Concordance of regional hypoperfusion by pCASL MRI and 15O-water PET in frontotemporal dementia: Is pCASL an efficacious alternative?

BACKGROUND: Clinical diagnosis of frontotemporal dementia (FTD) remains a challenge due to the overlap of symptoms among FTD subtypes and with other psychiatric disorders. Perfusion imaging by arterial spin labeling (ASL) is a promising non-invasive alternative to established PET techniques; however, its sensitivity to imaging parameters can hinder its ability to detect perfusion abnormalities. PURPOSE: This study evaluated the similarity of regional hypoperfusion patterns detected by ASL relative to the gold standard for imaging perfusion, PET with radiolabeled water (15O-water). METHODS AND MATERIALS: Perfusion by single-delay pseudo continuous ASL (SD-pCASL), free-lunch Hadamard encoded pCASL (FL_TE-pCASL), and 15O-water data were acquired on a hybrid PET/MR scanner in 13 controls and 9 FTD patients. Cerebral blood flow (CBF) by 15O-water was quantified by a non-invasive approach (PMRFlow). Regional hypoperfusion was determined by comparing individual patients to the control group. This was performed using absolute (aCBF) and CBF normalized to whole-brain perfusion (rCBF). Agreement was assessed based on the fraction of overlapping voxels. Sensitivity and specificity of pCASL was estimated using hypoperfused regions of interest identified by 15O-water. RESULTS: Region of interest (ROI) based perfusion measured by 15O-water strongly correlated with SD-pCASL (R = 0.85 ± 0.1) and FL_TE-pCASL (R = 0.81 ± 0.14). Good agreement in terms of regional hypoperfusion patterns was found between 15O-water and SD-pCASL (sensitivity = 70%, specificity = 78%) and between 15O-water and FL_TE-pCASL (sensitivity = 71%, specificity = 73%). However, SD-pCASL showed greater overlap (43.4 ± 21.3%) with 15O-water than FL_TE-pCASL (29.9 ± 21.3%). Although aCBF and rCBF showed no significant differences regarding spatial overlap and metrics of agreement with 15O-water, rCBF showed considerable variability across subtypes, indicating that care must be taken when selecting a reference region. CONCLUSIONS: This study demonstrates the potential of pCASL for assessing regional hypoperfusion related to FTD and supports its use as a cost-effective alternative to PET.

Noninvasive Quantification of Cerebral Blood Flow Using Hybrid PET/MR Imaging to Extract the [15 O]H2 O Image-Derived Input Function Free of Partial Volume Errors.

BACKGROUND: Quantification of cerebral blood flow (CBF) with [15 O]H2 O-positron emission tomography (PET) requires arterial sampling to measure the input function. This invasive procedure can be avoided by extracting an image-derived input function (IDIF); however, IDIFs are sensitive to partial volume errors due to the limited spatial resolution of PET. PURPOSE: To present an alternative hybrid PET/MR imaging of CBF (PMRFlowIDIF ) that uses phase-contrast (PC) MRI measurements of whole-brain (WB) CBF to calibrate an IDIF extracted from a WB [15 O]H2 O time-activity curve. STUDY TYPE: Technical development and validation. ANIMAL MODEL: Twelve juvenile Duroc pigs (83% female). POPULATION: Thirteen healthy individuals (38% female). FIELD STRENGTH/SEQUENCES: 3 T; gradient-echo PC-MRI. ASSESSMENT: PMRFlowIDIF was validated against PET-only in a porcine model that included arterial sampling. CBF maps were generated by applying PMRFlowIDIF and two previous PMRFlow methods (PC-PET and double integration method [DIM]) to [15 O]H2 O-PET data acquired from healthy individuals. STATISTICAL TESTS: PMRFlow and PET CBF measurements were compared with regression and correlation analyses. Paired t-tests were performed to evaluate differences. Potential biases were assessed using one-sample t-tests. Reliability was assessed by intraclass correlation coefficients. Statistical significance: α  = 0.05. RESULTS: In the animal study, strong agreement was observed between PMRFlowIDIF (average voxel-wise CBF, 58.0 ± 16.9 mL/100 g/min) and PET (63.0 ± 18.9 mL/100 g/min). In the human study, PMRFlowDIM (y = 1.11x - 5.16, R2  = 0.99 ± 0.01) and PMRFlowPC-PET (y = 0.87x + 3.82, R2  = 0.97 ± 0.02) performed similarly to PMRFlowIDIF, and CBF was within the expected range (eg, 49.7 ± 7.2 mL/100 g/min for gray matter). DATA CONCLUSION: Accuracy of PMRFlowIDIF was confirmed in the animal study with the primary source of error attributed to differences in WB CBF measured by PC MRI and PET. In the human study, differences in CBF from PMRFlowIDIF , PMRFlowDIM , and PMRFlowPC-PET were due to the latter two not accounting for blood-borne activity. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 1.

Sensitivity of Arterial Spin Labeling for Characterization of Longitudinal Perfusion Changes in Frontotemporal Dementia and Related Disorders.

BACKGROUND: Advances in the understanding of the pathophysiology of frontotemporal dementia (FTD) and related disorders, along with the development of novel candidate disease modifying treatments, have stimulated the need for tools to assess the efficacy of new therapies. While perfusion imaging by arterial spin labeling (ASL) is an attractive approach for longitudinal imaging biomarkers of neurodegeneration, sources of variability between sessions including arterial transit times (ATT) and fluctuations in resting perfusion can reduce its sensitivity. Establishing the magnitude of perfusion changes that can be reliably detected is necessary to delineate longitudinal perfusion changes related to disease processes from the effects of these sources of error. PURPOSE: To assess the feasibility of ASL for longitudinal monitoring of patients with FTD by quantifying between-session variability of perfusion on a voxel-by-voxel basis. METHODS AND MATERIALS: ASL data were collected in 13 healthy controls and 8 patients with FTD or progressive supra-nuclear palsy. Variability in cerebral blood flow (CBF) by single delay pseudo-continuous ASL (SD-pCASL) acquired one month apart were quantified by the coefficient of variation (CV) and intraclass correlation coefficient (ICC). Additionally, CBF by SD-pCASL and ATT by low-resolution multiple inversion time ASL (LowRes-pCASL) were compared to Hadamard encoded sequences which are able to simultaneously measure CBF and ATT with improved time-efficiency. RESULTS: Agreement of grey-matter perfusion between sessions was found for both patients and controls (CV = 10.8% and 8.3% respectively) with good reliability for both groups (ICC > 0.6). Intensity normalization to remove day-to-day fluctuations in resting perfusion reduced the CV by 28%. Less than 5% of voxels had ATTs above the chosen post labelling delay (2 s), indicating that the ATT was not a significant source of error. Hadamard-encoded perfusion imaging yielded systematically higher CBF compared to SD-pCASL, but produced similar transit-time measurements. Power analysis revealed that SD-pCASL has the sensitivity to detect longitudinal changes as low as 10% with as few as 10 patient participants. CONCLUSION: With the appropriate labeling parameters, SD-pCASL is a promising approach for assessing longitudinal changes in CBF associated with FTD.

A Noninvasive Method for Quantifying Cerebral Metabolic Rate of Oxygen by Hybrid PET/MRI: Validation in a Porcine Model.

The gold standard for imaging the cerebral metabolic rate of oxygen (CMRO2) is positron emission tomography (PET); however, it is an invasive and complex procedure that also requires correction for recirculating 15O-H2O and the blood-borne activity. We propose a noninvasive reference-based hybrid PET/magnetic resonance imaging (MRI) method that uses functional MRI techniques to calibrate 15O-O2-PET data. Here, PET/MR imaging of oxidative metabolism (PMROx) was validated in an animal model by comparison to PET-alone measurements. Additionally, we investigated if the MRI-perfusion technique arterial spin labelling (ASL) could be used to further simplify PMROx by replacing 15O-H2O-PET, and if the PMROx was sensitive to anesthetics-induced changes in metabolism. Methods: 15O-H2O and 15O-O2 PET data were acquired in a hybrid PET/MR scanner (3 T Siemens Biograph mMR), together with simultaneous functional MRI (OxFlow and ASL), from juvenile pigs (n = 9). Animals were anesthetized with 3% isoflurane and 6 mL/kg/h propofol for the validation experiments and arterial sampling was performed for PET-alone measurements. PMROx estimates were obtained using whole-brain (WB) CMRO2 from OxFlow and local cerebral blood flow (CBF) from either noninvasive 15O-H2O-PET or ASL (PMROxASL). Changes in metabolism were investigated by increasing the propofol infusion to 20 mL/kg/h. Results: Good agreement and correlation were observed between regional CMRO2 measurements from PMROx and PET-alone. No significant differences were found between OxFlow and PET-only measurements of WB oxygen extraction fraction (0.30 ± 0.09 and 0.31 ± 0.09) and CBF (54.1 ± 16.7 and 56.6 ± 21.0 mL/100 g/min), or between PMROx and PET-only CMRO2 estimates (1.89 ± 0.16 and 1.81 ± 0.10 mLO2/100 g/min). Moreover, PMROx and PMROxASL were sensitive to propofol-induced reduction in CMRO2 Conclusion: This study provides initial validation of a noninvasive PET/MRI technique that circumvents many of the complexities of PET CMRO2 imaging. PMROx does not require arterial sampling and has the potential to reduce PET imaging to 15O-O2 only; however, future validation involving human participants are required.

A non-invasive reference-based method for imaging the cerebral metabolic rate of oxygen by PET/MR: theory and error analysis.

Positron emission tomography (PET) remains the gold standard for quantitative imaging of the cerebral metabolic rate of oxygen (CMRO2); however, it is an invasive and complex procedure that requires accounting for recirculating [15O]H2O (RW) and the cerebral blood volume (CBV). This study presents a non-invasive reference-based technique for imaging CMRO2 that was developed for PET/magnetic resonance imaging (MRI) with the goal of simplifying the PET procedure while maintaining its ability to quantify metabolism. The approach is to use whole-brain (WB) measurements of oxygen extraction fraction (OEF) and cerebral blood flow (CBF) to calibrate [15O]O2-PET data, thereby avoiding the need for invasive arterial sampling. Here we present the theoretical framework, along with error analyses, sensitivity to PET noise and inaccuracies in input parameters, and initial assessment on PET data acquired from healthy participants. Simulations showed that neglecting RW and CBV corrections caused errors in CMRO2 of less than ±10% for changes in regional OEF of ±25%. These predictions were supported by applying the reference-based approach to PET data, which resulted in remarkably similar CMRO2 images to those generated by analyzing the same data using a modeling approach that incorporated the arterial input functions and corrected for CBV contributions. Significant correlations were observed between regional CMRO2 values from the two techniques (slope = 1.00 ± 0.04, R 2 > 0.98) with no significant differences found for integration times of 3 and 5 min. In summary, results demonstrate the feasibility of producing quantitative CMRO2 images by PET/MRI without the need for invasive blood sampling.

Using fMRI to investigate the potential cause of inverse oxygenation reported in fNIRS studies of motor imagery.

Motor imagery (MI) is a commonly used cognitive task in brain-computer interface (BCI) applications because it produces reliable activity in motor-planning regions. However, a number of functional near-infrared spectroscopy (fNIRS) studies have reported the unexpected finding of inverse oxygenation: increased deoxyhemoglobin and decreased oxyhemoglobin during task periods. This finding questions the reliability of fNIRS for BCI applications given that MI activation should result in a focal increase in blood oxygenation. In an attempt to elucidate this phenomenon, fMRI and fNIRS data were acquired on 15 healthy participants performing a MI task. The fMRI data provided global coverage of brain activity, thus allowing visualization of all potential brain regions activated and deactivated during task periods. Indeed, fMRI results from seven subjects included activation in the primary motor cortex and/or the pre-supplementary motor area during the rest periods in addition to the expected activation in the supplementary motor and premotor areas. Of these seven subjects, two showed inverse oxygenation with fNIRS. The proximity of the regions showing inverse oxygenation to the motor planning regions suggests that inverse activation detected by fNIRS may likely be a consequence of partial volume errors due to the sensitivity of the optodes to both primary motor and motor planning regions.

A Noninvasive Method for Quantifying Cerebral Blood Flow by Hybrid PET/MRI.

Although PET with 15O-water is the gold standard for imaging cerebral blood flow (CBF), quantification requires measuring the arterial input function (AIF), which is an invasive and noisy procedure. To circumvent this problem, we propose a noninvasive PET/MRI approach that eliminates the need to measure AIF by using global CBF determined by phase-contrast (PC) MRI as a reference region. This approach not only is noninvasive but also involves no additional imaging time, because PC MRI and 15O-water PET are acquired simultaneously. The purpose of this study was to test the accuracy of this hybrid method in an animal model in which AIF was measured directly and CBF was varied by changing the arterial CO2 tension. Methods: PET and MRI data were simultaneously acquired in juvenile pigs at hypocapnia (n = 5), normocapnia (n = 5), and hypercapnia (n = 4). CBF was measured by the MRI reference method and by PET alone using an MRI-compatible blood sampling system to measure AIF. Results: Global CBF estimates from PC MRI and 15O-water PET agreed well, with a correlation coefficient of 0.9 and a slope of 0.88. Strong positive correlations (R2 > 0.96) were also found between regional CBF generated by the PET-only and the MRI-reference methods. Conclusion: These findings demonstrate the accuracy of this hybrid PET/MRI approach, which might prove useful in patients for whom obtaining accurate CBF measurements is challenging.

Mapping Long-Term Functional Changes in Cerebral Blood Flow by Arterial Spin Labeling.

Although arterial spin labeling (ASL) is appealing for mapping long-term changes in functional activity, inter-sessional variations in basal blood flow, arterial transit times (ATTs), and alignment errors, can result in significant false activation when comparing images from separate sessions. By taking steps to reduce these sources of noise, this study assessed the ability of ASL to detect functional CBF changes between sessions. ASL data were collected in three sessions to image ATT, resting CBF and CBF changes associated with motor activation (7 participants). Activation maps were generated using rest and task images acquired in the same session and from sessions separated by up to a month. Good agreement was found when comparing between-session activation maps to within-session activation maps with only a 16% decrease in precision (within-session: 90 ± 7%) and a 13% decrease in the Dice similarity (within-session: 0.75 ± 0.07) coefficient after a month. In addition, voxel-wise reproducibility (within-session: 4.7 ± 4.5%) and reliability (within-session: 0.89 ± 0.20) of resting grey-matter CBF decreased by less than 18% for the between-session analysis relative to within-session values. ATT variability between sessions (5.0 ± 2.7%) was roughly half the between-subject variability, indicating that its effects on longitudinal CBF were minimal. These results demonstrate that conducting voxel-wise analysis on CBF images acquired on different days is feasible with only modest loss in precision, highlighting the potential of ASL for longitudinal studies.

Impaired Cerebrovascular Function in Coronary Artery Disease Patients and Recovery Following Cardiac Rehabilitation.

Coronary artery disease (CAD) poses a risk to the cerebrovascular function of older adults and has been linked to impaired cognitive abilities. Using magnetic resonance perfusion imaging, we investigated changes in resting cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) to hypercapnia in 34 CAD patients and 21 age-matched controls. Gray matter volume (GMV) images were acquired and used as a confounding variable to separate changes in structure from function. Compared to healthy controls, CAD patients demonstrated reduced CBF in the superior frontal, anterior cingulate (AC), insular, pre- and post-central gyri, middle temporal, and superior temporal regions. Subsequent analysis of these regions demonstrated decreased CVR in the AC, insula, post-central and superior frontal regions. Except in the superior frontal and precentral regions, regional reductions in CBF and CVR were identified in brain areas where no detectable reductions in GMV were observed, demonstrating that these vascular changes were independent of brain atrophy. Because aerobic fitness training can improve brain function, potential changes in regional CBF were investigated in the CAD patients after completion of a 6-months exercise-based cardiac rehabilitation program. Increased CBF was observed in the bilateral AC, as well as recovery of CBF in the dorsal aspect of the right AC, where the magnitude of increased CBF was roughly equal to the reduction in CBF at baseline compared to controls. These exercise-related improvements in CBF in the AC is intriguing given the role of this area in cognitive processing and regulation of cardiovascular autonomic control.

Feasibility of simultaneous whole-brain imaging on an integrated PET-MRI system using an enhanced 2-point Dixon attenuation correction method.

PURPOSE: To evaluate a potential approach for improved attenuation correction (AC) of PET in simultaneous PET and MRI brain imaging, a straightforward approach that adds bone information missing on Dixon AC was explored. METHODS: Bone information derived from individual T1-weighted MRI data using segmentation tools in SPM8, were added to the standard Dixon AC map. Percent relative difference between PET reconstructed with Dixon+bone and with Dixon AC maps were compared across brain regions of 13 oncology patients. The clinical potential of the improved Dixon AC was investigated by comparing relative perfusion (rCBF) measured with arterial spin labeling to relative glucose uptake (rPETdxbone) measured simultaneously with (18)F-flurodexoyglucose in several regions across the brain. RESULTS: A gradual increase in PET signal from center to the edge of the brain was observed in PET reconstructed with Dixon+bone. A 5-20% reduction in regional PET signals were observed in data corrected with standard Dixon AC maps. These regional underestimations of PET were either reduced or removed when Dixon+bone AC was applied. The mean relative correlation coefficient between rCBF and rPETdxbone was r = 0.53 (p < 0.001). Marked regional variations in rCBF-to-rPET correlation were observed, with the highest associations in the caudate and cingulate and the lowest in limbic structures. All findings were well matched to observations from previous studies conducted with PET data reconstructed with computed tomography derived AC maps. CONCLUSION: Adding bone information derived from T1-weighted MRI to Dixon AC maps can improve underestimation of PET activity in hybrid PET-MRI neuroimaging.