Developing blood-brain barrier arterial spin labelling as a non-invasive early biomarker of Alzheimer's disease (DEBBIE-AD): a prospective observational multicohort study protocol.

INTRODUCTION: Loss of blood-brain barrier (BBB) integrity is hypothesised to be one of the earliest microvascular signs of Alzheimer's disease (AD). Existing BBB integrity imaging methods involve contrast agents or ionising radiation, and pose limitations in terms of cost and logistics. Arterial spin labelling (ASL) perfusion MRI has been recently adapted to map the BBB permeability non-invasively. The DEveloping BBB-ASL as a non-Invasive Early biomarker (DEBBIE) consortium aims to develop this modified ASL-MRI technique for patient-specific and robust BBB permeability assessments. This article outlines the study design of the DEBBIE cohorts focused on investigating the potential of BBB-ASL as an early biomarker for AD (DEBBIE-AD). METHODS AND ANALYSIS: DEBBIE-AD consists of a multicohort study enrolling participants with subjective cognitive decline, mild cognitive impairment and AD, as well as age-matched healthy controls, from 13 cohorts. The precision and accuracy of BBB-ASL will be evaluated in healthy participants. The clinical value of BBB-ASL will be evaluated by comparing results with both established and novel AD biomarkers. The DEBBIE-AD study aims to provide evidence of the ability of BBB-ASL to measure BBB permeability and demonstrate its utility in AD and AD-related pathologies. ETHICS AND DISSEMINATION: Ethics approval was obtained for 10 cohorts, and is pending for 3 cohorts. The results of the main trial and each of the secondary endpoints will be submitted for publication in a peer-reviewed journal.

Associations between everyday activities and arterial spin labeling-derived cerebral blood flow: A longitudinal study in community-dwelling elderly volunteers.

Cerebral blood flow (CBF) is critical for brain metabolism and function. Age-related changes in CBF are associated with increased risk of neurocognitive disorders and vascular events such as stroke. Identifying correlates and positive modifiers of age-related changes in CBF before the emergence of incipient clinical decline may inform public health advice and clinical practice. Former research has been inconclusive regarding the association between regular physical activity and CBF, and there is a lack of studies on the association between level of everyday activities and CBF, in older adults. To investigate these relationships, 118 healthy community-dwelling adults (65-89 years) underwent pseudo-continuous arterial spin labeling (ASL) MRI, neurocognitive, physical, and activity assessments at baseline. Eighty-six participants completed a follow-up ASL MRI, on average 506 (SD = 113) days after the baseline scan. Cross-sectional analysis revealed credible evidence for positive associations between time spent on low intensity physical activity and CBF in multiple cortical and subcortical regions, time spent on moderate to vigorous intensity physical activity and accumbens CBF, participation in social activity and CBF in multiple cortical regions, and between reading and thalamic CBF, indicating higher regional CBF in more active adults. Longitudinal analysis revealed anecdotal evidence for an interaction between time and baseline level of gardening on occipital and parietal CBF, and baseline reading on pallidum CBF, indicating more change in CBF in adults with lower level of activity. The findings support that malleable lifestyle factors contribute to healthy brain aging, with relevance for public health guidelines.

The value of arterial spin labelling perfusion MRI in brain age prediction.

Current structural MRI-based brain age estimates and their difference from chronological age-the brain age gap (BAG)-are limited to late-stage pathological brain-tissue changes. The addition of physiological MRI features may detect early-stage pathological brain alterations and improve brain age prediction. This study investigated the optimal combination of structural and physiological arterial spin labelling (ASL) image features and algorithms. Healthy participants (n = 341, age 59.7 ± 14.8 years) were scanned at baseline and after 1.7 ± 0.5 years follow-up (n = 248, mean age 62.4 ± 13.3 years). From 3 T MRI, structural (T1w and FLAIR) volumetric ROI and physiological (ASL) cerebral blood flow (CBF) and spatial coefficient of variation ROI features were constructed. Multiple combinations of features and machine learning algorithms were evaluated using the Mean Absolute Error (MAE). From the best model, longitudinal BAG repeatability and feature importance were assessed. The ElasticNetCV algorithm using T1w + FLAIR+ASL performed best (MAE = 5.0 ± 0.3 years), and better compared with using T1w + FLAIR (MAE = 6.0 ± 0.4 years, p < .01). The three most important features were, in descending order, GM CBF, GM/ICV, and WM CBF. Average baseline and follow-up BAGs were similar (-1.5 ± 6.3 and - 1.1 ± 6.4 years respectively, ICC = 0.85, 95% CI: 0.8-0.9, p = .16). The addition of ASL features to structural brain age, combined with the ElasticNetCV algorithm, improved brain age prediction the most, and performed best in a cross-sectional and repeatability comparison. These findings encourage future studies to explore the value of ASL in brain age in various pathologies.

Decreased tissue stiffness in glioblastoma by MR elastography is associated with increased cerebral blood flow.

PURPOSE: Understanding how mechanical properties relate to functional changes in glioblastomas may help explain different treatment response between patients. The aim of this study was to map differences in biomechanical and functional properties between tumor and healthy tissue, to assess any relationship between them and to study their spatial distribution. METHODS: Ten patients with glioblastoma and 17 healthy subjects were scanned using MR Elastography, perfusion and diffusion MRI. Stiffness and viscosity measurements G' and G'', cerebral blood flow (CBF), apparent diffusion coefficient (ADC) and fractional anisotropy (FA) were measured in patients' contrast-enhancing tumor, necrosis, edema, and gray and white matter, and in gray and white matter for healthy subjects. A regression analysis was used to predict CBF as a function of ADC, FA, G' and G''. RESULTS: Median G' and G'' in contrast-enhancing tumor were 13% and 37% lower than in normal-appearing white matter (P < 0.01), and 8% and 6% lower in necrosis than in contrast-enhancing tumor, respectively (P < 0.05). Tumors showed both inter-patient and intra-patient heterogeneity. Measurements approached values in normal-appearing tissue when moving outward from the tumor core, but abnormal tissue properties were still present in regions of normal-appearing tissue. Using both a linear and a random-forest model, prediction of CBF was improved by adding MRE measurements to the model (P < 0.01). CONCLUSIONS: The inclusion of MRE measurements in statistical models helped predict perfusion, with stiffer tissue associated with lower perfusion values.

Multisite reproducibility and test-retest reliability of the T1w/T2w-ratio: A comparison of processing methods.

BACKGROUND: The ratio of T1-weighted (T1w) and T2-weighted (T2w) magnetic resonance imaging (MRI) images is often used as a proxy measure of cortical myelin. However, the T1w/T2w-ratio is based on signal intensities that are inherently non-quantitative and known to be affected by extrinsic factors. To account for this a variety of processing methods have been proposed, but a systematic evaluation of their efficacy is lacking. Given the dependence of the T1w/T2w-ratio on scanner hardware and T1w and T2w protocols, it is important to ensure that processing pipelines perform well also across different sites. METHODS: We assessed a variety of processing methods for computing cortical T1w/T2w-ratio maps, including correction methods for nonlinear field inhomogeneities, local outliers, and partial volume effects as well as intensity normalisation. These were implemented in 33 processing pipelines which were applied to four test-retest datasets, with a total of 170 pairs of T1w and T2w images acquired on four different MRI scanners. We assessed processing pipelines across datasets in terms of their reproducibility of expected regional distributions of cortical myelin, lateral intensity biases, and test-retest reliability regionally and across the cortex. Regional distributions were compared both qualitatively with histology and quantitatively with two reference datasets, YA-BC and YA-B1+, from the Human Connectome Project. RESULTS: Reproducibility of raw T1w/T2w-ratio distributions was overall high with the exception of one dataset. For this dataset, Spearman rank correlations increased from 0.27 to 0.70 after N3 bias correction relative to the YA-BC reference and from -0.04 to 0.66 after N4ITK bias correction relative to the YA-B1+ reference. Partial volume and outlier corrections had only marginal effects on the reproducibility of T1w/T2w-ratio maps and test-retest reliability. Before intensity normalisation, we found large coefficients of variation (CVs) and low intraclass correlation coefficients (ICCs), with total whole-cortex CV of 10.13% and whole-cortex ICC of 0.58 for the raw T1w/T2w-ratio. Intensity normalisation with WhiteStripe, RAVEL, and Z-Score improved total whole-cortex CVs to 5.91%, 5.68%, and 5.19% respectively, whereas Z-Score and Least Squares improved whole-cortex ICCs to 0.96 and 0.97 respectively. CONCLUSIONS: In the presence of large intensity nonuniformities, bias field correction is necessary to achieve acceptable correspondence with known distributions of cortical myelin, but it can be detrimental in datasets with less intensity inhomogeneity. Intensity normalisation can improve test-retest reliability and inter-subject comparability. However, both bias field correction and intensity normalisation methods vary greatly in their efficacy and may affect the interpretation of results. The choice of T1w/T2w-ratio processing method must therefore be informed by both scanner and acquisition protocol as well as the given study objective. Our results highlight limitations of the T1w/T2w-ratio, but also suggest concrete ways to enhance its usefulness in future studies.

Multimodal imaging improves brain age prediction and reveals distinct abnormalities in patients with psychiatric and neurological disorders.

The deviation between chronological age and age predicted using brain MRI is a putative marker of overall brain health. Age prediction based on structural MRI data shows high accuracy in common brain disorders. However, brain aging is complex and heterogenous, both in terms of individual differences and the underlying biological processes. Here, we implemented a multimodal model to estimate brain age using different combinations of cortical area, thickness and sub-cortical volumes, cortical and subcortical T1/T2-weighted ratios, and cerebral blood flow (CBF) based on arterial spin labeling. For each of the 11 models we assessed the age prediction accuracy in healthy controls (HC, n = 750) and compared the obtained brain age gaps (BAGs) between age-matched subsets of HC and patients with Alzheimer's disease (AD, n = 54), mild (MCI, n = 90) and subjective (SCI, n = 56) cognitive impairment, schizophrenia spectrum (SZ, n = 159) and bipolar disorder (BD, n = 135). We found highest age prediction accuracy in HC when integrating all modalities. Furthermore, two-group case-control classifications revealed highest accuracy for AD using global T1-weighted BAG, while MCI, SCI, BD and SZ showed strongest effects in CBF-based BAGs. Combining multiple MRI modalities improves brain age prediction and reveals distinct deviations in patients with psychiatric and neurological disorders. The multimodal BAG was most accurate in predicting age in HC, while group differences between patients and HC were often larger for BAGs based on single modalities. These findings indicate that multidimensional neuroimaging of patients may provide a brain-based mapping of overlapping and distinct pathophysiology in common disorders.

White matter microstructure is associated with functional, cognitive and emotional symptoms 12 months after mild traumatic brain injury.

Identifying patients at risk of poor outcome after mild traumatic brain injury (MTBI) is essential to aid prognostics and treatment. Diffuse axonal injury (DAI) may be the primary pathologic feature of MTBI but is normally not detectable by conventional imaging technology. This lack of sensitivity of clinical imaging techniques has impeded a pathophysiologic understanding of the long-term cognitive and emotional consequences of MTBI, which often remain unnoticed and are attributed to factors other than the injury. Diffusion tensor imaging (DTI) is sensitive to microstructural properties of brain tissue and has been suggested to be a promising candidate for the detection of DAI in vivo. In this study, we report strong associations between brain white matter DTI and self-reported cognitive, somatic and emotional symptoms at 12 months post-injury in 134 MTBI patients. The anatomical distribution suggested global associations, in line with the diffuse symptomatology, although the strongest effects were found in frontal regions including the genu of the corpus callosum and the forceps minor. These findings support the hypothesis that DTI may provide increased sensitivity to the diffuse pathophysiology of MTBI and suggest an important role of advanced Magnetic Resonance Imaging (MRI) in trauma care.

Voxel-Wise Perfusion Assessment in Cerebral White Matter with PCASL at 3T; Is It Possible and How Long Does It Take?

PURPOSE: To establish whether reliable voxel-wise assessment of perfusion in cerebral white matter (WM) is possible using arterial spin labeling (ASL) at 3T in a cohort of healthy subjects. MATERIALS AND METHODS: Pseudo-continuous ASL (PCASL) with background suppression (BS) optimized for WM measurements was performed at 3T in eight healthy male volunteers aged 25-41. Four different labeling schemes were evaluated by varying the labeling duration (LD) and post-labeling delay (PLD). Eight slices with voxel dimension 3.75x3.75x5 mm3 were acquired from the anterosuperior aspect of the brain, and 400 image/control pairs were collected for each run. Rigid head immobilization was applied using individually fitted thermoplastic masks. For each voxel in the resulting ASL time series, the time needed to reach a 95% significance level for the ASL signal to be higher than zero (paired t-test), was estimated. RESULTS: The four protocols detected between 88% and 95% (after Bonferroni correction: 75% and 88%) of WM voxels at 95% significance level. In the most efficient sequence, 80% was reached after 5 min and 95% after 53 min (after Bonferroni correction 40% and 88% respectively). For all protocols, the fraction of significant WM voxels increased in an asymptotic fashion with increasing scan time. A small subgroup of voxels was shown to not benefit at all from prolonged measurement. CONCLUSION: Acquisition of a significant ASL signal from a majority of WM voxels is possible within clinically acceptable scan times, whereas full coverage needs prohibitively long scan times, as a result of the asymptotic trajectory.

Multi-vendor reliability of arterial spin labeling perfusion MRI using a near-identical sequence: implications for multi-center studies.

INTRODUCTION: A main obstacle that impedes standardized clinical and research applications of arterial spin labeling (ASL), is the substantial differences between the commercial implementations of ASL from major MRI vendors. In this study, we compare a single identical 2D gradient-echo EPI pseudo-continuous ASL (PCASL) sequence implemented on 3T scanners from three vendors (General Electric Healthcare, Philips Healthcare and Siemens Healthcare) within the same center and with the same subjects. MATERIAL AND METHODS: Fourteen healthy volunteers (50% male, age 26.4±4.7years) were scanned twice on each scanner in an interleaved manner within 3h. Because of differences in gradient and coil specifications, two separate studies were performed with slightly different sequence parameters, with one scanner used across both studies for comparison. Reproducibility was evaluated by means of quantitative cerebral blood flow (CBF) agreement and inter-session variation, both on a region-of-interest (ROI) and voxel level. In addition, a qualitative similarity comparison of the CBF maps was performed by three experienced neuro-radiologists. RESULTS: There were no CBF differences between vendors in study 1 (p>0.1), but there were CBF differences of 2-19% between vendors in study 2 (p<0.001 in most gray matter ROIs) and 10-22% difference in CBF values obtained with the same vendor between studies (p<0.001 in most gray matter ROIs). The inter-vendor inter-session variation was not significantly larger than the intra-vendor variation in all (p>0.1) but one of the ROIs (p<0.001). CONCLUSION: This study demonstrates the possibility to acquire comparable cerebral CBF maps on scanners of different vendors. Small differences in sequence parameters can have a larger effect on the reproducibility of ASL than hardware or software differences between vendors. These results suggest that researchers should strive to employ identical labeling and readout strategies in multi-center ASL studies.

Analysis of diffusion tensor imaging metrics for gliomas grading at 3 T.

OBJECTIVES: To assess the diagnostic accuracy of axial diffusivity (AD), radial diffusivity (RD), apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values derived from DTI for grading of glial tumors, and to estimate the correlation between DTI parameters and tumor grades. METHODS: Seventy-eight patients with glial tumors underwent DTI. AD, RD, ADC and FA values of tumor, peritumoral edema and contralateral normal-appearing white matter (NAWM) and AD, RD, ADC and FA ratios: lowest average AD, RD, ADC and FA values in tumor or peritumoral edema to AD, RD, ADC and FA of NAWM were calculated. DTI parameters and tumor grades were analyzed statistically and with Pearson correlation. Receiver operating characteristic (ROC) curve analysis was also performed. RESULTS: The differences in ADC, AD and RD tumor values, and ADC and RD tumor ratios were statistically significant between grades II and III, grades II and IV, and between grades II and III-IV. The AD tumor ratio differed significantly among all tumor grades. Tumor ADC, AD, RD and glial tumor grades were strongly correlated. In the ROC curve analysis, the area under the curve (AUC) of the parameter tumor ADC was the largest for distinguishing grade II from grades III to IV (98.5%), grade II from grade IV (98.9%) and grade II from grade III (97.0%). CONCLUSION: ADC, RD and AD are useful DTI parameters for differentiation between low- and high-grade gliomas with a diagnostic accuracy of more than 90%. Our study revealed a good inverse correlation between ADC, RD, AD and WHO grades II-IV astrocytic tumors.

Determination of water compartments in rat myocardium using combined D-T1 and T1-T2 experiments.

We have used combined D-T1 and T1-T2 correlation experiments to explore water compartments in rat heart tissue (myocardium). The results show that two main compartments can be identified, which we assign to extracellular (ec) and intracellular (ic) water. The exchange rate of water across the cell membrane was found to be on the order of 0.1 Hz. In addition, the T1-T2 correlation measurements indicate that the ic compartment contain two T2 populations.

Manganese-calcium interactions with contrast media for cardiac magnetic resonance imaging: a study of manganese chloride supplemented with calcium gluconate in isolated Guinea pig hearts.

OBJECTIVES: Manganese ions (Mn) enter cardiomyocytes via calcium (Ca) channels and enhance relaxation intracellularly. To prevent negative inotropy, new Mn-releasing contrast agents have been supplemented with high Ca. The study aim was to investigate how this affects cardiac function and magnetic resonance efficacy. MATERIALS AND METHODS: MnCl2 based contrast agents, manganese and manganese-calcium (Ca:Mn 10:1), were infused during 4 repeated washin-washout sequences in perfused guinea pig hearts. [Mn] were 10, 50, 100 and 500 microM. RESULTS: During washin, manganese depressed left ventricular developed pressure (LVDP) by 4, 9, 17, and 53% whereas manganese-calcium increased LVDP by 13, 18, 25, and 56%. After experiments, tissue Mn contents (nmol/g dry wt) were control <40, manganese 3720, and manganese-calcium 1620. T1 was reduced by 85-92% in Mn-enriched hearts. CONCLUSIONS: High Ca supplements to Mn-releasing contrast agents may be counterproductive by inducing a strong positive inotropic response and by reducing the magnetic resonance efficacy.

Intracellular manganese ions provide strong T1 relaxation in rat myocardium.

The efficacy of manganese ions (Mn2+) as intracellular (ic) contrast agents was assessed in rat myocardium. T1 and T2 and Mn content were measured in ventricular tissue excised from isolated perfused hearts in which a 5-min wash-in with 0, 30, 100, 300, or 1000 microM of Mn dipyridoxyl diphosphate (MnDPDP) was followed by a 15-min wash-out to remove extracellular (ec) Mn2+. An inversion recovery (IR) analysis at 20 MHz revealed two T1 components: an ic and short T1-1 (650-251 ms), and an ec and longer T1-2 (2712-1042 ms). Intensities were about 68% and 32%, respectively. Tissue Mn content correlated particularly well with ic R1-1. A two-site water-exchange analysis of T1 data documented slow water exchange with ic and ec lifetimes of 11.3 s and 7.5 s, respectively, and no differences between apparent and intrinsic relaxation parameters. Ic relaxivity induced by Mn2+ ions in ic water was as high as 56 (s mM)(-1), about 8 times and 36 times higher than with Mn2+ aqua ions and MnDPDP, respectively, in vitro. This value is as high as any reported to date for any synthetic protein-bound metal chelate. The increased rotational correlation time (tauR) between proton and electron (Mn2+) spins, and maintained inner-sphere water access, might make ic Mn2+ ions and Mn2+ -ion-releasing contrast media surprisingly effective for T1-weighted imaging.

Manganese ions as intracellular contrast agents: proton relaxation and calcium interactions in rat myocardium.

Paramagnetic manganese (Mn) ions (Mn(2+)) are taken up into cardiomyocytes where they are retained for hours. Mn content and relaxation parameters, T(1) and T(2), were measured in right plus left ventricular myocardium excised from isolated perfused rat hearts. In the experiments 5 min wash-in of MnCl(2) were followed by 15 min wash-out to remove extracellular (ec) Mn(2+) MnCl(2), 25 and 100 micro M, elevated tissue Mn content to six and 12 times the level of control (0 micro M MnCl(2)). Variations in perfusate calcium (Ca(2+)) during wash-in of MnCl(2) and experiments including nifedipine showed that myocardial slow Ca(2+) channels are the main pathway for Mn(2+) uptake and that Mn(2+) acts as a pure Ca(2+) competitor and a preferred substrate for slow Ca(2+) channel entry. Inversion recovery analysis at 20 MHz revealed two components for longitudinal relaxation: a short T(1 - 1) and a longer T(1 - 2). Approximate values for control and Mn-treated hearts were in the range 600-125 ms for T(1 - 1) and 2200-750 ms for T(1 - 2). The population fractions were about 59 and 41% for the short and the long component, respectively. The intracellular (ic) R(1 - 1) and R(2 - 1) correlated best with tissue Mn content. Applying two-site exchange analyses on the obtained T(1) data yielded results in parallel to, but also differing from, results reported with an ec contrast agent. The calculated lifetime of ic water (tau(ic)) of about 10 s is compatible with a slow water exchange in the present excised cardiac tissue. The longitudinal relaxivity of Mn ions in ic water [60 (s mM)(-1)] was about one order of magnitude higher than that of MnCl(2) in water in vitro [6.9 (s mM)(-1)], indicating that ic Mn-protein binding is an important potentiating factor in relaxation enhancement.