Normal-appearing Gray Matter Research Articles

Repeatability and Reproducibility of pseudo-Continuous Arterial Spin Labeling Measured Brain Perfusion in Healthy Volunteers and Glioblastoma Patients.

Arterial spin labeled (ASL) MRI has gained recognition as a quantitative perfusion imaging method for managing patients with brain tumors. Limited studies have so far investigated the reproducibility of ASL-derived perfusion in patients with brain tumors. This study aims to evaluate intrasession repeatability and intersession reproducibility of perfusion measurements using 3D pseudo-continuous ASL (pCASL) with Cartesian TSE (TSE-CASPR) in healthy volunteers (HV) and glioblastoma (GBM) patients at 3 Tesla and compare against 3D pCASL with GRASE. This prospective study (NCT03922984) was approved by the institutional review board and written informed consent was obtained from all subjects. HV underwent repeated pCASL evaluations 2-4 weeks apart between November 2021 and October 2022. GBM patients were recruited for longitudinal MRI from September 2019 to February 2023. Intrasession repeatability (HV and GBM) and intersession reproducibility (HV only) of pCASL were assessed using linear regression, Bland-Altman analyses, intraclass correlation coefficient (ICC) with 95% confidence interval (CI), and within-subject coefficients of variation (wsCV). Twenty HV (9 men, age: 25.1±1.7 years, range 23-30 years) and 21 GBM patients (15 men; age: 59.8±14.3 years, range 28-81 years) were enrolled. Within imaging session, 3D pCASL measured perfusion with TSE-CASPR and GRASE respectively achieved high R2 values (0.88-0.95; 0.93-0.96), minimal biases (-0.46 to 0.81; -0.08 to 0.35 mL/100g/min), high ICC [95% CI] (0.96-0.98 [0.94-0.98]; 0.96-0.98 [0.92-0.99]), and low wsCV (6.64%-9.07%; 5.20%-8.16%) in HV (N=20) and GBM patients (N=21). Across imaging session, 3D pCASL in HV (N=20) achieved high R2 values (0.71; 0.82), minimal biases (-1.2; -0.90 mL/100g/min), high ICC [95% CI] values (0.85 [0.81-0.89]; 0.90 [0.87-0.93]), and low wsCV values (13.82%; 9.98%). Our study demonstrated excellent intrasession repeatability of 3D pCASL measured cerebral perfusion in HV and GBM patients and good to excellent intersession reproducibility in HV. 3D pCASL with GRASE performed slightly better than 3D pCASL with TSE-CASPR in HV; however, in GBM patients, 3D pCASL with TSE-CASPR showed better performance in tumor regions with nearly twofold higher SNR. ASL measured perfusion could serve as a non-contrast quantitative imaging biomarker to facilitate the management of GBM patients. ASL = arterial spin labeling; pCASL = pseudo-continuous arterial spin labeling; GBM = glioblastoma; CBF = cerebral blood flow; CASPR = Cartesian acquisition with spiral profile reordering; GRASE = gradient and spin echo; NAGM = normal-appearing gray matter.

Quantifying Remyelination Using χ-Separation in White Matter and Cortical Multiple Sclerosis Lesions.

Myelin and iron play essential roles in remyelination processes of multiple sclerosis (MS) lesions. χ-separation, a novel biophysical model applied to multiecho T2*-data and T2-data, estimates the contribution of myelin and iron to the obtained susceptibility signal. We used this method to investigate myelin and iron levels in lesion and nonlesion brain areas in patients with MS and healthy individuals. This prospective MS cohort study included patients with MS fulfilling the McDonald Criteria 2017 and healthy individuals, aged 18 years or older, with no other neurologic comorbidities. Participants underwent MRI at baseline and after 2 years, including multiecho GRE-(T2*) and FAST-(T2) sequences. Using χ-separation, we generated myelin-sensitive and iron-sensitive susceptibility maps. White matter lesions (WMLs), cortical lesions (CLs), surrounding normal-appearing white matter (NAWM), and normal-appearing gray matter were segmented on fluid-attenuated inversion recovery and magnetization-prepared 2 rapid gradient echo images, respectively. Cross-sectional group comparisons used Wilcoxon rank-sum tests, longitudinal analyses applied Wilcoxon signed-rank tests. Associations with clinical outcomes (disease phenotype, age, sex, disease duration, disability measured by Expanded Disability Status Scale [EDSS], neurofilament light chain levels, and T2-lesion number and volume) were assessed using linear regression models. Of 168 patients with MS (median [interquartile range (IQR)] age 47.0 [21.7] years; 101 women; 6,898 WMLs, 775 CLs) and 103 healthy individuals (age 33.0 [10.5] years, 57 women), 108 and 62 were followed for a median of 2 years, respectively (IQR 0.1; 5,030 WMLs, 485 CLs). At baseline, WMLs had lower myelin (median 0.025 [IQR 0.015] parts per million [ppm]) and iron (0.017 [0.015] ppm) than the corresponding NAWM (myelin 0.030 [0.012]; iron 0.019 [0.011] ppm; both p < 0.001). After 2 years, both myelin (0.027 [0.014] ppm) and iron had increased (0.018 [0.015] ppm; both p < 0.001). Younger age (p < 0.001, b = -5.111 × 10-5), lower disability (p = 0.04, b = -2.352 × 10-5), and relapsing-remitting phenotype (RRMS, 0.003 [0.01] vs primary progressive 0.002 [IQR 0.01], p < 0.001; vs secondary progressive 0.0004 [IQR 0.01], p < 0.001) at baseline were associated with remyelination. Increment of myelin correlated with clinical improvement measured by EDSS (p = 0.015, b = -6.686 × 10-4). χ-separation, a novel mathematical model applied to multiecho T2*-images and T2-images shows that young RRMS patients with low disability exhibit higher remyelination capacity, which correlated with clinical disability over a 2-year follow-up.

Exploring cognitive related microstructural alterations in normal appearing white matter and deep grey matter for small vessel disease: A quantitative susceptibility mapping study

Brain microstructural alterations possibly occur in the normal-appearing white matter (NAWM) and grey matter of small vessel disease (SVD) patients, and may contribute to cognitive impairment. The aim of this study was to explore cognitive related microstructural alterations in white matter and deep grey matter nuclei in SVD patients using magnetic resonance (MR) quantitative susceptibility mapping (QSM). 170 SVD patients, including 103 vascular mild cognitive impairment (VaMCI) and 67 no cognitive impairment (NCI), and 21 healthy control (HC) subjects were included, all underwent a whole-brain QSM scanning. Using a white matter and a deep grey matter atlas, subregion-based QSM analysis was conducted to identify and characterize microstructural alterations occurring within white matter and subcortical nuclei. Significantly different susceptibility values were revealed in NAWM and in several specific white matter tracts including anterior limb of internal capsule, corticospinal tract, medial lemniscus, middle frontal blade, superior corona radiata and tapetum among VaMCI, NCI and HC groups. However, no difference was found in white matter hyperintensities between VaMCI and NCI. A trend toward higher susceptibility in the caudate nucleus and globus pallidus of VaMCI patients compared to HC, indicating elevated iron deposition in these areas. Interestingly, some of these QSM parameters were closely correlated with both global and specific cognitive function scores, controlling age, gender and education level. Our study suggested that QSM may serve as a useful imaging tool for monitoring cognitive related microstructural alterations in brain. This is especially meaningful for white matter which previously lacks of attention.

Cortical CD200-CD200R and CD47-SIRPα expression is associated with multiple sclerosis pathology.

Control of microglia activity through CD200-CD200R and CD47-SIRPα interactions has been implicated in brain homeostasis. Here, we assessed CD200, CD47, CD200R and SIRPα expression with qPCR and immunohistochemistry in multiple sclerosis (MS) normal-appearing cortical grey matter (NAGM), normal-appearing white matter (NAWM), cortical grey matter (GM) lesions and perilesional GM, and compared this to control GM and white matter (WM), to investigate possible altered control of microglia in MS. In MS NAGM, CD200 expression is lower compared with control GM, specifically in cortical layers 1 and 2, and CD200 expression in NAGM negatively correlates with the cortical lesion rate. Interestingly, NAGM and NAWM CD200 expression is positively correlated, and NAGM CD200 expression negatively correlates with the proportion of active and mixed WM lesions. In GM lesions, CD200 and CD47 expressions are lower compared with NAGM and perilesional GM. CD200R expression is lower in MS NAGM, whereas SIRPα was increased in and around GM lesions. Taken together, our data indicate that CD200 and CD47 play a role in GM MS lesion formation and progression, respectively, and that targeting CD200 pathways may offer therapeutic avenues to mitigate MS pathology in both WM and GM.

Spin-lock based fast whole-brain 3D macromolecular proton fraction mapping of relapsing–remitting multiple sclerosis

A sensitive and efficient imaging technique is required to assess the subtle abnormalities occurring in the normal-appearing white matter (NAWM) and normal-appearing grey matter (NAGM) in patients with relapsing–remitting multiple sclerosis (RRMS). In this study, a fast 3D macromolecular proton fraction (MPF) quantification based on spin-lock (fast MPF-SL) sequence was proposed for brain MPF mapping. Thirty-four participants, including 17 healthy controls and 17 RRMS patients were prospectively recruited. We conducted group comparison and correlation between conventional MPF-SL, fast MPF-SL, and DWI, and compared differences in quantified parameters within MS lesions and the regional NAWM, NAGM, and normal-appearing deep grey matter (NADGN). MPF of MS lesions was significantly reduced (7.17% ± 1.15%, P\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$P$$\\end{document} < 0.01) compared to all corresponding normal-appearing regions. MS patients also showed significantly reduced mean MPF values compared with controls in NAGM (4.87% ± 0.38% vs 5.21% ± 0.32%, P\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$P$$\\end{document} = 0.01), NAWM (9.49% ± 0.69% vs 10.32% ± 0.59%, P\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$P$$\\end{document} < 0.01) and NADGM (thalamus 5.59% ± 0.67% vs 6.00% ± 0.41%, P\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$P$$\\end{document} = 0.04; caudate 5.10% ± 0.55% vs 5.53% ± 0.58%, P\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$P$$\\end{document} = 0.03). MPF and ADC showed abnormalities in otherwise normal appearing close to lesion areas (P < 0.01). In conclusion, time-efficient MPF mapping of the whole brain can be acquired efficiently (< 3 min) using fast MPF-SL. It offers a promising alternative way to detect white matter abnormalities in MS.

Identification of Y‒linked biomarkers and exploration of immune infiltration of normal-appearing gray matter in multiple sclerosis by bioinformatic analysis

BackgroundThe knowledge of normal‒appearing cortical gray matter (NAGM) in multiple sclerosis (MS) remains unclear. In this study, we aimed to identify diagnostic biomarkers and explore the immune infiltration characteristics of NAGM in MS through bioinformatic analysis and validation in vivo. MethodsDifferentially expressed genes (DEGs) were analyzed. Subsequently, the functional pathways of the DEGs were determined. After screening the overlapping DEGs of MS with two machine learning methods, the biomarkers’ efficacy and the expression levels of overlapping DEGs were calculated. Quantitative reverse transcription polymerase chain reaction (qRT‒PCR) identified the robust diagnostic biomarkers. Additionally, infiltrating immune cell populations were estimated and correlated with the biomarkers. Finally, the characteristics of immune infiltration of NAGM from MS were evaluated. ResultsA total of 98 DEGs were identified. They participated in sensory transduction of the olfactory system, synaptic signaling, and immune responses. Nine overlapping genes were screened by machine learning methods. After verified by ROC curve, four genes, namely HLA‒DRB1, RPS4Y1, EIF1AY and USP9Y, were screened as candidate biomarkers. The mRNA expression of RPS4Y1 and USP9Y was significantly lower in MS patients than that in the controls. They were selected as the robust diagnostic biomarkers for male MS patients. RPS4Y1 and USP9Y were both positively correlated with memory B cells. Moreover, naive CD4+ T cells and monocytes were increased in the NAGM of MS patients compared with those in controls. ConclusionsLow expressed Y‒linked genes, RPS4Y1 and USP9Y, were identified as diagnostic biomarkers for MS in male patients. The inhomogeneity of immune cells in NAGM might exacerbate intricate interplay between the CNS and the immune system in the MS.

Abstract WP219: Diffusion Weighted Imaging Characteristics in Deep White and Gray Matter Structures in Pediatric Patients With Moyamoya Disease

Background: Moyamoya Disease (MMD) is a steno-occlusive arteriopathy associated with transient ischemic attacks, stroke, and cognitive impairments. In adult MMD, normal-appearing deep gray and white matter structures (NADWM) show diffusion changes that are associated with cognitive impairments. Apparent diffusion coefficient [ADC] measures the mean diffusion and is sensitive to these changes. The association of ADC changes in NADWM in pediatric MMD is not clear. Our objective is to determine whether ADC is elevated in NADWM in pediatric MMD patients. Hypothesis: ADC values in NADWM will be elevated in MMD patients compared to controls. Methods: Twenty-nine MMD patients and no stroke and 7 healthy controls (HC) were included in a single center, retrospective study. Diffusion and T1-weighted images were analyzed. We constructed a script implementing a convolutional neural network (CNN) based approach to segment and binarize cortical regions of interest (ROI) and allow extraction of ADC values (units =[x10 -6 mm 2 /s]). Segmented ROIs included: 1) all white matter (WM), and NADWM including: 2) thalamus, 3) caudate, 4) putamen, 5) globus pallidus, 6) hippocampus. Mean ADC values were compared for: 1) all ROIs between MMD and controls, and 2) all ROIs in the MMD affected and the contralateral hemispheres within the MMD group. Results: Patients were on average 7.7 + 5.4 years at MMD diagnosis. In all WM, MMD patients had significantly higher ADC values than controls in the left (mean= 865.7 + 101.6 versus 762.4 + 21.6, p=0.01) and right hemispheres (mean= 869.9 + 104.9 versus 761.0 + 21.3, p=.01), respectively. In NADGM, there were no significant differences found between the MMD and control groups in any of the NADGM ROIs. In the NADGM of MMD patients, higher ADC values were found in the putamen (mean= 778.2 + 46.0, p=0.041), hippocampus (mean=1009.5 + 58.6, p=0.005) and all NAWM (mean= 860.3 + 57.0, p&lt;0.0001) in the MMD affected compared to the contra-lesional hemisphere. Conclusions: In pediatric patients with MMD, we found elevated ADC values in deep gray and white matter structures in the diseased hemisphere indicating alterations in the underlying microstructure. Our future analysis will integrate hemodynamic profiles and cognitive outcomes.

NODDI Identifies Cognitive Associations with In Vivo Microstructural Changes in Remote Cortical Regions and Thalamocortical Pathways in Thalamic Stroke.

The roles of cerebral structures distal to isolated thalamic infarcts in cognitive deficits remain unclear. We aimed to identify the in vivo microstructural characteristics of remote gray matter (GM) and thalamic pathways and elucidate their roles across cognitive domains. Patients with isolated ischemic thalamic stroke and healthy controls underwent neuropsychological assessment and magnetic resonance imaging. Neurite orientation dispersion and density imaging (NODDI) was modeled to derive the intracellular volume fraction (VFic) and orientation dispersion index. Fiber density (FD) was determined by constrained spherical deconvolution, and tensor-derived fractional anisotropy (FA) was calculated. Voxel-wise GM analysis and thalamic pathway tractography were performed. Twenty-six patients and 26 healthy controls were included. Patients exhibited reduced VFic in remote GM regions, including ipsilesional insular and temporal subregions. The microstructural metrics VFic, FD, and FA within ipsilesional thalamic pathways decreased (false discovery rate [FDR]-p < 0.05). Noteworthy associations emerged as VFic within insular cortices (ρ = -0.791 to -0.630; FDR-p < 0.05) and FD in tracts connecting the thalamus and insula (ρ = 0.830 to 0.971; FDR-p < 0.001) were closely associated with executive function. The VFic in Brodmann area 52 (ρ = -0.839; FDR-p = 0.005) and FA within its thalamic pathway (ρ = -0.799; FDR-p = 0.003) correlated with total auditory memory scores. In conclusion, NODDI revealed neurite loss in remote normal-appearing GM regions and ipsilesional thalamic pathways in thalamic stroke. Reduced cortical dendritic density and axonal density of thalamocortical tracts in specific subregions were associated with improved cognitive functions. Subacute microstructural alterations beyond focal thalamic infarcts might reflect beneficial remodeling indicating post-stroke plasticity.

A cluster of blood-based protein biomarkers associated with decreased cerebral blood flow relates to future cardiovascular events in patients with cardiovascular disease

Abstract Introduction Biological processes underlying decreased cerebral blood flow (CBF) in patients with cardiovascular disease (CVD) are largely unknown. We hypothesized that identification of protein clusters associated with lower CBF in patients with CVD may explain underlying processes. Methods In 428 participants (74% cardiovascular diseases; 26% reference participants) from the Heart-Brain Connection Study, CBF was measured with MRI in normal-appearing grey matter with pseudo-continuous arterial spin labeling. We assessed the relation between 92 plasma proteins from the Olink® cardiovascular III panel and CBF using cluster-based analyses and generated a Biomarker Compound Score (BCS). The BCS was related to cardiovascular risk and observed cardiovascular events within 2-year follow-up. Results Thirteen proteins were associated with CBF (ρSpearman range: -0.10 to -0.19, pFDR-corrected &amp;lt;0.05), and formed one cluster. The cluster primarily reflected extracellular matrix organization processes. The BCS was higher in patients with CVD compared to reference participants (pFDR-corrected &amp;lt;0.05) and was associated with cardiovascular risk (p &amp;lt;0.001) and cardiovascular events (OR 2.05, p &amp;lt;0.01). Conclusions We identified a cluster of plasma biomarkers related to CBF, which is related to future cardiovascular events in patients with CVD. The cluster primarily reflected extracellular matrix organization processes, which represent potential targets to preserve CBF in patients with CVD.

Magnetic resonance fingerprinting in multiple sclerosis

BackgroundIn this cross sectional study, we used MRF to investigate tissue properties of normal-appearing white matter, gray matter, and lesions in relapsing remitting MS (n = 21), secondary progressive MS (n = 16) and healthy controls (n = 9). A FISP-based MRF sequence was used for acquisition, imaging time 5 min 15 s. MRF T1 and T2 relaxation times were measured from lesional tissue, normal-appearing frontal white matter, corpus callous, thalamus, and caudate. Differences between healthy controls and MS were examined using ANCOVA adjusted for age and sex. Spearman rank correlations were assessed between T1 and T2 relaxation times and clinical measures. ObjectivesTo examine brain T1 and T2 values using magnetic resonance fingerprinting (MRF) in healthy controls and MS. MethodsThe subjects included 21 relapsing-remitting (RR) MS, 16 secondary progressive (SP) MS, and 9 age- and sex-matched HC without manifest neurological disease participating in a longitudinal MRI study. A 3T/ FISP-based MRF sequence was acquired. Regions of interest were drawn for lesions and normal appearing white matter. ANCOVA adjusted for age and sex were used to compare the groups with significance set at 0.05. ResultsA step-wise increase in T1 and T2 relaxation times was found between healthy controls, relapsing remitting MS, and secondary progressive MS. Significant differences were found in T1 and T2 between MS and healthy controls in the frontal normal-appearing white matter, corpus callosum, and thalamus (p < 0.04 for all). Significant differences in T1 and T2 between RR and SPMS were found in the frontal normal-appearing white matter and T2 lesions (p < 0.02 for all). T1 relaxation from the frontal normal-appearing white matter correlated with the Expanded Disability Status Scale [ρ = 0.62, p < 0.001], timed 25 foot walk (ρ = 0.45, p = 0.01), 9 hole peg test (ρ = 0.62, p < 0.001), and paced auditory serial addition test (ρ = −0.4, p = 0.01). ConclusionThese results suggest that MRF may be a clinically feasible quantitative approach for characterizing tissue damage in MS.

Deep learning reconstruction for brain diffusion-weighted imaging: efficacy for image quality improvement, apparent diffusion coefficient assessment, and intravoxel incoherent motion evaluation in in vitro and in vivo studies

Deep learning reconstruction (DLR) to improve imaging quality has already been introduced, but no studies have evaluated the effect of DLR on diffusion-weighted imaging (DWI) or intravoxel incoherent motion (IVIM) in in vitro or in vivo studies. The purpose of this study was to determine the effect of DLR for magnetic resonance imaging (MRI) in terms of image quality improvement, apparent diffusion coefficient (ADC) assessment, and IVIM index evaluation on DWI through in vitro and in vivo studies. For the in vitro study, a phantom recommended by the Quantitative Imaging Biomarkers Alliance was scanned and reconstructed with and without DLR, and 15 patients with brain tumors with normal-appearing gray and white matter examined using IVIM and reconstructed with and without DLR were included in the in vivo study. The ADCs of all phantoms for DWI with and without DLR, as well as the coefficient of variation percentage (CV%), and ADCs and IVIM indexes for each participant, were evaluated based on DWI with and without DLR by means of region-of-interest measurements. For the in vitro study, using the mean ADCs for all phantoms, a t-test was adopted to compare DWI with and without DLR. For the in vivo study, a Wilcoxon signed-rank test was used to compare the CV% between the two types of DWI. In addition, the Wilcoxon signed-rank test was used to compare the ADC, true diffusion coefficient (D), pseudodiffusion coefficient (D*), and percentage of water molecules in micro perfusion within 1 voxel (f) with and without DLR; the limits of agreement of each parameter were determined through a Bland-Altman analysis. The in vitro study identified no significant differences between the ADC values for DWI with and without DLR (P > 0.05), and the CV% was significantly different for DWI with and without DLR (P < 0.05) when b values ≥250 s/mm2 were used. The in vivo study revealed that D* and f with and without DLR were significantly different (P < 0.001). The limits of agreement of the ADC, D, and D* values for DWI with and without DLR were determined as 0.00 ± 0.51 × 10-3, 0.00 ± 0.06 × 10-3, and 1.13 ± 4.04 × 10-3 mm2/s, respectively. The limits of agreement of the f values for DWI with and without DLR were determined as -0.01 ± 0.07. Deep learning reconstruction for MRI has the potential to significantly improve DWI quality at higher b values. It has some effect on D* and f values in the IVIM index evaluation, but ADC and D values are less affected by DLR.

A cluster of blood-based protein biomarkers associated with decreased cerebral blood flow relates to future cardiovascular events in patients with cardiovascular disease

Biological processes underlying decreased cerebral blood flow (CBF) in patients with cardiovascular disease (CVD) are largely unknown. We hypothesized that identification of protein clusters associated with lower CBF in patients with CVD may explain underlying processes. In 428 participants (74% cardiovascular diseases; 26% reference participants) from the Heart-Brain Connection Study, we assessed the relationship between 92 plasma proteins from the Olink® cardiovascular III panel and normal-appearing grey matter CBF, using affinity propagation and hierarchical clustering algorithms, and generated a Biomarker Compound Score (BCS). The BCS was related to cardiovascular risk and observed cardiovascular events within 2-year follow-up using Spearman correlation and logistic regression. Thirteen proteins were associated with CBF (ρSpearman range: −0.10 to −0.19, pFDR-corrected <0.05), and formed one cluster. The cluster primarily reflected extracellular matrix organization processes. The BCS was higher in patients with CVD compared to reference participants (pFDR-corrected <0.05) and was associated with cardiovascular risk (ρSpearman 0.42, p < 0.001) and cardiovascular events (OR 2.05, p < 0.01). In conclusion, we identified a cluster of plasma proteins related to CBF, reflecting extracellular matrix organization processes, that is also related to future cardiovascular events in patients with CVD, representing potential targets to preserve CBF and mitigate cardiovascular risk in patients with CVD.

Quantitative magnetic resonance mapping of the myelin bilayer reflects pathology in multiple sclerosis brain tissue.

Multiple sclerosis (MS) is a neuroinflammatory disease characterized by loss of myelin (demyelination) and, to a certain extent, subsequent myelin repair (remyelination). To better understand the pathomechanisms underlying de- and remyelination and to monitor the efficacy of treatments aimed at regenerating myelin, techniques offering noninvasive visualizations of myelin are warranted. Magnetic resonance (MR) imaging has long been at the forefront of efforts to visualize myelin, but it has only recently become feasible to access the rapidly decaying resonance signals stemming from the myelin lipid-protein bilayer itself. Here, we show that direct MR mapping of the bilayer yields highly specific myelin maps in brain tissue from patients with MS. Furthermore, examination of the bilayer signal behavior is found to reveal pathological alterations in normal-appearing white and gray matter. These results indicate promise for in vivo implementations of the myelin bilayer mapping technique, with prospective applications in basic research, diagnostics, disease monitoring, and drug development.

Feasibility of diffusion kurtosis imaging in evaluating cervical spinal cord injury in multiple sclerosis.

This research aimed to assess gray matter (GM), white matter (WM), lesions of multiple sclerosis (MS) and the therapeutic effect using diffusion kurtosis imaging (DKI). From January 2018 to October 2019, 78 subjects (48 of MS and 30 of health) perform routine MR scan and DKI of cervical spinal cord. The MS patients were divided into 2 groups according to the presence or absence of T2 hyperintensity. DKI-metrics were measured in the lesions, normal-appearing GM and WM. Significant differences were detected in DKI metrics between MS and healthy (P < .05) and between patients with cervical spinal cord T2-hyperintense and without T2-hyperintense (P < .001). Compared to healthy, GM-mean kurtosis (MK), GM-radial kurtosis, and WM-fractional anisotropy, WM-axial diffusion were statistically reduced in patients without T2-hyperintense (P < .05). Significant differences were observed in DKI metrics between patients with T2-hyperintense after therapy (P < .05), as well as GM-MK and WM-fractional anisotropy, WM-axial diffusion in patients without T2-hyperintense (P < .05); Expanded Disability Status Scale was correlated with MK values, as well as Expanded Disability Status Scale scores and MK values after therapy. Our results indicate that DKI-metrics can detect and quantitatively evaluate the changes in cervical spinal cord micropathological structure.

Pathological ultrastructural alterations of myelinated axons in normal appearing white matter in progressive multiple sclerosis

Multiple sclerosis (MS) pathophysiology includes inflammation, demyelination and neurodegeneration, but the exact mechanisms of disease initiation and progression are unknown. A major feature of lesions is lack of myelin, which increases axonal energy demand and requires adaptation in number and size of mitochondria. Outside lesions, subtle and diffuse alterations are observed in normal appearing white matter (NAWM) and normal appearing grey matter (NAGM), including increased oxidative stress, reduced axon density and changes in myelin composition and morphology. On an ultrastructural level, only limited data is available on alterations in myelinated axons. We generated large scale 2D scanning transmission electron microscopy images (‘nanotomy’) of non-demyelinated brain tissue of control and progressive MS donors, accessible via an open-access online repository. We observed a reduced density of myelinated axons in NAWM, without a decrease in cross-sectional axon area. Small myelinated axons were less frequently and large myelinated axons were more frequently present in NAWM, while the g-ratio was similar. The correlation between axonal mitochondrial radius and g-ratio was lost in NAWM, but not in NAGM. Myelinated axons in control GM and NAGM had a similar g-ratio and radius distribution. We hypothesize that axonal loss in NAWM is likely compensated by swelling of the remaining myelinated axons and subsequent adjustment of myelin thickness to maintain their g-ratio. Failure of axonal mitochondria to adjust their size and fine-tuning of myelin thickness may render NAWM axons and their myelin more susceptible to injury.Graphical

Early metabolic alterations in the normal‑appearing grey and white matter of patients with clinically isolated syndrome suggestive of multiple sclerosis: A proton MR spectroscopic study.

Proton magnetic resonance spectroscopy (1H-MRS) is an advanced method of examining metabolic profiles. The present study aimed to assess in vivo metabolite levels in areas of normal-appearing grey (thalamus) and white matter (centrum semiovale) using 1H-MRS in patients with clinically isolated syndrome (CIS) suggestive of multiple sclerosis and compare them to healthy controls (HCs). Data from 35 patients with CIS (CIS group), of which 23 were untreated (CIS-untreated group) and 12 were treated (CIS-treated group) with disease-modifying-therapies (DMTs) at the time of 1H-MRS, and from 28 age- and sex-matched HCs were collected using a 3.0 T MRI and single-voxel 1H-MRS (point resolved spectroscopy sequence; repetition time, 2,000 msec; time to echo, 35 msec). Concentrations and ratios of total N-acetyl aspartate (tNAA), total creatine (tCr), total choline (tCho), myoinositol, glutamate (Glu), glutamine (Gln), Glu + Gln (Glx) and glutathione (Glth) were estimated in the thalamic-voxel (th) and centrum semiovale-voxel (cs). For the CIS group, the median duration from the first clinical attack to 1H-MRS was 102 days (interquartile range, 89.5.-131.5). Compared with HCs, significantly lower Glx(cs) (P=0.014) and ratios of tCho/tCr(th) (P=0.026), Glu/tCr(cs) (P=0.040), Glx/tCr(cs) (P=0.004), Glx/tNAA(th) (P=0.043) and Glx/tNAA(cs) (P=0.015) were observed in the CIS group. No differences in tNAA levels were observed between the CIS and the HC groups; however, tNAA(cs) was higher in the CIS-treated than in the CIS-untreated group (P=0.028). Compared with those in HC group, decreased Glu(cs) (P=0.019) and Glx(cs) levels (P=0.014) and lower ratios for tCho/tCr(th) (P=0.015), Gln/tCr(th) (P=0.004), Glu/tCr(cs) (P=0.021), Glx/tCr(th) (P=0.041), Glx/tCr(cs) (P=0.003), Glx/tNAA(th) (P=0.030) and Glx/tNAA(cs) (P=0.015) were found in the CIS-untreated group. The present findings showed alterations in the normal-appearing grey and white matter of patients with CIS; moreover, the present results suggested an early indirect treatment effect of DMTs on the brain metabolic profile of these patients.

Proteomics and relationship with axonal pathology in multiple sclerosis: 5-year diffusion tensor imaging study.

Blood-based biomarkers can be economic and easily accessible tools for monitoring and predicting disease activity in multiple sclerosis. The objective of this study was to determine the predictive value of a multivariate proteomic assay for concurrent and future microstructural/axonal brain pathology in a longitudinal study of a heterogeneous group of people with multiple sclerosis. A proteomic analysis was obtained on serum samples from 202 people with multiple sclerosis (148 relapsing-remitting and 54 progressive) at baseline and 5-year follow-up. The concentration of 21 proteins related to multiple pathways of multiple sclerosis pathophysiology was derived using Proximity Extension Assay on the Olink platform. Patients were imaged on the same 3T MRI scanner at both timepoints. Тhe rate of whole brain, white matter and grey matter atrophy over the 5-year follow-up was determined using the multi-timepoint Structural Image Evaluation, using Normalisation, of Atrophy algorithms. Lesion burden measures were also assessed. The severity of microstructural axonal brain pathology was quantified using diffusion tensor imaging. Fractional anisotropy and mean diffusivity of normal-appearing brain tissue, normal-appearing white matter, grey matter, T2 and T1 lesions were calculated. Age, sex and body mass index-adjusted step-wise regression models were used. Glial fibrillary acidic protein was the most common and highest-ranked proteomic biomarker associated with greater concurrent microstructural central nervous system alterations (P < 0.001). The rate of whole brain atrophy was associated with baseline levels of glial fibrillary acidic protein, protogenin precursor, neurofilament light chain and myelin oligodendrocyte (P < 0.009), whereas grey matter atrophy was associated with higher baseline neurofilament light chain, higher osteopontin and lower protogenin precursor levels (P < 0.016). Higher baseline glial fibrillary acidic protein level was a significant predictor of future severity of the microstructural CNS alterations as measured by normal-appearing brain tissue fractional anisotropy and mean diffusivity (standardized β = -0.397/0.327, P < 0.001), normal-appearing white matter fractional anisotropy (standardized β = -0.466, P < 0.0012), grey matter mean diffusivity (standardized β = 0.346, P < 0.011) and T2 lesion mean diffusivity (standardized β = 0.416, P < 0.001) at the 5-year follow-up. Serum levels of myelin-oligodendrocyte glycoprotein, neurofilament light chain, contactin-2 and osteopontin proteins were additionally and independently associated with worse concomitant and future axonal pathology. Higher glial fibrillary acidic protein levels were associated with future disability progression (Exp(B) = 8.65, P = 0.004). Multiple proteomic biomarkers are independently associated with greater severity of axonal brain pathology as measured by diffusion tensor imaging in multiple sclerosis. Baseline serum glial fibrillary acidic protein levels can predict future disability progression.

Gray Matter Microstructure Alterations in People with Multiple Sclerosis Based on Cell Body and Neurite Density Imaging (P10-3.007)

<h3>Objective:</h3> To evaluate a novel compartment-based model for apparent cell body and neurite density imaging (SANDI) in gray matter (GM) in people with multiple sclerosis (MS) compared to healthy controls (HC) and its correlation with brain atrophy. <h3>Background:</h3> MS features focal cortical lesions and microstructural changes in normal-appearing GM, which can impact clinical function and disability. High gradient diffusion MRI has potential to optimize GM tissue microstructure characterization by overcoming challenges due to the complexity of underlying components. <h3>Design/Methods:</h3> 41 people with MS and 37 age- and sex-matched HC were scanned on a 3T Connectom MRI scanner equipped with 300mT/m gradients using a multi-shell acquisition protocol consisting of eight b-values at 19msec diffusion time. Microstructural metrics of SANDI, including a measure of soma density (f_soma) in the cortex and deep GM, were compared between MS and HC and correlated with cortical and thalamic atrophy, correcting for multiple comparisons. <h3>Results:</h3> Cortical cell body signal fraction (f_soma) was decreased in MS compared to HC (0.56 vs. 0.58, <i>p</i>=0.027, not surviving FDR-correction). In deep GM, f_soma and extra-cellular signal fraction were significantly decreased in MS compared to HC (<i>FDR-p</i>=0.045 in both), which was most pronounced in progressive MS. Based on spatial analysis, f_soma of caudate nucleus and thalamus were significantly decreased in MS compared to HC (<i>FDR-p</i>=0.003 and <i>FDR-p</i>=0.027, respectively). Whereas cortical atrophy in MS was poorly correlated with cortical f_soma, thalamic atrophy in MS demonstrated moderate correlation with decreased thalamic f_soma (r=0.311, <i>p</i>=0.054) and decreased cortical f_soma (r=0.474, <i>p</i>=0.008). <h3>Conclusions:</h3> SANDI metrics, in particular f_soma, provide detailed GM characterization beyond cortical and thalamic volumes and are able to characterize MS-related microstructural pathology. Decreased cortical cell density correlates with declining thalamic volume and may precede volumetric measures of cortical atrophy in people with MS. <b>Disclosure:</b> Ms. Krijnen has nothing to disclose. Andrew Russo has nothing to disclose. Dr. Salim Karam has nothing to disclose. The institution of Menno M Schoonheim has received research support from Dutch MS Research Foundation. The institution of Menno M Schoonheim has received research support from Eurostars-EUREKA. The institution of Menno M Schoonheim has received research support from ARSEP. The institution of Menno M Schoonheim has received research support from Amsterdam Neuroscience. The institution of Menno M Schoonheim has received research support from MAGNIMS. The institution of Menno M Schoonheim has received research support from ZonMW. The institution of Menno M Schoonheim has received research support from Atara Biotherapeutics. The institution of Menno M Schoonheim has received research support from Biogen. The institution of Menno M Schoonheim has received research support from Celgene/Bristol Meyers Squibb. The institution of Menno M Schoonheim has received research support from Genzyme. The institution of Menno M Schoonheim has received research support from MedDay. The institution of Menno M Schoonheim has received research support from Merck. Dr. Huang has received personal compensation in the range of $0-$499 for serving as a Consultant for Siemens Healthineers. The institution of Dr. Huang has received research support from Siemens Healthineers. The institution of Dr. Huang has received research support from Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School. Dr. Klawiter has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Galen/Atlantica. Dr. Klawiter has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Genentech. Dr. Klawiter has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Banner Life Sciences. Dr. Klawiter has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Greenwich Biosciences. Dr. Klawiter has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for OM1. Dr. Klawiter has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for TG Therapeutics. The institution of Dr. Klawiter has received research support from Biogen. The institution of Dr. Klawiter has received research support from Abbvie. The institution of Dr. Klawiter has received research support from Genentech.

Influence of Residual Quadrupolar Interaction on Quantitative Sodium Brain Magnetic Resonance Imaging of Patients With Multiple Sclerosis.

The purpose of this work was to evaluate the influence of residual quadrupolar interaction on the determination of human brain apparent tissue sodium concentrations (aTSCs) using quantitative sodium magnetic resonance imaging ( 23 Na MRI) in healthy controls (HCs) and patients with multiple sclerosis (MS). Especially, it was investigated if the more detailed examination of residual quadrupolar interaction effects enables further analysis of the observed 23 Na MRI signal increase in MS patients. 23 Na MRI with a 7 T MR system was performed on 21 HC and 50 MS patients covering all MS subtypes (25 patients with relapsing-remitting MS, 14 patients with secondary progressive MS, and 11 patients with primary progressive MS) using 2 different 23 Na pulse sequences for quantification: a commonly used standard sequence (aTSC Std ) as well as a sequence with shorter excitation pulse length and lower flip angle for minimizing signal loss resulting from residual quadrupolar interactions (aTSC SP ). Apparent tissue sodium concentration was determined using the same postprocessing pipeline including correction of the receive profile of the radiofrequency coil, partial volume correction, and relaxation correction. Spin dynamic simulations of spin-3/2 nuclei were performed to aid in the understanding of the measurement results and to get deeper insight in the underlying mechanisms. In normal-appearing white matter (NAWM) of HC and all MS subtypes, the aTSC SP values were approximately 20% higher than the aTSC Std values ( P < 0.001). In addition, the ratio aTSC SP /aTSC Std was significantly higher in NAWM than in normal-appearing gray matter (NAGM) for all subject cohorts ( P < 0.002). In NAWM, aTSC Std values were significantly higher in primary progressive MS compared with HC ( P = 0.01) as well as relapsing-remitting MS ( P = 0.03). However, in contrast, no significant differences between the subject cohorts were found for aTSC SP . Spin simulations assuming the occurrence of residual quadrupolar interaction in NAWM were in good accordance with the measurement results, in particular, the ratio aTSC SP /aTSC Std in NAWM and NAGM. Our results showed that residual quadrupolar interactions in white matter regions of the human brain have an influence on aTSC quantification and therefore must be considered, especially in pathologies with expected microstructural changes such as loss of myelin in MS. Furthermore, the more detailed examination of residual quadrupolar interactions may lead to a better understanding of the pathologies themselves.

The Consistence of Dynamic Contrast-Enhanced MRI and Filter-Exchange Imaging in Measuring Water Exchange Across the Blood-Brain Barrier in High-Grade Glioma.

Water exchange across blood-brain barrier (BBB) (WEXBBB ) is an emerging biomarker of BBB dysfunction with potential applications in many brain diseases. Several MRI methods have been proposed to measure WEXBBB , but evidence remains scarce whether different methods can produce comparable WEXBBB . To explore whether dynamic contrast-enhanced (DCE)-MRI and vascular water exchange imaging (VEXI) could produce comparable WEXBBB in high-grade glioma (HGG) patients. Prospective cross-sectional. 13 HGG patients (58.4 ± 9.4 years, 9 females, 4 WHO III and 9 WHO IV). A 3 T, spoiled gradient-recalled-echo DCE-MRI and VEXI containing two pulsed-gradient spin-echo blocks separated by a mixing block. The enhanced tumor and contralateral normal-appearing white matter (cNAWM) volume-of-interests (VOIs) were drew by two neuroradiologists. And whole-brain NAWM and normal-appearing gray matter (NAGM) without tumor-affected regions were segmented by automated segmentation algorithm in FSL. Student's t-test was used to evaluate parameters difference between cNAWM and tumor, NAGM and NAWM, respectively. The correlation between vascular water efflux rate constant (kbo ) from DCE-MRI and apparent exchange rate across BBB (AXRBBB ) from VEXI was evaluated by Pearson correlation. P < 0.05 was considered statistically significant. Compared with cNAWM, both kbo and AXRBBB were significantly reduced in tumor (kbo = 3.50 ± 1.18 sec-1 vs. 1.03 ± 0.75 sec-1 ; AXRBBB = 3.54 ± 1.11 sec-1 vs. 1.94 ± 1.04 sec-1 ). Both kbo and AXRBBB showed significantly higher values in NAWM than NAGM (kbo = 3.50 ± 0.59 sec-1 vs. 2.10 ± 0.56 sec-1 ; AXRBBB = 3.35 ± 0.77 sec-1 vs. 2.07 ± 0.52 sec-1 ). The VOI-averaged kbo and AXRBBB were also linearly correlated in tumor, NAWM, and NAGM (r = 0.59). DCE-MRI and VEXI showed comparable and correlated WEXBBB in HGG patients, suggesting that the consistence and reliability of these two MRI methods in measuring WEXBBB . 2. Stage 1.