Isoflurane is one of the most widely used anesthetic agents in rodent imaging studies. However, the impact of isoflurane on brain metabolism has not been fully characterized to date, primarily due to a scarcity of noninvasive technologies to quantitatively measure the brain\'s metabolic rate in vivo. In this study, using noncontrast MRI techniques, we dynamically measured cerebral metabolic rate of oxygen (CMRO2) under varying doses of isoflurane anesthesia in mice. Concurrently, systemic parameters of heart and respiration rates were recorded alongside CMRO2. Additionally, electroencephalogram (EEG) recording was used to identify changes in neuronal activities under the same anesthetic regimen employed in the MRI experiments. We found suppression of the CMRO2 by isoflurane in a dose-dependent manner, concomitant with a diminished high-frequency EEG activity. The degree of metabolic suppression by isoflurane was strongly correlated with the respiration rate, which offers a potential approach to calibrate CMRO2 measurements. Furthermore, the metabolic level associated with neural responses of the somatosensory and motor cortices in mice was estimated as 308.2 μmol/100 g/min. These findings may facilitate the integration of metabolic parameters into future studies involving animal disease models and anesthesia usage.

Sickle cell disease (SCD) is the most common genetic blood disorder, characterized by red cell hemolysis, anemia, and corresponding increased compensatory cerebral blood flow (CBF). SCD patients are at high risk for cerebral infarcts and CBF quantification is likely critical to assess infarct risk. Infarcts primarily localize to white matter (WM), yet arterial spin labeling (ASL) MRI, the most common non-invasive CBF approach, has poor WM CBF sensitivity owing to low WM CBF and long WM bolus arrival time (BAT). We hypothesize that anemia, and associated cerebral hyperemia, in SCD leads to improved WM detection with ASL. We performed 3-Tesla multi-delay pulsed ASL in SCD (n = 35; age = 30.5 ± 8.3 years) and control (n = 15; age = 28.7 ± 4.5 years) participants and applied t-tests at each inversion time within different flow territories, and determined which regions were significantly above noise floor (criteria: one-sided p < 0.05). Total WM CBF-weighted signal was primarily detectable outside of borderzone regions in SCD (CBF = 17.7 [range = 12.9-25.0] mL/100 g/min), but was largely unphysiological in control (CBF = 8.1 [range = 7.6-9.9)] mL/100 g/min) participants. WM BAT was reduced in SCD versus control participants (ΔBAT = 37 [range = 46-70] ms) and BAT directly correlated with hematocrit (Spearman\'s-ρ = 0.62; p < 0.001). Findings support the feasibility of WM CBF quantification using ASL in SCD participants for appropriately parameterized protocols.

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.

The aim was to examine the effects of modalities of acute resistance exercise (RE) on cognition and hemodynamics including internal carotid artery (ICA) blood flow (BF). Twenty adults completed familiarization and experimental visits. One-repetition maximum (1RM) for bilateral leg extension was quantified, and baseline executive functioning was determined from three run-in visits. Subsequent visits included three randomized, volume-equated, acute exercise bouts of 30 %1RM+blood flow restriction (BFR), 30 %1RM, and 70 %1RM. Both 30 %1RM trials completed four sets of exercise (1 × 30, 3 × 15), and the 70 %1RM condition completed four sets of 8 repetitions. BFR was induced with 40 % of the pressure to occlude the femoral arteries. 11 min following each exercise, participants completed the Stroop and Shifting Attention Tests. Baseline and post-exercise values were used to calculate change scores. The resulting mean change scores were evaluated with mixed factorial ANOVAs. A p≤0.05 was considered significant. All measured outcome variables increased in response to exercise. The ANOVAs for cognitive scores indicated no significant (p>0.05) interactions. For cognitive flexibility and executive function index, there were main effects of Sex. Change scores of the females were significantly greater than the males for cognitive flexibility (7.6 ± 5.9 vs. -2.6 ± 8.4 au; p=0.007) and executive function index (7.4 ± 4.6 vs. -2.5 ± 6.5 au; p=0.001). For ICA BF, there was no significant interaction or any main effect. The females exhibited a smaller exercise-induced increase in blood pressure compared to the males (17.7 ± 5.9 vs. 11.0 ± 4.1 mmHg; p=0.010). Each RE modality yielded acute improvements in cognition, but only for females. There were no cognitive improvements related to BFR such that each RE bout yielded similar results.

Water exchange rate (Kw) across the blood-brain barrier (BBB) is an important physiological parameter that may provide new insight into ageing and neurodegenerative disease. Recently, two non-invasive arterial spin labelling (ASL) MRI methods have been developed to measure Kw, but results from the different methods have not been directly compared. Furthermore, the association of Kw with age for each method has not been investigated in a single cohort. Thirty participants (70% female, 63.8 ± 10.4 years) were scanned at 3 T with Diffusion-Prepared ASL (DP-ASL) and Multi-Echo ASL (ME-ASL) using previously implemented acquisition and analysis protocols. Grey matter Kw, cerebral blood flow (CBF) and arterial transit time (ATT) were extracted. CBF values were consistent; approximately 50 ml/min/100 g for both methods, and a strong positive correlation in CBF from both methods across participants (r = 0.82, p < 0.001). ATT was significantly different between methods (on average 147.7 ms lower when measured with DP-ASL compared to ME-ASL) but was positively correlated across participants (r = 0.39, p < 0.05). Significantly different Kw values of 106.6 ± 19.7 min-1 and 306.8 ± 71.7 min-1 were measured using DP-ASL and ME-ASL, respectively, and DP-ASL Kw and ME-ASL Kw were negatively correlated across participants (r = -0.46, p < 0.01). Kw measured using ME-ASL had a significant linear relationship with age (p < 0.05). In conclusion, DP-ASL and ME-ASL provided estimates of Kw with significantly different quantitative values and inconsistent dependence with age. We propose future standardisation of modelling and fitting methods for DP-ASL and ME-ASL, to evaluate the effect on Kw quantification. Also, sensitivity and bias analyses should be performed for both approaches, to assess the effect of varying acquisition and fitting parameters. Lastly, comparison with independent measures of BBB water transport, and with physiological and clinical biomarkers known to be associated with changes in BBB permeability, are essential to validate the ASL methods, and to demonstrate their clinical utility.

UNASSIGNED: Patients with coronary artery disease (CAD) have a higher risk of developing cognitive impairment and mental health disorders compared to the general population. Physical exercise might improve their brain health. The overall goal of the HEART-BRAIN randomized controlled trial (RCT) is to investigate the effects of different types of exercise on brain health outcomes in patients with CAD, and the underlying mechanisms.
UNASSIGNED: This three-arm, single-blinded RCT will include 90 patients with CAD (50-75 years). Participants will be randomized into: (1) control group-usual care (n = 30), (2) aerobic high-intensity interval training (HIIT) (n = 30), or (3) HIIT combined with resistance exercise training (n = 30). The 12-week intervention includes 3 supervised sessions (45-min each) per week for the exercise groups. Outcomes will be assessed at baseline and post-intervention. The primary outcome is to determine changes in cerebral blood flow assessed by magnetic resonance imaging. Secondary outcomes include changes in brain vascularization, cognitive measures (i.e., general cognition, executive function and episodic memory), and cardiorespiratory fitness. Additional health-related outcomes, and several potential mediators and moderators will be investigated (i.e., brain structure and function, cardiovascular and brain-based biomarkers, hemodynamics, physical function, body composition, mental health, and lifestyle behavior).
UNASSIGNED: The HEART-BRAIN RCT will provide novel insights on how exercise can impact brain health in patients with CAD and the potential mechanisms explaining the heart-brain connection, such as changes in cerebral blood flow. The results may have important clinical implications by increasing the evidence on the effectiveness of exercise-based strategies to delay cognitive decline in this high-risk population.
UNASSIGNED: ClinicalTrials.gov, identifier [NCT06214624].

In the brain, a microvascular sensory web coordinates oxygen delivery to regions of neuronal activity. This involves a dense network of capillaries that send conductive signals upstream to feeding arterioles to promote vasodilation and blood flow. Although this process is critical to the metabolic supply of healthy brain tissue, it may also be a point of vulnerability in disease. Deterioration of capillary networks is a feature of many neurological disorders and injuries and how this web is engaged during vascular damage remains unknown. We performed in vivo two-photon microscopy on young adult mural cell reporter mice and induced focal capillary injuries using precise two-photon laser irradiation of single capillaries. We found that ~59% of the injuries resulted in regression of the capillary segment 7 to 14 d following injury, and the remaining repaired to reestablish blood flow within 7 d. Injuries that resulted in capillary regression induced sustained vasoconstriction in the upstream arteriole-capillary transition (ACT) zone at least 21 days postinjury in both awake and anesthetized mice. The degree of vasomotor dynamics was chronically attenuated in the ACT zone consequently reducing blood flow in the ACT zone and in secondary, uninjured downstream capillaries. These findings demonstrate how focal capillary injury and regression can impair the microvascular sensory web and contribute to cerebral hypoperfusion.

BACKGROUND: The periaqueductal gray (PAG) is at the center of a powerful descending antinociceptive neuronal network, and is a key node in the descending pain regulatory system of pain. However, less is known about the altered perfusion of PAG in chronic migraine (CM).
OBJECTIVE: To measure the perfusion of PAG matter, an important structure in pain modulation, in CM with magnetic resonance (MR) perfusion without contrast administration.
METHODS: Three-dimensional pseudocontinuous arterial spin labeling (3D-PCASL) and brain structure imaging were performed in 13 patients with CM and 15 normal subjects. The inverse deformation field generated by brain structure image segmentation was applied to the midbrain PAG template to generate individualized PAG. Then the perfusion value of the PAG area of the midbrain was extracted based on the individual PAG mask.
RESULTS: Cerebral blood flow (CBF) value of PAG in CM patients (47.98 ± 8.38 mL/100 mg min) was significantly lower than that of the control group (59.87 ± 14.24 mL/100 mg min). Receiver operating characteristic (ROC) curve analysis showed that the area under the curve was 0.77 (95% confidence interval [CI], 0.60, 0.94), and the cutoff value for the diagnosis of CM was 54.83 mL/100 mg min with a sensitivity 84.60% and a specificity 60%.
CONCLUSIONS: Imaging evidence of the impaired pain conduction pathway in CM may be related with the decreased perfusion in the PAG, which could be considered as an imaging biomarker for the diagnosis and therapy evaluation.

BACKGROUND: Intracranial atherosclerotic stenosis (ICAS) is one of the most important independent risk factors for stroke that is closely related to the occurrence of cognitive impairment. The relationship between ICAS and vascular cognitive impairment (VCI) remains unclear. Cerebral hemodynamic changes are one of the main causes of cognitive impairment. Computed tomographic perfusion (CTP) imaging can quantitatively analyze cerebral blood perfusion and quantify cerebral hemodynamic changes. Previous research on the relationship between hypoperfusion induced by ICAS and cognitive impairment, as well as its underlying mechanisms, remains relatively insufficient. This study is dedicated to elucidating the characteristics and potential mechanisms of cognitive impairment in ICAS patients with abnormal perfusion, utilizing CTP imaging as our primary investigative tool.
METHODS: This study recruited 82 patients who suffer from non-disabling ischemic stroke (IS group) and 28 healthy controls. All participants underwent comprehensive neuropsychological assessments both collectively and individually, in addition to CTP imaging. Within the patient group, we further categorized individuals into two subgroups: the ischemic penumbra group (IP, N = 28) and the benign oligemia group (BO, N = 54), based on CTP parameters-Tmax. The correlations between cognitive function and abnormal perfusion were explored.
RESULTS: The cognitive function, including the overall cognitive, memory, attention, executive functions, and language, was significantly impaired in the IS group compared with that in the control group. Further, there are statistical differences in the stroop color-word test-dot (Stroop-D) and Montreal Cognitive Assessment (MoCA) sub-items (memory + language) between the BO and IP groups. In the BO group, the score of Stroop-D is lower, and the MoCA sub-items are higher than the IP group. There is no correlation between CTP parameters and cognitive function.
CONCLUSIONS: Cognitive function is significantly impaired in patients with ICAS, which is related to cerebral perfusion. Executive, memory, and language function were better preserved in ICAS patients without IP. Hence, this study posits that managing hypoperfusion induced by ICAS may play a pivotal role in the development of VCI.

UNASSIGNED: Frontotemporal lobar degeneration (FTLD) is associated with FTLD due to tau (FTLD-tau) or TDP (FTLD-TDP) inclusions found at autopsy. Arterial Spin Labeling (ASL) MRI is often acquired in the same session as a structural T1-weighted image (T1w), enabling detection of regional changes in cerebral blood flow (CBF). We hypothesize that ASL-T1w registration with more degrees of freedom using boundary-based registration (BBR) will better align ASL and T1w images and show increased sensitivity to regional hypoperfusion differences compared to manual registration in patient participants. We hypothesize that hypoperfusion will be associated with a clinical measure of disease severity, the FTLD-modified clinical dementia rating scale sum-of-boxes (FTLD-CDR).
UNASSIGNED: Patients with sporadic likely FTLD-tau (sFTLD-tau; N = 21), with sporadic likely FTLD-TDP (sFTLD-TDP; N = 14), and controls (N = 50) were recruited from the Connectomic Imaging in Familial and Sporadic Frontotemporal Degeneration project (FTDHCP). Pearson\'s Correlation Coefficients (CC) were calculated on cortical vertex-wise CBF between each participant for each of 3 registration methods: (1) manual registration, (2) BBR initialized with manual registration (manual+BBR), (3) and BBR initialized using FLIRT (FLIRT+BBR). Mean CBF was calculated in the same regions of interest (ROIs) for each registration method after image alignment. Paired t-tests of CC values for each registration method were performed to compare alignment. Mean CBF in each ROI was compared between groups using t-tests. Differences were considered significant at p < 0.05 (Bonferroni-corrected). We performed linear regression to relate FTLD-CDR to mean CBF in patients with sFTLD-tau and sFTLD-TDP, separately (p < 0.05, uncorrected).
UNASSIGNED: All registration methods demonstrated significant hypoperfusion in frontal and temporal regions in each patient group relative to controls. All registration methods detected hypoperfusion in the left insular cortex, middle temporal gyrus, and temporal pole in sFTLD-TDP relative to sFTLD-tau. FTLD-CDR had an inverse association with CBF in right temporal and orbitofrontal ROIs in sFTLD-TDP. Manual+BBR performed similarly to FLIRT+BBR.
UNASSIGNED: ASL is sensitive to distinct regions of hypoperfusion in patient participants relative to controls, and in patients with sFTLD-TDP relative to sFTLD-tau, and decreasing perfusion is associated with increasing disease severity, at least in sFTLD-TDP. BBR can register ASL-T1w images adequately for controls and patients.