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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 (Aβ42/40, total tau, and Aβ42/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. [ABSTRACT FROM AUTHOR]

Blood oxygenation level-dependent (BOLD) or arterial spin labeling (ASL) MRI with hypercapnic stimuli allow for measuring cerebrovascular reactivity (CVR). Hypercapnic stimuli are also employed in calibrated BOLD functional MRI for quantifying neuronally-evoked changes in cerebral oxygen metabolism (CMRO2). It is often assumed that hypercapnic stimuli (with or without hyperoxia) are iso-metabolic; increasing arterial CO2 or O2 does not affect CMRO2. We evaluated the null hypothesis that two common hypercapnic stimuli, 'CO2 in air' and carbogen, are iso-metabolic. TRUST and ASL MRI were used to measure the cerebral venous oxygenation and cerebral blood flow (CBF), from which the oxygen extraction fraction (OEF) and CMRO2 were calculated for room-air, 'CO2 in air' and carbogen. As expected, CBF significantly increased (9.9% ± 9.3% and 12.1% ± 8.8% for 'CO2 in air' and carbogen, respectively). CMRO2 decreased for 'CO2 in air' (−13.4% ± 13.0%, p < 0.01) compared to room-air, while the CMRO2 during carbogen did not significantly change. Our findings indicate that 'CO2 in air' is not iso-metabolic, while carbogen appears to elicit a mixed effect; the CMRO2 reduction during hypercapnia is mitigated when including hyperoxia. These findings can be important for interpreting measurements using hypercapnic or hypercapnic-hyperoxic (carbogen) stimuli. [ABSTRACT FROM AUTHOR]

Much attention has been paid to the effects of mild traumatic brain injury (mTBI) on cerebrovascular reactivity in adult populations, yet it remains understudied in pediatric injury. In this study, 30 adolescents (12–18 years old) with pediatric mTBI (pmTBI) and 35 age- and sex-matched healthy controls (HC) underwent clinical and neuroimaging assessments during sub-acute (6.9 ± 2.2 days) and early chronic (120.4 ± 11.7 days) phases of injury. Relative to controls, pmTBI reported greater initial post-concussion symptoms, headache, pain, and anxiety, resolving by four months post-injury. Patients reported increased sleep issues and exhibited deficits in processing speed and attention across both visits. In grey-white matter interface areas throughout the brain, pmTBI displayed increased maximal fit/amplitude of a time-shifted end-tidal CO2 regressor to blood oxygen-level dependent response relative to HC, as well as increased latency to maximal fit. The alterations persisted through the early chronic phase of injury, with maximal fit being associated with complaints of ongoing sleep disturbances during post hoc analyses but not cognitive measures of processing speed or attention. Collectively, these findings suggest that deficits in the speed and degree of cerebrovascular reactivity may persist longer than current conceptualizations about clinical recovery within 30 days. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background and purpose Vascular risk factors have been associated with decreased cerebral blood flow (CBF) but this is etiologically nonspecific and may result from vascular insufficiency or a response to decreased brain metabolic activity. We apply new MRI techniques to measure oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen consumption (CMRO2), hypothesizing that decreased CBF related to these vascular risk factors will be associated with increased OEF, confirming a primary vascular insufficiency. Methods 3T MRI was obtained on 70 community-based participants in this IRB-approved study with informed consent, with previous assessment of systolic blood pressure, hypertension medication, elevated serum triglycerides, low serum HDL, and diabetes mellitus. CBF was measured using phase contrast adjusted for brain volume (ml/100 g/min), OEF (%) was obtained from T2-Relaxation-Under-Spin-Tagging (TRUST), and CMRO2 (μmol/100 g/min) was derived using the Fick principle. Stepwise linear regression identified optimal predictors of CBF with age, sex, and hematocrit included for adjustment. This predictive model was then evaluated against OEF and CMRO2. Results Hypertriglyceridemia was associated with low CBF and high OEF. High systolic blood pressure was associated with high CBF and low OEF, which was primarily attributable to those with pressures above 160 mmHg. Neither risk factor was associated with significant differences in cerebral metabolic rate. Conclusion Low CBF related to hypertriglyceridemia was accompanied by high OEF with no significant difference in CMRO2, confirming subclinical vascular insufficiency. High CBF related to high systolic blood pressure likely reflected limitations of autoregulation at higher blood pressures. [ABSTRACT FROM AUTHOR]

White matter (WM) comprises about half of the brain and its dysfunction is implicated in many brain disorders. While structural properties in healthy and diseased WM have been extensively studied, relatively little is known about the physiology underlying these structural characteristics. Recent advances in magnetic resonance (MR) technologies provided new opportunities to better understand perfusion and microvasculature in the WM. Here, we aim to evaluate vasodilatory capacity of the WM vasculature, which is thought to be important in tissue ischemia and autoregulation. Fifteen younger and fifteen older subjects performed a CO2 inhalation task while blood-oxygenation-level-dependent (BOLD) magnetic resonance imaging (MRI) images were continuously collected. The cerebrovascular reactivity (CVR) index showed that the value of CVR in the WM (0.03±0.002%/mm Hg) was positive, but was significantly lower than that in the gray matter (GM) (0.22±0.01%/mm Hg). More strikingly, the WM response showed a temporal delay of 19±3 seconds compared with GM, which was attributed to the longer time it takes for extravascular CO2 to change. With age, WM CVR response becomes greater and faster, which is opposite to the changes seen in the GM. These data suggest that characteristics of WM CVR are different from that of GM and caution should be used when interpreting pathologic WM CVR results. [ABSTRACT FROM AUTHOR]

Characterizing the effect of oxygen (O2) modulation on the brain may provide a better understanding of several clinically relevant problems, including acute mountain sickness and hyperoxic therapy in patients with traumatic brain injury or ischemia. Quantifying the O2 effects on brain metabolism is also critical when using this physiologic maneuver to calibrate functional magnetic resonance imaging (fMRI) signals. Although intuitively crucial, the question of whether the brain's metabolic rate depends on the amount of O2 available has not been addressed in detail previously. This can be largely attributed to the scarcity and complexity of measurement techniques. Recently, we have developed an MR method that provides a noninvasive (devoid of exogenous agents), rapid (<5 minutes), and reliable (coefficient of variant, CoV <3%) measurement of the global cerebral metabolic rate of O2 (CMRO2). In the present study, we evaluated metabolic and vascular responses to manipulation of the fraction of inspired O2 (FiO2). Hypoxia with 14% FiO2 was found to increase both CMRO2 (5.0±2.0%, N=16, P=0.02) and cerebral blood flow (CBF) (9.8±2.3%, P<0.001). However, hyperoxia decreased CMRO2 by 10.3±1.5% (P<0.001) and 16.9±2.7% (P<0.001) for FiO2 of 50% and 98%, respectively. The CBF showed minimal changes with hyperoxia. Our results suggest that modulation of inspired O2 alters brain metabolism in a dose-dependent manner. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]