Assessment of Microvascular Disease in Heart and Brain by MRI: Application in Heart Failure with Preserved Ejection Fraction and Cerebral Small Vessel Disease

The objective of this review is to investigate the commonalities of microvascular (small vessel) disease in heart failure with preserved ejection fraction (HFpEF) and cerebral small vessel disease (CSVD). Furthermore, the review aims to evaluate the current magnetic resonance imaging (MRI) diagnostic techniques for both conditions. By comparing the two conditions, this review seeks to identify potential opportunities to improve the understanding of both HFpEF and CSVD

Evaluation of miCRovascular rarefaction in vascUlar Cognitive Impairment and heArt faiLure (CRUCIAL): Study protocol for an observational study

INTRODUCTION: Microvascular rarefaction, the functional reduction in perfused microvessels and structural reduction of microvascular density, seems to be an important mechanism in the pathophysiology of small blood vessel related disorders including vascular cognitive impairment (VCI) due to cerebral small vessel disease and heart failure with preserved ejection fraction (HFpEF). Both diseases share common risk factors including hypertension, diabetes mellitus, obesity, and ageing; in turn, these co-morbidities are associated with microvascular rarefaction. Our consortium aims to investigate novel non-invasive tools to quantify microvascular health and rarefaction in both organs, as well as surrogate biomarkers for cerebral and/or cardiac rarefaction (via sublingual capillary health, vascular density of the retina, and RNA content of circulating extracellular vesicles), and to determine whether microvascular density relates to disease severity. METHODS/DESIGN: The clinical research program of CRUCIAL consists of four observational cohort studies. We aim to recruit 75 VCI patients, 60 HFpEF patients, 60 patients with severe aortic stenosis (AS) undergoing surgical aortic valve replacement as a pressure overload HFpEF model, and 200 elderly participants with mixed comorbidities to serve as controls. Data collected will include medical history, physical examination, cognitive testing, advanced brain and cardiac MRI, ECG, echocardiography, sublingual capillary health, optical coherence tomography angiography (OCTa), extracellular vesicles RNA analysis and myocardial remodelling-related serum biomarkers. The AS cohort undergoing surgery will also have myocardial biopsy for histological microvascular assessment. DISCUSSION: CRUCIAL will examine the pathophysiological role of microvascular rarefaction in VCI and HFpEF using advanced brain and cardiac MRI techniques. Furthermore, we will investigate surrogate biomarkers for non-invasive, faster, easier, and cheaper assessment of microvascular density since these are more likely to be disseminated into widespread clinical practice. If microvascular rarefaction is an early marker of developing small vessel diseases, then measuring rarefaction may allow pre-clinical diagnosis, with implications for screening, risk stratification, and prevention. Further knowledge of the relevance of microvascular rarefaction and its underlying mechanisms may provide new avenues for research and therapeutic targets

Assessment of Microvascular Disease in Heart and Brain by MRI:Application in Heart Failure with Preserved Ejection Fraction and Cerebral Small Vessel Disease

The objective of this review is to investigate the commonalities of microvascular (small vessel) disease in heart failure with preserved ejection fraction (HFpEF) and cerebral small vessel disease (CSVD). Furthermore, the review aims to evaluate the current magnetic resonance imaging (MRI) diagnostic techniques for both conditions. By comparing the two conditions, this review seeks to identify potential opportunities to improve the understanding of both HFpEF and CSVD

Spectral diffusion analysis of intravoxel incoherent motion MRI in cerebral small vessel disease

\u3cp\u3eBackground: Cerebral intravoxel incoherent motion (IVIM) imaging assumes two components. However, more compartments are likely present in pathologic tissue. We hypothesized that spectral analysis using a nonnegative least-squares (NNLS) approach can detect an additional, intermediate diffusion component, distinct from the parenchymal and microvascular components, in lesion-prone regions. Purpose: To investigate the presence of this intermediate diffusion component and its relation with cerebral small vessel disease (cSVD)-related lesions. Study Type: Prospective cross-sectional study. Population: Patients with cSVD (n = 69, median age 69.8) and controls (n = 39, median age 68.9). Field Strength/Sequence: Whole-brain inversion recovery IVIM acquisition at 3.0T. Assessment: Enlarged perivascular spaces (PVS) were rated by three raters. White matter hyperintensities (WMH) were identified on a fluid attenuated inversion recovery (FLAIR) image using a semiautomated algorithm. Statistical Tests: Relations between IVIM measures and cSVD-related lesions were studied using the Spearman's rank order correlation. Results: NNLS yielded diffusion spectra from which the intermediate volume fraction f \u3csub\u3eint\u3c/sub\u3e was apparent between parenchymal diffusion and microvasular pseudodiffusion. WMH volume and the extent of MRI-visible enlarged PVS in the basal ganglia (BG) and centrum semiovale (CSO) were correlated with f \u3csub\u3eint\u3c/sub\u3e in the WMHs, BG, and CSO, respectively. f \u3csub\u3eint\u3c/sub\u3e was 4.2 ± 1.7%, 7.0 ± 4.1% and 13.6 ± 7.7% in BG and 3.9 ± 1.3%, 4.4 ± 1.4% and 4.5 ± 1.2% in CSO for the groups with low, moderate, and high number of enlarged PVS, respectively, and increased with the extent of enlarged PVS (BG: r = 0.49, P < 0.01; CSO: r = 0.23, P = 0.02). f \u3csub\u3eint\u3c/sub\u3e in the WMHs was 27.1 ± 13.1%, and increased with the WMH volume (r = 0.57, P < 0.01). Data Conclusion: We revealed the presence of an intermediate diffusion component in lesion-prone regions of cSVD and demonstrated its relation with enlarged PVS and WMHs. In tissue with these lesions, tissue degeneration or perivascular edema can lead to more freely diffusing interstitial fluid contributing to f \u3csub\u3eint\u3c/sub\u3e. Level of Evidence: 2. Technical Efficacy: Stage 2. J. Magn. Reson. Imaging 2020;51:1170–1180. \u3c/p\u3

Semi-automated Computed Tomography Volumetry as a Proxy for Intracranial Pressure in Patients with Severe Traumatic Brain Injury:Clinical Feasibility Study

INTRODUCTION: Traumatic brain injury (TBI) is associated with high mortality due to intracranial pressure (ICP). Whether computed tomography (CT) scanning of the brain within the first 24 h is indicative of intracranial hypertension is largely unknown. We assessed the feasibility of semi-automated CT segmentation in comparison with invasive ICP measurements. RELEVANCE: CT volumetry of the brain might provide ICP data when invasive monitoring is not possible or is undesirable. METHODS: We identified 33 patients with TBI who received a CT scan at admission and ICP monitoring within 24 h. Semi-automated segmentation of CT images in Matlab yielded cerebrospinal fluid (CSF) and intracranial volume (ICV) data. The ratio CSF/ICV × 100 (expressed as a percentage) was used as a proxy for ICP. The association between invasive ICP and the CSF/ICV ratio was evaluated using a simple linear regression model and a mono-exponential function derived from previous research in animals. RESULTS: ICP is moderately but significantly associated with the CSF/ICV ratio (r = -0.44, p = 0.01). The mono-exponential function provided a better fit of the relationship between ICP and the CSF/ICV ratio than the linear model. CONCLUSION: Our feasibility TBI data show that cross-sectional volumetric CT measures are associated with ICP. This non-invasive method can be used in future studies to monitor patients who are not candidates for invasive monitoring or to evaluate therapy effects objectively

Spectral Diffusion Analysis of Intravoxel Incoherent Motion MRI in Cerebral Small Vessel Disease

Background: Cerebral intravoxel incoherent motion (IVIM) imaging assumes two components. However, more compartments are likely present in pathologic tissue. We hypothesized that spectral analysis using a nonnegative least-squares (NNLS) approach can detect an additional, intermediate diffusion component, distinct from the parenchymal and microvascular components, in lesion-prone regions. Purpose: To investigate the presence of this intermediate diffusion component and its relation with cerebral small vessel disease (cSVD)-related lesions. Study Type: Prospective cross-sectional study. Population: Patients with cSVD (n = 69, median age 69.8) and controls (n = 39, median age 68.9). Field Strength/Sequence: Whole-brain inversion recovery IVIM acquisition at 3.0T. Assessment: Enlarged perivascular spaces (PVS) were rated by three raters. White matter hyperintensities (WMH) were identified on a fluid attenuated inversion recovery (FLAIR) image using a semiautomated algorithm. Statistical Tests: Relations between IVIM measures and cSVD-related lesions were studied using the Spearman's rank order correlation. Results: NNLS yielded diffusion spectra from which the intermediate volume fraction f int was apparent between parenchymal diffusion and microvasular pseudodiffusion. WMH volume and the extent of MRI-visible enlarged PVS in the basal ganglia (BG) and centrum semiovale (CSO) were correlated with f int in the WMHs, BG, and CSO, respectively. f int was 4.2 ± 1.7%, 7.0 ± 4.1% and 13.6 ± 7.7% in BG and 3.9 ± 1.3%, 4.4 ± 1.4% and 4.5 ± 1.2% in CSO for the groups with low, moderate, and high number of enlarged PVS, respectively, and increased with the extent of enlarged PVS (BG: r = 0.49, P < 0.01; CSO: r = 0.23, P = 0.02). f int in the WMHs was 27.1 ± 13.1%, and increased with the WMH volume (r = 0.57, P < 0.01). Data Conclusion: We revealed the presence of an intermediate diffusion component in lesion-prone regions of cSVD and demonstrated its relation with enlarged PVS and WMHs. In tissue with these lesions, tissue degeneration or perivascular edema can lead to more freely diffusing interstitial fluid contributing to f int. Level of Evidence: 2. Technical Efficacy: Stage 2. J. Magn. Reson. Imaging 2020;51:1170–1180

Time-efficient measurement of subtle blood-brain barrier leakage using a T-1 mapping MRI protocol at 7 T

Purpose Blood-brain barrier (BBB) disruption is commonly measured with DCE-MRI using continuous dynamic scanning. For precise measurement of subtle BBB leakage, a long acquisition time (&gt;20 minutes) is required. As extravasation of the contrast agent is slow, discrete sampling at strategic time points might be beneficial, and gains scan time for additional sequences. Here, we aimed to explore the feasibility of a sparsely sampled MRI protocol at 7 T.Methods The scan protocol consisted of a precontrast quantitative T-1 measurement, using an MP2RAGE sequence, and after contrast agent injection, a fast-sampling dynamic gradient-echo perfusion scan and two postcontrast quantitative T-1 measurements were applied. Simulations were conducted to determine the optimal postcontrast sampling time points for measuring subtle BBB leakage. The graphical Patlak approach was used to quantify the leakage rate (K-i) and blood plasma volume (v(p)) of normal-appearing white and gray matter.Results The simulations showed that two postcontrast T-1 maps are sufficient to detect subtle leakage, and most sensitive when the last T-1 map is acquired late, approximately 30 minutes, after contrast agent administration. The in vivo measurements found K-i and v(p) values in agreement with other studies, and significantly higher values in gray matter compared with white matter (both p = .04).Conclusion The sparsely sampled protocol was demonstrated to be sensitive to quantify subtle BBB leakage, despite using only three T-1 maps. Due to the time-efficiency of this method, it will become more feasible to incorporate BBB leakage measurements in clinical research MRI protocols.</p

Improving microstructural integrity, interstitial fluid, and blood microcirculation images from multi-b-value diffusion MRI using physics-informed neural networks in cerebrovascular disease

Purpose: To obtain better microstructural integrity, interstitial fluid, and microvascular images from multi-b-value diffusion MRI data by using a physics-informed neural network (PINN) fitting approach.Methods: Test-retest whole-brain inversion recovery diffusion-weighted images with multiple b-values (IVIM: intravoxel incoherent motion) were acquired on separate days for 16 patients with cerebrovascular disease on a 3.0T MRI system. The performance of the PINN three-component IVIM (3C-IVIM) model fitting approach was compared with conventional fitting approaches (i.e., non-negative least squares and two-step least squares) in terms of (1) parameter map quality, (2) test-retest repeatability, and (3) voxel-wise accuracy. Using the in vivo data, the parameter map quality was assessed by the parameter contrast-to-noise ratio (PCNR) between normal-appearing white matter and white matter hyperintensities, and test-retest repeatability was expressed by the coefficient of variation (CV) and intraclass correlation coefficient (ICC). The voxel-wise accuracy of the 3C-IVIM parameters was determined by 10,000 computer simulations mimicking our in vivo data. Differences in PCNR and CV values obtained with the PINN approach versus conventional fitting approaches were assessed using paired Wilcoxon signed-rank tests.Results: The PINN-derived 3C-IVIM parameter maps were of higher quality and more repeatable than those of conventional fitting approaches, while also achieving higher voxel-wise accuracy.Conclusion: Physics-informed neural networks enable robust voxel-wise estimation of three diffusion components from the diffusion-weighted signal. The repeatable and high-quality biological parameter maps generated with PINNs allow for visual evaluation of pathophysiological processes in cerebrovascular disease

Blood-Brain Barrier Disruption and Perivascular Spaces in Small Vessel Disease and Neurodegenerative Diseases:A Review on MRI Methods and Insights

Perivascular spaces (PVS) and blood-brain barrier (BBB) disruption are two key features of cerebral small vessel disease (cSVD) and neurodegenerative diseases that have been linked to cognitive impairment and are involved in the cerebral waste clearance system. Magnetic resonance imaging (MRI) offers the possibility to study these pathophysiological processes noninvasively in vivo. This educational review provides an overview of the MRI techniques used to assess PVS functionality and BBB disruption. MRI-visible PVS can be scored on structural images by either (subjectively) counting or (automatically) delineating the PVS. We highlight emerging (diffusion) techniques to measure proxies of perivascular fluid and its movement, which may provide a more comprehensive understanding of the role of PVS in diseases. For the measurement of BBB disruption, we explain the most commonly used MRI technique, dynamic contrast-enhanced (DCE) MRI, as well as a more recently developed technique based on arterial spin labeling (ASL). DCE MRI and ASL are thought to measure complementary characteristics of the BBB. Furthermore, we describe clinical studies that have utilized these MRI techniques in cSVD and neurodegenerative diseases, particularly Alzheimer's disease (AD). These studies demonstrate the role of PVS and BBB dysfunction in these diseases and provide insight into the large overlap, but also into the differences between cSVD and AD. Overall, MRI techniques may provide valuable insights into the pathophysiological mechanisms underlying these diseases and have the potential to be used as markers for disease progression and treatment response. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2

Retinal microvascular function is associated with the cerebral microcirculation as determined by intravoxel incoherent motion MRI

BACKGROUND AND AIMS: The easily accessible retinal vessels provide a unique opportunity to study a proxy for cerebral small vessels. Associations between retinal vessel diameters and macrostructural brain white matter changes have already been demonstrated. Alterations in microvascular function, likely precede these structural abnormalities. We examined whether retinal microvascular function is related to cerebral microvascular properties, assessed by the intravoxel incoherent motion (IVIM) effect in brain MRI. METHODS: Seventy participants (age 60 ± 8 years, 41% women) from the population-based Maastricht Study underwent brain IVIM diffusion imaging (3 Tesla) to determine the microvascular measures f (perfusion volume fraction) and D* (pseudo-diffusion of circulating blood). The retinal arteriolar and venular dilation response to flicker light stimulation were measured by a dynamic vessel analyzer. Linear regression analysis was used to investigate associations between retinal vasoreactivity and IVIM measures in white matter hyperintensities (WMH), normal-appearing white matter (NAWM) and cortical gray matter (CGM). RESULTS: More retinal arteriolar dilation was significantly associated with stronger pseudo-diffusion (D*) in the NAWM and CGM (β 0.280 [95% CI 0.084-0.475], and β 0.310 [95% CI 0.091-0.528], respectively), but not with the cerebral blood volume fraction (f). No associations were observed between retinal venular dilation response and cerebrovascular IVIM measures. CONCLUSIONS: Variations in retinal arteriolar microvascular function and microcirculatory properties in the brain are linked. The retina could serve as a proxy for early detection of brain microvascular dysfunction