Normal-appearing White Matter Research Articles

A multi-reader comparison of normal-appearing white matter normalization techniques for perfusion and diffusion MRI in brain tumors

PurposeThere remains no consensus normal-appearing white matter (NAWM) normalization method to compute normalized relative cerebral blood volume (nrCBV) and apparent diffusion coefficient (nADC) in brain tumors. This reader study explored nrCBV and nADC differences using different NAWM normalization methods.MethodsThirty-five newly diagnosed glioma patients were studied. For each patient, two readers created four NAWM regions of interests: (1) a single plane in the centrum semiovale (CSOp), (2) 3 spheres in the centrum semiovale (CSOs), (3) a single plane in the slice of the tumor center (TUMp), and (4) 3 spheres in the slice of the tumor center (TUMs). Readers repeated NAWM segmentations 1 month later. Differences in nrCBV and nADC of the FLAIR hyperintense tumor, inter-/intra-reader variability, and time to segment NAWM were assessed. As a validation step, the diagnostic performance of each method for IDH-status prediction was evaluated.ResultsBoth readers obtained significantly different nrCBV (P < .001), nADC (P < .001), and time to segment NAWM (P < .001) between the four normalization methods. nrCBV and nADC were significantly different between CSO and TUM methods, but not between planar and spherical methods in the same NAWM region. Broadly, CSO methods were quicker than TUM methods, and spherical methods were quicker than planar methods. For all normalization techniques, inter-reader reproducibility and intra-reader repeatability were excellent (intraclass correlation coefficient > 0.9), and the IDH-status predictive performance remained similar.ConclusionThe selected NAWM region significantly impacts nrCBV and nADC values. CSO methods, particularly CSOs, may be preferred because of time reduction, similar reader variability, and similar diagnostic performance compared to TUM methods.

Retinal capillary microvessel morphology changes are associated with vascular damage and dysfunction in cerebral small vessel disease

Cerebral small vessel disease (SVD) is a cause of stroke and dementia. Retinal capillary microvessels revealed by optical coherence tomography angiography (OCTA) are developmentally related to brain microvessels. We quantified retinal vessel density (VD) and branching complexity, investigating relationships with SVD lesions, white matter integrity on diffusion tensor imaging (DTI) and cerebrovascular reactivity (CVR) to CO2 in patients with minor stroke. We enrolled 123 patients (mean age 68.1 ± SD 9.9 years), 115 contributed retinal data. Right (R) and left (L) eyes are reported. After adjusting for age, eye disease, diabetes, blood pressure and image quality, lower VD remained associated with higher mean diffusivity (MD) (standardized β; R −0.16 [95%CI −0.32 to −0.01]) and lower CVR (L 0.17 [0.03 to 0.31] and R 0.19 [0.02 to 0.36]) in normal appearing white matter (NAWM). Sparser branching remained associated with sub-visible white matter damage shown by higher MD (R −0.24 [−0.08 to −0.40]), lower fractional anisotropy (FA) (L 0.17 [0.01 to 0.33]), and lower CVR (R 0.20 [0.02 to 0.38]) in NAWM. OCTA-derived metrics provide evidence of microvessel abnormalities that may underpin SVD lesions in the brain.

Comparison of Diffusion Tensor Imaging Metrics in Normal-Appearing White Matter to Cerebrovascular Lesions and Correlation with Cerebrovascular Disease Risk Factors and Severity.

Alterations in tissue microstructure in normal-appearing white matter (NAWM), specifically measured by diffusion tensor imaging (DTI) fractional anisotropy (FA), have been associated with cognitive outcomes following stroke. The purpose of this study was to comprehensively compare conventional DTI measures of tissue microstructure in NAWM to diverse vascular brain lesions in people with cerebrovascular disease (CVD) and to examine associations between FA in NAWM and cerebrovascular risk factors. DTI metrics including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were measured in cerebral tissues and cerebrovascular anomalies from 152 people with CVD participating in the Ontario Neurodegenerative Disease Research Initiative (ONDRI). Ten cerebral tissue types were segmented including NAWM, and vascular lesions including stroke, periventricular and deep white matter hyperintensities, periventricular and deep lacunar infarcts, and perivascular spaces (PVS) using T1-weighted, proton density-weighted, T2-weighted, and fluid attenuated inversion recovery MRI scans. Mean DTI metrics were measured in each tissue region using a previously developed DTI processing pipeline and compared between tissues using multivariate analysis of covariance. Associations between FA in NAWM and several CVD risk factors were also examined. DTI metrics in vascular lesions differed significantly from healthy tissue. Specifically, all tissue types had significantly different MD values, while FA was also found to be different in most tissue types. FA in NAWM was inversely related to hypertension and modified Rankin scale (mRS). This study demonstrated the differences between conventional DTI metrics, FA, MD, AD, and RD, in cerebral vascular lesions and healthy tissue types. Therefore, incorporating DTI to characterize the integrity of the tissue microstructure could help to define the extent and severity of various brain vascular anomalies. The association between FA within NAWM and clinical evaluation of hypertension and disability provides further evidence that white matter microstructural integrity is impacted by cerebrovascular function.

Quantitative susceptibility mapping (QSM) and R2* of silent cerebral infarcts in sickle cell anemia.

Silent cerebral infarction (SCI) is the most commonly reported radiological abnormality in patients with sickle cell anemia (SCA) and is associated with future clinical stroke risk. To date, there have been few histological and quantitative MRI studies of SCI and multiple radiological definitions exist. As a result, the tissue characteristics and composition of SCI remain elusive. The objective of this work was therefore to investigate the composition of segmented SCI lesions using quantitative MRI for R and quantitative magnetic susceptibility mapping (QSM). 211 SCI lesions were segmented from 32 participants with SCA and 6 controls. SCI were segmented according to two definitions (FLAIR+/-T1w-based threshold) using a semi-automated pipeline. Magnetic susceptibility (χ) and R maps were calculated from a multi-echo gradient echo sequence and mean SCI values were compared to an equivalent region of interest in normal appearing white matter (NAWM). SCI χ and R were investigated as a function of SCI definition, patient demographics, anatomical location, and cognition. Compared to NAWM, SCI were significantly less diamagnetic (χ = -0.0067 ppm vs. -0.0153 ppm, p < 0.001) and had significantly lower R (16.7 s-1 vs. 19.2 s-1, p < 0.001). SCI definition had a significant effect on the mean SCI χ and R , with lesions becoming significantly less diamagnetic and having significantly lower R after the application of a more stringent T1w-based threshold. SCI-NAWM R decrease was significantly greater in patients with SCA compared with controls (-2.84 s-1 vs. -0.64 s-1, p < 0.0001). No significant association was observed between mean SCI-NAWM χ or R2* differences and subject age, lesion anatomical location, or cognition. The increased χ and decreased R in SCI relative to NAWM observed in both patients and controls is indicative of lower myelin or increased water content within the segmented lesions. The significant SCI-NAWM R differences observed between SCI in patients with SCA and controls suggests there may be differences in tissue composition relative to NAWM in SCI in the two populations. Quantitative MRI techniques such as QSM and R mapping can be used to enhance our understanding of the pathophysiology and composition of SCI in patients with SCA as well as controls.

Characteristics of cerebral blood flow in an Eastern sample of multiple sclerosis patients: A potential quantitative imaging marker associated with disease severity.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system that is rare in China. At present, there are no widespread quantitative imaging markers associated with disease severity in MS. Despite several previous studies reporting cerebral blood flow (CBF) changes in MS, no consensus has been reached. In this study, we enrolled 30 Eastern MS patients to investigate CBF changes in different brain regions using the arterial spin labeling technique and their relationship with disease severity. The average CBF in MS patients were higher than those in health controls in various brain regions except cerebellum. The results indicated that MS patients with strongly increased CBF showed worse disease severity, including higher Expanded Disability Status Scale (EDSS) scores and serum neurofilament light chain (sNfL) values than those with mildly increased CBF in the parietal lobes, temporal lobes, basal ganglia, and damaged white matter (DWM). From another perspective, MS patients with worse disease severity (higher EDSS score and sNfL values, longer disease duration) showed increased CBF in parietal lobes, temporal lobes, basal ganglia, normal-appearing white matter (NAWM), and DWM. Correlation analysis showed that there was a strong association among CBF, EDSS score and sNfL. MS patients with strongly increased CBF in various brain regions had more ratio in relapsing phase than patients with mildly increased CBF. And relapsing patients showed significantly higher CBF in some regions (temporal lobes, left basal ganglia, right NAWM) compared to remitting patients. In addition, MS patients with cognitive impairment had higher CBF than those without cognitive impairment in the right parietal lobe and NAWM. However, there were no significant differences in CBF between MS patients with and without other neurologic dysfunctions (e.g., motor impairment, visual disturbance, sensory dysfunction). These findings expand our understanding of CBF in MS and imply that CBF could be a potential quantitative imaging marker associated with disease severity.

Characterization of meningiomas with synthetic imaging.

Synthetic magnetic resonance imaging (SyMRI) is a novel quantitative and qualitative technique that permits the reconstruction of multiple image contrasts and quantitative maps from a single scan, thereby providing quantitative information and reducing scan times. The purpose of this study is to characterize intracranial meningiomas using SyMRI. The study included 35 patients with meningiomas (6 males, 29 females; mean age 61±17 years; range 21-90 years). Using 3T MR scanners, SyMRI was performed in addition to conventional FSET2, FLAIR, DWI, T1, and T1 with gadolinium. SyMRI software was used to generate T1, T2, and PD quantitative maps. Osirix MD was used to measure quantitative values of T1, T2, and PD using a ROI. We analyzed 42 meningiomas, 8 of which were associated with edema, and 5 contained calcifications. Mean relaxivity values of meningiomas on synthetic T1, T2, and PD maps at 3T MRI were 1382.6±391.7ms, 95.6±36.5ms, and 89.1±9.7 pu, respectively. Signal intensities in terms of T1, T2, and PD did not differ significantly between meningiomas with and without edema (p=.994, p=.356, and p=.221, respectively), nor between meningiomas containing and not containing calcifications (p=.840, p=.710, and p=.455, respectively). Values of T1 and T2 measured in meningiomas and the normal-appearing white matter approximated reference values found in the literature with other quantitative methods. The presented method offers a novel approach to characterize meningiomas through their relaxation parameters measured with a SyMRI sequence.

NODDI, diffusion tensor microstructural abnormalities and atrophy of brain white matter and gray matter contribute to cognitive impairment in multiple sclerosis.

Pathologically specific MRI measures may elucidate in-vivo the heterogeneous processes contributing to cognitive impairment in multiple sclerosis (MS). Using diffusion tensor and neurite orientation dispersion and density imaging (NODDI), we explored the contribution of focal lesions and normal-appearing (NA) tissue microstructural abnormalities to cognitive impairment in MS. One hundred and fifty-two MS patients underwent 3T brain MRI and a neuropsychological evaluation. Forty-eight healthy controls (HC) were also scanned. Fractional anisotropy (FA), mean diffusivity (MD), intracellular volume fraction (ICV_f) and orientation dispersion index (ODI) were assessed in cortical and white matter (WM) lesions, thalamus, NA cortex and NAWM. Predictors of cognitive impairment were identified using random forest. Fifty-two MS patients were cognitively impaired. Compared to cognitively preserved, impaired MS patients had higher WM lesion volume (LV), lower normalized brain volume (NBV), cortical volume (NCV), thalamic volume (NTV), and WM volume (p ≤ 0.021). They also showed lower NAWM FA, higher NAWM, NA cortex and thalamic MD, lower NAWM ICV_f, lower WM lesion ODI, and higher NAWM ODI (false discovery rate-p ≤ 0.026). Cortical lesion number and microstructural abnormalities were not significantly different. The best MRI predictors of cognitive impairment (relative importance) (out-of-bag area under the curve = 0.727) were NAWM FA (100%), NTV (96.0%), NBV (84.7%), thalamic MD (43.4%), NCV (40.6%), NA cortex MD (26.0%), WM LV (23.2%) and WM lesion ODI (17.9%). Our multiparametric MRI study including NODDI measures suggested that neuro-axonal damage and loss of microarchitecture integrity in focal WM lesions, NAWM, and GM contribute to cognitive impairment in MS.

T-cells in human trigeminal ganglia express canonical tissue-resident memory T-cell markers

BackgroundTrigeminal ganglia (TG) neurons are the main site of lifelong latent herpes simplex virus type 1 (HSV-1) infection. T-cells in ganglia contribute to long-term control of latent HSV-1 infection, but it is unclear whether these cells are bona fide tissue-resident memory T-cells (TRM). We optimized the processing of human post-mortem nervous tissue to accurately phenotype T-cells in human TG ex vivo and in situ.MethodsPeripheral blood mononuclear cells (PBMC; 5 blood donors) were incubated with several commercial tissue digestion enzyme preparations to determine off-target effect on simultaneous detection of 15 specific T-cell subset markers by flow cytometry. Next, optimized enzymatic digestion was applied to ex vivo phenotype T-cells in paired PBMC, normal appearing white matter (NAWM) and TG of 8 deceased brain donors obtained < 9 h post-mortem by flow cytometry. Finally, the phenotypic and functional markers, and spatial orientation of T-cells in relation to neuronal somata, were determined in TG tissue sections of five HSV-1-latently infected individuals by multiparametric in situ analysis.ResultsCollagenase IV digestion of human nervous tissue was most optimal to obtain high numbers of viable T-cells without disrupting marker surface expression. Compared to blood, majority T-cells in paired NAWM and TG were effector memory T-cells expressing the canonical TRM markers CD69, CXCR6 and the immune checkpoint marker PD1, and about half co-expressed CD103. A trend of relatively higher TRM frequencies were detected in TG of latently HSV-1-infected compared to HSV-1 naïve individuals. Subsequent in situ analysis of latently HSV-1-infected TG showed the presence of cytotoxic T-cells (TIA-1+), which occasionally showed features of proliferation (KI-67+) and activation (CD137+), but without signs of degranulation (CD107a+) nor damage (TUNEL+) of TG cells. Whereas majority T-cells expressed PD-1, traits of T-cell senescence (p16INK4a+) were not detected.ConclusionsThe human TG represents an immunocompetent environment in which both CD4 and CD8 TRM are established and retained. Based on our study insights, we advocate for TRM-targeted vaccine strategies to bolster local HSV-1-specific T-cell immunity, not only at the site of recurrent infection but also at the site of HSV-1 latency.

Relationship between cerebrospinal fluid biomarkers of inflammation and tissue damage in primary progressive multiple sclerosis

Background and ObjectivesIt is unclear to what extent intrathecal inflammation contributes to the pathogenesis in primary progressive multiple sclerosis (PPMS). We conducted an exploratory study to investigate the degree of intrathecal inflammation and its association with biomarkers of disease activity and severity in patients with PPMS. MethodsWe included patients with PPMS who participated in a randomized controlled trial conducted at the Danish Multiple Sclerosis Center, patients with relapsing-remitting multiple sclerosis (RRMS) and healthy controls. We analyzed concentrations of a panel of cytokines in CSF using electrochemiluminescence assays. We then explored the relationship between cytokines found in increased CSF concentrations in patients with PPMS (compared with healthy controls) with CSF concentrations of neurofilament light chain (NFL) and myelin basic protein (MBP), IgG-index, and magnetic resonance imaging (MRI) metrics (volume, magnetization transfer ratio and diffusion tensor imaging) from lesions, normal-appearing white matter, and cortical grey matter. ResultsWe included 59 patients with PPMS, 40 patients with RRMS, and 21 healthy controls. In patients with PPMS, CSF concentrations of CC chemokine ligand 3 (CCL-3), CXC chemokine ligand 8 (CXCL-8), CXCL-10, interleukin (IL)-10, IL-15, and vascular endothelial growth factor (VEGF)-A were increased compared with healthy controls and comparable with CSF concentrations in patients with RRMS. In addition, patients with PPMS had increased CSF concentrations of IL-12p40, IL-17A, tumor necrosis factor (TNF)-α, and lymphotoxin (LT)-α compared with healthy controls, but concentrations of these cytokines were even higher in patients with RRMS. For the remaining seven cytokines (CCL22, interferon-γ, IL-5, IL-7, IL-16, IL-22, IL-27), we found no difference between patients with PPMS and healthy controls. CSF concentrations of NFL and MBP correlated weakly with concentrations of IL-15, while the remaining proinflammatory cytokines were not associated with CSF concentrations of NFL or MBP. The IgG-index correlated with four cytokines (IL-10, IL-12p40, TNF-α, and LT-α). We did not observe any significant associations between MRI metrics and CSF biomarkers of inflammation. DiscussionIn this exploratory study, we found few and weak associations between intrathecal inflammation and the extent of neuroaxonal damage and demyelination, and no associations between intrathecal inflammation and MRI metrics, in patients with PPMS. Our findings suggest that, for patients with PPMS, these measures of intrathecal inflammation are not associated with the extent of neuroaxonal injury, demyelination, and disease severity, and these processes may therefore have less relevance in PPMS than in relapsing forms of MS.

Characterization of white matter over 1-2 years in small vessel disease using MR-based quantitative susceptibility mapping and free-water mapping.

PurposeThe aim of this study was to investigate alterations in white matter lesions (WMLs) and normal-appearing white matter (NAWM) with small vessel disease (SVD) over 1–2 years using quantitative susceptibility mapping (QSM) and free-water (FW) mapping.MethodsFifty-one SVD patients underwent MRI brain scans and neuropsychological testing both at baseline and follow-up. The main approach for treating these patients is the management of risk factors. Quantitative susceptibility (QS), fractional anisotropy (FA), mean diffusivity (MD), FW, FW-corrected FA (FAT), and FW-corrected MD (MDT) maps within WMLs and NAWM were generated. Furthermore, the JHU-ICBM-DTI label atlas was used as an anatomic guide, and the measurements of the segmented NAWMs were calculated. The average regional values were extracted, and a paired t-test was used to analyze the longitudinal change. Partial correlations were used to assess the relationship between the MRI indices changes (e.g., ΔQSfollowup − baseline/QSbaseline) and the cognitive function changes (e.g., ΔMoCAfollowup − baseline/MoCAbaseline).ResultsAfter SVD risk factor control, no gradual cognitive decline occurred during 1–2 years. However, we still found that the QS values (index of demyelination) increased in the NAWM at follow-up, especially in the NAWM part of the left superior frontal blade (SF), left occipital blade, right uncinate fasciculus, and right corticospinal tract (CST). FW (index of neuroinflammation/edema) analysis revealed that the follow-up group differed from the baseline group in the NAWM part of the right CST and inferior frontal blade (IF). Decreased FAT (index of axonal loss) was observed in the NAWM part of the right SF and IF at follow-up. In addition, the FAT changes in the NAWM part of the right IF were associated with overall cognitive performance changes. In contrast, no significant differences were found in the WMLs.ConclusionThe NAWM was still in the progressive injury process over time, while WMLs remained relatively stable, which supports the notion that SVD is a chronic progressive disease. The process of axonal loss in the NAWM part of the prefrontal lobe might be a biomarker of cognitive changes in the evolution of SVD.

Deep white matter hyperintensity is spatially correlated to MRI-visible perivascular spaces in cerebral small vessel disease on 7 Tesla MRI

BackgroundThe association between perivascular space (PVS) and white matter hyperintensity (WMH) has been unclear. Normal-appearing white matter (NAWM) around WMH is also found correlated with the development of focal WMH....

In vivo quantification of brain soma and neurite density abnormalities in multiple sclerosis.

Soma and neurite density imaging (SANDI) is a new biophysical model that incorporates soma in addition to neurite density, thus possibly providing more specific information about the complex pathological processes of multiple sclerosis (MS). To discriminate the pathological abnormalities of MS white matter (WM) lesions, normal-appearing (NA) WM and cortex and to evaluate the associations among SANDI-derived measures, clinical disability, and conventional MRI variables. Twenty healthy controls (HC) and 23 MS underwent a 3T brain MRI. Using SANDI on diffusion-weighted sequence, the fractions of neurite (fneurite) and soma (fsoma) were assessed in WM lesions, NAWM, and cortex. Compared to HC WM, MS NAWM showed lower fneurite (false discovery rate [FDR]-p = 0.011). In MS patients, WM lesions showed lower fneurite and fsoma compared to both HC and MS NAWM (FDR-p < 0.001 for all). In the cortex, MS patients had lower fneurite and fsoma compared to HC (FDR-p ≤ 0.009). Compared to both HC and RRMS, PMS patients had lower fneurite in NAWM (vs HC: FDR-p < 0.001; vs RRMS: FDR-p = 0.003) and cortex (vs HC: FDR-p < 0.001; vs RRMS: p = 0.031, not surviving FDR correction), and lower cortical fsoma (vs HC: FDR-p < 0.001; vs RRMS: FDR-p = 0.009). Compared to HC, PMS also showed a higher fsoma in NAWM (FDR-p = 0.015). Fneurite and fsoma in the different brain compartments were correlated with age, phenotype, disease duration, disability, WM lesion volumes, normalized brain, cortical, and WM volumes (r from -0.761 to 0.821, FDR-p ≤ 0.4). SANDI may represent a clinically relevant model to discriminate different neurodegenerative phenomena that gradually accumulate through MS disease course.

Evaluation of Brain Tumors Using Amide Proton Transfer Imaging: A Comparison of Normal Amide Proton Transfer Signal With Abnormal Amide Proton Transfer Signal Value.

The aim of the study was to evaluate the relationship of amide proton transfer (APT) signal characteristics in brain tumors and uninvolved brain tissue for patients with glioblastoma and those with brain metastases. Using the mDIXON 3D-APT sequence of the fast spin echo method, an APT image was obtained. The mean APT signal values of tumor core, peritumor edema, ipsilateral normal-appearing white matter (INAWM), and contralateral normal white matter (CNAWM) were obtained and compared between glioblastoma and brain metastases. Receiver operating characteristic curves were used to evaluate parameters for distinguishing between glioblastoma and brain metastases. In addition, the difference and change rate in APT signal values between tumor core and peritumoral edema (PE) and CNAWM were evaluated, respectively. The APT signal values of glioblastoma were the highest in tumor core (3.41% ± 0.49%), followed by PE (2.24% ± 0.29%), INAWM (1.35% ± 0.15%), and CNAWM (1.26% ± 0.12%, P < 0.001). The APT signal value of brain metastases was the highest in tumor core (2.74% ± 0.34%), followed by PE (1.86% ± 0.35%), INAWM (1.17% ± 0.13%), and CNAWM (1.2% ± 0.09%, P < 0.01). The APT change rate (between PE and CNAWM) was not significantly different at 78% and 56% for glioblastoma and brain metastases, respectively ( P > 0.05). Performing APT imaging under the same parameters used in this study may aid in the identification of brain tumors.

Evaluation of white matter microstructure in pediatric onset multiple sclerosis with diffusion compartment imaging.

Pediatric-onset multiple sclerosis (POMS) shows earlier axonal involvement and greater axonal loss than in adults. We aim to characterize the white matter (WM) microstructural changes in POMS using a diffusion compartment imaging (DCI) model and compare it to standard diffusion tensor imaging (DTI). Eleven patients (2 males, mean age 18.8±3.9years) with a diagnosis of relapsing and remitting POMS (mean age at disease onset 13.8±2.9years, mean duration 5.1±1.9years) and healthy controls (8 males, mean age 26.4±6.5years) were recruited and imaged at 3T. A 90-gradient set Cube and Sphere acquisition and a novel DCI model known as DIstribution of Anisotropic MicrOstructural eNvironments with Diffusion-weighted imaging (DIAMOND) were used to calculate a single anisotropic compartment, an isotropic compartment, and a free diffusion compartment. Lesions and contralateral normal-appearing white matter (NAWM) in patients and whole brain WM for controls were labeled. Eleven patients and 11 controls were recruited. When comparing lesions and contralateral NAWM in patients using DCI, compartmental axial diffusivity, radial diffusivity (cRD), and mean diffusivity (cMD) were higher in lesions. Conversely, compartmental fractional anisotropy (cFA) and heterogeneity index were lower in lesions. An analysis of DTI equivalents showed the same trends. In whole-brain NAWM of patients compared to controls, cRD and cMD were higher and cFA was lower in patients. Lesions in POMS can be accurately characterized by a DCI model. Incipient changes in NAWM seen in DCI may not be readily observable by DTI.

Lesion-Specific Metabolic Alterations in Relapsing-Remitting Multiple Sclerosis Via 7 T Magnetic Resonance Spectroscopic Imaging.

Magnetic resonance spectroscopic imaging (MRSI) of the brain enables in vivo assessment of metabolic alterations in multiple sclerosis (MS). This provides complementary insights into lesion pathology that cannot be obtained via T1- and T2-weighted conventional magnetic resonance imaging (cMRI). The aims of this study were to assess focal metabolic alterations inside and at the periphery of lesions that are visible or invisible on cMRI, and to correlate their metabolic changes with T1 hypointensity and the distance of lesions to cortical gray matter (GM). A 7 T MRSI was performed on 51 patients with relapsing-remitting MS (30 female/21 male; mean age, 35.4 ± 9.9 years). Mean metabolic ratios were calculated for segmented regions of interest (ROIs) of normal-appearing white matter, white matter lesions, and focal regions of increased mIns/tNAA invisible on cMRI. A subgroup analysis was performed after subdividing based on T1 relaxation and distance to cortical GM. Metabolite ratios were correlated with T1 and compared between different layers around cMRI-visible lesions. Focal regions of, on average, 2.8-fold higher mIns/tNAA than surrounding normal-appearing white matter and with an appearance similar to that of MS lesions were found, which were not visible on cMRI (ie, ~4% of metabolic hotspots). T1 relaxation was positively correlated with mIns/tNAA ( P ≤ 0.01), and negatively with tNAA/tCr ( P ≤ 0.01) and tCho/tCr ( P ≤ 0.01). mIns/tCr was increased outside lesions, whereas tNAA/tCr distributions resembled macroscopic tissue damage inside the lesions. mIns/tCr was -21% lower for lesions closer to cortical GM ( P ≤ 0.05). 7 T MRSI allows in vivo visualization of focal MS pathology not visible on cMRI and the assessment of metabolite levels in the lesion center, in the active lesion periphery and in cortical lesions. This demonstrated the potential of MRSI to image mIns as an early biomarker in lesion development.

Advanced diffusion MRI and image texture analysis detect widespread brain structural differences between relapsing-remitting and secondary progressive multiple sclerosis.

IntroductionDisease development in multiple sclerosis (MS) causes dramatic structural changes, but the exact changing patterns are unclear. Our objective is to investigate the differences in brain structure locally and spatially between relapsing-remitting MS (RRMS) and its advanced form, secondary progressive MS (SPMS), through advanced analysis of diffusion magnetic resonance imaging (MRI) and image texture.MethodsA total of 20 patients with RRMS and nine patients with SPMS from two datasets underwent 3T anatomical and diffusion tensor imaging (DTI). The DTI was harmonized, augmented, and then modeled, which generated six voxel- and sub-voxel-scale measures. Texture analysis focused on T2 and FLAIR MRI, which produced two phase-based measures, namely, phase congruency and weighted mean phase. Data analysis was 3-fold, i.e., histogram analysis of whole-brain normal appearing white matter (NAWM); region of interest (ROI) analysis of NAWM and lesions within three critical white matter tracts, namely, corpus callosum, corticospinal tract, and optic radiation; and along-tract statistics. Furthermore, by calculating the z-score of core-rim pathology within lesions based on diffusion measures, we developed a novel method to define chronic active lesions and compared them between cohorts.ResultsHistogram features from diffusion and all but one texture measure differentiated between RRMS and SPMS. Within-tract ROI analysis detected cohort differences in both NAWM and lesions of the corpus callosum body in three measures of neurite orientation and anisotropy. Along-tract statistics detected cohort differences from multiple measures, particularly lesion extent, which increased significantly in SPMS in posterior corpus callosum and optic radiations. The number of chronic active lesions were also significantly higher (by 5–20% over z-scores 0.5 and 1.0) in SPMS than RRMS based on diffusion anisotropy, neurite content, and diameter.ConclusionAdvanced diffusion MRI and texture analysis may be promising approaches for thorough understanding of brain structural changes from RRMS to SPMS, thereby providing new insight into disease development mechanisms in MS.

Quantitative 7T sodium magnetic resonance imaging of the human brain using a 32-channel phased-array head coil: Application to patients with secondary progressive multiple sclerosis.

Apparent tissue sodium concentrations (aTSCs) determined by 23 Na brain magnetic resonance imaging (MRI) have the potential to serve as a biomarker in pathologies such as multiple sclerosis (MS). However, the quantification is hindered by the intrinsically low signal-to-noise ratio of 23 Na MRI. The purpose of this study was to improve the accuracy and reliability of quantitative 23 Na brain MRI by implementing a dedicated postprocessing pipeline and to evaluate the applicability of the developed approach for the examination of MS patients. 23 Na brain MRI measurements of 13 healthy volunteers and 17 patients with secondary progressive multiple sclerosis (SPMS) were performed at 7T using a dual-tuned 23 Na/1 H birdcage coil with a receive-only 32-channel phased array. The aTSC values were determined for normal appearing white matter (NAWM) and normal appearing gray matter (NAGM) in healthy subjects and SPMS patients. Signal intensities were normalized using the mean cerebrospinal fluid (CSF) sodium concentration determined in 37 separate patients receiving a spinal tap for routine diagnostic purposes. Five volunteers underwent MRI examinations three times in a row to assess repeatability. Coefficients of variation (CoVs) were used to quantify the repeatability of the proposed method. aTSC values were compared regarding brain regions and subject cohort using the paired-samples Wilcoxon rank-sum test. Laboratory CSF sodium concentration did not differ significantly between patients without and with MS (p = 0.42). The proposed quantification workflow for 23 Na MRI was highly repeatable with CoVs averaged over all five volunteers of 1.9% ± 0.9% for NAWM and 2.2% ± 1.6% for NAGM. Average NAWM aTSC was significantly higher in patients with SPMS compared with the control group (p = 0.009). Average NAGM aTSC did not differ significantly between healthy volunteers and MS patients (p = 0.98). The proposed postprocessing pipeline shows high repeatability and the results can serve as a baseline for further studies establishing 23 Na brain MRI as a biomarker in diseases such as MS.

Associations between cerebral blood flow and progression of white matter hyperintensity in community-dwelling adults: a longitudinal cohort study.

BackgroundWhite matter hyperintensity (WMH) is prevalent in elderly populations. Ischemia is characterized by a decline in cerebral blood flow (CBF) and may play a key role in the pathogenesis of WMH. However, the association between CBF reduction and WMH progression remains controversial. This study aimed to investigate the association between CBF and the progression of WMH at a 2-year follow-up of community-based, asymptomatic adults in a longitudinal cohort study across the lifespan.MethodsAsymptomatic adults who participated in a community-based study were recruited and underwent brain structural and perfusion magnetic resonance imaging (MRI) at baseline and at a 2-year follow-up visit. The CBF was measured on pseudo-continuous arterial spin-labeling (pCASL) MRI. The WMH was evaluated on T2-weighted fluid-attenuated inversion recovery (T2-FLAIR) images. Tissue segmentation was conducted on T1-weighted (T1W) images to derive binary masks of gray matter and normal-appearing white matter. Linear mixed effect models were conducted to analyze the cross-sectional and longitudinal associations between CBF and WMH.ResultsA total of 229 adults (mean age 57.3±12.6 years; 94 males) were enrolled at baseline, among whom 84 participants (mean age 54.1±11.9 years; 41 males) completed a follow-up visit with a mean time interval of 2.77±0.44 years. At baseline, there was a decreasing trend in gray matter (GM) CBF with an increase of WMH burden (P=0.063), but this association was attenuated after adjusting for age (P=0.362). In the longitudinal analysis, baseline WMH volume was significantly associated with the reduction of perfusion in GM [coefficient =−1.96, 95% confidence interval (CI): −3.25 to −0.67; P=0.004] and normal appearing white matter (coefficient =−0.99, 95% CI: −1.66 to −0.31; P=0.005) during follow-up. On the contrary, neither baseline CBF in GM (P=0.888) nor normal appearing white matter (P=0.850) was associated with WMH progression. In addition, CBF changes within WMH were significantly associated with both baseline (coefficient =−0.014, 95% CI: −0.025 to −0.003; P=0.017) and progression (coefficient =−1.01, 95% CI: −1.81 to −0.20; P=0.015) of WMH volume.ConclusionsA WMH burden was not found to be directly associated with cortex perfusion at baseline due to the effects of age on both CBF and WMH. However, baseline WMH volume could predict the reduction of perfusion.

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

Background and aimsThe 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. MethodsSeventy 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). ResultsMore 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. ConclusionsVariations 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.

Permanent tissue damage in multiple sclerosis lesions is associated with reduced pre-lesion myelin and axon volume fractions

Background: The use of advanced magnetic resonance imaging (MRI) techniques in MS research has led to new insights in lesion evolution and disease outcomes. It has not yet been determined if, or how, pre-lesional abnormalities in normal-appearing white matter (NAWM) relate to the long-term evolution of new lesions. Objective: To investigate the relationship between abnormalities in MRI measures of axonal and myelin volume fractions (AVF and MVF) in NAWM preceding development of black-hole (BH) and non-BH lesions in people with MS. Methods: We obtained magnetization transfer and diffusion MRI at 6-month intervals in patients with MS to estimate MVF and AVF during lesion evolution. Lesions were classified as either BH or non-BH on the final imaging visit using T1 maps. Results: Longitudinal data from 97 new T2 lesions from 9 participants were analyzed; 25 lesions in 8 participants were classified as BH 6–12 months after initial appearance. Pre-lesion MVF, AVF, and MVF/AVF were significantly lower, and T1 was significantly higher, in the lesions that later became BHs (p < 0.001) compared to those that did not. No significant pre-lesion abnormalities were found in non-BH lesions (p > 0.05). Conclusion: The present work demonstrated that pre-lesion abnormalities are associated with worse long-term lesion-level outcome.