Progressive supranuclear palsy and idiopathic Parkinson's disease are associated with local reduction of in vivo brain viscoelasticity.

OBJECTIVES: To apply three-dimensional multifrequency MR-elastography (3DMRE) for the measurement of local cerebral viscoelasticity changes in patients with Parkinson's disease (PD) and progressive supranuclear palsy (PSP). METHODS: T1-weighted anatomical imaging and 3DMRE were performed in 17 PD and 20 PSP patients as well as 12 controls. Two independent viscoelasticity parameters, |G*| and φ, were reconstructed combining seven harmonic vibration frequencies (30-60 Hz). Spatially averaged values were compared by one-way ANOVA, groups were compared using unpaired t test and Mann-Whitney test, respectively. Correlation between clinical data and parameters of brain elasticity and volume were calculated by Pearson's correlation coefficient. RESULTS: In patients, |G*| was significantly reduced in the frontal and mesencephalic regions (p < 0.05). Beyond that, reduced mesencephalic |G*| discriminated PSP from PD (p < 0.05). Neurodegeneration causes significant brain atrophy (p < 0.01) and is pronounced in PSP patients (p < 0.05 vs. PD). Reduced brain viscoelasticity is correlated with brain atrophy in PSP (r=0.64, p=0.002) and PD (r=0.65, p=0.005) patients but not in controls. CONCLUSIONS: MRE-measured viscoelasticity reflects local structural changes of brain tissue in PSP and in PD and provides a useful parameter to differentiate neurodegenerative movement disorders based on imaging examinations. KEY POINTS: • 3D multifrequency MR-elastography reveals diffuse regional changes in brain viscoelasticity in neurodegenerative disorders. • Reduced mesencephalic viscoelasticity separates PD and PSP. • Reduced brain viscoelasticity and brain atrophy as independent hallmarks of neurodegeneration hypothesized.

Increasing the spatial resolution and sensitivity of magnetic resonance elastography by correcting for subject motion and susceptibility-induced image distortions.

PURPOSE: To improve the resolution of elasticity maps by adapting motion and distortion correction methods for phase-based magnetic resonance imaging (MRI) contrasts such as magnetic resonance elastography (MRE), a technique for measuring mechanical tissue properties in vivo. MATERIALS AND METHODS: MRE data of the brain were acquired with echo-planar imaging (EPI) at 3T (n = 14) and 7T (n = 18). Motion and distortion correction parameters were estimated using the magnitude images. The real and imaginary part of the complex MRE data were corrected separately and recombined. The width of the point-spread function (PSF) and the position variability were calculated. The images were normalized to the Montreal Neurological Institute (MNI) anatomical template. The gray-to-white matter separability of the elasticity maps was tested. RESULTS: Motion correction sharpened the |G*| maps as demonstrated by a narrowing of the PSF by 0.78 ± 0.51 mm at 7T and 0.52 ± 0.63 mm at 3T. The amount of individual head motion during MRE acquisition correlated with the decrease in the width of the PSF at 7T (r = 0.53, P = 0.025) and at 3T (r = 0.69, P = 0.006) and with the increase of gray-to-white matter separability after motion correction at 7T (r = 0.64, P = 0.0039) and at 3T (r = 0.57, P = 0.0319). Improved spatial accuracy after distortion correction results in a significant increase in separability of gray and white matter stiffness (P = 0.0067), especially in inferior parts of the brain suffering from strong B0 inhomogeneities. CONCLUSION: We demonstrate that our method leads to sharper images and higher spatial accuracy, raising the prospect of the investigation of smaller brain areas with increased sensitivity in studies using MRE. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 1 J. MAGN. RESON. IMAGING 2017;46:134-141.

Multifrequency magnetic resonance elastography of the brain reveals tissue degeneration in neuromyelitis optica spectrum disorder.

OBJECTIVES: Application of multifrequency magnetic resonance elastography (MMRE) of the brain parenchyma in patients with neuromyelitis optica spectrum disorder (NMOSD) compared to age matched healthy controls (HC). METHODS: 15 NMOSD patients and 17 age- and gender-matched HC were examined using MMRE. Two three-dimensional viscoelastic parameter maps, the magnitude |G*| and phase angle φ of the complex shear modulus were reconstructed by simultaneous inversion of full wave-field data in 1.9-mm isotropic resolution at 7 harmonic drive frequencies from 30 to 60 Hz. RESULTS: In NMOSD patients, a significant reduction of |G*| was observed within the white matter fraction (p = 0.017), predominantly within the thalamic regions (p = 0.003), compared to HC. These parameters exceeded the reduction in brain volume measured in patients versus HC (p = 0.02 whole-brain volume reduction). Volumetric differences in white matter fraction and the thalami were not detectable between patients and HC. However, phase angle φ was decreased in patients within the white matter (p = 0.03) and both thalamic regions (p = 0.044). CONCLUSIONS: MMRE reveals global tissue degeneration with accelerated softening of the brain parenchyma in patients with NMOSD. The predominant reduction of stiffness is found within the thalamic region and related white matter tracts, presumably reflecting Wallerian degeneration. KEY POINTS: • Magnetic resonance elastography reveals diffuse cerebral tissue changes in patients with NMOSD. • Premature tissue softening in NMOSD patients indicates tissue degeneration. • Hypothesis of a widespread cerebral neurodegeneration in form of diffuse tissue alteration.

Higher-resolution MR elastography reveals early mechanical signatures of neuroinflammation in patients with clinically isolated syndrome.

PURPOSE: To assess if higher-resolution magnetic resonance elastography (MRE) is a technique that can measure the in vivo mechanical properties of brain tissue and is sensitive to early signatures of brain tissue degradation in patients with clinically isolated syndrome (CIS). MATERIALS AND METHODS: Seventeen patients with CIS and 33 controls were investigated by MRE with a 3T MRI scanner. Full-wave field data were acquired at seven drive frequencies from 30 to 60 Hz. The spatially resolved higher-resolution maps of magnitude |G*| and phase angle φ of the complex-valued shear modulus were obtained in addition to springpot model parameters. These parameters were spatially averaged in white matter (WM) and whole-brain regions and correlated with clinical and radiological parameters. RESULTS: Spatially resolved MRE revealed that CIS reduced WM viscoelasticity, independent of imaging markers of multiple sclerosis and clinical scores. |G*| was reduced by 14% in CIS (1.4 ± 0.2 kPa vs. 1.7 ± 0.2 kPa, P < 0.001, 95% confidence interval [CI] [-0.4, -0.1] kPa), while φ (0.66 ± 0.04 vs. 0.67 ± 0.04, P = 0.65, 95% CI [-0.04, 0.02]) remained unaltered. Springpot-based shear elasticity showed only a trend of CIS-related reduction (3.4 ± 0.5 kPa vs. 3.7 ± 0.5 kPa, P = 0.06, 95% CI [-0.6, 0.02] kPa) in the whole brain. CONCLUSION: We demonstrate that CIS leads to significantly reduced elasticity of brain parenchyma, raising the prospect of using MRE as an imaging marker for subtle and diffuse tissue damage in neuroinflammatory diseases. J. Magn. Reson. Imaging 2016;44:51-58.

In vivo multifrequency magnetic resonance elastography of the human intervertebral disk.

PURPOSE: To test in vivo magnetic resonance elastography (MRE) of the human intervertebral disk (IVD). METHODS: The feasibility of MRE in IVD was demonstrated in ex vivo bovine disks. Sixteen asymptomatic volunteers underwent multifrequency MRE of the lumbar spine (IVD L3/4 and L4/5, n = 32) using a posterior plate transducer connected to a loudspeaker and operated at five frequencies from 50 to 70 Hz. Full wave field data were acquired in 10 transverse slices of 2 × 2 × 2 mm(3) resolution. High-resolution maps of magnitude |G*| and phase angle φ of complex shear modulus G* were generated by multifrequency dual elasto visco (MDEV) inversion. Disk morphology was assessed by the Pfirrmann score (Pf). RESULTS: Morphological Pf was 1 in 25, 2 in 3, and 3 in 4 disks. |G*| decreased with Pf by a Pearson's linear correlation coefficient of R = -0.592 (P = 0.0004), while φ remained unchanged. Group mean mechanical parameters for Pf = 1 to 3 were |G*| = 6.51 ± 1.27, 5.29 ± 0.95, 4.03 ± 0.99 kPa, and φ = 1.190 ± 0.181, 1.170 ± 0.156, 1.088 ± 0.084 rad, respectively (p[Pf1-Pf3] < 0.001). The variability of mechanical parameters in one volunteer including diurnal changes was approximately 11%. CONCLUSION: Multifrequency MRE with MDEV inversion allows measurement of in vivo mechanical properties of IVDs and may provide additional information in disc degeneration beyond standard morphological changes.

Cerebral multifrequency MR elastography by remote excitation of intracranial shear waves.

The aim of this study was to introduce remote wave excitation for high-resolution cerebral multifrequency MR elastography (mMRE). mMRE of 25-45-Hz drive frequencies by head rocker stimulation was compared with mMRE by remote wave excitation based on a thorax mat in 12 healthy volunteers. Maps of the magnitude |G*| and phase φ of the complex shear modulus were reconstructed using multifrequency dual elasto-visco (MDEV) inversion. After the scan, the subjects and three operators assessed the comfort and convenience of cerebral mMRE using two methods of stimulating the brain. Images were acquired in a coronal view in order to identify anatomical regions along the spinothalamic pathway. In mMRE by remote actuation, all subjects and operators appreciated an increased comfort and simplified procedural set-up. The resulting strain amplitudes in the brain were sufficiently large to analyze using MDEV inversion, and yielded high-resolution viscoelasticity maps which revealed specific anatomical details of brain mechanical properties: |G*| was lowest in the pons (0.97 ± 0.08 kPa) and decreased within the corticospinal tract in the caudal-cranial direction from the crus cerebri (1.64 ± 0.26 kPa) to the capsula interna (1.29 ± 0.14 kPa). By avoiding onerous mechanical stimulation of the head, remote excitation of intracranial shear waves can be used to measure viscoelastic parameters of the brain with high spatial resolution. Therewith, the new mMRE method is suitable for neuroradiological examinations in the clinic.

Heterogeneous Multifrequency Direct Inversion (HMDI) for magnetic resonance elastography with application to a clinical brain exam.

A new viscoelastic wave inversion method for MRE, called Heterogeneous Multifrequency Direct Inversion (HMDI), was developed which accommodates heterogeneous elasticity within a direct inversion (DI) by incorporating first-order gradients and combining results from a narrow band of multiple frequencies. The method is compared with a Helmholtz-type DI, Multifrequency Dual Elasto-Visco inversion (MDEV), both on ground-truth Finite Element Method simulations at varied noise levels and a prospective in vivo brain cohort of 48 subjects ages 18-65. In simulated data, MDEV recovered background material within 5% and HMDI within 1% of prescribed up to SNR of 20 dB. In vivo HMDI and MDEV were then combined with segmentation from SPM to create a fully automated "brain palpation" exam for both whole brain (WB), and brain white matter (WM), measuring two parameters, the complex modulus magnitude |G*| , which measures tissue "stiffness", and the slope of |G*| values across frequencies, a measure of viscous dispersion. |G*| values for MDEV and HMDI were comparable to the literature (for a 3-frequency set centered at 50 Hz, WB means were 2.17 and 2.15 kPa respectively, and WM means were 2.47 and 2.49 kPa respectively). Both methods showed moderate correlation to age in both WB and WM, for both |G*| and |G*| slope, with Pearson's r ≥ 0.4 in the most sensitive frequency sets. In comparison to MDEV, HMDI showed better preservation of recovered target shapes, more noise-robustness, and stabler recovery values in regions with rapid property change, however summary statistics for both methods were quite similar. By eliminating homogeneity assumptions within a fast, fully automatic, regularization-free direct inversion, HMDI appears to be a worthwhile addition to the MRE image reconstruction repertoire. In addition to supporting the literature showing decrease in brain viscoelasticity with age, our work supports a wide range of inter-individual variation in brain MRE results.

Perfusion alters stiffness of deep gray matter.

Viscoelastic properties of the brain reflect tissue architecture at multiple length scales. However, little is known about the relation between vital tissue functions, such as perfusion, and the macroscopic mechanical properties of cerebral tissue. In this study, arterial spin labelling is paired with magnetic resonance elastography to investigate the relationship between tissue stiffness and cerebral blood flow (CBF) in the in vivo human brain. The viscoelastic modulus, | G*|, and CBF were studied in deep gray matter (DGM) of 14 healthy male volunteers in the following sub-regions: putamen, nucleus accumbens, hippocampus, thalamus, globus pallidus, and amygdala. CBF was further normalized by vessel area data to obtain the flux rate q which is proportional to the perfusion pressure gradient. The striatum (represented by putamen and nucleus accumbens) was distinct from the other DGM regions by displaying markedly higher stiffness and perfusion values. q was a predictive marker for DGM stiffness as analyzed by linear regression | G*| = q·(4.2 ± 0.6)kPa·s + (0.80 ± 0.06)kPa ( R2 = 0.92, P = 0.006). These results suggest a high sensitivity of MRE in DGM to perfusion pressure. The distinct mechano-vascular properties of striatum tissue, as compared to the rest of DGM, may reflect elevated perfusion pressure, which could explain the well-known susceptibility of the putamen to hemorrhages.

Combining viscoelasticity, diffusivity and volume of the hippocampus for the diagnosis of Alzheimer's disease based on magnetic resonance imaging.

Dementia due to Alzheimer's Disease (AD) is a neurodegenerative disease for which treatment strategies at an early stage are of great clinical importance. So far, there is still a lack of non-invasive diagnostic tools to sensitively detect AD in early stages and to predict individual disease progression. Magnetic resonance elastography (MRE) of the brain may be a promising novel tool. In this proof-of-concept study, we investigated whether multifrequency-MRE (MMRE) can detect differences in hippocampal stiffness between patients with clinical diagnosis of dementia due to AD and healthy controls (HC). Further, we analyzed if the combination of three MRI-derived parameters, i.e., hippocampal stiffness, hippocampal volume and mean diffusivity (MD), improves diagnostic accuracy. Diagnostic criteria for probable dementia due to AD were in line with the NINCDS-ADRDA criteria and were verified through history-taking (patient and informant), neuropsychological testing, routine blood results and routine MRI to exclude other medical causes of a cognitive decline. 21 AD patients and 21 HC (median age 75 years) underwent MMRE and structural MRI, from which hippocampal volume and MD were calculated. From the MMRE-images maps of the magnitude |G*| and phase angle φ of the complex shear modulus were reconstructed using multifrequency inversion. Median values of |G*| and φ were extracted within three regions of interest (hippocampus, thalamus and whole brain white matter). To test the predictive value of the main outcome parameters, we performed receiver operating characteristic (ROC) curve analyses. Hippocampal stiffness (|G*|) and viscosity (φ) were significantly lower in the patient group (both p < 0.001). ROC curve analyses showed an area under the curve (AUC) for | G*| of 0.81 [95%CI 0.68-0.94]; with sensitivity 86%, specificity 67% for cutoff at |G*| = 980 Pa) and for φ an AUC of 0.79 [95%CI 0.66-0.93]. In comparison, the AUC of MD and hippocampal volume were 0.83 [95%CI 0.71-0.95] and 0.86 [95%CI 0.74-0.97], respectively. A combined ROC curve of |G*|, MD and hippocampal volume yielded a significantly improved AUC of 0.90 [95%CI 0.81-0.99]. In conclusion, we demonstrated reduced hippocampal stiffness and reduced hippocampal viscosity, as determined by MMRE, in patients with clinical diagnosis of dementia of the AD type. Diagnostic sensitivity was further improved by the combination with two other MRI-based hippocampal parameters. These findings motivate further investigation whether MMRE can detect decreased brain stiffness already in pre-dementia stages, and whether these changes predict cognitive decline.

Measurement of in vivo cerebral volumetric strain induced by the Valsalva maneuver.

Compressibility of biological tissues such as brain parenchyma is related to its poroelastic nature characterized by the geometry and pressure of vasculature and interconnected fluid-filled spaces. Thus, cerebral volumetric strain may be sensitive to intracranial pressure which can be altered under physiological conditions. So far volumetric strain has attained little attention in studies of the mechanical behavior of the brain. This paper reports a study of measuring the in vivo cerebral volumetric strain induced by the Valsalva maneuver (VM) where forced expiration against a closed glottis leads to a transient increase in the intracranial pressure. For this purpose we applied three-dimensional magnetic resonance imaging equipped with a patient-controlled acquisition system to five healthy volunteers. With each volunteer, three experiments were performed: one with VM and two in resting state. i.e. normal ventilation, which were conducted before and after VM. The VM data were registered to reference data by morphology based non-rigid deformation, yielding 3D maps of total displacements and volumetric strain. On average, VM induced volumetric strain correlated to whole-brain dilatation of -3.14±0.87% and -2.80±0.71% compared to the reference states before and after VM, respectively. These values were well reproduced by repetitive experiments during the same scan as well as by repeated measurements in one volunteer on different days. Combined with literature data of intracranial pressure changes, our volumetric strain values can be used to elucidate the static compression modulus of the in vivo human brain. These results add knowledge to the understanding of the brain׳s biomechanical properties under physiological conditions.

Towards an elastographic atlas of brain anatomy.

Cerebral viscoelastic constants can be measured in a noninvasive, image-based way by magnetic resonance elastography (MRE) for the detection of neurological disorders. However, MRE brain maps of viscoelastic constants are still limited by low spatial resolution. Here we introduce three-dimensional multifrequency MRE of the brain combined with a novel reconstruction algorithm based on a model-free multifrequency inversion for calculating spatially resolved viscoelastic parameter maps of the human brain corresponding to the dynamic range of shear oscillations between 30 and 60 Hz. Maps of two viscoelastic parameters, the magnitude and the phase angle of the complex shear modulus, |G*| and φ, were obtained and normalized to group templates of 23 healthy volunteers in the age range of 22 to 72 years. This atlas of the anatomy of brain mechanics reveals a significant contrast in the stiffness parameter |G*| between different anatomical regions such as white matter (WM; 1.252±0.260 kPa), the corpus callosum genu (CCG; 1.104±0.280 kPa), the thalamus (TH; 1.058±0.208 kPa) and the head of the caudate nucleus (HCN; 0.649±0.101 kPa). φ, which is sensitive to the lossy behavior of the tissue, was in the order of CCG (1.011±0.172), TH (1.037±0.173), CN (0.906±0.257) and WM (0.854±0.169). The proposed method provides the first normalized maps of brain viscoelasticity with anatomical details in subcortical regions and provides useful background data for clinical applications of cerebral MRE.

Cerebral magnetic resonance elastography in supranuclear palsy and idiopathic Parkinson's disease.

Detection and discrimination of neurodegenerative Parkinson syndromes are challenging clinical tasks and the use of standard T1- and T2-weighted cerebral magnetic resonance (MR) imaging is limited to exclude symptomatic Parkinsonism. We used a quantitative structural MR-based technique, MR-elastography (MRE), to assess viscoelastic properties of the brain, providing insights into altered tissue architecture in neurodegenerative diseases on a macroscopic level. We measured single-slice multifrequency MRE (MMRE) and three-dimensional MRE (3DMRE) in two neurodegenerative disorders with overlapping clinical presentation but different neuropathology - progressive supranuclear palsy (PSP: N = 16) and idiopathic Parkinson's disease (PD: N = 18) as well as in controls (N = 18). In PSP, both MMRE (Δµ = - 28.8%, Δα = - 4.9%) and 3DMRE (Δ|G*|: - 10.6%, Δφ: - 34.6%) were significantly reduced compared to controls, with a pronounced reduction within the lentiform nucleus (Δµ = - 34.6%, Δα = - 8.1%; Δ|G*|: - 7.8%, Δφ: - 44.8%). MRE in PD showed a comparable pattern, but overall reduction in brain elasticity was less severe reaching significance only in the lentiform nucleus (Δµ n.s., Δα = - 7.4%; Δ|G*|: - 6.9%, Δφ: n.s.). Beyond that, patients showed a close negative correlation between MRE constants and clinical severity. Our data indicate that brain viscoelasticity in PSP and PD is differently affected by the underlying neurodegeneration; whereas in PSP all MRE constants are reduced and changes in brain softness (reduced µ and |G*|) predominate those of viscosity (α and φ) in PD.