Evaluating cerebrovascular reactivity measured by velocity selective inversion arterial spin labeling with different post-labeling delays: The effect of fast flow.

PURPOSE: Velocity selective arterial spin labeling (VSASL) quantification assumes that the labeled bolus continuously moves into the imaging voxel during the post-labeling delay (PLD). Faster blood flow could lead to a bolus duration shorter than the applied PLD of VSASL and cause underestimation of cerebral blood flow (CBF). This study aims to evaluate the performance of velocity-selective inversion (VSI) prepared arterial spin labeling (ASL) with different PLDs and pseudo-continuous ASL (PCASL) for quantification of hypercapnia-induced cerebrovascular reactivity (CVR), using phase-contrast (PC) MRI as a global reference. METHODS: We compared CVR obtained by VSI-ASL with PLD of 1520 ms (VSASL-1520), 1000 ms (VSASL-1000), and 500 ms (VSASL-500), PCASL with PLD of 1800 ms (PCASL-1800), and PC MRI on eight healthy volunteers at two sessions. RESULTS: Compared with PC MRI, VSASL-1520 produced significantly lower global CVR values, while PCASL-1800, VSASL-1000, and VSASL-500 yielded more consistent results. The reduced CVR in VSASL-1520 was more pronounced in carotid territories including frontal and temporal lobes than in vertebral territories such as the occipital lobe. This is largely caused by the underestimated perfusion during hypercapnia due to the reduced bolus duration being less than the PLD. CONCLUSION: Although VSASL offers certain advantages over spatially selective ASL due to its reduced susceptibility to delayed ATT, this technique is prone to biases when the ATT is excessively short. Therefore, a short PLD should be employed for reliable perfusion and CVR quantification in populations or conditions with fast flow.

Evaluation of calibrated and uncalibrated optical imaging approaches for relative cerebral oxygen metabolism measurements in awake mice.

Objective. The continuous delivery of oxygen is critical to sustain brain function, and therefore, measuring brain oxygen consumption can provide vital physiological insight. In this work, we examine the impact of calibration and cerebral blood flow (CBF) measurements on the computation of the relative changes in the cerebral metabolic rate of oxygen consumption (rCMRO2) from hemoglobin-sensitive intrinsic optical imaging data. Using these data, we calculate rCMRO2, and calibrate the model using an isometabolic stimulus.Approach. We used awake head-fixed rodents to obtain hemoglobin-sensitive optical imaging data to test different calibrated and uncalibrated rCMRO2models. Hypercapnia was used for calibration and whisker stimulation was used to test the impact of calibration.Main results. We found that typical uncalibrated models can provide reasonable estimates of rCMRO2with differences as small as 7%-9% compared to their calibrated models. However, calibrated models showed lower variability and less dependence on baseline hemoglobin concentrations. Lastly, we found that supplying the model with measurements of CBF significantly reduced error and variability in rCMRO2change calculations.Significance. The effect of calibration on rCMRO2calculations remains understudied, and we systematically evaluated different rCMRO2calculation scenarios that consider including different measurement combinations. This study provides a quantitative comparison of these scenarios to evaluate trade-offs that can be vital to the design of blood oxygenation sensitive imaging experiments for rCMRO2calculation.

Older adults with reduced cerebrovascular reactivity exhibit high white matter hyperintensity burden.

Cerebrovascular reactivity (CVR) deficits may contribute to small vessel disease, such as white matter hyperintensities (WMH). Moreover, apolipoprotein-e4 (APOE4) carriers at genetic risk for Alzheimer's disease exhibit cerebrovascular dysfunction relative to non-carriers. We examined whether older adults, and APOE4 carriers specifically, with diminished CVR would exhibit higher WMH burden. Independently living older adults (N = 125, mean age = 69.2 years; SD = 7.6; 31.2% male) free of dementia or clinical stroke underwent brain MRI to quantify cerebral perfusion during CVR to hypercapnia and hypocapnia and determine WMH volume. Adjusting for age, sex and intracranial volume, hierarchical regression analysis revealed a significant association between whole brain CVR to hypercapnia and WMH overall [B = -.02, 95% CI (-.04, -.008), p =.003] and in APOE4 carriers [B = -.03, 95% CI (-.06, -.009), p =.009]. Findings suggest deficits in cerebral vasodilatory capacity are associated with WMH burden in older adults and future studies are warranted to further delineate the effect of APOE4 on precipitating WMH.

Cerebrovascular reactivity to hypercapnia in patients with migraine: A dual-echo arterial spin labeling MRI study.

OBJECTIVE: This study aimed to compare cerebrovascular reactivity between patients with migraine and controls using state-of-the-art magnetic resonance imaging (MRI) techniques. BACKGROUND: Migraine is associated with an increased risk of cerebrovascular disease, but the underlying mechanisms are still not fully understood. Impaired cerebrovascular reactivity has been proposed as a link. Previous studies have evaluated cerebrovascular reactivity with different methodologies and results are conflicting. METHODS: In this single-center, observational, case-control study, we included 31 interictal patients with migraine without aura (aged 19-66 years, 17 females) and 31 controls (aged 22-64 years, 18 females) with no history of vascular disease. Global and regional cerebrovascular reactivities were assessed with a dual-echo arterial spin labeling (ASL) 3.0 T MRI scan of the brain which measured the change in cerebral blood flow (CBF) and BOLD (blood oxygen level dependent) signal to inhalation of 5% carbon dioxide. RESULTS: When comparing patients with migraine to controls, cerebrovascular reactivity values were similar between the groups, including mean gray matter CBF-based cerebrovascular reactivity (3.2 ± 0.9 vs 3.4 ± 1% ΔCBF/mmHg CO2 ; p = 0.527), mean gray matter BOLD-based cerebrovascular reactivity (0.18 ± 0.04 vs 0.18 ± 0.04% ΔBOLD/mmHg CO2 ; p = 0.587), and mean white matter BOLD-based cerebrovascular reactivity (0.08 ± 0.03 vs 0.08 ± 0.02% ΔBOLD/mmHg CO2 ; p = 0.621).There was no association of cerebrovascular reactivity with monthly migraine days or migraine disease duration (all analyses p > 0.05). CONCLUSION: Cerebrovascular reactivity to carbon dioxide seems to be preserved in patients with migraine without aura.

Oxygen imaging of hypoxic pockets in the mouse cerebral cortex.

Consciousness is lost within seconds upon cessation of cerebral blood flow. The brain cannot store oxygen, and interruption of oxidative phosphorylation is fatal within minutes. Yet only rudimentary knowledge exists regarding cortical partial oxygen tension (Po2) dynamics under physiological conditions. Here we introduce Green enhanced Nano-lantern (GeNL), a genetically encoded bioluminescent oxygen indicator for Po2 imaging. In awake behaving mice, we uncover the existence of spontaneous, spatially defined "hypoxic pockets" and demonstrate their linkage to the abrogation of local capillary flow. Exercise reduced the burden of hypoxic pockets by 52% compared with rest. The study provides insight into cortical oxygen dynamics in awake behaving animals and concurrently establishes a tool to delineate the importance of oxygen tension in physiological processes and neurological diseases.

Increased Risk of Recurrent Stroke in Symptomatic Large Vessel Disease With Impaired BOLD Cerebrovascular Reactivity.

BACKGROUND: Impaired cerebrovascular reactivity (CVR) has been correlated with recurrent ischemic stroke. However, for clinical purposes, most CVR techniques are rather complex, time-consuming, and lack validation for quantitative measurements. The recent adaptation of a standardized hypercapnic stimulus in combination with a blood-oxygenation-level-dependent (BOLD) magnetic resonance imaging signal as a surrogate for cerebral blood flow offers a potential universally comparable CVR assessment. We investigated the association between impaired BOLD-CVR and risk for recurrent ischemic events. METHODS: We conducted a retrospective analysis of patients with symptomatic cerebrovascular large vessel disease who had undergone a prospective hypercapnic-challenged BOLD-CVR protocol at a single tertiary stroke referral center between June 2014 and April 2020. These patients were followed up for recurrent acute ischemic events for up to 3 years. BOLD-CVR (%BOLD signal change per mm Hg CO2) was calculated on a voxel-by-voxel basis. Impaired BOLD-CVR of the affected (ipsilateral to the vascular pathology) hemisphere was defined as an average BOLD-CVR, falling 2 SD below the mean BOLD-CVR of the right hemisphere in a healthy age-matched reference cohort (n=20). Using a multivariate Cox proportional hazards model, the association between impaired BOLD-CVR and ischemic stroke recurrence was assessed and Kaplan-Meier survival curves to visualize the acute ischemic stroke event rate. RESULTS: Of 130 eligible patients, 28 experienced recurrent strokes (median, 85 days, interquartile range, 5-166 days). Risk factors associated with an increased recurrent stroke rate included impaired BOLD-CVR, a history of atrial fibrillation, and heart insufficiency. After adjusting for sex, age group, and atrial fibrillation, impaired BOLD-CVR exhibited a hazard ratio of 10.73 (95% CI, 4.14-27.81; P<0.001) for recurrent ischemic stroke. CONCLUSIONS: Among patients with symptomatic cerebrovascular large vessel disease, those exhibiting impaired BOLD-CVR in the affected hemisphere had a 10.7-fold higher risk of recurrent ischemic stroke events compared with individuals with nonimpaired BOLD-CVR.

Assessing cerebrovascular reactivity (CVR) in rhesus macaques (Macaca mulatta) using a hypercapnic challenge and pseudo-continuous arterial spin labeling (pCASL).

Cerebrovascular reactivity (CVR) is a measure of cerebral small vessels' ability to respond to changes in metabolic demand and can be quantified using magnetic resonance imaging (MRI) coupled with a vasoactive stimulus. Reduced CVR occurs with neurodegeneration and is associated with cognitive decline. While commonly measured in humans, few studies have evaluated CVR in animal models. Herein, we describe methods to induce hypercapnia in rhesus macaques (Macaca mulatta) under gas anesthesia to measure cerebral blood flow (CBF) and CVR using pseudo-continuous arterial spin labeling (pCASL). Fifteen (13 M, 2 F) adult rhesus macaques underwent pCASL imaging that included a baseline segment (100% O2) followed by a hypercapnic challenge (isoflurane anesthesia with 5% CO2, 95% O2 mixed gas). Relative hypercapnia was defined as an end-tidal CO2 (ETCO2) ≥5 mmHg above baseline ETCO2. The mean ETCO2 during the baseline segment of the pCASL sequence was 34 mmHg (range: 23-48 mmHg). During this segment, mean whole-brain CBF was 51.48 ml/100g/min (range: 21.47-77.23 ml/100g/min). Significant increases (p<0.0001) in ETCO2 were seen upon inspiration of the mixed gas (5% CO2, 95% O2). The mean increase in ETCO2 was 8.5 mmHg and corresponded with a mean increase in CBF of 37.1% (p<0.0001). The mean CVR measured was 4.3%/mmHg. No anesthetic complications occurred as a result of the CO2 challenge. Our methods were effective at inducing a state of relative hypercapnia that corresponds with a detectable increase in whole brain CBF using pCASL MRI. Using these methods, a CO2 challenge can be performed in conjunction with pCASL imaging to evaluate CBF and CVR in rhesus macaques. The measured CVR in rhesus macaques is comparable to human CVR highlighting the translational utility of rhesus macaques in neuroscience research. These methods present a feasible means to measure CVR in comparative models of neurodegeneration and cerebrovascular dysfunction.

Assessment of Cerebrovascular Reactivity Using CO2-BOLD MRI: A 15-Year, Single Center Experience.

BACKGROUND: Cerebrovascular reactivity (CVR) is a measure of the change in cerebral blood flow (CBF) in response to a vasoactive challenge. It is a useful indicator of the brain's vascular health. PURPOSE: To evaluate the factors that influence successful and unsuccessful CVR examinations using precise arterial and end-tidal partial pressure of CO2 control during blood oxygen level-dependent (BOLD) MRI. STUDY TYPE: Retrospective. SUBJECTS: Patients that underwent a CVR between October 2005 and May 2021 were studied (total of 1162 CVR examinations). The mean (±SD) age was 46.1 (±18.8) years, and 352 patients (43%) were female. FIELD STRENGTH/SEQUENCE: 3 T; T1-weighted images, T2*-weighed two-dimensional gradient-echo sequence with standard echo-planar readout. ASSESSMENT: Measurements were obtained following precise hypercapnic stimuli using BOLD MRI as a surrogate of CBF. Successful CVR examinations were defined as those where: 1) patients were able to complete CVR testing, and 2) a clinically useful CVR map was generated. Unsuccessful examinations were defined as those where patients were not able to complete the CVR examination or the CVR maps were judged to be unreliable due to, for example, excessive head motion, and poor PETCO2 targeting. STATISTICAL ANALYSIS: Successful and unsuccessful CVR examinations between hypercapnic stimuli, and between different patterns of stimulus were compared with Chi-Square tests. Interobserver variability was determined by using the intraclass correlation coefficient (P < 0.05 is significant). RESULTS: In total 1115 CVR tests in 662 patients were included in the final analysis. The success rate of generating CVR maps was 90.8% (1012 of 1115). Among the different hypercapnic stimuli, those containing a step plus a ramp protocol was the most successful (95.18%). Among the unsuccessful examinations (9.23%), most were patient related (89.3%), the most common of which was difficulty breathing. DATA CONCLUSION: CO2-BOLD MRI CVR studies are well tolerated with a high success rate. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 3.

Dynamic Magnetic Resonance Vascular Fingerprinting During Hypercapnia for Quantitative and Multiparametric Cerebrovascular Reactivity Measures.

Magnetic resonance fingerprinting (MRF) represents a potential paradigm shift in MR image acquisition, reconstruction, and analysis using computational biophysical modelling in parallel to image acquisition. Its flexibility allows for examination of cerebrovascular metrics through MR vascular fingerprinting (MRvF), and this has been extended even further to produce quantitative cerebral blood volume (CBV), microvascular vessel radius, and tissue oxygen saturation (SO2) maps of the whole brain simultaneously every few seconds. This allows for observation of rapid physiological changes like cerebrovascular reactivity (CVR), which is the ability of vessels to dilate in response to a vasoactive stimulus. Here we demonstrated a novel protocol in which a rapid, spin- and gradient-echo pulse sequence allowed for dynamic, and simultaneous acquisition of MRvF and blood oxygen level dependent (BOLD) measures. By combining this with a tailored hypercapnic (5% CO2) breathing paradigm we were able to show how these quantitative CBV, radius, and SO2 parameters changed in response to a stimulus and directly compare those to a colocalized, traditionally used BOLD CVR. We also compared these measures to another traditionally utilized technique in cerebral blood flow CVR from an arterial spin labelling sequence. These imaging, processing, and analysis techniques will allow for further investigation into the magnitude and rate of CVR based on BOLD and MRvF-based metrics and enable investigations to better understand vascular function in healthy aging and cerebrovascular diseases.Clinical Relevance- The development of dynamic magnetic resonance vascular fingerprinting has the potential to enable rapid, quantitative, and multiparametric functional imaging biomarkers of cerebrovascular diseases like vascular cognitive impairment, dementia, and Alzheimer's disease.

Hemodynamic imaging parameters in brain metastases patients - Agreement between multi-delay ASL and hypercapnic BOLD.

Arterial spin labeling (ASL) MRI is a routine clinical imaging technique that provides quantitative cerebral blood flow (CBF) information. A related technique is blood oxygenation level-dependent (BOLD) MRI during hypercapnia, which can assess cerebrovascular reactivity (CVR). ASL is weighted towards arteries, whereas BOLD is weighted towards veins. Their associated parameters in heterogeneous tissue types or under different hemodynamic conditions remains unclear. Baseline multi-delay ASL MRI and BOLD MRI during hypercapnia were performed in fourteen patients with brain metastases. In the ROI analysis, the CBF and CVR values were positively correlated in regions showing sufficient reserve capacity (i.e. non-steal regions, rrm = 0.792). Additionally, longer hemodynamic lag times were related to lower baseline CBF (rrm = -0.822) and longer arterial arrival time (AAT; rrm = 0.712). In contrast, in regions exhibiting vascular steal an inverse relationship was found with higher baseline CBF related to more negative CVR (rrm = -0.273). These associations were confirmed in voxelwise analyses. The relationship between CBF, AAT and CVR measures seems to be dependent on the vascular status of the underlying tissue. Healthy tissue relationships do not hold in tissues experiencing impaired or exhausted autoregulation. CVR metrics can possibly identify at-risk areas before perfusion deficiencies become visible on ASL MRI, specifically within vascular steal regions.

Functional magnetic particle imaging (fMPI) of cerebrovascular changes in the rat brain during hypercapnia.

Objective.Non-invasive functional brain imaging modalities are limited in number, each with its own complex trade-offs between sensitivity, spatial and temporal resolution, and the directness with which the measured signals reflect neuronal activation. Magnetic particle imaging (MPI) directly maps the cerebral blood volume (CBV), and its high sensitivity derives from the nonlinear magnetization of the superparamagnetic iron oxide nanoparticle (SPION) tracer confined to the blood pool. Our work evaluates functional MPI (fMPI) as a new hemodynamic functional imaging modality by mapping the CBV response in a rodent model where CBV is modulated by hypercapnic breathing manipulation.Approach.The rodent fMPI time-series data were acquired with a mechanically rotating field-free line MPI scanner capable of 5 s temporal resolution and 3 mm spatial resolution. The rat's CBV was modulated for 30 min with alternating 5 min hyper-/hypocapnic states, and processed using conventional fMRI tools. We compare our results to fMRI responses undergoing similar hypercapnia protocols found in the literature, and reinforce this comparison in a study of one rat with 9.4T BOLD fMRI using the identical protocol.Main results.The initial image in the time-series showed mean resting brain voxel SNR values, averaged across rats, of 99.9 following the first 10 mg kg-1SPION injection and 134 following the second. The time-series fit a conventional General Linear Model with a 15%-40% CBV change and a peak pixel CNR between 12 and 29, 2-6× higher than found in fMRI.Significance.This work introduces a functional modality with high sensitivity, although currently limited spatial and temporal resolution. With future clinical-scale development, a large increase in sensitivity could supplement other modalities and help transition functional brain imaging from a neuroscience tool focusing on population averages to a clinically relevant modality capable of detecting differences in individual patients.

Venous Blood Oxygenation Measurements Using TRUST and T2-TRIR MRI During Hypoxic and Hypercapnic Gas Challenges.

BACKGROUND: Oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2 ) may serve as biomarkers in several diseases. OEF and CMRO2 can be estimated from venous blood oxygenation (Yv ) levels, which in turn can be calculated from venous blood T2 values (T2b ). T2b can be measured using different MRI sequences, including T2-relaxation-under-spin-tagging (TRUST) and T2-prepared-blood-relaxation-imaging-with-inversion-recovery (T2-TRIR). The latter measures both T2b and T1 (T1b ) but was found previously to overestimate T2b compared to TRUST. It remained unclear, however, if this bias is constant across higher and lower oxygen saturations. PURPOSE: To compare TRUST and T2-TRIR across a range of O2 saturations using hypoxic and hypercapnic gas challenges. STUDY TYPE: Prospective. POPULATION: Twelve healthy volunteers (four female, age 36 ± 10 years). FIELD STRENGTH/SEQUENCE: A 3T; turbo-field echo-planar-imaging (TFEPI), echo-planar-imaging (EPI), and fast-field-echo (FFE). ASSESSMENT: TRUST- and T2-TRIR-derived T2b , Yv , OEF, and CMRO2 were compared across different respiratory challenges. T1b from T2-TRIR was used to estimate Hct (HctTRIR ) and compared with venipuncture (HctVP ). STATISTICAL TESTS: Shapiro-Wilk, one-sample and paired-sample t-test, repeated measures ANOVA, Friedman test, Bland-Altman, and correlation analysis. Bonferroni multiple-comparison correction was performed. Significance level was 0.05. RESULTS: A significant bias was observed between TRUST- and T2-TRIR-derived T2b , Yv , and OEF values (-13 ± 11 msec, -5.3% ± 3.5% and 5.9 ± 4.1%, respectively). For Yv and OEF, this bias was constant across the range of measured values. T1b was significantly lower during severe hypoxia and hypercapnia compared to baseline (1712 ± 86 msec and 1634 ± 79 msec compared to 1757 ± 90 msec). While no significant bias was found between HctVP and HctTRIR (0.02% ± 0.06%, P = 0.20), the correlation between these Hct values was significant but weak (r = 0.19). DATA CONCLUSION: Given the constant bias, TRUST- and T2-TRIR-derived venous T2b values can be used interchangeably to estimate Yv , OEF, and CMRO2 across a broad range of oxygen saturations. Hct from T2-TRIR-derived T1-values only weakly correlated with Hct from venipuncture. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

CADASIL Affects Multiple Aspects of Cerebral Small Vessel Function on 7T-MRI.

OBJECTIVE: Cerebral small vessel diseases (cSVDs) are a major cause of stroke and dementia. We used cutting-edge 7T-MRI techniques in patients with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), to establish which aspects of cerebral small vessel function are affected by this monogenic form of cSVD. METHODS: We recruited 23 CADASIL patients (age 51.1 ± 10.1 years, 52% women) and 13 age- and sex-matched controls (46.1 ± 12.6, 46% women). Small vessel function measures included: basal ganglia and centrum semiovale perforating artery blood flow velocity and pulsatility, vascular reactivity to a visual stimulus in the occipital cortex and reactivity to hypercapnia in the cortex, subcortical gray matter, white matter, and white matter hyperintensities. RESULTS: Compared with controls, CADASIL patients showed lower blood flow velocity and higher pulsatility index within perforating arteries of the centrum semiovale (mean difference - 0.09 cm/s, p = 0.03 and 0.20, p = 0.009) and basal ganglia (mean difference - 0.98 cm/s, p = 0.003 and 0.17, p = 0.06). Small vessel reactivity to a short visual stimulus was decreased (blood-oxygen-level dependent [BOLD] mean difference -0.21%, p = 0.04) in patients, while reactivity to hypercapnia was preserved in the cortex, subcortical gray matter, and normal appearing white matter. Among patients, reactivity to hypercapnia was decreased in white matter hyperintensities compared to normal appearing white matter (BOLD mean difference -0.29%, p = 0.02). INTERPRETATION: Multiple aspects of cerebral small vessel function on 7T-MRI were abnormal in CADASIL patients, indicative of increased arteriolar stiffness and regional abnormalities in reactivity, locally also in relation to white matter injury. These observations provide novel markers of cSVD for mechanistic and intervention studies. ANN NEUROL 2023;93:29-39.

Older adults with perivascular spaces exhibit cerebrovascular reactivity deficits.

BACKGROUND: Perivascular spaces on brain magnetic resonance imaging (MRI) may indicate poor fluid drainage in the brain and have been associated with numerous neurological conditions. Cerebrovascular reactivity (CVR) is a marker of cerebrovascular function and represents the ability of cerebral blood vessels to regulate cerebral blood flow in response to vasodilatory or vasoconstrictive stimuli. We aimed to examine whether pathological widening of the perivascular space in older adults may be associated with deficits in CVR. METHODS: Independently living older adults free of dementia or clinical stroke were recruited from the community and underwent brain MRI. Pseudo-continuous arterial spin labeling MRI quantified whole brain cerebral perfusion at rest and during CVR to hypercapnia and hypocapnia induced by visually guided breathing exercises. Perivascular spaces were visually scored using existing scales. RESULTS: Thirty-seven independently living older adults (mean age = 66.3 years; SD = 6.8; age range 55-84 years; 29.7% male) were included in the current analysis. Multiple linear regression analysis revealed a significant negative association between burden of perivascular spaces and global CVR to hypercapnia (B = -2.0, 95% CI (-3.6, -0.4), p = .015), adjusting for age and sex. Perivascular spaces were not related to CVR to hypocapnia. DISCUSSION: Perivascular spaces are associated with deficits in cerebrovascular vasodilatory response, but not vasoconstrictive response. Enlargement of perivascular spaces could contribute to, or be influenced by, deficits in CVR. Additional longitudinal studies are warranted to improve our understanding of the relationship between cerebrovascular function and perivascular space enlargement.

Cerebrovascular reactivity deficits in cognitively unimpaired older adults: vasodilatory versus vasoconstrictive responses.

Cerebrovascular reactivity (CVR) deficits may index vulnerability to vascular brain injury and cognitive impairment, but findings on age-related changes in CVR have been mixed, and no studies to date have directly compared age-related changes in CVR to hypercapnia versus hypocapnia. The present study compared CVR in 31 cognitively unimpaired older adults (ages 55-87) and 30 healthy younger adults (ages 18-28). Breath control tasks induced CVR to hypocapnia (0.1 Hz paced breathing) and hypercapnia (15s breath holds) during pseudo-continuous arterial spin labeling MRI. Relative to younger adults, cognitively unimpaired older adults displayed lower levels of global CVR under both hypocapnia and hypercapnia. In region-of-interest analyses, older adults exhibited attenuated CVR to hypocapnia in select frontal and temporal regions, and lower CVR to hypercapnia in all cortical, limbic, and subcortical regions examined, relative to younger adults. Results indicate age-related deficits in CVR are detectible even in cognitively unimpaired older adults and are disproportionately related to vasodilatory (hypercapnia) responses relative to vasoconstrictive (hypocapnia) responses. Findings may offer means for early detection of cerebrovascular dysfunction.

Hypercapnia: An Added Culprit in Gray Matter Injury in Preterm Neonates.

Over the last decade, there has been increased recognition of diverse forms of primary gray matter injury (GMI) in postpreterm neonates. In this study, we aimed to assess whether early neonatal hypercapnia in the preterm infant was associated with GMI on magnetic resonance imaging (MRI) at term equivalent age (TEA). All blood gases taken during the first 2 weeks of life were analyzed for hypercapnia. MRI was performed at TEA postpreterm infants using a unique neonatal MRI 1T scanner. The neonatal MRI scans were assessed using a standardized scoring system, the Kidokoro scoring system, a method used to assess abnormal brain metrics and the presence and severity of brain abnormalities. Subscores are assigned for different regions of the brain. Twenty-nine infants were studied, about half of whom had evidence of some gray matter abnormality. Fifteen of the infants were hypercapnic. The hypercapnic infants had significantly higher deep gray matter abnormality readings as compared with the nonhypercapnic infants (12 [11; 12] vs. 10 [8; 11], respectively; p = 0.0106). Correlations were observed between peak pCO2 over the first 2 weeks of life and the overall gray matter abnormality score (GMAS) at TEA, and between the percentage of hypercapnic blood gases during the first 2 weeks of life and the GMAS. All of the infants in our population who had severe GMI at TEA were hypercapnic in the first 2 weeks of life. In conclusion, our data show a correlation between early hypercapnia in preterm neonates and GMI at TEA.

Medullary vein architecture modulates the white matter BOLD cerebrovascular reactivity signal response to CO2: Observations from high-resolution T2* weighted imaging at 7T.

Brain stress testing using blood oxygenation level-dependent (BOLD) MRI to evaluate changes in cerebrovascular reactivity (CVR) is of growing interest for evaluating white matter integrity. However, even under healthy conditions, the white matter BOLD-CVR response differs notably from that observed in the gray matter. In addition to actual arterial vascular control, the venous draining topology may influence the WM-CVR response leading to signal delays and dispersions. These types of alterations in hemodynamic parameters are sometimes linked with pathology, but may also arise from differences in normal venous architecture. In this work, high-resolution T2*weighted anatomical images combined with BOLD imaging during a hypercapnic breathing protocol were acquired using a 7 tesla MRI system. Hemodynamic parameters including base CVR, hemodynamic lag, lag-corrected CVR, response onset and signal dispersion, and finally ΔCVR (corrected CVR minus base CVR) were calculated in 8 subjects. Parameter maps were spatially normalized and correlated against an MNI-registered white matter medullary vein atlas. Moderate correlations (Pearson's rho) were observed between medullary vessel frequency (MVF) and ΔCVR (0.52; 0.58 for total WM), MVF and hemodynamic lag (0.42; 0.54 for total WM), MVF and signal dispersion (0.44; 0.53 for total WM), and finally MVF and signal onset (0.43; 0.52 for total WM). Results indicate that, when assessed in the context of the WM venous architecture, changes in the response shape may only be partially reflective of the actual vascular reactivity response occurring further upstream by control vessels. This finding may have implications when attributing diseases mechanisms and/or progression to presumed impaired WM BOLD-CVR.

Diabetic mice have retinal and choroidal blood flow deficits and electroretinogram deficits with impaired responses to hypercapnia.

PURPOSE: The purpose of this study was to investigate neuronal and vascular functional deficits in the retina and their association in a diabetic mouse model. We measured electroretinography (ERG) responses and choroidal and retinal blood flow (ChBF, RBF) with magnetic resonance imaging (MRI) in healthy and diabetic mice under basal conditions and under hypercapnic challenge. METHODS: Ins2Akita diabetic (Diab, n = 8) and age-matched, wild-type C57BL/6J mice (Ctrl, n = 8) were studied under room air and moderate hypercapnia (5% CO2). Dark-adapted ERG a-wave, b-wave, and oscillatory potentials (OPs) were measured for a series of flashes. Regional ChBF and RBF under air and hypercapnia were measured using MRI in the same mice. RESULTS: Under room air, Diab mice had compromised ERG b-wave and OPs (e.g., b-wave amplitude was 422.2±10.7 µV in Diab vs. 600.1±13.9 µV in Ctrl, p < 0.001). Under hypercapnia, OPs and b-wave amplitudes were significantly reduced in Diab (OPs by 30.3±3.0% in Diab vs. -3.0±3.6% in Ctrl, b-wave by 17.9±1.4% in Diab vs. 1.3±0.5% in Ctrl). Both ChBF and RBF had significant differences in regional blood flow, with Diab mice having substantially lower blood flow in the nasal region (ChBF was 5.4±1.0 ml/g/min in Diab vs. 8.6±1.0 ml/g/min in Ctrl, RBF was 0.91±0.10 ml/g/min in Diab vs. 1.52±0.24 ml/g/min in Ctrl). Under hypercapnia, ChBF increased in both Ctrl and Diab without significant group difference (31±7% in Diab vs. 17±7% in Ctrl, p > 0.05), but an increase in RBF was not detected for either group. CONCLUSIONS: Inner retinal neuronal function and both retinal and choroidal blood flow were impaired in Diab mice. Hypercapnia further compromised inner retinal neuronal function in diabetes, while the blood flow response was not affected, suggesting that the diabetic retina has difficulty adapting to metabolic challenges due to factors other than impaired blood flow regulation.