Elevated Cerebral Blood Flow Research Articles

Cerebral microvascular changes in healthy carriers of the APOE-ɛ4 Alzheimer's disease risk gene.

APOE-ɛ4 is a genetic risk factor for Alzheimer's disease (AD). AD is associated with reduced cerebral blood flow (CBF) and with microvascular changes that limit the transport of oxygen from blood into brain tissue: reduced microvascular cerebral blood volume and high relative transit time heterogeneity (RTH). Healthy APOE-ɛ4 carriers reveal brain regions with elevated CBF compared with carriers of the common ɛ3 allele. Such asymptomatic hyperemia may reflect microvascular dysfunction: a vascular disease entity characterized by suboptimal tissue oxygen uptake, rather than limited blood flow per se. Here, we used perfusion MRI to show that elevated regional CBF is accompanied by reduced capillary blood volume in healthy APOE-ɛ4 carriers (carriers) aged 30-70 years compared with similarly aged APOE-ɛ3 carriers (noncarriers). Younger carriers have elevated hippocampal RTH and more extreme RTH values throughout both white matter (WM) and cortical gray matter (GM) compared with noncarriers. Older carriers have reduced WM CBF and more extreme GM RTH values than noncarriers. Across all groups, lower WM and hippocampal RTH correlate with higher educational attainment, which is associated with lower AD risk. Three days of dietary nitrate supplementation increased carriers' WM CBF but caused older carriers to score worse on two of six aggregate neuropsychological scores. The intervention improved late recall in younger carriers and in noncarriers. The APOE-ɛ4 gene is associated with microvascular changes that may impair tissue oxygen extraction. We speculate that vascular risk factor control is particularly important for APOE-ɛ4 carriers' healthy aging.

Elevated cerebral blood flow proxy with increased beta-amyloid burden in Alzheimer’s disease preclinical phase evaluated by dual-phase 18F-florbetaben positron emission tomography

This study investigated the earliest change of cerebral blood flow (CBF) and its relationship with β-amyloid (Aβ) burden in preclinical Alzheimer’s disease (AD) employing dual-phase 18F-florbetaben (FBB) PET. Seventy-one cognitively normal (NC) individuals were classified as Aβ negative (Aβ−NC) or positive (Aβ+NC) based on two different cutoff values: an SUVR of > 1.08 and a Centiloid scale of > 20. The PET scans were acquired in two phases: an early phase (0–10 min, eFBB) and a delayed phase (90–110 min, dFBB), which were averaged to generate single-frame images for each phase. Furthermore, an R1 parametric map was generated from the early phase data using a simplified reference tissue model. We conducted regional and voxel-based analyses to compare the eFBB, dFBB, and R1 images between the Aβ positive and negative groups. In addition, the correlations between the CBF proxy R1 and the dFBB SUVR were analyzed. The Aβ+NC group showed significantly higher dFBB SUVR in both the global cerebral cortex and target regions compared to the Aβ−NC group, while no significant differences were observed in eFBB SUVR between the two groups. Furthermore, the Aβ+NC group exhibited significantly higher R1 values, a proxy for cerebral perfusion, in both the global cerebral cortex and target regions compared to the Aβ−NC group. Significant positive correlations were observed between R1 and dFBB SUVR in both the global cerebral cortex and target regions, which remained significant after controlling for demographics and cognitive profiles, except for the medial temporal and occipital cortices. The findings reveal increased CBF in preclinical AD and a positive correlation between CBF and amyloid pathology. The positive correlation between R1 and amyloid burden may indicate a compensatory mechanism in the preclinical stage of Alzheimer’s disease, but to elucidate this hypothesis, further longitudinal observational studies are necessary.

Intracranial aneurysms in sickle cell disease are associated with hemodynamic stress and anemia

AbstractAlthough hemodynamic stress plays a key role in aneurysm formation outside of sickle cell disease (SCD), its role is understudied in patients with SCD. We hypothesized that tissue-based markers of hemodynamic stress are associated with aneurysm presence in a prospective SCD cohort. Children and adults with SCD, with and without aneurysms, underwent longitudinal brain magnetic resonance imaging/magnetic resonance angiography (MRA) to assess cerebral blood flow (CBF) and oxygen extraction fraction (OEF). Baseline characteristics were recorded. In the subgroup of adults, stepwise mixed-effect logistic regression examined clinical variables, CBF, and OEF as predictors of aneurysm presence. Cumulative rates of new aneurysm formation were estimated using Kaplan-Meier analyses. Forty-three aneurysms were found in 27 of 155 patients (17%). Most aneurysms were ≤3 mm and in the intracranial internal carotid artery. On univariate analysis, older age (P = .07), lower hemoglobin (P = .002), higher CBF (P = .03), and higher OEF (P = .02) were associated with aneurysm presence. On multivariable analysis, age and CBF remained independently associated with aneurysm presence. Seventy-six patients (49% of enrollment) received follow-up MRAs (median, 3.5 years). No aneurysm grew or ruptured, however, 7 new aneurysms developed in 6 patients. The 3-year cumulative rate of aneurysm formation was 3.5%. In 155 patients with SCD, 17% had intracranial aneurysms. Three-year aneurysm formation rate was 3.5%, although limited by small longitudinal sample size and short follow-up duration. Aneurysm presence was associated with elevated CBF in adults, as a tissue-based marker of cerebral hemodynamic stress. Future studies may examine the predictive role of CBF in aneurysm development in SCD.

Changes of cerebral structure and perfusion in subtypes of systemic sclerosis: a brain magnetic resonance imaging study.

The characteristics of brain impairment in different subtypes of systemic sclerosis (SSc) (dcSSc, diffuse cutaneous SSc; lcSSc, limited cutaneous SSc) remain unclear. This study aimed to characterize cerebral structure and perfusion changes in different subtype of SSc patients using magnetic resonance (MR) imaging. Seventy SSc patients (46.0 ± 11.7 years, 62 females) and 30 healthy volunteers (44.8 ± 13.7 years, 24 females) were recruited and underwent brain MR imaging and Montreal Cognitive Assessment (MoCA) test. Gray matter (GM) volumes were measured using voxel-based morphometry analysis on T1-weighted images. Voxel-based and regional cerebral blood flow (CBF) was calculated on arterial spin labelling images. The cerebral structural and perfusion measurements by MR imaging were compared among dcSSc, lcSSc and healthy subjects using one-way ANOVA. The correlations between clinical characteristics and MR imaging measurements were also analyzed. The dcSSc patients exhibited a significant reduction in GM volume in the para-hippocampal region (cluster p < 0.01, FWE corrected) compared with healthy volunteers. Whereas, SSc patients, particularly lcSSc patients, showed elevated CBF in cerebellum, insula, cerebral cortex, and subcortical structures (regional analyses: all p < 0.05; voxel-based analyses: cluster p < 0.01, FWE corrected). Furthermore, clinical characteristics of modified Rodnan skin score (mRSS) (r value ranged from -0.29 to -0.45), MoCA scores (r = 0.40) and antinuclear antibody (ANA) positivity (r=-0.33) were significantly associated with CBF in some regions (all p < 0.05). The manifestations of brain involvement vary among different subtypes of SSc. In addition, severe skin sclerosis may indicate higher risk of brain involvement in SSc patients.

Hydroxyurea to prevent brain injury in children with sickle cell disease (HU Prevent)-A randomized, placebo-controlled phase II feasibility/pilot study.

Central nervous system (CNS) injury is common in sickle cell disease (SCD) and occurs early in life. Hydroxyurea is safe and efficacious for treatment of SCD, but high-quality evidence from randomized trials to estimate its neuroprotective effect is scant. HU Prevent was a randomized (1:1), double-blind, phase II feasibility/pilot trial of dose-escalated hydroxyurea vs. placebo for the primary prevention of CNS injury in children with HbSS or HbS-β0-thalassemia subtypes of SCD age 12-48 months with normal neurological examination, MRI of the brain, and cerebral blood flow velocity. We hypothesized that hydroxyurea would reduce by 50% the incidence of CNS injury. Two outcomes were compared: primary-a composite of silent cerebral infarction, elevated cerebral blood flow velocity, transient ischemic attack, or stroke; secondary-a weighted score estimating the risk of suffering the consequences of stroke (the Stroke Consequences Risk Score-SCRS), based on the same outcome events. Six participants were randomized to each group. One participant in the hydroxyurea group had a primary outcome vs. four in the placebo group (incidence rate ratio [90% CI] 0.216 [0.009, 1.66], p = .2914) (~80% reduction in the hydroxyurea group). The mean SCRS score was 0.078 (SD 0.174) in the hydroxyurea group, 0.312 (SD 0.174) in the placebo group, p = .072, below the p-value of .10 often used to justify subsequent phase III investigations. Serious adverse events related to study procedures occurred in 3/41 MRIs performed, all related to sedation. These results suggest that hydroxyurea may have profound neuroprotective effect in children with SCD and support a definitive phase III study to encourage the early use of hydroxyurea in all infants with SCD.

Cerebral Blood Flow and Mood in Adolescents With Bipolar Disorder

ObjectiveMultiple prior studies have examined cerebral blood flow (CBF) in relation to mood states in adults with bipolar disorder (BD). This study examined CBF related to mood states in adolescents early in the course of BD, about which little is known. MethodThe study recruited 155 adolescents (mean [SD] age = 17.23 [1.62] years), including 81 with BD (32 hypomanic/mixed, 25 depressed, 24 euthymic) and 74 healthy controls. CBF was ascertained using pseudocontinuous arterial spin labeling magnetic resonance imaging. Region-of-interest analysis (amygdala, anterior cingulate cortex, middle frontal gyrus) controlling for age, sex, and race was complemented by whole-brain voxel-wise analyses. Within-BD regression analysis using age and sex as covariates examined the association of mania and depression severity with CBF. ResultsIn region-of-interest analyses, there were no group differences in CBF. Within the overall BD group, higher depression scores were associated with lower anterior cingulate cortex CBF (β = −.27, p = .01). In corrected voxel-wise analyses, CBF in the euthymic BD group was significantly higher compared with healthy controls in temporal and precentral regions. ConclusionThe finding of elevated regional CBF in adolescents with euthymic BD diverges from prior findings of reduced regional CBF in adults with BD. Higher CBF in adolescents with euthymic BD may reflect a developmentally specific compensatory perfusion mechanism required to maintain euthymia. However, longitudinal studies are needed to understand the temporal association of CBF and mood state in adolescents with BD, ideally followed into adulthood. Diversity & Inclusion StatementWe worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented sexual and/or gender groups in science. We actively worked to promote sex and gender balance in our author group. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work.

Targeting blood brain barrier-Remote ischemic conditioning alleviates cognitive impairment in female APP/PS1 rats.

Alzheimer's disease (AD) is a significant global health concern, and it is crucial that we find effective methods to prevent or slow down AD progression. Recent studies have highlighted the essential role of blood vessels in clearing Aβ, a protein that contributes to AD. Scientists are exploring blood biomarkers as a potential tool for future AD diagnosis. One promising method that may help prevent AD is remote ischemic conditioning (RIC). RIC involves using sub-lethal ischemic-reperfusion cycles on limbs. However, a comprehensive understanding of how RIC can prevent AD and its long-term effectiveness is still lacking. Further research is essential to fully comprehend the potential benefits of RIC in preventing AD. Female wild-type (WT) and APP/PS1 transgenic rats, aged 12 months, underwent ovariectomy and were subsequently assigned to WT, APP/PS1, and APP/PS1 + RIC groups. RIC was conducted five times a week for 4 weeks. The rats' depressive and cognitive behaviors were evaluated using force swimming, open-field tests, novel objective recognition, elevated plus maze, and Barnes maze tests. Evaluation of the neurovascular unit (NVU), synapses, vasculature, astrocytes, and microglia was conducted using immunofluorescence staining (IF), Western blot (WB), and transmission electron microscopy (TEM). Additionally, the cerebro-vasculature was examined using micro-CT, and cerebral blood flow (CBF) was measured using Speckle Doppler. Blood-brain barrier (BBB) permeability was determined by measuring the Evans blue leakage. Finally, Aβ levels in the rat frontal cortex were measured using WB, ELISA, or IF staining. RIC enhanced memory-related protein expression and rescued depressive-like behavior and cognitive decline in APP/PS1 transgenic rats. Additionally, the intervention protected NVU in the rat frontal cortex, as evidenced by (1) increased expression of TJ (tight junction) proteins, pericyte marker PDGFRβ, and glucose transporter 1 (GLUT1), as well as decreased VCAM1; (2) mitigation of ultrastructure impairment in neuron, cerebral vascular, and astrocyte; (3) upregulation of A2 astrocyte phenotype markers and downregulation of A1 phenotype markers, indicating a shift toward a healthier phenotype. Correspondingly, RIC intervention alleviated neuroinflammation, as evidenced by the decreased Iba1 level, a microglia marker. Meanwhile, RIC intervention elevated CBF in frontal cortex of the rats. Notably, RIC intervention effectively suppressed Aβ toxicity, as demonstrated by the enhancement of α-secretase and attenuation of β-secretase (BACE1) and γ- secretase and Aβ1-42 and Aβ1-40 levels as well. Chronic RIC intervention exerts vascular and neuroprotective roles, suggesting that RIC could be a promising therapeutic strategy targeting the BBB and NVU during AD development.

Loop gain response to increased cerebral blood flow at high altitude.

To compare loop gain (LG) before and during pharmacological increases in cerebral blood flow (CBF) at high altitude (HA). Loop gain (LG) describes stability of a negative-feedback control system; defining the magnitude of response to a disturbance, such as hyperpnea to an apnea in periodic breathing (PB). "Controller-gain" sensitivity from afferent peripheral (PCR) and central-chemoreceptors (CCR) plays a key role in perpetuating PB. Changes in CBF may have a critical role via effects on central chemo-sensitivity during sleep. Polysomnography (PSG) was performed on volunteers after administration of I.V. Acetazolamide (ACZ-10mg/kg) + Dobutamine (DOB-2-5 μg/kg/min) to increase CBF (via Duplex-ultrasound). Central sleep apnea (CSA) was measured from NREM sleep. The duty ratio (DR) was calculated as ventilatory duration (s) divided by cycle duration (s) (hyperpnea/hyperpnea + apnea), LG = 2π/(2πDR-sin2πDR). A total of 11 volunteers were studied. Compared to placebo-control, ACZ/DOB showed a significant increase in the DR (0.79 ± 0.21 vs 0.52 ± 0.03, P = 0.002) and reduction in LG (1.90 ± 0.23 vs 1.29 ± 0.35, P = 0.0004). ACZ/DOB increased cardiac output (CO) (8.19 ± 2.06 vs 6.58 ± 1.56L/min, P = 0.02) and CBF (718 ± 120 vs 526 ± 110ml/min, P < 0.001). There was no significant change in arterial blood gases, minute ventilation (VE), or hypoxic ventilatory response (HVR). However, there was a reduction of hypercapnic ventilatory response (HCVR) by 29% (5.9 ± 2.7 vs 4.2 ± 2.8 L/min, P = 0.1). Pharmacological elevation in CBF significantly reduced LG and severity of CSA. We speculate the effect was on HCVR "controller gain," rather than "plant gain," because PaCO2 and VE were unchanged. An effect via reduced circulation time is unlikely, as the respiratory-cycle length did not change.

Cerebral perfusion is elevated in a novel model of aged hAβKI APOE4 mice

AbstractBackgroundThe Model Organism Development and Evaluation for Late‐Onset Alzheimer’s Disease (MODEL‐AD) Consortium is developing the next generation of Alzheimer’s disease (AD) models based on human genomic and imaging data. Recently, MODEL‐AD has generated a new human Aβ Knock‐In (hAβKI) mouse carrying the APOE4 allele. APOE4 carriers are at increased risk for AD. Previous studies have demonstrated altered cerebrovascular integrity and function. We examined the cerebrovascular function in the hAβKI APOE4 mice at 18mo of age using perfusion‐weighted magnetic resonance imaging (PWI). We investigated brain‐wide perfusion alterations in conjunction with histopathological vessel painting.MethodsContrast‐enhanced PWI MRI (9.4T) was undertaken from hAβKI APOE4 (n = 6) and WT (n = 5) mice at 18mo of age following tail vein cannulation for Gadolinium infusion. Imaging sequences included: T1‐pre and post‐infusion, PWI (10min) and susceptibility‐weighted imaging (SWI) for blood extravasation and iron content. All data were processed using JIM v9 software for maps of cerebral blood flow (CBF), volumes (CBV), time to peak, mean transit time and dynamic susceptibility measures for blood‐brain barrier dysfunction. Manual regions of interest (ROI) were performed for cortex, temporal lobe cortex, dorsal hippocampus and thalamus, and semi‐automatic 30+ regions based on the Allen mouse brain atlas. At the end of the in vivo experiments all mice underwent vessel painting followed by microscopic analyses.ResultsCompared to WT mice at 18mo of age, hAβKI APOE4 mice exhibited elevated CBF in virtually all regions examined. CBF was elevated approx. 16%, 11%, 4% and 23% in the cortex, hippocampus, thalamus and temporal lobe cortex, respectively. CBF was significantly elevated in the retrosplenial and temporal lobe cortices (p&lt;0.05). CBV was also significantly increased in temporal lobe. Ongoing analyses will correlate vascular network measures (density, junctions, length) to PWI metrics as well as to hAβKI only mice.ConclusionsThe 18mo hAβKI APOE4 mouse compared to WT exhibited consistent brain‐wide elevations in cerebrovascular measures. This increase may represent a compensatory mechanism to maintain decreased metabolism that occurs with aging. The MODEL‐AD consortium (UCI/IUSM/JAX) continues to develop new and novel AD mouse models. All data will be made available to AD researchers via the Sage Knowledge Network (https://adknowledgeportal.synapse.org/).

Cerebral perfusion is elevated in a novel model of aged hAβKI APOE4 mice

AbstractBackgroundThe Model Organism Development and Evaluation for Late‐Onset Alzheimer’s Disease (MODEL‐AD) Consortium is developing the next generation of Alzheimer’s disease (AD) models based on human genomic and imaging data. Recently, MODEL‐AD has generated a new human Aß Knock‐In (hAßKI) mouse carrying the APOE4 allele. APOE4 carriers are at increased risk for AD. Previous studies have demonstrated altered cerebrovascular integrity and function. We examined the cerebrovascular function in the hAßKI APOE4 mice at 18mo of age using perfusion‐weighted magnetic resonance imaging (PWI). We investigated brain‐wide perfusion alterations in conjunction with histopathological vessel painting.MethodContrast‐enhanced PWI MRI (9.4T) was undertaken from hAßKI APOE4 (n = 6) and WT (n = 5) mice at 18mo of age following tail vein cannulation for Gadolinium infusion. Imaging sequences included: T1‐pre and post‐infusion, PWI (10min) and susceptibility‐weighted imaging (SWI) for blood extravasation and iron content. All data were processed using JIM v9 software for maps of cerebral blood flow (CBF), volumes (CBV), time to peak, mean transit time and dynamic susceptibility measures for blood‐brain barrier dysfunction. Manual regions of interest (ROI) were performed for cortex, temporal lobe cortex, dorsal hippocampus and thalamus, and semi‐automatic 30+ regions based on the Allen mouse brain atlas. At the end of the in vivo experiments all mice underwent vessel painting followed by microscopic analyses.ResultCompared to WT mice at 18mo of age, hAßKI APOE4 mice exhibited elevated CBF in virtually all regions examined. CBF was elevated approx. 16%, 11%, 4% and 23% in the cortex, hippocampus, thalamus and temporal lobe cortex, respectively. CBF was significantly elevated in the retrosplenial and temporal lobe cortices (p&lt;0.05). CBV was also significantly increased in temporal lobe. Ongoing analyses will correlate vascular network measures (density, junctions, length) to PWI metrics as well as to hAßKI only mice.ConclusionThe 18mo hAßKI APOE4 mouse compared to WT exhibited consistent brain‐wide elevations in cerebrovascular measures. This increase may represent a compensatory mechanism to maintain decreased metabolism that occurs with aging. The MODEL‐AD consortium (UCI/IUSM/JAX) continues to develop new and novel AD mouse models. All data will be made available to AD researchers via the Sage Knowledge Network (https://adknowledgeportal.synapse.org/).

Early Detection of hyperemia with Magnetic Resonance Fluid Attenuation Inversion Recovery Imaging after Superficial Temporal Artery to Middle Cerebral Artery Anastomosis.

Cerebral hyperperfusion syndrome (CHS) manifests as a collection of symptoms brought on by heightened focal cerebral blood flow (CBF), afflicting nearly 30% of patients who have undergone superficial temporal artery (STA)-middle cerebral artery (MCA) anastomosis. The aim of this study was to investigate whether the amalgamation of magnetic resonance imaging (MRI) fluid-attenuated inversion recovery (FLAIR) and apparent diffusion coefficient (ADC) imaging via MRI can discern cerebral hyperemia after STA-MCA anastomosis surgery. A retrospective study was performed of patients who underwent STA-MCA anastomosis due to Moyamoya disease or atherosclerotic steno-occlusive disease. A protocol aimed at preventing CHS was instituted, leveraging the use of MRI FLAIR. Patients underwent MRI diffusion with FLAIR imaging 24 hours after STA-MCA anastomosis. A high signal on FLAIR images signified the presence of hyperemia at the bypass site, triggering a protocol of hyperemia care. All patients underwent hemodynamic evaluations, including perfusion MRI, single-photon emission computed tomography (SPECT), and digital subtraction angiography, both before and after the surgery. If a high signal intensity is observed on MRI FLAIR within 24 hours of the surgery, a repeat MRI is performed to confirm the presence of hyperemia. Patients with confirmed hyperemia are managed according to a protocol aimed at preventing further progression. Out of a total of 162 patients, 24 individuals (comprising 16 women and 8 men) exhibited hyperemia on their MRI FLAIR scans following the procedure. SPECT was conducted on 23 patients, and 11 of them yielded positive results. All 24 patients underwent perfusion MRI, but nine of them showed no significant findings. Among the patients, 10 displayed elevations in both CBF and cerebral blood volume (CBV), three only showed elevation in CBF, and two only showed elevation in CBV. Follow-up MRI FLAIR scans conducted 6 months later on these patients revealed complete normalization of the previously observed high signal intensity, with no evidence of ischemic injury. The study determined that the use of MRI FLAIR and ADC mapping is a competent means of early detection of hyperemia after STA-MCA anastomosis surgery. The protocol established can be adopted by other neurosurgical institutions to enhance patient outcomes and mitigate the hazard of permanent cerebral injury caused by cerebral hyperemia.

NIMG-24. RECURRENT OLIGODENDROGLIOMA DEMONSTRATES EARLY INCREASE IN CEREBRAL BLOOD FLOW AND NORMALIZATION IN RESPONSE TO TREATMENT

Abstract Oligodendrogliomas, molecularly defined by the presence of both IDH mutation and 1p/19q codeletion, are more treatment responsive than other gliomas, and due to short capillary segments, demonstrate elevated CBF regardless of grade or contrast enhancement. Arterial Spin Labeling (ASL) allows noninvasive perfusion imaging assessment of cerebral blood flow (CBF) without contrast administration. Changes in CBF are recognized in association with malignant transformation of gliomas however in the setting of treatment, CBF has only been studied to assist in differentiating radiation treatment effect from progressive glioma. This single center retrospective study was undertaken to evaluate if CBF, measured by ASL, might normalize following treatment of recurrent oligodendrogliomas. Clinical database query identified 151 patients with molecularly confirmed oligodendroglioma, 34 of which had available ASL imaging. Expert reader review of all available MRI sequences, blinded to treatment timeline, were performed by two independent radiologists at a PACS station. There were 6 radiographic recurrences identified and in 5/6 CBF was the first radiographic change. Contrast enhancement did not develop for 1.5-12 months after change in CBF for 4/5 recurrences. ASL imaging before and after non-surgical therapy for recurrent disease was available for 4 patients. Two patients were treated with lomustine, one with bevacizumab and one with proton re-radiation. By the second MRI following treatment initiation, all patients had normalization of CBF. At the first post treatment MRI, 3/4 of patients demonstrated normalization of CBF while only 2/4 demonstrated normalization of dynamic susceptibility contrast-derived cerebral blood volume. During the subsequent 6 months, FLAIR hyperintensities remained stable in all patients. This work supports further study if normalization of ASL-derived CBF may be an early radiographic biomarker for response to treatment, especially in non or minimally enhancing recurrent gliomas.

Molecular mechanisms underlying physical exercise-induced brain BDNF overproduction.

Accumulating evidence supports that physical exercise (EX) is the most effective non-pharmacological strategy to improve brain health. EX prevents cognitive decline associated with age and decreases the risk of developing neurodegenerative diseases and psychiatric disorders. These positive effects of EX can be attributed to an increase in neurogenesis and neuroplastic processes, leading to learning and memory improvement. At the molecular level, there is a solid consensus to involve the neurotrophin brain-derived neurotrophic factor (BDNF) as the crucial molecule for positive EX effects on the brain. However, even though EX incontestably leads to beneficial processes through BDNF expression, cellular sources and molecular mechanisms underlying EX-induced cerebral BDNF overproduction are still being elucidated. In this context, the present review offers a summary of the different molecular mechanisms involved in brain's response to EX, with a specific focus on BDNF. It aims to provide a cohesive overview of the three main mechanisms leading to EX-induced brain BDNF production: the neuronal-dependent overexpression, the elevation of cerebral blood flow (hemodynamic hypothesis), and the exerkine signaling emanating from peripheral tissues (humoral response). By shedding light on these intricate pathways, this review seeks to contribute to the ongoing elucidation of the relationship between EX and cerebral BDNF expression, offering valuable insights into the potential therapeutic implications for brain health enhancement.

Arterial Spin Labelling Magnetic Resonance Perfusion Imaging for the Diagnosis of Acute Cerebral Venous Thrombosis

Abstract&#x0D; &#x0D; Background: Early diagnosis of cerebral venous thrombosis (CVT) is crucial for a favourable prognosis as CVT can lead to severe outcomes. However, certain scenarios, such as during pregnancy, restrict the use of contrast agents, thus rendering conventional magnetic resonance imaging (MRI) methods insufficient for accurate diagnosis. In light of these challenges, our study endeavours to assess the diagnostic potential of the arterial spin labelling magnetic resonance perfusion (ASL-MRP) technique, a contrast-agent–free approach, in the context of CVT diagnosis. &#x0D; &#x0D; Materials and Methods: Between 1 March 2022 and 30 May 2022, patients diagnosed with CVT via contrast-enhanced MR venography in the neurology clinic of our hospital were evaluated through ASL-MRP. Patient-specific demographics, including age, gender, presenting symptoms, underlying causes, impacted cortical sinus structures and MRI findings, were documented. Within the framework of ASL-MRP, an elevation in cerebral blood flow (CBF) detected within the affected sinus and/or neighbouring structures was deemed indicative of pathological conditions.&#x0D; &#x0D; Results: Among the 13 patients included in our study, six were diagnosed with acute CVT, whereas seven were diagnosed with chronic CVT. The assessment of CBF using ASL-MRP revealed CBF elevation in five out of the six cases (83.3%) exhibiting acute CVT. However, no anomalous findings were observed in the ASL-MRP scans of patients presenting with chronic CVT. &#x0D; &#x0D; Discussion: The utilisation of ASL-MRP eliminates the need for contrast agent administration. It is a promising technique in facilitating the diagnosis of acute CVT and distinguishing it from chronic CVT cases.

Recent insights into mechanisms of hypoxia-induced vasodilatation in the human brain.

The cerebral vasculature manages oxygen delivery by adjusting arterial blood in-flow in the face of reductions in oxygen availability. Hypoxic cerebral vasodilatation, and the associated hypoxic cerebral blood flow reactivity, involve many vascular, erythrocytic and cerebral tissue mechanisms that mediate elevations in cerebral blood flow via micro- and macrovascular dilatation. This contemporary review focuses on in vivo human work - with reference to seminal preclinical work where necessary - on hypoxic cerebrovascular reactivity, particularly where recent advancements have been made. We provide updates with the following information: in humans, hypoxic cerebral vasodilatation is partially mediated via a - likely non-obligatory - combination of: (1) nitric oxide synthases, (2) deoxygenation-coupled S-nitrosothiols, (3) potassium channel-related vascular smooth muscle hyperpolarization, and (4) prostaglandin mechanisms with some contribution from an interrelationship with reactive oxygen species. And finally, we discuss the fact that, due to the engagement of deoxyhaemoglobin-related mechanisms, reductions in O2 content via haemoglobin per se seem to account for ∼50% of that seen with hypoxic cerebral vasodilatation during hypoxaemia. We further highlight the issue that methodological impediments challenge the complete elucidation of hypoxic cerebral reactivity mechanisms in vivo in healthy humans. Future research is needed to confirm recent advancements and to reconcile human and animal findings. Further investigations are also required to extend these findings to address questions of sex-, heredity-, age-, and disease-related differences. The final step is to then ultimately translate understanding of these mechanisms into actionable, targetable pathways for the prevention and treatment of cerebral vascular dysfunction and cerebral hypoxic brain injury.

Increased posterior cingulate cortex blood flow in cancer-related fatigue.

Fatigue is a common symptom associated with cancer treatments. Brain mechanisms underlying cancer-related fatigue (CRF) and its progression following therapy are poorly understood. Previous studies have suggested a role of the default mode network (DMN) in fatigue. In this study we used arterial spin labeling (ASL) perfusion functional magnetic resonance imaging (fMRI) and compared resting cerebral blood flow (CBF) differences in the posterior cingulate cortex (PCC), a core hub of the DMN, between 16 patients treated with radiation therapy (RAT) for prostate (9 males) or breast (7 females) cancer and 18 healthy controls (HC). Resting CBF in patients was also measured immediately after the performance of a fatiguing 20-min psychomotor vigilance task (PVT). Twelve of 16 cancer patients were further followed between 3 and 7 months after completion of the RAT (post-RAT). Patients reported elevated fatigue on RAT in comparison to post-RAT, but no change in sleepiness, suggesting that the underlying neural mechanisms of CRF progression are distinct from those regulating sleep drive progression. Compared to HC, patients showed significantly increased resting CBF in the PCC and the elevated PCC CBF persisted during the follow up visit. Post-PVT, but not pre-PVT, resting CBF changes in the PCC correlated with fatigue changes after therapy in patients with CRF, suggesting that PCC CBF following a fatiguing cognitive task may be a biomarker for CRF recovery.

Association of Cerebral Hemodynamics and Anemia on Processing Speed in Adults with Sickle Cell Disease.

Compared to healthy controls, adult patients with Sickle Cell Disease (SCD) are anemic, and therefore have higher cardiac output and Cerebral Blood Flow (CBF) to maintain brain oxygenation. They also demonstrate comparatively more cognitive deficits due to either overt strokes or silent cerebral ischemia. However, there are few correlative studies between CBF and cognitive deficits, specifically processing speed in SCD. Such studies are important to develop biomarkers of central brain processing and ischemia for diagnosis, prognosis, and evaluating the effectiveness of potential interventions. This pilot cross-sectional study tested the hypotheses that adults with SCD and elevated CBF demonstrate lower central brain processing speed than controls on average and that CBF is inversely correlated with processing speed. We conducted a pilot cross-sectional study to assess the relation-ships between CBF, central brain processing speed, and hemoglobin levels in asymptomatic adults with SCD and controls from an urban academic medical center. MRI acquisitions at 3T consisted of 2D phase-contrast quantitative arteriograms (Qflow) of the bilateral internal carotid and vertebral arteries and 3D pseudo-continuous arterial spin labeling (pCASL) of the brain. Participants were patients with SCD (hemoglobin [Hb]SS, [Hb] SBetaThal°, or [Hb]SC) aged 22-52 years of African American descent (N=7) or community controls (Hb AA) (n=3). Processing speed was assessed as an in-direct functional marker of ischemia using a recommended test from the NIH Toolbox for Assessment of Neurological and Behavioral Function, the Pattern Comparison Processing Speed Test. t-tests were used to compare means of CBF, hemoglobin, and cognition between SCD patients and healthy controls. Among SCD patients only multivariate correla-tions were used to evaluate relationships between brain perfusion in specific brain regions vs. processing speed and CBF. The significance level was set at p≤0.05. Adults with SCD reported higher CBF compared to healthy con-trols (72.15±28.90 vs. 47.23±12.30 ml/min/100g, p=0.04), and lower hemoglobin concentration (8.64±2.33 vs. 13.33±0.58, p=0.001). Heart rate in SCD patients was higher than in controls (86.29±1.37 vs. 74.00±2.10, p=0.04). Patients with SCD demonstrated lower processing speed (96.14±21.04 vs.123±13.74, p=0.02) than controls. Among adult patients with SCD, perfusion in specific regions of the brain showed an inverse relationship with processing speed, as did whole-brain CBF (p=0.0325). These findings, although from a small sample, lend a degree of validity to the claim that processing speed is slower in people with SCD than in controls and that CBF is significantly higher in SCD patients com-pared to controls. The results also lend credence to the finding that the degree of processing speed deficiencies among adults with SCD is correlated with the degree of elevated CBF, which is known to correspond with the degree of anemia associated with SCD.

Evaluation of cerebral hemodynamic alterations by transcranial Doppler in neonatal sepsis

Background Transcranial Doppler is a noninvasive approach with high temporal resolution, permitting continuous cerebral blood flow velocity recording through major cerebral arteries. Aim To determine cerebral blood flow (CBF) changes in neonatal sepsis (NS) by ultrasound (US) Doppler examination. Patients and methods This prospective case–control trial was conducted on 60 neonates who were divided into two groups: group I (sepsis): 32 neonates with NS diagnosed by clinical and laboratory data and group II (control): 28 healthy neonates with gestational age and sex matched. All cases underwent detailed antenatal and natal history, clinical and laboratory investigations and transcranial Doppler examination with assessment of CBF. Results As regards anterior cerebral artery (ACA) and middle cerebral artery (MCA), peak systolic velocity (PSV) (cm/s) and end-diastolic velocity (EDV) (cm/s) were significantly increased in the sepsis group than in the control group (P&lt;0.001), but both resistive index and pulsatility index were significantly decreased, in the sepsis group than in the control group (P&lt;0.001). Validity of MCA PSV with a cut-off point of 55.4 detects a sensitivity of 94% and specificity of 86%; validity of MCA EDV with a cutoff point of 18 detects a sensitivity of 94% and specificity of 89%; validity of ACA PSV with a cutoff point of 49.3 detects a sensitivity of 88% and specificity of 93%; validity of ACA EDV with a cutoff point of 21 detects a sensitivity of 91% and specificity of 93%. Conclusion NS was found to elevate both PSV, EDV, decrease resistivity, and pulsatility indices causing an elevated CBF and a decreased resistance.

Impact of hydrogen gas inhalation during therapeutic hypothermia on cerebral hemodynamics and oxygenation in the asphyxiated piglet

We previously reported the neuroprotective potential of combined hydrogen (H2) gas ventilation therapy and therapeutic hypothermia (TH) by assessing the short-term neurological outcomes and histological findings of 5-day neonatal hypoxic-ischemic (HI) encephalopathy piglets. However, the effects of H2 gas on cerebral circulation and oxygen metabolism and on prognosis were unknown. Here, we used near-infrared time-resolved spectroscopy to compare combined H2 gas ventilation and TH with TH alone. Piglets were divided into three groups: HI insult with normothermia (NT, n = 10), HI insult with hypothermia (TH, 33.5 ± 0.5 °C, n = 8), and HI insult with hypothermia plus H2 ventilation (TH + H2, 2.1–2.7%, n = 8). H2 ventilation and TH were administered and the cerebral blood volume (CBV) and cerebral hemoglobin oxygen saturation (ScO2) were recorded for 24 h after the insult. CBV was significantly higher at 24 h after the insult in the TH + H2 group than in the other groups. ScO2 was significantly lower throughout the 24 h after the insult in the TH + H2 group than in the NT group. In conclusion, combined H2 gas ventilation and TH increased CBV and decreased ScO2, which may reflect elevated cerebral blood flow to meet greater oxygen demand for the surviving neurons, compared with TH alone.

Erbb4 Deletion From Inhibitory Interneurons Causes Psychosis-Relevant Neuroimaging Phenotypes.

Converging lines of evidence suggest that dysfunction of cortical GABAergic inhibitory interneurons is a core feature of psychosis. This dysfunction is thought to underlie neuroimaging abnormalities commonly found in patients with psychosis, particularly in the hippocampus. These include increases in resting cerebral blood flow (CBF) and glutamatergic metabolite levels, and decreases in ligand binding to GABAA α5 receptors and to the synaptic density marker synaptic vesicle glycoprotein 2A (SV2A). However, direct links between inhibitory interneuron dysfunction and these neuroimaging readouts are yet to be established. Conditional deletion of a schizophrenia susceptibility gene, the tyrosine kinase receptor Erbb4, from cortical and hippocampal inhibitory interneurons leads to synaptic defects, and behavioral and cognitive phenotypes relevant to psychosis in mice. Here, we investigated how this inhibitory interneuron disruption affects hippocampal in vivo neuroimaging readouts. Adult Erbb4 conditional mutant mice (Lhx6-Cre;Erbb4F/F, n = 12) and their wild-type littermates (Erbb4F/F, n = 12) were scanned in a 9.4T magnetic resonance scanner to quantify CBF and glutamatergic metabolite levels (glutamine, glutamate, GABA). Subsequently, we assessed GABAA receptors and SV2A density using quantitative autoradiography. Erbb4 mutant mice showed significantly elevated ventral hippccampus CBF and glutamine levels, and decreased SV2A density across hippocampus sub-regions compared to wild-type littermates. No significant GABAA receptor density differences were identified. These findings demonstrate that specific disruption of cortical inhibitory interneurons in mice recapitulate some of the key neuroimaging findings in patients with psychosis, and link inhibitory interneuron deficits to non-invasive measures of brain function and neurochemistry that can be used across species.