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.

Cerebrovascular reactivity MRI as a biomarker for cerebral small vessel disease-related cognitive decline: Multi-site validation in the MarkVCID Consortium.

INTRODUCTION: Vascular contributions to cognitive impairment and dementia (VCID) represent a major factor in cognitive decline in older adults. The present study examined the relationship between cerebrovascular reactivity (CVR) measured by magnetic resonance imaging (MRI) and cognitive function in a multi-site study, using a predefined hypothesis. METHODS: We conducted the study in a total of three analysis sites and 263 subjects. Each site performed an identical CVR MRI procedure using 5% carbon dioxide inhalation. A global cognitive measure of Montreal Cognitive Assessment (MoCA) and an executive function measure of item response theory (IRT) score were used as outcomes. RESULTS: CVR and MoCA were positively associated, and this relationship was reproduced at all analysis sites. CVR was found to be positively associated with executive function. DISCUSSION: The predefined hypothesis on the association between CVR and a global cognitive score was validated in three independent analysis sites, providing support for CVR as a biomarker in VCID. HIGHLIGHTS: This study measured a novel functional index of small arteries referred to as cerebrovascular reactivity (CVR). CVR was positively associated with global cognition in older adults. This finding was observed in three independent cohorts at three sites. Our statistical analysis plan was predefined before beginning data collection.

Altered linear coupling between stimulus-evoked blood flow and oxygen metabolism in the aging human brain.

Neural-vascular coupling (NVC) is the process by which oxygen and nutrients are delivered to metabolically active neurons by blood vessels. Murine models of NVC disruption have revealed its critical role in healthy neural function. We hypothesized that, in humans, aging exerts detrimental effects upon the integrity of the neural-glial-vascular system that underlies NVC. To test this hypothesis, calibrated functional magnetic resonance imaging (cfMRI) was used to characterize age-related changes in cerebral blood flow (CBF) and oxygen metabolism during visual cortex stimulation. Thirty-three younger and 27 older participants underwent cfMRI scanning during both an attention-controlled visual stimulation task and a hypercapnia paradigm used to calibrate the blood-oxygen-level-dependent signal. Measurement of stimulus-evoked blood flow and oxygen metabolism permitted calculation of the NVC ratio to assess the integrity of neural-vascular communication. Consistent with our hypothesis, we observed monotonic NVC ratio increases with increasing visual stimulation frequency in younger adults but not in older adults. Age-related changes in stimulus-evoked cerebrovascular and neurometabolic signal could not fully explain this disruption; increases in stimulus-evoked neurometabolic activity elicited corresponding increases in stimulus-evoked CBF in younger but not in older adults. These results implicate age-related, demand-dependent failures of the neural-glial-vascular structures that comprise the NVC system.

Cerebrovascular reactivity mapping using intermittent breath modulation.

Cerebrovascular reactivity (CVR), an index of brain vessel's dilatory capacity, is typically measured using hypercapnic gas inhalation or breath-holding as a vasoactive challenge. However, these methods require considerable subject cooperation and could be challenging in clinical studies. More recently, there have been attempts to use resting-state BOLD data to map CVR by utilizing spontaneous changes in breathing pattern. However, in subjects who have small fluctuations in their spontaneous breathing pattern, the CVR results could be noisy and unreliable. In this study, we aim to develop a new method for CVR mapping that does not require gas-inhalation yet provides substantially higher sensitivity than resting-state CVR mapping. This new method is largely based on resting-state scan, but introduces intermittent modulation of breathing pattern in the subject to enhance fluctuations in their end-tidal CO2 (EtCO2) level. Here we examined the comfort level, sensitivity, and accuracy of this method in two studies. First, in 8 healthy young subjects, we developed the intermittent breath-modulation method using two different modulation frequencies, 6 â€‹s per breath and 12 â€‹s per breath, respectively, and compared the results to three existing CVR methods, specifically hypercapnic gas inhalation, breath-holding, and resting-state. Our results showed that the comfort level of the 6-s breath-modulation method was significantly higher than breath-holding (p â€‹= â€‹0.007) and CO2-inhalation (p â€‹= â€‹0.015) methods, while not different from the resting-state, i.e. free breathing method (p â€‹= â€‹0.52). When comparing the sensitivity of CVR methods, the breath-modulation methods revealed higher Z-statistics compared to the resting-state scan (p â€‹< â€‹0.008) and was comparable to breath-holding results. Next, we tested the feasibility of breath-modulation CVR mapping (6 â€‹s per breath) in 21 cognitively normal elderly participants and compared quantitative CVR values to that obtained with the CO2-inhalation method. Whole-brain CVR was found to be 0.150 â€‹± â€‹0.055 and 0.154 â€‹± â€‹0.032 %ΔBOLD/mmHg for the breath-modulation and CO2-inhalation method, respectively, with a significant correlation between them (y â€‹= â€‹0.97x, p â€‹= â€‹0.007). CVR mapping with intermittent breath modulation may be a useful method that combines the advantages of resting-state and CO2-inhalation based approaches.

Brain Oxygen Extraction Is Differentially Altered by Alzheimer's and Vascular Diseases.

BACKGROUND: Alzheimer's disease and vascular cognitive impairment (VCI), as well as their concurrence, represent the most common types of cognitive dysfunction. Treatment strategies for these two conditions are quite different; however, there exists a considerable overlap in their clinical manifestations, and most biomarkers reveal similar abnormalities between these two conditions. PURPOSE: To evaluate the potential of cerebral oxygen extraction fraction (OEF) as a biomarker for differential diagnosis of Alzheimer's disease and VCI. We hypothesized that in Alzheimer's disease OEF will be reduced (decreased oxygen consumption due to decreased neural activity), while in vascular diseases OEF will be elevated (increased oxygen extraction due to abnormally decreased blood flow). STUDY TYPE: Prospective cross-sectional. POPULATION: Sixty-five subjects aged 52-89 years, including 33 mild cognitive impairment (MCI), 7 dementia, and 25 cognitively normal subjects. FIELD STRENGTH/SEQUENCE: 3T T2 -relaxation-under-spin-tagging (TRUST) and fluid-attenuated inversion recovery imaging (FLAIR). ASSESSMENT: OEF, consensus diagnoses of cognitive impairment, vascular risk factors (such as hypertension, hypercholesterolemia, diabetes, smoking, and obesity), cognitive assessments, and cerebrospinal fluid concentration of amyloid and tau were assessed. STATISTICAL TESTS: Multiple linear regression analyses of OEF with diagnostic category (normal, MCI, or dementia), vascular risks, cognitive performance, amyloid and tau pathology. RESULTS: When evaluating the entire group, OEF was found to be lower with more severe cognitive impairment (ß = -2.70 ± 1.15, T = -2.34, P = 0.02), but was higher with greater vascular risk factors (ß = 1.36 ± 0.55, T = 2.48, P = 0.02). Further investigation of the subgroup of participants with low vascular risks (N = 44) revealed that lower OEF was associated with worse cognitive performance (ß = 0.04 ± 0.01, T = 3.27, P = 0.002) and greater amyloid burden (ß = 92.12 ± 41.23, T = 2.23, P = 0.03). Among cognitively impaired individuals (N = 40), higher OEF was associated with greater vascular risk factors (ß = 2.19 ± 0.71, T = 3.08, P = 0.004). DATA CONCLUSION: These findings suggest that OEF is differentially affected by Alzheimer's disease and VCI pathology and may be useful in etiology-based diagnosis of cognitive impairment. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 3 J. MAGN. RESON. IMAGING 2020;52:1829-1837.

Brain Frontal-Lobe Misery Perfusion in COVID-19 ICU Survivors: An MRI Pilot Study.

Post-acute COVID-19 syndrome (PCS) is highly prevalent. Critically ill patients requiring intensive care unit (ICU) admission are at a higher risk of developing PCS. The mechanisms underlying PCS are still under investigation and may involve microvascular damage in the brain. Cerebral misery perfusion, characterized by reduced cerebral blood flow (CBF) and elevated oxygen extraction fraction (OEF) in affected brain areas, has been demonstrated in cerebrovascular diseases such as carotid occlusion and stroke. This pilot study aimed to examine whether COVID-19 ICU survivors exhibited regional misery perfusion, indicating cerebral microvascular damage. In total, 7 COVID-19 ICU survivors (4 female, 20-77 years old) and 19 age- and sex-matched healthy controls (12 female, 22-77 years old) were studied. The average interval between ICU admission and the MRI scan was 118.6 ± 30.3 days. The regional OEF was measured using a recently developed technique, accelerated T2-relaxation-under-phase-contrast MRI, while the regional CBF was assessed using pseudo-continuous arterial spin labeling. COVID-19 ICU survivors exhibited elevated OEF (ß = 5.21 ± 2.48%, p = 0.047) and reduced relative CBF (ß = -0.083 ± 0.025, p = 0.003) in the frontal lobe compared to healthy controls. In conclusion, misery perfusion was observed in the frontal lobe of COVID-19 ICU survivors, suggesting microvascular damage in this critical brain area for high-level cognitive functions that are known to manifest deficits in PCS. Physiological biomarkers such as OEF and CBF may provide new tools to improve the understanding and treatment of PCS.

CO2 cerebrovascular reactivity measured with CBF-MRI in older individuals: Association with cognition, physical function, amyloid and tau proteins.

Vascular pathology is the second leading cause of cognitive impairment and represents a major contributing factor in mixed dementia. However, biomarkers for vascular cognitive impairment and dementia (VCID) are under-developed. Here we aimed to investigate the potential role of CO2 Cerebrovascular Reactivity (CVR) measured with phase-contrast quantitative flow MRI in cognitive impairment and dementia. Forty-five (69 ± 7 years) impaired (37 mild-cognitive-impairment and 8 mild-dementia by syndromic diagnosis) and 22 cognitively-healthy-control (HC) participants were recruited and scanned on a 3 T MRI. Biomarkers of AD pathology were measured in cerebrospinal fluid. We found that CBF-CVR was lower (p = 0.027) in the impaired (mean±SE, 3.70 ± 0.15%/mmHg) relative to HC (4.28 ± 0.21%/mmHg). After adjusting for AD pathological markers (Aß42/40, total tau, and Aß42/p-tau181), higher CBF-CVR was associated with better cognitive performance, including Montreal Cognitive Assessment, MoCA (p = 0.001), composite cognitive score (p = 0.047), and language (p = 0.004). Higher CBF-CVR was also associated with better physical function, including gait-speed (p = 0.006) and time for five chair-stands (p = 0.049). CBF-CVR was additionally related to the Clinical-Dementia-Rating, CDR, including global CDR (p = 0.026) and CDR Sum-of-Boxes (p = 0.015). CBF-CVR was inversely associated with hemoglobin A1C level (p = 0.017). In summary, CBF-CVR measured with phase-contrast MRI shows associations with cognitive performance, physical function, and disease-severity, independent of AD pathological markers.

Dependence of resting-state-based cerebrovascular reactivity (CVR) mapping on spatial resolution.

Cerebrovascular reactivity (CVR) is typically assessed with a carbon dioxide (CO2) stimulus combined with BOLD fMRI. Recently, resting-state (RS) BOLD fMRI has been shown capable of generating CVR maps, providing a potential for broader CVR applications in neuroimaging studies. However, prior RS-CVR studies have primarily been performed at a spatial resolution of 3-4 mm voxel sizes. It remains unknown whether RS-CVR can also be obtained at high-resolution without major degradation in image quality. In this study, we investigated RS-CVR mapping based on resting-state BOLD MRI across a range of spatial resolutions in a group of healthy subjects, in an effort to examine the feasibility of RS-CVR measurement at high resolution. Comparing the results of RS-CVR with the maps obtained by the conventional CO2-inhalation method, our results suggested that good CVR map quality can be obtained at a voxel size as small as 2 mm isotropic. Our results also showed that, RS-CVR maps revealed resolution-dependent sensitivity. However, even at a high resolution of 2 mm isotropic voxel size, the voxel-wise sensitivity is still greater than that of typical task-evoked fMRI. Scan duration affected the sensitivity of RS-CVR mapping, but had no significant effect on its accuracy. These findings suggest that RS-CVR mapping can be applied at a similar resolution as state-of-the-art fMRI studies, which will broaden the use of CVR mapping in basic science and clinical applications including retrospective analysis of previously collected fMRI data.

Blood-brain barrier breakdown in COVID-19 ICU survivors: an MRI pilot study.

Objectives: Coronavirus disease 2019 (COVID-19) results in severe inflammation at the acute stage. Chronic neuroinflammation and abnormal immunological response have been suggested to be the contributors to neuro-long-COVID, but direct evidence has been scarce. This study aims to determine the integrity of the blood-brain barrier (BBB) in COVID-19 intensive care unit (ICU) survivors using a novel MRI technique. Methods: COVID-19 ICU survivors (n=7) and age and sex-matched control participants (n=17) were recruited from June 2021 to March 2023. None of the control participants were hospitalized due to COVID-19 infection. The COVID-19 ICU survivors were studied at 98.6 ± 14.9 days after their discharge from ICU. A non-invasive MRI technique was used to assess the BBB permeability to water molecules, in terms of permeability surface area-product (PS) in the units of mL/100 g/min. Results: PS was significantly higher in COVID-19 ICU survivors (p=0.038) when compared to the controls, with values of 153.1 ± 20.9 mL/100 g/min and 132.5 ± 20.7 mL/100 g/min, respectively. In contrast, there were no significant differences in whole-brain cerebral blood flow (p=0.649) or brain volume (p=0.471) between the groups. Conclusions: There is preliminary evidence of a chronic BBB breakdown in COVID-19 survivors who had a severe acute infection, suggesting a plausible contributor to neurological long-COVID symptoms.

Quantitative Cerebrovascular Reactivity in Normal Aging: Comparison Between Phase-Contrast and Arterial Spin Labeling MRI.

Purpose: Cerebrovascular reactivity (CVR) is an index of the dilatory function of cerebral blood vessels and has shown great promise in the diagnosis of risk factors in cerebrovascular disease. Aging is one such risk factor; thus, it is important to characterize age-related differences in CVR. CVR can be measured by BOLD MRI but few studies have measured quantitative cerebral blood flow (CBF)-based CVR in the context of aging. This study aims to determine the age effect on CVR using two quantitative CBF techniques, phase-contrast (PC), and arterial spin labeling (ASL) MRI. Methods: In 49 participants (32 younger and 17 older), CVR was measured with PC, ASL, and BOLD MRI. These CVR methods were compared across young and older groups to determine their dependence on age. PC and ASL CVR were also studied for inter-correlation and mean differences. Gray and white matter CVR values were also studied. Results: PC CVR was higher in younger participants than older participants (by 17%, p = 0.046). However, there were no age differences in ASL or BOLD CVR. ASL CVR was significantly correlated with PC CVR (p = 0.042) and BOLD CVR (p = 0.016), but its values were underestimated compared to PC CVR (p = 0.045). ASL CVR map revealed no difference between gray matter and white matter tissue types, whereas gray matter was significantly higher than white matter in the BOLD CVR map. Conclusion: This study compared two quantitative CVR techniques in the context of brain aging and revealed that PC CVR is a more sensitive method for detection of age differences, despite the absence of spatial information. The ASL method showed a significant correlation with PC and BOLD, but it tends to underestimate CVR due to confounding factors associated with this technique. Importantly, our data suggest that there is not a difference in CBF-based CVR between the gray and white matter, in contrast to previous observation using BOLD MRI.

Normal variations in brain oxygen extraction fraction are partly attributed to differences in end-tidal CO2.

Cerebral oxygen extraction fraction is an important physiological index of the brain's oxygen consumption and supply and has been suggested to be a potential biomarker for a number of diseases such as stroke, Alzheimer's disease, multiple sclerosis, sickle cell disease, and metabolic disorders. However, in order for oxygen extraction fraction to be a sensitive biomarker for personalized disease diagnosis, inter-subject variations in normal subjects must be minimized or accounted for, which will otherwise obscure its interpretation. Therefore, it is essential to investigate the physiological underpinnings of normal differences in oxygen extraction fraction. This work used two studies, one discovery study and one verification study, to examine the extent to which an individual's end-tidal CO2 can explain variations in oxygen extraction fraction. It was found that, across normal subjects, oxygen extraction fraction is inversely correlated with end-tidal CO2. Approximately 50% of the inter-subject variations in oxygen extraction fraction can be attributed to end-tidal CO2 differences. In addition, oxygen extraction fraction was found to be positively associated with age and systolic blood pressure. By accounting for end-tidal CO2, age, and systolic blood pressure of the subjects, normal variations in oxygen extraction fraction can be reduced by 73%, which is expected to substantially enhance the utility of oxygen extraction fraction as a disease biomarker.

Association of cerebrovascular reactivity and Alzheimer pathologic markers with cognitive performance.

OBJECTIVE: To determine whether MRI-based cerebrovascular reactivity (CVR) can predict cognitive performance independently of Alzheimer pathologic markers, we studied the relationship between cognition, CVR, and CSF-derived ß-amyloid42 (Aß42) and tau in a group of elderly individuals with mixed Alzheimer and vascular cognitive impairment and dementia. METHODS: This was a cross-sectional study of 72 participants 69 ± 8 years of age consisting of individuals with normal cognition (n = 28) and cognitive impairment (n = 44) (including 36 with mild cognitive impairment [MCI] and 8 with mild dementia). CVR was measured with hypercapnia-MRI. Whole-brain CVR (percent blood oxygen level-dependent per 1 mm Hg Etco2) was used to estimate vasodilatory capacity. Montreal Cognitive Assessment (MoCA) scores, cognitive domains scores, and a global composite cognitive score were obtained. AD biomarkers included CSF assays of Aß42 and tau. RESULTS: Whole-brain CVR was lower in the impaired (mean ± SE, 0.132 ± 0.006%/mm Hg) compared to the normal (0.151 ± 0.007%/mm Hg) group (ß = -0.02%/mm Hg; 95% confidence interval [CI] -0.038 to -0.001). After adjustment for CSF Aß42 and tau, higher whole-brain CVR was associated with better performance on the MoCA (ß = 29.64, 95% CI 9.94-49.34) and with a global composite cognitive score (ß = 4.32, 95% CI 0.05-8.58). When the CVR marker was compared with the Fazekas score based on white matter hyperintensities and vascular risk-score in a single regression model predicting the MoCA score, only CVR revealed a significant effect (ß = 28.09, 95% CI 6.14-50.04), while the other 2 measures were not significant. CONCLUSIONS: CVR was significantly associated with cognitive performance independently of AD pathology. Whole-brain CVR may be a useful biomarker for evaluating cognitive impairment related to vascular disease in older individuals. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that CVR was significantly associated with cognitive performance independent of AD pathology.