Application of calibrated fMRI in Alzheimer's disease.

Calibrated fMRI based on arterial spin-labeling (ASL) and blood oxygen-dependent contrast (BOLD), combined with periods of hypercapnia and hyperoxia, can provide information on cerebrovascular reactivity (CVR), resting blood flow (CBF), oxygen extraction fraction (OEF), and resting oxidative metabolism (CMRO2). Vascular and metabolic integrity are believed to be affected in Alzheimer's disease (AD), thus, the use of calibrated fMRI in AD may help understand the disease and monitor therapeutic responses in future clinical trials. In the present work, we applied a calibrated fMRI approach referred to as Quantitative O2 (QUO2) in a cohort of probable AD dementia and age-matched control participants. The resulting CBF, OEF and CMRO2 values fell within the range from previous studies using positron emission tomography (PET) with 15O labeling. Moreover, the typical parietotemporal pattern of hypoperfusion and hypometabolism in AD was observed, especially in the precuneus, a particularly vulnerable region. We detected no deficit in frontal CBF, nor in whole grey matter CVR, which supports the hypothesis that the effects observed were associated specifically with AD rather than generalized vascular disease. Some key pitfalls affecting both ASL and BOLD methods were encountered, such as prolonged arterial transit times (particularly in the occipital lobe), the presence of susceptibility artifacts obscuring medial temporal regions, and the challenges associated with the hypercapnic manipulation in AD patients and elderly participants. The present results are encouraging and demonstrate the promise of calibrated fMRI measurements as potential biomarkers in AD. Although CMRO2 can be imaged with 15O PET, the QUO2 method uses more widely available imaging infrastructure, avoids exposure to ionizing radiation, and integrates with other MRI-based measures of brain structure and function.

The impact of inspired oxygen levels on calibrated fMRI measurements of M, OEF and resting CMRO2 using combined hypercapnia and hyperoxia.

Recent calibrated fMRI techniques using combined hypercapnia and hyperoxia allow the mapping of resting cerebral metabolic rate of oxygen (CMRO2) in absolute units, oxygen extraction fraction (OEF) and calibration parameter M (maximum BOLD). The adoption of such technique necessitates knowledge about the precision and accuracy of the model-derived parameters. One of the factors that may impact the precision and accuracy is the level of oxygen provided during periods of hyperoxia (HO). A high level of oxygen may bring the BOLD responses closer to the maximum M value, and hence reduce the error associated with the M interpolation. However, an increased concentration of paramagnetic oxygen in the inhaled air may result in a larger susceptibility area around the frontal sinuses and nasal cavity. Additionally, a higher O2 level may generate a larger arterial blood T1 shortening, which require a bigger cerebral blood flow (CBF) T1 correction. To evaluate the impact of inspired oxygen levels on M, OEF and CMRO2 estimates, a cohort of six healthy adults underwent two different protocols: one where 60% of O2 was administered during HO (low HO or LHO) and one where 100% O2 was administered (high HO or HHO). The QUantitative O2 (QUO2) MRI approach was employed, where CBF and R2* are simultaneously acquired during periods of hypercapnia (HC) and hyperoxia, using a clinical 3 T scanner. Scan sessions were repeated to assess repeatability of results at the different O2 levels. Our T1 values during periods of hyperoxia were estimated based on an empirical ex-vivo relationship between T1 and the arterial partial pressure of O2. As expected, our T1 estimates revealed a larger T1 shortening in arterial blood when administering 100% O2 relative to 60% O2 (T1LHO = 1.56±0.01 sec vs. T1HHO = 1.47±0.01 sec, P < 4*10-13). In regard to the susceptibility artifacts, the patterns and number of affected voxels were comparable irrespective of the O2 concentration. Finally, the model-derived estimates were consistent regardless of the HO levels, indicating that the different effects are adequately accounted for within the model.

Regional Reproducibility of BOLD Calibration Parameter M, OEF and Resting-State CMRO2 Measurements with QUO2 MRI.

The current generation of calibrated MRI methods goes beyond simple localization of task-related responses to allow the mapping of resting-state cerebral metabolic rate of oxygen (CMRO2) in micromolar units and estimation of oxygen extraction fraction (OEF). Prior to the adoption of such techniques in neuroscience research applications, knowledge about the precision and accuracy of absolute estimates of CMRO2 and OEF is crucial and remains unexplored to this day. In this study, we addressed the question of methodological precision by assessing the regional inter-subject variance and intra-subject reproducibility of the BOLD calibration parameter M, OEF, O2 delivery and absolute CMRO2 estimates derived from a state-of-the-art calibrated BOLD technique, the QUantitative O2 (QUO2) approach. We acquired simultaneous measurements of CBF and R2* at rest and during periods of hypercapnia (HC) and hyperoxia (HO) on two separate scan sessions within 24 hours using a clinical 3 T MRI scanner. Maps of M, OEF, oxygen delivery and CMRO2, were estimated from the measured end-tidal O2, CBF0, CBFHC/HO and R2*HC/HO. Variability was assessed by computing the between-subject coefficients of variation (bwCV) and within-subject CV (wsCV) in seven ROIs. All tests GM-averaged values of CBF0, M, OEF, O2 delivery and CMRO2 were: 49.5 ± 6.4 mL/100 g/min, 4.69 ± 0.91%, 0.37 ± 0.06, 377 ± 51 µmol/100 g/min and 143 ± 34 µmol/100 g/min respectively. The variability of parameter estimates was found to be the lowest when averaged throughout all GM, with general trends toward higher CVs when averaged over smaller regions. Among the MRI measurements, the most reproducible across scans was R2*0 (wsCVGM = 0.33%) along with CBF0 (wsCVGM = 3.88%) and R2*HC (wsCVGM = 6.7%). CBFHC and R2*HO were found to have a higher intra-subject variability (wsCVGM = 22.4% and wsCVGM = 16% respectively), which is likely due to propagation of random measurement errors, especially for CBFHC due to the low contrast-to-noise ratio intrinsic to ASL. Reproducibility of the QUO2 derived estimates were computed, yielding a GM intra-subject reproducibility of 3.87% for O2 delivery, 16.8% for the M value, 13.6% for OEF and 15.2% for CMRO2. Although these results focus on the precision of the QUO2 method, rather than the accuracy, the information will be useful for calculation of statistical power in future validation studies and ultimately for research applications of the method. The higher test-retest variability for the more extensively modeled parameters (M, OEF, and CMRO2) highlights the need for further improvement of acquisition methods to reduce noise levels.

Test-retest reliability of cerebral blood flow and blood oxygenation level-dependent responses to hypercapnia and hyperoxia using dual-echo pseudo-continuous arterial spin labeling and step changes in the fractional composition of inspired gases.

PURPOSE: To assess the reproducibility of blood oxygenation level-dependent / cerebral blood flow (BOLD/CBF) responses to hypercapnia/hyperoxia using dual-echo pseudo-continuous arterial spin labeling (pCASL) and step changes in inspired doses. MATERIALS AND METHODS: Eight subjects were scanned twice, within 24 hours, using the same respiratory manipulation and imaging protocol. Imaging comprised a 5-minute anatomical acquisition, allowing segmentation of the gray matter (GM) tissue for further analysis, and an 18-minute pCASL functional scan. Hypercapnia/hyperoxia were induced by increasing the fraction of inspired CO2 to 5% and inspired O2 to 60%, alternately. Reproducibility of BOLD and CBF pCASL measures was assessed by computing the inter-session coefficient of variation (CV) of the respective signals in GM. RESULTS: BOLD and CBF measures in GM were robust and consistent, yielding CV values below 10% for BOLD hypercapnic/hyperoxic responses (which averaged 1.9 ± 0.1% and 1.14 ± 0.02%) and below 20% for the CBF hypercapnic response (which averaged 35 ± 2 mL/min/100g). The CV for resting CBF was 3.5%. CONCLUSION: It is possible to attain reproducible measures of the simultaneous BOLD and CBF responses to blood gases, within a reasonable scan time and with whole brain coverage, using a simple respiratory manipulation and dual-echo pCASL.

A simple breathing circuit allowing precise control of inspiratory gases for experimental respiratory manipulations.

BACKGROUND: Respiratory manipulations modulating blood flow and oxygenation levels have become an important component of modern functional MRI applications. Manipulations often consist of temporarily switching inspired fractions of CO2 and O2; and have typically been performed using simple oxygen masks intended for applications in respiratory therapy. However, precise control of inspired gas composition is difficult using this type of mask due to entrainment of room air and resultant dilution of inspired gases. We aimed at developing a gas delivery apparatus allowing improved control over the fractional concentration of inspired gases, to be used in brain fMRI studies. FINDINGS: The breathing circuit we have conceived allowed well controlled step changes in FiO2 and FiCO2, at moderate flow rates achievable on standard clinical flow regulators. In a two run test inside the scanner we demonstrate that tightly controlled simple gas switching manipulations can afford good intra-subject reproducibility of induced hyperoxia/hypercapnia responses. Although our approach requires a non-vented mask fitting closely to the subject's face, the circuit ensures a continuous supply of breathable air even if the supply of medical gases is interrupted, and is easily removable in case of an emergency. The apparatus we propose is also compact and MRI compatible, allowing subject placement in confined spaces such as an MRI scanner for brain examinations. CONCLUSIONS: We have reported a new approach for the controlled administration of medical gases, and describe an implementation of the breathing circuit that is MRI compatible and uses commercially available parts. The resultant apparatus allows simple, safe and precise manipulations of FiO2 and FiCO2.

Comparison of cerebral vascular reactivity measures obtained using breath-holding and CO2 inhalation.

Stimulation of cerebral vasculature using hypercapnia has been widely used to study cerebral vascular reactivity (CVR), which can be expressed as the quantitative change in cerebral blood flow (CBF) per mm Hg change in end-tidal partial pressure of CO2 (PETCO2). We investigate whether different respiratory manipulations, with arterial spin labeling used to measure CBF, lead to consistent measures of CVR. The approaches included: (1) an automated system delivering variable concentrations of inspired CO2 for prospective targeting of PETCO2, (2) administration of a fixed concentration of CO2 leading to subject-dependent changes in PETCO2, (3) a breath-hold (BH) paradigm with physiologic modeling of CO2 accumulation, and (4) a maneuver combining breath-hold and hyperventilation. When CVR was expressed as the percent change in CBF per mm Hg change in PETCO2, methods 1 to 3 gave consistent results. The CVR values using method 4 were significantly lower. When CVR was expressed in terms of the absolute change in CBF (mL/100 g per minute per mm Hg), greater discrepancies became apparent: methods 2 and 3 gave lower absolute CVR values compared with method 1, and the value obtained with method 4 was dramatically lower. Our findings indicate that care must be taken to ensure that CVR is measured over the linear range of the CBF-CO2 dose-response curve, avoiding hypocapnic conditions.

Comparison of pulsed and pseudocontinuous arterial spin-labeling for measuring CO2 -induced cerebrovascular reactivity.

PURPOSE: To compare the performance of pulsed and pseudocontinuous arterial spin-labeling (PASL and pCASL) methods in measuring CO(2) -induced cerebrovascular reactivity (CVR). MATERIALS AND METHODS: Subjects were scanned using both ASL sequences during a controlled hypercapnia procedure and visual stimulation. CVR was computed as the percent CO(2) -induced increase in cerebral blood flow (Δ%CBF) per mmHg increase in end-tidal PCO(2) . Visually evoked responses were expressed as Δ%CBF. Resting CBF and temporal signal-to-noise ratio were also computed. Regionally averaged values for the different quantities were compared in gray matter (GM) and visual cortex (VC) using t-tests. RESULTS: Both PASL and pCASL yielded comparable respective values for resting CBF (56 ± 3 and 56 ± 4 mL/min/100g) and visually evoked responses (75 ± 5% and 81 ± 4%). Values of CVR determined using pCASL (GM 4.4 ± 0.2, VC 8 ± 1 Δ%CBF/mmHg), however, were significantly higher than those measured using PASL (GM 3.0 ± 0.6, VC 5 ± 1 Δ%CBF/mmHg) in both GM and VC. The percentage of GM voxels in which statistically significant hypercapnia responses were detected was also higher for pCASL (27 ± 5% vs. 16 ± 3% for PASL). CONCLUSION: pCASL may be less prone to underestimation of CO(2) -induced flow changes due to improved label timing control.