Silent cerebral infarcts (SCIs) are present in patients with sickle cell disease (SCD) and thalassemia, but the pathophysiology of SCIs is not fully understood. Previous studies mainly focused on cerebral hemodynamics and oxygen metabolism in patients with severe SCD (HbSS/HbSβ°) but not in milder forms of SCD (HbSC/HbSβ+) and thalassemia despite the high prevalence of SCIs in these patients. In this work, we studied the cerebral hemodynamics and oxygen metabolism, and SCI lesion load in 75 severe and 26 mild adult SCD patients, 18 thalassemia patients (as anemic comparison group), and 30 healthy controls before and after a vasodilatory challenge with acetazolamide. Cerebral blood flow was significantly higher in patients with severe SCD and thalassemia compared to patients with mild SCD and controls (p < 0.05). Conversely, oxygen extraction fraction and cerebral metabolic rate of oxygen (CMRO2) were significantly lower in patients with severe SCD and thalassemia compared to other groups (p < 0.01). In contrast, no difference in SCI volumes was found between mild and severe SCD and thalassemia patients. After acetazolamide administration, oxygen delivery increased less in severe SCD and thalassemia patients compared to other groups (p < 0.01) and CMRO2 decreased only in severe SCD patients (p < 0.01). Given the reduced CMRO2 values in severe SCD and thalassemia patients, we conclude that reduced cerebral oxygen consumption in these patient groups is mostly related to anemia. Our data suggest that the pathophysiology of SCIs in patients with milder forms of SCD might be more related to prior episodes of anemia or other sickle cell-related factors.

Deoxygenation-based dynamic susceptibility contrast (dDSC) MRI uses respiratory challenges as a source of endogenous contrast as an alternative to gadolinium injection. These gas challenges induce T2*-weighted MRI signal losses, after which tracer kinetics modeling was applied to calculate cerebral perfusion. This work compares three gas challenges, desaturation (transient hypoxia), resaturation (transient normoxia), and SineO 2 (sinusoidal modulation of end-tidal oxygen pressures) in a cohort of 10 healthy volunteers (age 37 ± 11 years; 60% female). Perfusion estimates consisted of cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT). Calculations were computed using a traditional tracer kinetics model in the time domain for desaturation and resaturation and in the frequency domain for SineO 2 . High correlations and limits of agreement were observed among the three deoxygenation-based paradigms for CBV, although MTT and CBF estimates varied with the hypoxic stimulus. Cross-modality correlation with gadolinium DSC was lower, particularly for MTT, but on a par with agreement between the other perfusion references. Overall, this work demonstrated the feasibility and reliability of oxygen respiratory challenges to measure brain perfusion. Additional work is needed to assess the utility of dDSC in the diagnostic evaluation of various pathologies such as ischemic strokes, brain tumors, and neurodegenerative diseases.

Purpose: Congenital anemias, including sickle cell anemia and thalassemia, are associated with cerebral tissue hypoxia and heightened stroke risks. Recent works in sickle cell disease mouse models have suggested that hyperoxia respiratory challenges can identify regions of the brain having chronic tissue hypoxia. Therefore, this work investigated differences in hyperoxic response and regional cerebral oxygenation between anemic and healthy subjects.Methods: A cohort of 38 sickle cell disease subjects (age 22 +/- 8 years, female 39%), 25 non-sickle anemic subjects (age 25 +/- 11 years, female 52%), and 31 healthy controls (age 25 +/- 10 years, female 68%) were examined. A hyperoxic gas challenge was performed with concurrent acquisition of blood oxygen level-dependent (BOLD) MRI and near-infrared spectroscopy (NIRS). In addition to hyperoxia-induced changes in BOLD and NIRS, global measurements of cerebral blood flow, oxygen delivery, and cerebral metabolic rate of oxygen were obtained and compared between the three groups.Results: Regional BOLD changes were not able to identify brain regions of flow limitation in chronically anemic patients. Higher blood oxygen content and tissue oxygenation were observed during hyperoxia gas challenge. Both control and anemic groups demonstrated lower blood flow, oxygen delivery, and metabolic rate compared to baseline, but the oxygen metabolism in anemic subjects were abnormally low during hyperoxic exposure.Conclusion: These results indicated that hyperoxic respiratory challenge could not be used to identify chronically ischemic brain. Furthermore, the low hyperoxia-induced metabolic rate suggested potential negative effects of prolonged oxygen therapy and required further studies to evaluate the risk for hyperoxia-induced oxygen toxicity and cerebral dysfunction.

Introduction: Moderate iron deficiency anemia(IDA), defined as a hemoglobin below 11 g/dl, occurs in 1.5% of the United States population and is overrepresented in minority populations. IDA is known to cause permanent structural and function damage in children, but IDA's cognitive and neurovascular phenotype in adults is poorly characterized. We performed brain MRI and cognitive testing in 34 otherwise healthy women with IDA to determine whether oxygen delivery and metabolism are preserved as well as the association of IDA with brain volumes and cognitive function. Methods: We recruited potential blood donors from four hospital-based donor centers, Children's Hospital Los Angeles, University of California Los Angeles, Cedar's Sinai, and City of Hope, whose point-of-care hemoglobin values were less than 10.5 g/dl. We also recruited individuals from the community using social media advertisements, with anemia documented by screening hemoglobin assessment. All participants were free from inflammatory, infectious, or malignant diseases that may impact blood counts and iron metabolism. IDA was confirmed by laboratory assessment of CBC, reticulocyte count, iron indices, methyl malonic acid, hemoglobin electrophoresis, homocysteine, and high-sensitivity C-reactive protein. Patients underwent a four-hour neurocognitive assessment consisting of subsets from the Weschler Abbreviated Scale of Intelligence (WASI-II), the California Verbal Learning Test (CVLT), the Rey Complex Figure Test (RCFT), and the NIH Cognitive Toolkit. MRI was performed on a 3T Philips Achieva using a 32-element head coil. Anatomic imaging consisted of 3D T1, 3D T2, 3D T2*/QSM, and 2D multishell diffusion imaging. Phase contrast and arterial spin labeling measured total and regional brain blood flow, respectively. Cerebral venous oximetry was performed using T2 relaxation under spin tagging. Results: The study population demonstrated a classic IDA phenotype characterized by low ferritin and transferrin saturation, high iron binding capacity, decreased MCV and MCHC, and hypochromic microcytosis on blood smear (not shown). Neurocognitive function was impaired across multiple domains for women having hemoglobin values less than 10.0 g/dl (Figure 1, left), with Cohen's D values ranging from 0.7 - 1.5. Cerebral blood flow (CBF) rose slightly as oxygen content declined (Figure 1, right), but much less than predicted based on historical controls 1,2 leading to impaired brain oxygen delivery. Oxygen extraction fraction was independent of hemoglobin concentration, thus cerebral metabolic rate was also decreased. Grey matter volume was smaller in the right temporal lobe and correlated with 2/3 of the abnormal cognitive indices (in Figure 1, left). White matter volume was decreased in the right cingulate gyrus, corpus callosum, and cerebellum, correlating with the remaining abnormal cognitive indices. Discussion: Our study demonstrates that iron deficiency has serious effects on cognitive performance; individuals with hemoglobin less than 10.0 g/dl scored more than one standard deviation below their peers with milder anemia. Poor cognitive performance was correlated with demonstrable brain shrinkage whose reversibility is unknown. The failure of the brain to upregulate CBF in response to IDA was striking because most patients with chronic anemia preserve cerebral oxygen delivery through compensatory hyperemia 1,2. While both anemia and iron deficiency can impair brain function on their own, it is likely that iron deficiency is the primary contributor to the cognitive and neurovascular effects. We will test this hypothesis in subsequent work by reexamining women with IDA shortly after intravenous iron administration, thus creating a window where the iron deficiency has been corrected but the anemia persists(NCT05929729). We will also determine whether the cerebrovascular, anatomic, and functional deficits are reversible with iron repletion. References 1. Brown MM, Marshall J. Regulation of cerebral blood flow in response to changes in blood viscosity. Lancet. 1985;1(8429):604-609. 2. Bush AM, Borzage MT, Choi S, et al. Determinants of resting cerebral blood flow in sickle cell disease. Am J Hematol. 2016;91(9):912-917.

Topic: 26. Sickle cell disease Background: Sickle cell disease (SCD) is complicated by cerebral infarctions. These include silent cerebral infarcts (SCIs) which can be found in 40% of the patients by the age of 20 years and progress further with age. Studies in patients with severe (HbSS and HbSβ0) SCD have reported reduced oxygen metabolism compared to controls despite the preserved oxygen delivery (OD). Whereas previous studies have found similar lesion load in mild SCD patients (HbSC and HbSβ+), cerebral oxygen metabolism has not been studied in this group forming almost 30% of the SCD patients. In this study, we investigated the differences between milder and severe SCD patients by comparing parameters of cerebral hemodynamics and oxygen metabolism between different anemic groups. Aims: We aimed to assess the cerebral blood flow (CBF), OD, cerebral oxygen extraction fraction (OEF), cerebral metabolic rate of oxygen (CMRO2), and SCI volumes in adult patients with severe and milder SCD and compared these results with thalassemia patients (as anemic control) and healthy controls. In addition, the effect of a vasodilatory stimulus on the cerebral parameters was studied to test if increased CBF influences cerebral oxygen consumption. Methods: Venous blood T2 was measured in the superior sagittal sinus using T2-Relaxation-Under-Spin-Tagging (TRUST). White matter (WM) and gray matter (GM) CBF were measured using time-encoded pseudo-continuous ASL (te-ASL). TRUST and te-ASL scans were performed before and after acetazolamide (ACZ) administration as a vasodilatory stimulus. Fluid-Attenuated Inversion Recovery (FLAIR) scans were acquired for the assessment and segmentation of SCIs. OEF was calculated from arterial saturation measured by pulse oximetry and venous saturation calculated from TRUST-derived venous blood T2. Subsequently, CMRO2 was calculated by multiplying CBF, OEF, and oxygen content (calculated from hemoglobin and arterial saturation). To test the effect of ACZ-induced vasodilation, ∆CBF, ∆OD, ∆OEF, and ∆CMRO2 were calculated. Results: In this study, 75 patients with severe SCD, 26 patients with mild SCD, 18 patients with thalassemia (7 NTDT and 11 TDT) and 30 healthy controls were included. WM and GM CBF were significantly higher in severe SCD and thalassemia patients compared to mild SCD patients and healthy controls (Table 1). OEF was significantly lower in severe SCD patients compared to other groups and significantly lower in thalassemia patients compared to mild SCD patients and healthy controls. CMRO2 was significantly lower in severe SCD and thalassemia patients compared to mild SCD patients and healthy controls (Table 1). ACZ administration reduced the CMRO2 in severe SCD patients compared to the other groups (Table 1). SCI volume was significantly larger in the severe SCD group compared to the healthy controls but did not differ between the other groups (Table 1). Summary/Conclusion: This study demonstrated that severe SCD and thalassemia patients have reduced cerebral oxygen consumption, which is most likely associated with the severity of anemia. Conversely, mild SCD patients showed a more balanced oxygen supply versus demand, even though they had similar SCI volumes. This suggests that the pathophysiology of SCIs in mild SCD may not be solely driven by anemia and that more sickle cell-specific aspects like reduced RBC deformability and higher viscosity, may contribute. Notably, we found that elevated CBF induced by ACZ reduced CMRO2 in severe SCD patients, indicating that functional shunting may be a contributing factor in the more severe cases of SCD.Keywords: Sickle cell anemia, Sickle cell disease, Thalassemia, Hemoglobinopathy

Cerebrovascular reactivity (CVR) is a prognostic indicator of cerebrovascular health. Estimating CVR from endogenous end-tidal carbon dioxide (CO2) fluctuation and MRI signal recorded under resting state can be difficult due to the poor signal-to-noise ratio (SNR) of signals. Thus, we aimed to improve the method of estimating CVR from end-tidal CO2 and MRI signals. We proposed a coherence weighted general linear model (CW-GLM) to estimate CVR from the Fourier coefficients weighted by the signal coherence in frequency domain, which confers two advantages. First, it requires no signal alignment in time domain, which simplifies experimental methods. Second, it limits the GLM analysis within the frequency band where CO2 and MRI signals are highly correlated, which automatically suppresses noise and nuisance signals. We compared the performance of our method with time-domain GLM (TD-GLM) and frequency-domain GLM (FD-GLM) in both synthetic and in-vivo data; wherein we calculated CVR from signals recorded under both resting state and sinusoidal stimulus. In synthetic data, CW-GLM has a remarkable performance on CVR estimation from narrow band signals with a mean-absolute error of 0.7 % (gray matter) and 1.2 % (white matter), which was lower than all the other methods. Meanwhile, CW-GLM maintains a comparable performance on CVR estimation from resting signals, with a mean-absolute error of 4.1 % (gray matter) and 8 % (white matter). The superior performance was maintained across the 36 in-vivo measurements, with CW-GLM exhibiting limits of agreement of -16.7 % – 9.5 % between CVR calculated from the resting and sinusoidal CO2 paradigms which was 12 % – 209 % better than current time-domain methods. Evaluating of the cross-coherence spectrum revealed highest signal coherence within the frequency band from 0.01 Hz to 0.05 Hz, which overlaps with previously recommended frequency band (0.02 Hz to 0.04 Hz) for CVR analysis. Our data demonstrates that CW-GLM can work as a self-adaptive band-pass filter to improve CVR robustness, while also avoiding the need for signal temporal alignment.

Introduction: Deoxygenation-based dynamic susceptibility contrast (dDSC) has previously leveraged respiratory challenges to modulate blood oxygen content as an endogenous source of contrast alternative to gadolinium injection in perfusion-weighted MRI. This work proposed the use of sinusoidal modulation of end-tidal CO2 pressures (SineCO 2 ), which has previously been used to measure cerebrovascular reactivity, to induce susceptibility-weighted gradient-echo signal loss to measure brain perfusion. Methods: SineCO 2 was performed in 10 healthy volunteers (age 37 ± 11, 60% female), and tracer kinetics model was applied in the frequency domain to calculate cerebral blood flow, cerebral blood volume, mean transit time, and temporal delay. These perfusion estimates were compared against reference techniques, including gadolinium-based DSC, arterial spin labeling, and phase contrast. Results: Our results showed regional agreement between SineCO 2 and the clinical comparators. SineCO 2 was able to generate robust CVR maps in conjunction to baseline perfusion estimates. Discussion: Overall, this work demonstrated feasibility of using sinusoidal CO2 respiratory paradigm to simultaneously acquire both cerebral perfusion and cerebrovascular reactivity maps in one imaging sequence.

Sickle cell disease (SCD) is caused by a single amino acid mutation in hemoglobin, causing chronic anemia and neurovascular complications. However, the effects of chronic anemia on oxygen extraction fraction (OEF), especially in deep brain structures, are less well understood. Conflicting OEF values have been reported in SCD patients, but have largely attributed to different measurement techniques, faulty calibration, and different locations of measurement. Thus, in this study, we investigated the reliability and agreement of two susceptibility-based methods, quantitative susceptibility mapping (QSM) and complex image summation around a spherical or a cylindrical object (CISSCO), for OEF measurements in internal cerebral vein (ICV), reflecting oxygen saturation in deep brain structures. Both methods revealed that SCD patients and non-sickle anemia patients (ACTL) have increased OEF in ICV (42.6% ± 5.6% and 30.5% ± 3.6% in SCD by CISSCO and QSM respectively, 37.0% ± 4.1% and 28.5% ± 2.3% in ACTL) compared with controls (33.0% ± 2.3% and 26.8% ± 1.8%). OEF in ICV varied reciprocally with hematocrit (r 2 = 0.92, 0.53) and oxygen content (r 2 = 0.86, 0.53) respectively. However, an opposite relationship was observed for OEF measurements in sagittal sinus (SS) with the widely used T2-based oximetry, T2-Relaxation-Under-Spin-Tagging (TRUST), in the same cohorts (31.2% ± 6.6% in SCD, 33.3% ± 5.9% in ACTL and 36.8% ± 5.6% in CTL). Importantly, we demonstrated that hemoglobin F and other fast moving hemoglobins decreased OEF by TRUST and explained group differences in sagittal sinus OEF between anemic and control subjects. These data demonstrate that anemia causes deep brain hypoxia in anemia subjects with concomitant preservation of cortical oxygenation, as well as the key interaction of the hemoglobin dissociation curve and cortical oxygen extraction.

Chronic anemia is commonly observed in patients with hemoglobinopathies, mainly represented by disorders of altered hemoglobin (Hb) structure (sickle cell disease, SCD) and impaired Hb synthesis (e.g. thalassemia syndromes, non-SCD anemia). Both hemoglobinopathies have been associated with white matter (WM) alterations. Novel structural MRI research in our laboratory demonstrated that WM volume was diffusely lower in deep, watershed areas proportional to anemia severity. Furthermore, diffusion tensor imaging analysis has provided evidence that WM microstructure is disrupted proportionally to Hb level and oxygen saturation. SCD patients have been widely studied and demonstrate lower fractional anisotropy (FA) in the corticospinal tract and cerebellum across the internal capsule and corpus callosum. In the present study, we compared 19 SCD and 15 non-SCD anemia patients with a wide range of Hb values allowing the characterization of the effects of chronic anemia in isolation of sickle Hb. We performed a tensor analysis to quantify FA changes in WM connectivity in chronic anemic patients. We calculated the volumetric mean of FA along the pathway of tracks connecting two regions of interest defined by BrainSuite's BCI-DNI atlas. In general, we found lower FA values in anemic patients; indicating the loss of coherence in the main diffusion direction that potentially indicates WM injury. We saw a positive correlation between FA and hemoglobin in these same regions, suggesting that decreased WM microstructural integrity FA is highly driven by chronic hypoxia. The only connection that did not follow this pattern was the connectivity within the left middle-inferior temporal gyrus. Interestingly, more reductions in FA were observed in non-SCD patients (mainly along with intrahemispheric WM bundles and watershed areas) than the SCD patients (mainly interhemispheric).

INTRODUCTION:Sickle cell disease (SCD) is a hereditary blood disorder in which the oxygen-carrying hemoglobin molecule in red blood cells is abnormal. SCD patients are at increased risks for strokes and neurocognitive deficit, even though neurovascular screening and treatments have lowered the rate of overt strokes. Tract-specific analysis (TSA) is a statistical method to evaluate microstructural WM damage in neurodegenerative disorders, using diffusion tensor imaging (DTI).METHODS:We utilized TSA and compared 11 major brain WM tracts between SCD patients with no history of overt stroke, anemic controls, and healthy controls. We additionally examined the relationship between the most commonly used DTI metric of WM tracts and neurocognitive performance in the SCD patients and healthy controls.RESULTS:Disruption of WM microstructure orientation-dependent metrics for the SCD patients was found in the genu of the corpus callosum (CC), cortico-spinal tract, inferior fronto-occipital fasciculus, right inferior longitudinal fasciculus, superior longitudinal fasciculus, and left uncinate fasciculus. Neurocognitive performance indicated slower processing speed and lower response inhibition skills in SCD patients compared to controls. TSA abnormalities in the CC were significantly associated with measures of processing speed, working memory, and executive functions.CONCLUSION:Decreased DTI-derived metrics were observed on six tracts in chronically anemic patients, regardless of anemia subtype, while two tracks with decreased measures were unique to SCD patients. Patients with WMHs had more significant FA abnormalities. Decreased FA values in the CC significantly correlated with all nine neurocognitive tests, suggesting a critical importance for CC in core neurocognitive processes.

PurposeTo demonstrate the feasibility of mapping cerebral perfusion metrics with BOLD MRI during modulation of pulmonary venous oxygen saturation.MethodsA gas blender with a sequential gas delivery breathing circuit was used to implement rapid isocapnic changes in the partial pressure of oxygen of the arterial blood. Partial pressure of oxygen was initially lowered to a baseline of 40 mmHg. It was then rapidly raised to 95 mmHg for 20 s before rapidly returning to baseline. The induced cerebral changes in deoxyhemoglobin concentration were tracked over time using BOLD MRI in 6 healthy subjects and 1 patient with cerebral steno‐occlusive disease. BOLD signal change, contrast‐to‐noise ratio, and time delay metrics were calculated. Perfusion metrics such as mean transit time, relative cerebral blood volume, and relative cerebral blood flow were calculated using a parametrized method with a mono‐exponential residue function. An arterial input function from within the middle cerebral artery was used to scale relative cerebral blood volume and calculate absolute cerebral blood volume and cerebral blood flow.ResultsIn normal subjects, average gray and white matter were: BOLD change = 6.3 ± 1.2% and 2.5 ± 0.6%, contrast‐to‐noise ratio = 4.3 ± 1.3 and 2.6 ± 0.7, time delay = 2.3 ± 0.6 s and 3.6 ± 0.7 s, mean transit time = 3.9 ± 0.6 s and 5.5 ± 0.6 s, relative cerebral blood volume = 3.7 ± 0.9 and 1.6 ± 0.4, relative cerebral blood flow = 70.1 ± 8.3 and 20.6 ± 4.0, cerebral blood flow volume = 4.1 ± 0.9 mL/100 g and 1.8 ± 0.5 mL/100 g, and cerebral blood flow = 97.2 ± 18.7 mL/100 g/min and 28.7 ± 5.9 mL/100 g/min.ConclusionThis study demonstrates that induced abrupt changes in deoxyhemoglobin can function as a noninvasive vascular contrast agent that may be used for cerebral perfusion imaging.

Purpose: Cerebral T-2 oximetry is a non-invasive imaging method to measure blood T-2 and cerebral venous oxygenation. Measured T-2 values are converted to oximetry estimates using carefully validated and potentially disease-specific calibrations. In sickle cell disease, red blood cells have abnormal cell shape and membrane properties that alter T-2 oximetry calibration relationships in clinically meaningful ways. Previous in vitro works by two independent groups established potentially competing calibration models. Methods: This study analyzed pooled datasets from these two studies to establish a unified and more robust sickle-specific calibration to serve as a reference standard in the field. Results: Even though the combined calibration did not demonstrate statistical superiority compared to previous models, the calibration was unbiased compared to blood-gas co-oximetry and yielded limits of agreement of (-10.1%, 11.6%) in non-transfused subjects with sickle cell disease. In transfused patients, this study proposed a simple correction method based on individual hemoglobin S percentage that demonstrated reduced bias in saturation measurement compared to previous uncorrected sickle calibrations. Conclusion: The combined calibration is based on a larger range of hematocrit, providing greater confidence in the hematocrit-dependent model parameters, and yielded unbiased estimates to blood-gas co-oximetry measurements from both sites. Additionally, this work also demonstrated the need to correct for transfusion in T-2 oximetry measurements for hyper-transfused sickle cell disease patients and proposes a correction method based on patient-specific hemoglobin S concentration.

Anemia is the most common blood disorder in the world. In patients with chronic anemia, such as sickle cell disease or major thalassemia, cerebral blood flow increases to compensate for decreased oxygen content. However, the effects of chronic anemia on oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2 ) are less well understood. In this study, we examined 47 sickle-cell anemia subjects (age 21.7 ± 7.1, female 45%), 27 non-sickle anemic subjects (age 25.0 ± 10.4, female 52%) and 44 healthy controls (age 26.4 ± 10.6, female 71%) using MRI metrics of brain oxygenation and flow. Phase contrast MRI was used to measure resting cerebral blood flow, while T2 -relaxation-under-spin-tagging (TRUST) MRI with disease appropriate calibrations were used to measure OEF and CMRO2 . We observed that patients with sickle cell disease and other chronic anemias have decreased OEF and CMRO2 (respectively 27.4 ± 4.1% and 3.39 ± 0.71 ml O2 /100 g/min in sickle cell disease, 30.8 ± 5.2% and 3.53 ± 0.64 ml O2 /100 g/min in other anemias) compared to controls (36.7 ± 6.0% and 4.00 ± 0.65 ml O2 /100 g/min). Impaired CMRO2 was proportional to the degree of anemia severity. We further demonstrate striking concordance of the present work with pooled historical data from patients having broad etiologies for their anemia. The reduced cerebral oxygen extraction and metabolism are consistent with emerging data demonstrating increased non-nutritive flow, or physiological shunting, in sickle cell disease patients.

PurposeGadolinium‐based dynamic susceptibility contrast (DSC) is commonly used to characterize blood flow in patients with stroke and brain tumors. Unfortunately, gadolinium contrast administration has been associated with adverse reactions and long‐term accumulation in tissues. In this work, we propose an alternative deoxygenation‐based DSC (dDSC) method that uses a transient hypoxia gas paradigm to deliver a bolus of paramagnetic deoxygenated hemoglobin to the cerebral vasculature for perfusion imaging.MethodsThrough traditional DSC tracer kinetic modeling, the MR signal change induced by this hypoxic bolus can be used to generate regional perfusion maps of cerebral blood flow, cerebral blood volume, and mean transit time. This gas paradigm and blood‐oxygen‐level‐dependent (BOLD)‐MRI were performed concurrently on a cohort of 66 healthy and chronically anemic subjects (age 23.5 ± 9.7, female 64%).ResultsOur results showed reasonable global and regional agreement between dDSC and other flow techniques, such as phase contrast and arterial spin labeling.ConclusionIn this proof‐of‐concept study, we demonstrated the feasibility of using transient hypoxia to generate a contrast bolus that mimics the effect of gadolinium and yields reasonable perfusion estimates. Looking forward, optimization of the hypoxia boluses and measurement of the arterial‐input function is necessary to improve the accuracy of dDSC. Additionally, a cross‐validation study of dDSC and DSC in brain tumor and ischemic stroke subjects is warranted to evaluate the clinical diagnostic utility of this approach.

Background Obstructive sleep apnea and nocturnal oxygen desaturations, which are prevalent in sickle cell disease (SCD) and chronic anemia disorders, have been linked to risks of stroke and silent cerebral infarcts (SCI). Cerebrovascular response to intermittent desaturations has not been well studied and may identify patients at greatest risk. Purpose To investigate the cerebral dynamic response to induced desaturation in SCD patients with and without SCI, chronic anemia, and healthy subjects. Study Type Prospective. Subjects Twenty‐six SCD patients (age = 21 ± 8.2, female 46.2%), including 15 subjects without SCI and nine subjects with SCI , 15 nonsickle anemic patients (age = 22 ± 5.8, female 66.7%), and 31 controls (age = 28 ± 12.3, female 77.4%). Field Strength/Sequence 3T, gradient‐echo echo‐planar imaging. Assessment A transient hypoxia challenge of five breaths of 100% nitrogen gas was performed with blood oxygen level‐dependent (BOLD) MRI and near‐infrared spectroscopy (NIRS) acquisitions. Hypoxia responses were characterized by desaturation depth, time‐to‐peak, return‐to‐baseline half‐life, and posthypoxia recovery in the BOLD and NIRS time courses. SCI were documented by T 2 fluid‐attenuation inversion recovery (FLAIR). Statistical Tests Univariate and multivariate regressions were performed between hypoxic parameters and anemia predictors. Voxelwise two‐sample t ‐statistic maps were used to assess the regional difference in hypoxic responses between anemic and control groups. Results Compared to controls, SCD and chronically anemic patients demonstrated significantly higher desaturation depth ( P < 0.01) and shorter return‐to‐baseline timing response ( P < 0.01). Patients having SCI had shorter time‐to‐peak ( P < 0.01), return‐to‐baseline ( P < 0.01), and larger desaturation depth ( P < 0.01) in both white matter regions at risk and normal‐appearing white matter than patients without infarcts. On multivariate analysis, desaturation depth and timing varied with age, sex, blood flow, white blood cells, and cell‐free hemoglobin ( r 2 = 0.25 for desaturation depth; r 2 = 0.18 for time‐to‐peak; r 2 = 0.37 for return‐to‐baseline). Data Conclusion Transient hypoxia revealed global and regional response differences between anemic and healthy subjects. SCI was associated with extensive heterogeneity of desaturation dynamics, consistent with extensive underlying microvascular remodeling.

Although modern medical management has lowered overt stroke occurrence in patients with sickle cell disease (SCD), progressive white matter (WM) damage remains common. It is known that cerebral blood flow (CBF) increases to compensate for anemia, but sufficiency of cerebral oxygen delivery, especially in the WM, has not been systematically investigated. Cerebral perfusion was measured by arterial spin labeling in 32 SCD patients (age range: 10-42 years old, 14 males, 7 with HbSC, 25 HbSS) and 25 age and race-matched healthy controls (age range: 15-45 years old, 10 males, 12 with HbAS, 13 HbAA); 8/24 SCD patients were receiving regular blood transfusions and 14/24 non-transfused SCD patients were taking hydroxyurea. Imaging data from control subjects were used to calculate maps for CBF and oxygen delivery in SCD patients and their T-score maps. Whole brain CBF was increased in SCD patients with a mean T-score of 0.5 and correlated with lactate dehydrogenase (r2  = 0.58, P < 0.0001). When corrected for oxygen content and arterial saturation, whole brain and gray matter (GM) oxygen delivery were normal in SCD, but WM oxygen delivery was 35% lower than in controls. Age and hematocrit were the strongest predictors for WM CBF and oxygen delivery in patients with SCD. There was spatial co-localization between regions of low oxygen delivery and WM hyperintensities on T2 FLAIR imaging. To conclude, oxygen delivery is preserved in the GM of SCD patients, but is decreased throughout the WM, particularly in areas prone to WM silent strokes.

Introduction: In subjects with chronic anemia syndromes, such as sickle cell disease and major thalassemia, cerebral blood flow (CBF) has been shown to increase in compensation for the decreased oxygen content. In previous works using pseudo-continuous arterial spin labeling, our laboratory has demonstrated the phenomenon of venous outflow suggestive of physiological arteriovenous shunting in anemic subjects with high CBF and short microvascular transit time (Bush et al., 2018). In this study, we evaluated CBF, oxygen delivery (DO2), oxygen extraction fraction (OEF) and cerebral metabolic rate (CMRO2) in three subject groups: sickle cell disease (SCD), non-sickle anemia (ACTL) and healthy controls (CTL). We hypothesize that even though DO2 is preserved in the presence of chronic anemia, due to physiological shunting, OEF and CMRO2 are impaired in anemic subjects compared to controls. Methods: Three study groups of 50 SCD subjects, 27 ACTL subjects and 44 healthy controls were tested (Table 1). Oxygen content, DO2, OEF and CMRO2 were computed from the hemoglobin level, CBF from phase contrast MRI and venous saturation from TRUST MRI. Results: Table 2 shows the global DO2, OEF and CMRO2. As expected, anemic patients had approximately 50% higher CBF but similar DO2 levels compared to healthy controls. Despite normal delivery, both CMRO2 and OEF are significantly decreased in SCD and ACTL subjects. Resting DO2, whether entered as CBF and O2 content separately or as their product, was the strongest predictor of the brain's metabolic rate, explaining approximately 21% of the variation in baseline CMRO2. Even after controlling for the variations in delivery, our subjects still demonstrated significant differences based on disease state, with the lowest CMRO2 in SCD patients, followed by ACTL and then healthy controls (p<0.01). After correcting for both DO2 and disease state, CMRO2 was independent of transfusion status, age, sex, hemolytic indices, fetal hemoglobin levels and mean corpuscular volume but remained directly proportional to hemoglobin (p=0.01) and platelets (p=0.01) with a combined r2=0.62. Discussion: Using a larger cohort, our results recapitulated the compensatory hyperemic response previously described in anemic subjects. Despite the ability to maintain a normal level of oxygen supply to the brain, these anemic patients had significantly lower cerebral metabolism, consistent with reports from two other laboratories (Vaclavu et al., 2019; Croal et al., 2019). We postulate that poor oxygen utilization is caused by non-nutritive perfusion or physiological arteriovenous shunting. This phenomenon has been previously characterized in SCD and other anemias with high CBF and reduced microvascular transit times. Microvascular oxygen unloading requires sufficient transit time in the capillaries network for efficient oxygen extraction, but transit times had been demonstrated to be significantly shorter in the presence of anemia due to compensatory hyperemia. In chronic anemia syndromes, the elevated CBF that preserves normal DO2 shortens transit times and impairs oxygen unloading, leading to a decrease in OEF and CMRO2 in both SCD and ACTL subjects. The predictors of baseline CMRO2 yielded interesting insights into the physiological impact of chronic anemia on cerebral oxygen availability and utilization. In acute normovolemic anemia, CMRO2 is preserved despite declining O2 carrying capacity. However, in our chronically anemic cohort, CMRO2 was strongly proportional to resting DO2; this result suggests that there is a divergence in physiological responses to acute versus chronic anemia. While DO2 was the strongest predictor of CMRO2, disease state, hemoglobin level and platelets remained in the multivariate model, confirming the roles of anemia, inflammation, and disease-specific factors in the modulating CMRO2. In summary, this report demonstrates impaired cerebral oxygen supply-demand matching in chronically anemic subjects. Cerebral hyperemia appears to simultaneously preserve DO2 while diminishing OEF and CMRO2. This observation may explain why absolute hemoglobin level remains the strongest predictor of poor neurovascular outcome in SCD patients, and raises questions regarding the proper hemoglobin target level for hydroxyurea and chronic transfusion therapy. Disclosures Coates: celgene: Consultancy, Honoraria, Other: steering committee of clinical study; vifor: Consultancy, Honoraria; agios pharma: Consultancy, Honoraria; apo pharma: Consultancy, Honoraria, Speakers Bureau. Wood:National Institutes of Health: Research Funding; Philips Healthcare: Research Funding; BluebirdBio: Consultancy; Celgene: Consultancy; BiomedInformatics: Consultancy; Imago Biosciences: Consultancy; Apopharma: Consultancy; WorldcareClinical: Consultancy.

Progressive white matter disease, especially silent cerebral infarction (SCI), is a major problem in sickle cell disease (SCD).1,2 Although the risk of symptomatic ischemic stroke has been reduced by chronic transfusion therapy and hydroxyurea, the prevalence of SCI in SCD patients continues to be 1% to 2% per age year with no plateau.2 Many studies have focused on the structural and hemodynamic aspects of SCI,3-5 but few have examined brain iron accumulation6,7 and its possible role in reinforcing white matter injury. Brain iron has been shown to increase with recurrent ischemia-reperfusion injuries,8,9 chronic hypoxia,10,11 and microvasculaturedamage,12 which are common conditions in SCD.13,14 As a consequence, excessive brain iron could potentially aggravate white matter damage15,16 and accelerate neurodegeneration.12

Long-term outcomes for Tetralogy of Fallot (TOF) have improved dramatically in recent years, but survivors are still afflicted by cerebral damage. In this paper, we characterized the prevalence and predictors of cerebral silent infarction (SCI) and their relationship to cerebral blood flow (CBF) in 46 adult TOF patients. We calculated both whole brain and regional CBF using 2D arterial spin labeling (ASL) images, and investigated the spatial overlap between voxel-wise CBF values and white matter hyperintensities (WMHs) identified from T2-FLAIR images. SCIs were found in 83% of subjects and were predicted by the year of the patient's first cardiac surgery and patient's age at scanning (combined r 2 0.44). CBF was not different in brain regions prone to stroke compared with healthy white matter.

White matter (WM) lesion identification and segmentation has proved of clinical importance for diagnosis, treatment and neurological outcomes. Convolutional neural networks (CNN) have demonstrated their success for large lesion load segmentation, but are not sensitive to small deep WM and sub-cortical lesion segmentation. We propose to use multi-scale and supervised fully convolutional networks (FCN) to segment small WM lesions in 22 anemic patients. The multiple scales enable us to identify the small lesions while reducing many false alarms, and the multi-supervised scheme allows a better management of the unbalanced data. Compared to a single FCN (Dice score ~ 0.31), the performance on the testing dataset of our proposed networks achieved a Dice score of 0.78.