There is evidence for a beneficial effect of aerobic exercise on cognition, but underlying mechanisms are unclear. In this study, we test the hypothesis that aerobic exercise increases cerebral blood flow (CBF) in patients with vascular cognitive impairment (VCI). This study is a multicenter single-blind randomized controlled trial among 80 patients with VCI. Most important inclusion criteria are a diagnosis of VCI with Mini-Mental State Examination ≥22 and Clinical Dementia Rating ≤0.5. Participants are randomized into an aerobic exercise group or a control group. The aerobic exercise program aims to improve cardiorespiratory fitness and takes 14 weeks, with a frequency of three times a week. Participants are provided with a bicycle ergometer at home. The control group receives two information meetings. Primary outcome measure is change in CBF. We expect this study to provide insight into the potential mechanism by which aerobic exercise improves hemodynamic status.@en

Background: Hemodynamic balance in the heart-brain axis is increasingly recognized as a crucial factor in maintaining functional and structural integrity of the brain and thereby cognitive functioning. Patients with heart failure (HF), carotid occlusive disease (COD), and vascular cognitive impairment (VCI) present themselves with complaints attributed to specific parts of the heart-brain axis, but hemodynamic changes often go beyond the part of the axis for which they primarily seek medical advice. The Heart-Brain Study hypothesizes that the hemodynamic status of the heart and the brain is an important but underestimated cause of VCI. We investigate this by studying to what extent hemodynamic changes contribute to VCI and what the mechanisms involved are. Here, we provide an overview of the design and protocol. Methods: The Heart-Brain Study is a multicenter cohort study with a follow-up measurement after 2 years among 645 participants (175 VCI, 175 COD, 175 HF, and 120 controls). Enrollment criteria are the following: 1 of the 3 diseases diagnosed according to current guidelines, age ≥50 years, no magnetic resonance contraindications, ability to undergo cognitive testing, and independence in daily life. A core clinical dataset is collected including sociodemographic factors, cardiovascular risk factors, detailed neurologic, cardiac, and medical history, medication, and a physical examination. In addition, we perform standardized neuropsychological testing, cardiac, vascular and brain MRI, and blood sampling. In subsets of participants we assess Alz­heimer biomarkers in cerebrospinal fluid, and assess echocardiography and 24-hour blood pressure monitoring. Follow-up measurements after 2 years include neuropsychological testing, brain MRI, and blood samples for all participants. We use centralized state-of-the-art storage platforms for clinical and imaging data. Imaging data are processed centrally with automated standardized pipelines. Results and Conclusions: The Heart-Brain Study investigates relationships between (cardio-)vascular factors, the hemodynamic status of the heart and the brain, and cognitive impairment. By studying the complete heart-brain axis in patient groups that represent components of this axis, we have the opportunity to assess a combination of clinical and subclinical manifestations of disorders of the heart, vascular system and brain, with hemodynamic status as a possible binding factor.@en

T2-hyperintense lesions are the key imaging marker of multiple sclerosis (MS). Previous studies have shown that the white matter surrounding such lesions is often also affected by MS. Our aim was to develop a new method to visualize and quantify the extent of white matter tissue changes in MS based on relaxometry properties. We applied a fast, multi-parametric quantitative MRI approach and used a multi-component MR Fingerprinting (MC-MRF) analysis. We assessed the differences in the MRF component representing prolongedrelaxation time between patients with MS and controls and studied the relation between this component's volume and structural white matter damage identified on FLAIR MRI scans in patients with MS. A total of 48 MS patients at two different sites and 12 healthy controls were scanned with FLAIR and MRF-EPI MRI scans. MRF scans were analyzed with a joint-sparsity multi-component analysis to obtain magnetization fraction maps of different components, representing tissues such as myelin water, white matter, gray matter and cerebrospinal fluid. In the MS patients, an additional component was identified with increased transverse relaxation times compared to the white matter, likely representing changes in free water content. Patients with MS had a higher volume of the long- component in the white matter of the brain compared to healthy controls (B (95%-CI) = 0.004 (0.0006–0.008), p = 0.02). Furthermore, this MRF component had a moderate correlation (correlation coefficient R 0.47) with visible structural white matter changes on the FLAIR scans. Also, the component was found to be more extensive compared to structural white matter changes in 73% of MS patients. In conclusion, our MRF acquisition and analysis captured white matter tissue changes in MS patients compared to controls. In patients these tissue changes were more extensive compared to visually detectable white matter changes on FLAIR scans. Our method provides a novel way to quantify the extent of white matter changes in MS patients, which is underestimated using only conventional clinical MRI scans.@en

MR fingerprinting (MRF) is a promising method for quantitative characterization of tissues. Often, voxel-wise measurements are made, assuming a single tissue-type per voxel. Alternatively, the Sparsity Promoting Iterative Joint Non-negative least squares Multi-Component MRF method (SPIJN-MRF) facilitates tissue parameter estimation for identified components as well as partial volume segmentations. The aim of this paper was to evaluate the accuracy and repeatability of the SPIJN-MRF parameter estimations and partial volume segmentations. This was done (1) through numerical simulations based on the BrainWeb phantoms and (2) using in vivo acquired MRF data from 5 subjects that were scanned on the same week-day for 8 consecutive weeks. The partial volume segmentations of the SPIJN-MRF method were compared to those obtained by two conventional methods: SPM12 and FSL. SPIJN-MRF showed higher accuracy in simulations in comparison to FSL- and SPM12-based segmentations: Fuzzy Tanimoto Coefficients (FTC) comparing these segmentations and Brainweb references were higher than 0.95 for SPIJN-MRF in all the tissues and between 0.6 and 0.7 for SPM12 and FSL in white and gray matter and between 0.5 and 0.6 in CSF. For the in vivo MRF data, the estimated relaxation times were in line with literature and minimal variation was observed. Furthermore, the coefficient of variation (CoV) for estimated tissue volumes with SPIJN-MRF were 10.5% for the myelin water, 6.0% for the white matter, 5.6% for the gray matter, 4.6% for the CSF and 1.1% for the total brain volume. CoVs for CSF and total brain volume measured on the scanned data for SPIJN-MRF were in line with those obtained with SPM12 and FSL. The CoVs for white and gray matter volumes were distinctively higher for SPIJN-MRF than those measured with SPM12 and FSL. In conclusion, the use of SPIJN-MRF provides accurate and precise tissue relaxation parameter estimations taking into account intrinsic partial volume effects. It facilitates obtaining tissue fraction maps of prevalent tissues including myelin water which can be relevant for evaluating diseases affecting the white matter.@en

Characterization of tumor microvasculature is important in tumor assessment and studying treatment response. This is possible by acquiring vascular biomarkers with magnetic resonance imaging (MRI) based on dynamic susceptibility contrast (DSC). We propose magnetic resonance vascular fingerprinting (MRVF) for hybrid echo planar imaging (HEPI) acquired during the first passage of the contrast agent (CA). The proposed approach was evaluated in patients with gliomas, and we simultaneously estimated vessel radius and relative cerebral blood volume. These parameters were also compared to the respective values estimated using the previously introduced vessel size imaging (VSI) technique. The results of both methods were found to be consistent. MRVF was also found to be robust to noise in the estimation of the parameters. DSC-HEPI-based MRVF provides characterization of microvasculature in gliomas with a short acquisition time and can be further improved in several ways to increase our understanding of tumor physiology.@en

Purpose: To develop a method for MR Fingerprinting (MRF) sequence optimization that takes both the applied undersampling pattern and a realistic reference map into account. Methods: A predictive model for the undersampling error leveraging on perturbation theory was exploited to optimize the MRF flip angle sequence for improved robustness against undersampling artifacts. In this framework parameter maps from a previously acquired MRF scan were used as reference. Sequences were optimized for different sequence lengths, smoothness constraints and undersampling factors. Numerical simulations and in vivo measurements in eight healthy subjects were performed to assess the effect of the performed optimization. The optimized MRF sequences were compared to a conventionally shaped flip angle pattern and an optimized pattern based on the Cramér–Rao lower bound (CRB). Results: Numerical simulations and in vivo results demonstrate that the undersampling errors can be suppressed by flip angle optimization. Analysis of the in vivo results show that a sequence optimized for improved robustness against undersampling with a flip angle train of length 400 yielded significantly lower median absolute errors in (Formula presented.) : (Formula presented.) and (Formula presented.) : (Formula presented.) compared to the conventional ((Formula presented.) : (Formula presented.), (Formula presented.) : (Formula presented.)) and CRB-based ((Formula presented.) : (Formula presented.), (Formula presented.) : (Formula presented.)) sequences. Conclusion: The proposed method is able to optimize the MRF flip angle pattern such that significant mitigation of the artifacts from strong k-space undersampling in MRF is achieved.@en

The arterial input function (AIF) plays a crucial role in estimating quantitative perfusion properties from dynamic susceptibility contrast (DSC) MRI. An important issue, however, is that measuring the AIF in absolute contrast-agent concentrations is challenging, due to uncertainty in relation to the measured (Formula presented.) -weighted signal, signal depletion at high concentration, and partial-volume effects. A potential solution could be to derive the AIF from separately acquired dynamic contrast enhanced (DCE) MRI data. We aim to compare the AIF determined from DCE MRI with the AIF from DSC MRI, and estimated perfusion coefficients derived from DSC data using a DCE-driven AIF with perfusion coefficients determined using a DSC-based AIF. AIFs were manually selected in branches of the middle cerebral artery (MCA) in both DCE and DSC data in each patient. In addition, a semi-automatic AIF-selection algorithm was applied to the DSC data. The amplitude and full width at half-maximum of the AIFs were compared statistically using the Wilcoxon rank-sum test, applying a 0.05 significance level. Cerebral blood flow (CBF) was derived with different AIF approaches and compared further. The results showed that the AIFs extracted from DSC scans yielded highly variable peaks across arteries within the same patient. The semi-automatic DSC–AIF had significantly narrower width compared with the manual AIFs, and a significantly larger peak than the manual DSC–AIF. Additionally, the DCE-based AIF provided a more stable measurement of relative CBF and absolute CBF values estimated with DCE–AIFs that were compatible with previously reported values. In conclusion, DCE-based AIFs were reproduced significantly better across vessels, showed more realistic profiles, and delivered more stable and reasonable CBF measurements. The DCE–AIF can, therefore, be considered as an alternative AIF source for quantitative perfusion estimations in DSC MRI.@en

Hadamard time-encoded pseudo-continuous arterial spin labeling (te-pCASL) is a signal-to-noise ratio (SNR)-efficient MRI technique for acquiring dynamic pCASL signals that encodes the temporal information into the labeling according to a Hadamard matrix. In the decoding step, the contribution of each sub-bolus can be isolated resulting in dynamic perfusion scans. When acquiring te-ASL both with and without flow-crushing, the ASL-signal in the arteries can be isolated resulting in 4D-angiographic information. However, obtaining multi-timepoint perfusion and angiographic data requires two acquisitions. In this study, we propose a 3D Dense-Unet convolutional neural network with a multi-level loss function for reconstructing multi-timepoint perfusion and angiographic information from an interleaved 50 % -sampled crushed and 50 % -sampled non-crushed data, thereby negating the additional scan time. We present a framework to generate dynamic pCASL training and validation data, based on models of the intravascular and extravascular te-pCASL signals. The proposed network achieved SSIM values of 97.3 ± 1.1 and 96.2 ± 11.1 respectively for 4D perfusion and angiographic data reconstruction for 313 test data-sets.@en

Hadamard time-encoded pseudo-continuous arterial spin labeling (te-pCASL) is a signal-to-noise ratio (SNR)-efficient MRI technique for acquiring dynamic pCASL signals that encodes the temporal information into the labeling according to a Hadamard matrix. In the decoding step, the contribution of each sub-bolus can be isolated resulting in dynamic perfusion scans. When acquiring te-ASL both with and without flow-crushing, the ASL-signal in the arteries can be isolated resulting in 4D-angiographic information. However, obtaining multi-timepoint perfusion and angiographic data requires two acquisitions. In this study, we propose a 3D Dense-Unet convolutional neural network with a multi-level loss function for reconstructing multi-timepoint perfusion and angiographic information from an interleaved 50 % -sampled crushed and 50 % -sampled non-crushed data, thereby negating the additional scan time. We present a framework to generate dynamic pCASL training and validation data, based on models of the intravascular and extravascular te-pCASL signals. The proposed network achieved SSIM values of 97.3 ± 1.1 and 96.2 ± 11.1 respectively for 4D perfusion and angiographic data reconstruction for 313 test data-sets.@en