Spin Labeling Research Articles

Evaluating the Potential of Quantitative Susceptibility Mapping for Detecting Iron Deposition of Renal Fibrosis in a Rabbit Model.

As ferroptosis is a key factor in renal fibrosis (RF), iron deposition monitoring may help evaluating RF. The capability of quantitative susceptibility mapping (QSM) for detecting iron deposition in RF remains uncertain. To investigate the potential of QSM to detect iron deposition in RF. Animal model. Eighty New Zealand rabbits were randomly divided into control (N = 10) and RF (N = 70) groups, consisting of baseline, 7, 14, 21, and 28 days (N = 12 in each), and longitudinal (N = 10) subgroups. RF was induced via unilateral renal arteria stenosis. 3 T, QSM with gradient echo, arterial spin labeling with gradient spin echo. Bilateral kidney QSM values (χ) in the cortex (χCO) and outer medulla (χOM) were evaluated with histopathology. Analysis of variance, Kruskal-Wallis, Spearman's correlation, and the area under the receiver operating characteristic curve (AUC). P < 0.05 was significant. In fibrotic kidneys, χCO decreased at 7 days ([-6.69 ± 0.98] × 10-2 ppm) and increased during 14-28 days ([-1.85 ± 2.11], [0.14 ± 0.58], and [1.99 ± 0.60] × 10-2 ppm, respectively), while the χOM had the opposite trend. Both significantly correlated with histopathology (|r| = 0.674-0.849). AUC of QSM for distinguishing RF degrees was 0.692-0.993. In contralateral kidneys, the χCO initially decreased ([-6.67 ± 0.84] × 10-2 ppm) then recovered to baseline ([-4.81 ± 0.89] × 10-2 ppm), while the χOM at 7-28 days ([2.58 ± 1.40], [2.25 ± 1.83], [2.49 ± 2.11], [2.43 ± 1.32] × 10-2 ppm, respectively) were significantly higher than baseline ([0.54 ± 0.18] × 10-2 ppm). Different iron deposition patterns were observed in RF with QSM values, suggesting the potential of QSM for iron deposition monitoring in RF. Renal fibrosis (RF) is a common outcome in most kidney diseases, leading to scarring and loss of kidney function. Increasing evidence suggests that abnormal iron metabolism plays an important role in RF. This study used a technique called quantitative susceptibility mapping (QSM) to measure kidney iron levels in rabbits with RF. Specifically, rabbits with advanced RF exhibited higher kidney iron concentrations, and moderate to strong correlations between QSM values and histopathology demonstrated that QSM could accurately detect changes in iron levels and assess RF severity. Overall, QSM shows promise as a tool for monitoring iron deposition in RF progression. 2 TECHNICAL EFFICACY: Stage 3.

New physiological insights using multi-TE ASL MRI measuring blood-brain barrier water exchange after caffeine intake.

Caffeine, a known neurostimulant and adenosine antagonist, affects brain physiology by decreasing cerebral blood flow. It interacts with adenosine receptors to induce vasoconstriction, potentially disrupting brain homeostasis. However, the impact of caffeine on blood-brain barrier (BBB) permeability to water remains underexplored. This study investigated the water exchange via the BBB in a perturbed physiological condition caused by caffeine ingestion, using the multiple echo time (multi-TE) arterial spin labeling (ASL) technique. Ten healthy, regular coffee drinkers (age = 31 ± 9years, 3 females) were scanned to acquire five measurements before and six measurements after caffeine ingestion. Data were analyzed with a multi-TE two-compartment model to estimate exchange time (Tex), serving as a proxy for BBB permeability to water. Additionally, cerebral blood flow (CBF), arterial transit time (ATT), and intravoxel transit time (ITT) were investigated. Following caffeine intake, mean gray matter CBF showed a significant time-dependent decrease (P < 0.01). In contrast, Tex, ATT, and ITT did not exhibit significant time-dependent change. However, a non-significant decreasing trend was observed for Tex and ITT, respectively, while ATT showed an increasing trend over time. The observed decreasing trend in Tex after caffeine ingestion suggests a potential increase in water flux across the BBB, which may represent a compensatory mechanism to maintain brain homeostasis in response to the caffeine-induced reduction in CBF. Further studies with larger sample sizes are needed to validate and expand upon these findings.

A Set of Three GdIII Spin Labels with Methanethiosulfonyl Groups for Bioconjugation Covering a Wide Range of EPR Line Widths.

Spin labels based on GdIII complexes are important tools for the elucidation of the structure, dynamics and interaction of biomolecules by electron paramagnetic resonance (EPR) spectroscopy. Their EPR spectroscopic properties line width and relaxation times influence their performance in a particular application. To be able to apply a complex well-suited for a specific application, a set of GdIII complexes with different EPR spectroscopic properties ready-made for spin labeling will be highly useful. We prepared three GdIII complexes with DO3APic, NO3Pic, and PyMTA as the basic ligand units. They cover a wide range of EPR line widths but have in common a cysteine-targeting methanethiosulfonyl (MTS) group connected to a pyridine ring, which is an intrinsic part of the ligand. The reaction with a cysteine-containing pentapeptide (0.45 mM in the peptide, pH ∼ 7) was complete within 90 s and chemoselective. The MTS group hydrolyzed with half-lives of >24, 8, 2, and 1 h at pH 5, 6, 7, and 8, respectively. The structurally related nicotinic acid-substituted disulfide (NDS) group was found to be hydrolytically much more stable. However, the MTS spin label clearly won the competition for the pentapeptide over the NDS spin label. If high reactivity is essential, MTS is clearly the better choice.

The prognostic impact of arterial spin labeling hyperperfusion in acute ischemic stroke: a systematic review and meta-analysis.

Hyperperfusion is related to vessel recanalization, tissue reperfusion, and collateral circulation. To determine the prognostic impact of hyperperfusion after an acute ischemic stroke (AIS) identified by arterial spin labeling (ASL) cerebral blood flow. Studies published in PubMed, Embase, and Cochrane Library databases were searched. Studies assessing the diagnostic performance of ASL hyperperfusion after AIS were included. Functional prognosis, hemorrhagic transformation (HT), infarction volume, and penumbra salvage volume were evaluated. The standardized mean difference or risk ratio was pooled, implementing a random effect model. Multiple subgroup analyses were performed. Seven studies including 617 participants were included in this meta-analysis. ASL hyperperfusion in AIS was correlated well with symptom severity and outcome after 24 h National Institutes of Health Stroke Scale (NIHSS) and 90-day modified Rankin Scale (mRS). Earlier ASL hyperperfusion was associated with a smaller infarction volume and a larger penumbra salvage volume, while also indicating a higher risk of HT. In addition, in subgroup analysis, our results demonstrated that thrombolysis, mechanical thrombectomy treatment, early improvement of NIHSS, and involving infarction in cortical territory are associated with ASL hyperperfusion. ASL hyperperfusion was related to a favorable functional outcome but an increased risk of HT. Stroke patients with hyperperfusion showed smaller infarction volume and larger penumbra salvage volume than those with non-hyperperfusion.

RIDME Spectroscopy: New Topics Beyond the Determination of Electron Spin-Spin Distances.

Relaxation-induced dipolar modulation enhancement (RIDME) is a pulse EPR experiment originally designed to determine distances between spin labels. However, RIDME has several features that make it an efficient tool in a number of "nonconventional" applications, away from the original purpose of this pulse experiment. RIDME appears to be an interesting experiment to probe longitudinal electron spin dynamics, e.g., in relation to qubits research, to probe distributions of exchange couplings, useful for the design of molecular magnets, and to determine important details of electron spin interactions with the nuclear spin bath, which is related to the dynamic nuclear polarization and soft materials research. We also anticipate interesting applications of RIDME in the structural biology of biopolymers as well as their interactions, aggregation, and phase separation. It is not excluded that in the near future such "nonconventional" topics could grow in number and evolve into the main application area of RIDME.

Electron-spin decoherence in trityl radicals in the absence and presence of microwave irradiation

Abstract. Trityl radicals feature prominently as polarizing agents in solid-state dynamic nuclear polarization experiments and as spin labels in distance distribution measurements by pulsed dipolar EPR spectroscopy techniques. Electron-spin coherence lifetime is a main determinant of performance in these applications. We show that protons in these radicals contribute substantially to decoherence, although the radicals were designed with the aim of reducing proton hyperfine interaction. By spin dynamics simulations, we can trace back the nearly complete Hahn echo decay for a Finland trityl radical variant within 7 µs to the contribution from tunnelling of the 36 methyl protons in the radical core. This contribution, as well as the contribution of methylene protons in OX063 and OX071 trityl radicals, to Hahn echo decay can be predicted rather well by the previously introduced analytical pair product approximation. In contrast, predicting decoherence of electron spins dressed by a microwave field proves to be a hard problem where correlations between more than two protons contribute substantially. Cluster correlation expansion (CCE) becomes borderline numerically unstable already at order 3 at times comparable to the decoherence time T2ρ and cannot be applied at order 4. We introduce partial CCE that alleviates this problem and reduces computational effort at the expense of treating only part of the correlations at a particular order. Nevertheless, dressed-spin decoherence simulations for systems with more than 100 protons remain out of reach, whereas they provide only semi-quantitative predictions for 24 to 48 protons. Our experimental and simulation results indicate that solid-state magnetic resonance experiments with trityl radicals will profit from perdeuteration of the compounds.

Functional MRI study of neurovascular coupling in patients with non-lesional epilepsy

ObjectiveThe diagnosis of patients with non-lesional epilepsy (NLE) is relatively challenging because of the absence of a clear focus on imaging, and the underlying pathological mechanism remains unclear. The neuronal activity and functional connectivity of NLE patients are significantly abnormal, and the neuronal activity of epilepsy patients is closely related to cerebral blood flow (CBF). Neurovascular coupling (NVC) offers insights into the relationship between neuronal activity and CBF. Hence, we intend to explore the alterations of NVC in NLE patients and their influences on cognitive function.MethodsClinical data of 24 patients with NLE (15 female; age range 19–40 years; median age 30.5 years) and 39 healthy controls (27 female; age range 19–40 years; median age 30 years) were collected, and resting-state functional magnetic resonance imaging (rs-fMRI) and 3D arterial spin labeling (ASL) were performed. The imaging indexes of amplitude of low-frequency fluctuation (ALFF) and CBF were calculated, respectively, by post-processing analysis. The differences in CBF, ALFF and CBF/ALFF ratio between the two groups were analyzed, along with correlation with clinical data of NLE patients.ResultsCompared with the healthy controls, the CBF of the right parahippocampal gyrus was significantly decreased, and the CBF/ALFF ratio of the right inferior parietal, but supramarginal and angular gyri was significantly increased in NLE patients (p &amp;lt; 0.001). Moreover, the CBF/ALFF ratio was positively correlated with epilepsy depression score (r = 0.546, p = 0.006).ConclusionNLE patients showed abnormal local NVC, which was associated with the severity of depression. The combined application of rs-fMRI and ASL can comprehensively evaluate the neuronal activity and cerebral blood perfusion in patients with NLE. The abnormal NVC is of great significance for us to explore the central mechanism of the occurrence and development of NLE.

Evaluating the added value of multiparametric functional MRI in predicting renal function response to renal artery stenting in severe atherosclerotic renal artery stenosis.

To explore the potential of Intravoxel Incoherent Motion Diffusion (IVIM) and Arterial Spin Labeling (ASL) in predicting the short-term effectiveness of post-revascularization for severe atherosclerotic renal artery stenosis. A retrospective analysis of 88 cases from October 2018 to February 2023 was conducted. Patients were divided into Responder and Non-Responder groups based on renal function outcomes at their last follow-up. Clinical data were compared between the groups, and preoperative functional MRI images were analyzed. ROIs were outlined for the affected and both kidneys. Measurements included ASL-derived renal blood flow (RBF), IVIM's pseudo-diffusion coefficient (D*), perfusion fraction (f), true diffusion coefficient (D), and the conventional apparent diffusion coefficient (ADC).Multivariate logistic regression identified independent clinical predictors of benefit, and a clinical prediction model was developed. Model performance was assessed using Receiver Operating Characteristic (ROC) curves and Decision Curve Analysis(DCA) curves. In the training cohort of 54 non-responders and 34 responders, no quantitative parameters of bilateral kidneys showed statistical significance in predicting Responders (all p > 0.05). Pre-treatment eGFR, presence of diabetes, and the D value of the affected kidney were identified as independent factors for predicting short-term treatment effectiveness. The combined clinical-functional imaging model yielded the higher AUC at 0.796 (95 % CI: 0.690-0.897) . Decision curve analysis further confirmed the better net benefit of combined model. Beyond clinical characteristics, functional MRI had the potential to predict response of stenting for severe atherosclerotic renal artery stenosis.

Uncovering cerebral blood flow patterns corresponding to Amyloid-beta accumulations in patients across the Alzheimer's disease continuum using the arterial spin labeling.

Alzheimer's disease (AD)is a progressive neurodegenerative disorder ranging from mild cognitive impairment (MCI) to AD dementia. Abnormal cerebral perfusion alterations, influenced by amyloid-beta (Aβ) accumulations, have been implicated in cognitive decline along this spectrum. This study investigates the relationship between cerebrospinal fluid (CSF) Aβ1-42 levels and regional cerebral blood flow (CBF) changes across the AD continuum using the Arterial Spin Labeling (ASL) technique. We analyzed data from 229 participants extracted from the ADNI cohort, comprising of50 cognitively normal (CN), 13 subjective memory complaints (SMC), 83 early MCI (EMCI), 52 late MCI (LMCI), and 31 AD participants with complete ASL and CSF data. Correlations between Aβ1-42 levels and regional mean CBF values were assessed. Multiple linear regression models accounted for confounders, including age, gender, and education level. Preliminary unadjusted analyses revealed strong positive correlations between Aβ1-42 levels and CBF in multiple regions, predominantly in the AD group. After adjusting for confounders, significant correlations in AD participants emerged in the left pars triangularis and left caudal middle frontal cortex. In the LMCI group, significant associations were identified in the right lateral occipital cortex, right inferior parietal cortex, and left amygdala. These findings highlight the critical role of Aβ-driven CBF alterations in regions associated with higher cognitive functions and suggest that these patterns may serve as potential biomarkers for diagnosing and monitoring disease progression.

The cortical high-flow sign in oligodendroglioma, IDH-mutant and 1p/19q-codeleted is correlated with histological cortical vascular density.

The cortical high-flow sign has been more commonly reported in oligodendroglioma, IDH-mutant and 1p/19q-codeleted (ODG IDHm-codel) compared to diffuse glioma with IDH-wildtype or astrocytoma, IDH-mutant. Besides tumor types, higher grades of glioma might also contribute to the cortical high flow. Therefore, we investigated whether the histological cortical vascular density or CNS WHO grade was associated with the cortical high-flow sign in patients with ODG IDHm-codel. This retrospective study consisted of pathologically confirmed 25 adult patients with ODG IDHm-codel. We implemented pseudo-continuous arterial spin labeling technique with background suppression. Subtraction images were generated from paired control and label images. Tumor-affecting cortices without intense contrast enhancement on conventional MR imaging were targeted for the determination of the cortical high-flow sign. Immunohistochemical staining of CD31 antibody was performed for the identification of vascular endothelial cells. A microscopic field of the most intense vascularization was captured in each specimen. The vessel number and the relative vascular density (%Vessel) were compared between the positive cortical high-flow sign (CHFS+) and the negative cortical high-flow sign (CHFS-) groups using the Mann-Whitney U test. Second, Fisher's exact test was used to compare the difference between the presence or absence of cortical high-flow sign and CNS WHO grades. Finally, the vessel number and %Vessel were compared between the CNS WHO grade 2 and grade 3 using the Mann-Whitney U test. The vessel number and %Vessel were higher in patients with the CHFS+ group than in patients with CHFS- group (p = 0.016 and p = 0.005, respectively). We observed no significant differences (p = 1.00) in the frequency of cortical high-flow sign between the CNS WHO grade 2 and grade 3. In addition, no significant differences are found in the vessel number and %Vessel between the CNS WHO grade 2 and grade 3 (p = 0.121 and p = 0.475, respectively). The cortical high-flow sign on ASL, which is more commonly found in ODG IDHm-codel than in diffuse glioma with IDH-wildtype or astrocytoma, is associated with the histological cortical vascular density in patients with ODG IDHm-codel.

Neurovascular coupling dysfunction associated with inflammatory factors in sudden sensorineural hearing loss.

The neuropathologic mechanisms of sudden sensorineural hearing loss (SSNHL) are unknown. The aim of this study was to investigate the alterations of neurovascular coupling (NVC) in patients with SSNHL and its association with hematologic inflammatory factors. The amplitude of low-frequency fluctuations (ALFF), fractional amplitude of low-frequency fluctuations (fALFF), regional homogeneity (ReHo), and degree centrality (DC) were calculated in 48 patients with SSNHL and 54 age-, gender-, and education-matched healthy control (HC), and also utilized the arterial spin labeling imaging (ASL) to calculate cerebral blood flow (CBF). Four indices of NVC (CBF-ALFF, CBF-fALFF, CBF-ReHo, and CBF-DC) in the whole brain gray matter as well as the NVC ratio were compared between two groups. In addition, correlation analyses were performed with inflammatory factors for the NVC indexes at the global level and regional level, respectively. The NVC at global level was lower in SSNHL group than in HC, except for CBF-ALFF. At the regional level, most of the brain regions with abnormal NVC in SSNHL patients involved auditory and sensorimotor language centers and limbic system compared to HC. In addition, both at the global and regional levels, NVC metrics were shown to correlate with partial inflammatory factors or hematologic parameters, including platelet-lymphocyte ratio (PLR), neutrophil-lymphocyte ratio (NLR), systemic immunoinflammatory index (SII), blood platelet count (PLT), and lymphocyte count (Lym). From the view of the NVC metrics, these findings provide new perspectives on the neuropathologic mechanisms and clinical treatment of SSNHL.

Associations between potential risk factors and blood-brain barrier water permeability in middle-aged and older adults.

Background: Blood-brain barrier (BBB) dysfunction is suggested to be a potential mediator between vascular risk factors and cognitive impairment, leading to vascular cognitive impairment. Objective: To investigate the relationships between age, sex, and vascular risk factors and BBB water permeability as well as their relationship with cognition. Methods: To measure BBB permeability, a novel arterial spin labelling MRI technique (ME-ASL) was applied to derive the time of exchange (Tex), arterial time transit (ATT), and cerebral blood flow (CBF). The association of potential risk factors, such as age, sex, body mass index (BMI), blood pressure (BP), and medical history, with these BBB parameters were assessed in 144 community-dwelling adults (median age 59 years, 57% females). The relationship between BBB permeability and cognitive performance measured by the Montreal Cognitive Assessment (MoCA) was also assessed. Results: We found that increased BMI was significantly associated with decreased CBF (β = -0.06). Systolic BP and diastolic BP showed significant associations with all ASL parameters; systolic BP was negatively correlated with Tex (β = -0.02) and CBF (β = -0.01) but positively with ATT (β = 0.02). Diastolic BP was negatively associated with Tex (β = -0.03) and CBF (β = -0.03) but positively with ATT (β = 0.03). MoCA scores had a borderline significant association with Tex (OR = 1.51) and a significant association with CBF (OR = 1.84), which became non-significant after adjusting for confounders. Conclusions: These outcomes underscore the potential of using ME-ASL, warranting further research to strengthen these findings.

Resting state BOLD-perfusion coupling patterns using multiband multi-echo pseudo-continuous arterial spin label imaging

The alteration of neurovascular coupling (NVC), where acute localized blood flow increases following neural activity, plays a key role in several neurovascular processes including aging and neurodegeneration. While not equivalent to NVC, the coupling between simultaneously measured cerebral blood flow (CBF) with arterial spin labeling (ASL) and blood oxygenation dependent (BOLD) signals, can also be affected. Moreover, the acquisition of BOLD data allows the assessment of resting state (RS) fMRI metrics. In this study a multiband, multi-echo (MBME) pseudo-continuous ASL (pCASL) sequence was used to collect simultaneous BOLD and ASL data in a group of healthy control subjects, and the patterns of BOLD-CBF coupling were evaluated. Coupling was also correlated with the BOLD RS measures. The variability, reproducibility, and reliability of the metrics were also computed in a multi-session subgroup. Areas of higher coupling were observed in the visual, motor, parietal, and frontal cortices and corresponded to major brain networks. Areas of significant correlation between coupling and BOLD RS measures corresponded to areas of heightened coupling. Higher variability and lower reliability were found for coupling metrics compared to BOLD RS metrics. These results indicate BOLD-CBF coupling metrics may be useful for studying neurovascular physiology.

Noninvasive in vivo assessment of placental insufficiency using pCASL: a prospective case–control study

BackgroundArterial spin labeling is a noninvasive imaging modality that does not use contrast for evaluation of placental perfusion in the placental pathological conditions. Our study enrolled 30 pregnant females with different risk factors for developing IUGR and other 30 females with the same age group having normal pregnancy. The two groups were evaluated by free breathing arterial spin labeling magnetic resonance imaging. Image findings of pseudo-continuous arterial spin labeling were compared to color duplex Doppler ultrasound of umbilical and middle cerebral arteries.AimThe aim of the present study was to evaluate the role of pseudo-continuous arterial spin labeling in measurement of placental perfusion with quantitative analysis of regional placental blood flow.MethodsThis prospective case–control study enrolled 30 pregnant females who had different causes of placental insufficiency, and another healthy group of matched ages, all were evaluated by 2D and color duplex Doppler ultrasound, conventional non-contrast magnetic resonance imaging and MRI perfusion using arterial spin labeling technique. The study was carried out from October 2021 to October 2023.ResultsSignificant relation was found between placental perfusion values and umbilical and middle cerebral artery resistive indices as indicator for placental insufficiency with sensitivity and specificity 77.8%, 80%, respectively, for umbilical artery resistive index and 90%, 83.3%, respectively, for middle cerebral artery resistive index. While the diagnostic value of ASL perfusion was as follows, it had sensitivity = 90%, specificity = 83.3%, PPV = 84.4%, NPV = 89.3% and accuracy = 86.7%.ConclusionsASL-MRI is an excellent noninvasive in vivo MRI technique for evaluation of placental perfusion and quantitative analysis of regional placental blood flow in cases of placental insufficiency. This study supported the value of the new noninvasive MRI techniques in the elaboration of placental pathology.

Cerebral Hemodynamic Responses to Disease-Modifying and Curative Sickle Cell Disease Therapies.

Sickle cell disease (SCD) is a hemoglobinopathy resulting in hemoglobin-S production, hemolytic anemia, and elevated stroke risk. Treatments include oral hydroxyurea, blood transfusions, and hematopoietic stem cell transplantation (HSCT). Our objective was to evaluate the neurologic relevance of these therapies by characterizing how treatment-induced changes in hemoglobin (Hb) affect brain health biomarkers. In this interventional study, adults with and without SCD underwent a 3T-MRI at Vanderbilt University Medical Center at 2 time points before and after clinically indicated transfusion or HSCT or at 2 time points without the introduction of a new Hb-altering therapy (adult controls and patients with SCD on hydroxyurea). Cerebral blood flow (CBF; mL/100 g/min) and cerebral venous blood relaxation rate (s-1; a marker of Hb and blood oxygen content) responses were assessed to understand how these markers of brain health vary with Hb modulation. CBF was assessed with arterial spin labeling MRI, and blood relaxation rate was assessed using T2 relaxation under spin tagging MRI. Measures were pairwise compared within each cohort using a 2-tailed Wilcoxon signed-rank test, and regression was applied to evaluate the parameter and Hb change relationships. The significance criterion was 2-sided p < 0.05. Adults with (n = 43; age 28.7 ± 7.7 years; 42% male) and without (n = 13; age 33.5 ± 12.2 years; 46% male) SCD were evaluated. In adults receiving hydroxyurea (n = 10), neither Hb, CBF, nor venous relaxation rate changed between time 1 (Hb = 8.6 ± 1.2 g/dL) and time 2 (Hb = 9.0 ± 1.8 g/dL) (all p > 0.05). In transfusion patients (n = 19), Hb increased from 8.2 ± 1.4 g/dL to 9.3 ± 1.3 g/dL before vs after transfusion (p < 0.001), paralleling a CBF decrease of 14.2 mL/100 g/min (p < 0.001) toward control levels. The venous relaxation rate did not change after transfusion (p = 0.71). In HSCT patients (n = 14), Hb increased from 8.9 ± 1.9 g/dL to 12.9 ± 2.7 g/dL (p < 0.001) before vs after transplant, paralleling CBF decreases from 68.16 ± 20.24 to 47.43 ± 12.59 mL/100 g/min (p < 0.001) and increase in venous relaxation rate (p = 0.004). Across the Hb spectrum, a CBF decrease of 5.02 mL/100 g/min per g/dL increase in Hb was observed. Findings demonstrate improvement in cerebral hemodynamics after transfusion and transplant therapies compared with hydroxyurea therapy; quantitative relationships should provide a framework for using these measures as trial end points to assess how new SCD therapies affect brain health.

Cerebral Metabolic Rate of Oxygen and Accelerometry-Based Fatigability in Community-Dwelling Older Adults.

Alterations in energy metabolism may drive fatigue in older age, but prior research primarily focused on skeletal muscle energetics without assessing other systems, and utilized self-reported measures of fatigue. We tested the association between energy metabolism in the brain and an objective measure of fatigability in the Study of Muscle, Mobility and Aging (N=119, age 76.8±4.0 years, 59.7% women). Total brain cerebral metabolic rate of oxygen (CMRO 2 ) was measured using arterial spin labeling and T 2 -relaxation under spin tagging MRI protocols. Accelerometry-based fatigability status during a fast-paced 400m walk was determined using the Pittsburgh Fatigability Index (PPFI, higher=worse). Confounders included skeletal muscle energetics, measured in vivo using spectroscopy and ex vivo using respirometry, cardiorespiratory fitness (VO 2 peak), weight, medication count, and multimorbidity. Multivariable logistic regression models were used to estimate the association (odds ratio (OR)) of CMRO 2 with PPFI>0 compared to the referent group PPFI=0. Models were first adjusted for age and sex, and further adjusted for confounders. In this sample, 41.2% had PPFI>0 (median 3.3% [0.4-8.0%]). CMRO 2 was positively associated with PPFI>0 (age and sex adjusted OR=1.61, 95% CI: 1.06, 2.45, p=0.03); adjustment for confounders attenuated the association. The positive association of brain energetics and fatigability warrants further study in older adults.

Sex-specific associations of serum testosterone with gray matter volume and cerebral blood flow in midlife individuals at risk for Alzheimer's disease.

Testosterone, an essential sex steroid hormone, influences brain health by impacting neurophysiology and neuropathology throughout the lifespan in both genders. However, human research in this area is limited, particularly in women. This study examines the associations between testosterone levels, gray matter volume (GMV) and cerebral blood flow (CBF) in midlife individuals at risk for Alzheimer's disease (AD), according to sex and menopausal status. A cohort of 294 cognitively normal midlife participants, 83% female, ages 35-65 years, with an AD family history and/or Apolipoprotein E epsilon 4 (APOE-4) genotype, underwent volumetric Magnetic Resonance Imaging (MRI) to measure GMV and MR-Arterial Spin Labeling (ASL) for measurement of CBF. We used voxel-based analysis and volumes of interest to test for associations between testosterone (both total and free testosterone) and brain imaging outcomes, stratified by sex and menopausal status. Higher total and free testosterone levels were associated with larger GMV in men, with peak effects in frontal and temporal regions. Conversely, in women, higher testosterone levels correlated with higher CBF, with peak effects in frontal and limbic regions, subcortical areas and hypothalamus. Among women, associations between testosterone and GMV were observed at the premenopausal and perimenopausal stages, but not postmenopause, whereas associations of testosterone with CBF were significant starting at the perimenopausal stage and were more pronounced among hormone therapy non-users. Results were independent of age, APOE-4 status, midlife health indicators, and sex hormone-binding globulin levels. These findings indicate sex-specific neurophysiological effects of testosterone in AD-vulnerable regions in midlife individuals at risk for AD, with variations observed across sex and menopausal status. This underscores the need for further research focusing on the neuroprotective potential of testosterone in both sexes.

Impaired insight in schizophrenia is associated with higher frontoparietal cerebral blood flow: an arterial spin labeling study

Impaired insight into illness occurs in up to 98% of patients with schizophrenia, depending on the stage of illness, and leads to negative clinical outcomes. Previous neuroimaging studies suggest that impaired insight in patients with schizophrenia may be related to structural and functional anomalies in frontoparietal brain regions. To date, limited studies have investigated the association between regional cerebral blood flow (CBF) and impaired insight in schizophrenia. Therefore, we sought to investigate the relationship between regional CBF, as measured by arterial spin labeling (ASL), and impaired insight in participants with schizophrenia. A total of 32 participants were included in the analysis. Impaired insight in patients with schizophrenia was measured using the VAGUS, Self-report (VAGUS-SR). Resting-state regional CBF was measured using pseudo-continuous ASL (pCASL) and extracted using SPM12 and REX toolbox. Whole brain analysis found that impaired insight was associated with higher regional CBF in the right angular gyrus, left supramarginal gyrus, and right superior frontal region when controlling for age, gender, smoking status, and illness severity. The results indicate that impaired insight in schizophrenia is related to regional CBF in frontoparietal areas. These neuroimaging findings can serve as therapeutic targets for intervention, such as with non-invasive brain stimulation.

Noninvasive blood-brain barrier integrity mapping in patients with high-grade glioma and metastasis by multi-echo time-encoded arterial spin labeling.

In brain tumors, disruption of the blood-brain barrier (BBB) indicates malignancy. Clinical assessment is qualitative; quantitative evaluation is feasible using the K2 leakage parameter from dynamic susceptibility contrast MRI. However, contrast agent-based techniques are limited in patients with renal dysfunction and insensitive to subtle impairments. Assessing water transport times across the BBB (Tex) by multi-echo arterial spin labeling promises to detect BBB impairments noninvasively and potentially more sensitively. We hypothesized that reduced Tex indicates impaired BBB. Furthermore, we assumed higher sensitivity for Tex than dynamic susceptibility contrast-based K2, because arterial spin labeling uses water as a freely diffusible tracer. We acquired 3T MRI data from 28 patients with intraparenchymal brain tumors (World Health Organization Grade 3 & 4 gliomas [n = 17] or metastases [n = 11]) and 17 age-matched healthy controls. The protocol included multi-echo and single-echo Hadamard-encoded arterial spin labeling, dynamic susceptibility contrast, and conventional clinical imaging. Tex was calculated using a T2-dependent multi-compartment model. Areas of contrast-enhancing tissue, edema, and normal-appearing tissue were automatically segmented, and parameter values were compared across volumes of interest and between patients and healthy controls. Tex was significantly reduced (-20.3%) in contrast-enhancing tissue compared with normal-appearing gray matter and correlated well with |K2| (r = -0.347). Compared with healthy controls, Tex was significantly lower in tumor patients' normal-appearing gray matter (Tex,tumor = 0.141 ± 0.032 s vs. Tex,HC = 0.172 ± 0.036 s) and normal-appearing white matter (Tex,tumor = 0.116 ± 0.015 vs. Tex,HC = 0.127 ± 0.017 s), whereas |K2| did not differ significantly. Receiver operating characteristic analysis showed a larger area under the curve for Tex (0.784) than K2 (0.604). Tex is sensitive to pathophysiologically impaired BBB. It agrees with contrast agent-based K2 in contrast-enhancing tissue and indicates sensitivity to subtle leakage.

Cerebral perfusion alterations in healthy young adults due to two genetic risk factors of Alzheimer's disease: APOE and MAPT.

Functional brain changes such as altered cerebral blood flow occur long before the onset of clinical symptoms in Alzheimer's disease (AD) and other neurodegenerative disorders. While cerebral hypoperfusion occurs in established AD, middle-aged carriers of genetic risk factors for AD, including APOE ε4, display regional hyperperfusion due to hypothesised pleiotropic or compensatory effects, representing a possible early biomarker of AD and facilitating earlier AD diagnosis. However, it is not clear whether hyperperfusion already exists even earlier in life. Here, 160 young and cognitively healthy participants from the Chinese PREVENT cohort underwent 3 T arterial spin labelling and T1 MRI and genetic testing for APOE and MAPT rs242557 status. Using FSL, we performed a whole brain voxel-wise analysis and a global mean grey matter analysis comparing for the effects of both risk genes on cerebral perfusion. No significant alterations were seen for APOE genotype, but in MAPT rs242557 A carriers, we observed a significantly hyperperfusion in the left anterior cingulate cortex and left insular cortex. There were no effects of APOE or MAPT status on the global perfusion. These results are novel and may suggest that MAPT genotypes demonstrated a distinct hemodynamic profile in a very young age.