, and 48h after Ang II administration. The effect of AT1 and AT2 receptor blocker (candesartan and PD123,319, respectively), AChE inhibitor (donepezil), and antioxidant melatonin was studied on memory, CBF, and biochemical parameters. Ang II caused spatial memory impairment by affecting acquisition, consolidation, and recall in the MWM test along with a significant reduction in CBF. Ang II significantly reduced ACh level and caused oxidative stress in the rat brain 1h post-injection. No significant change was observed in BDNF, AChE, and ATP level. Candesartan and donepezil prevented Ang II-induced memory impairment, reduction in CBF and ACh level. However, PD123,319 and melatonin failed to prevent Ang II-induced memory impairment but improved CBF partially. This study suggests that Ang II, via the AT1 receptor, affects spatial memory formation, CBF, and ACh level while AT2 receptor has no significant role.

Detection of symptomatic vasospasm after subarachnoid haemorrhage: initial findings from single time-point and serial measurements with arterial spin labelling

To detect symptomatic hemispheres during the postoperative course of subarachnoid haemorrhage (SAH) using arterial spin labelling (ASL). Eighteen patients with aneurysmal SAH were included; four exhibited symptomatic vasospasm postoperatively. All patients underwent ASL on days 9-10 (single time-point ASL). Nine patients underwent serial measurements of ASL (serial ASL) on days 1-2, 9-10 and 13-21, and seven patients also underwent imaging on days 4-7. CBF in the posterior part of the MCA territory was measured, and the ipsilateral/contralateral ratio of CBF was calculated. Differences between symptomatic hemispheres and others underwent ROC analysis. Single time-point ASL revealed that CBF(day9-10) and CBF(i/c_day9-10) were significantly lower in symptomatic hemispheres than in asymptomatic hemispheres (P < 0.001). Serial ASL was significantly decreased on CBF(day4-7) compared with CBF(day1-2) and on CBF(day9-10) compared with CBF(day4-7), and significantly increased on CBF(day13-21) compared with CBF(day9-10). ROC analysis of single time-point ASL revealed that AUC for CBF(day9-10) was 0.95, significantly higher than CBF(i/c_day9-10) (P < 0.001). ROC analysis of serial ASL showed that AUC for CBF(day9-10) was 0.93 and significantly higher than CBF(day9-10/day1-2) and CBF(i/c_day9-10) (P < 0.001). Single time-point ASL revealed significant CBF reduction in symptomatic hemispheres compared with asymptomatic hemispheres. Serial ASL showed time-dependent CBF changes after SAH. • MR arterial spin labelling (ASL) can non-invasively assess cerebral blood flow (CBF) • ASL revealed significant CBF reduction in symptomatic hemispheres compared with asymptomatic hemispheres • Serial ASL measurements enable observation of time-dependent CBF changes after SAH • ASL is non- invasive and suitable for serial repeated examinations.

Central angiotensin converting enzyme facilitates memory impairment in intracerebroventricular streptozotocin treated rats

Preclinical and clinical studies indicated involvement of renin angiotensin system (RAS) in memory functions. However, exact role of RAS in cognition is still ambiguous. Our aim was to explore how angiotensin converting enzyme (ACE) modulates memory in experimental model of memory impairment. Memory deficit was induced by intracerebroventricular administration of streptozotocin (STZ, 3 mg/kg) in rats. Perindopril, an ACE inhibitor, was given for 21 days and memory function was evaluated by Morris water maze test. Cerebral blood flow (CBF) was measured by laser doppler flowmetry. The biochemical and expression studies were done in cortex and hippocampus of rat brain after the completion of behavioral studies. STZ caused impairment in memory along with significant reduction in CBF, ATP level and elevated oxidative and nitrosative stress. The activity and mRNA expression of acetylcholinesterase (AChE) and ACE were also increased in rat brain regions following STZ administration. However, serum ACE activity remained unaffected. Treatment with perindopril dose dependently improved memory by increasing energy metabolism and CBF. Perindopril also decreased oxidative and nitrosative stress, activity and mRNA expression of AChE and ACE in STZ treated rat. Further, ACE inhibition mitigated STZ induced neurodegeneration as observed in histopathological studies. Moreover, perindopril per se improved memory and CBF, decreased oxidative stress with no effect on AChE activity and expression. However, perindopril per se significantly reduced ACE activity but increased mRNA expression of ACE in rat brain. These results suggest that ACE occupies a pivotal role in STZ induced memory deficit thus implicating central RAS in cognition.