Imaging chronic active lesions in multiple sclerosis: a consensus statement.

Chronic active lesions (CAL) are an important manifestation of chronic inflammation in multiple sclerosis and have implications for non-relapsing biological progression. In recent years, the discovery of innovative MRI and PET-derived biomarkers has made it possible to detect CAL, and to some extent quantify them, in the brain of persons with multiple sclerosis, in vivo. Paramagnetic rim lesions on susceptibility-sensitive MRI sequences, MRI-defined slowly expanding lesions on T1-weighted and T2-weighted scans, and 18-kDa translocator protein-positive lesions on PET are promising candidate biomarkers of CAL. While partially overlapping, these biomarkers do not have equivalent sensitivity and specificity to histopathological CAL. Standardization in the use of available imaging measures for CAL identification, quantification and monitoring is lacking. To fast-forward clinical translation of CAL, the North American Imaging in Multiple Sclerosis Cooperative developed a consensus statement, which provides guidance for the radiological definition and measurement of CAL. The proposed manuscript presents this consensus statement, summarizes the multistep process leading to it, and identifies the remaining major gaps in knowledge.

Myelin biomarkers in the healthy adult brain: Correlation, reproducibility, and the effect of fiber orientation.

PURPOSE: We investigated the correlation, reproducibility, and effect of white matter fiber orientation for three myelin-sensitive MRI techniques: magnetization transfer ratio (MTR), inhomogeneous magnetization transfer ratio (ihMTR), and gradient and spin echo-derived myelin water fraction (MWF). METHODS: We measured the three metrics in 17 white and three deep grey matter regions in 17 healthy adults at 3 T. RESULTS: We found a strong correlation between ihMTR and MTR (r = 0.70, p < 0.001) and ihMTR and MWF (r = 0.79, p < 0.001), and a weaker correlation between MTR and MWF (r = 0.54, p < 0.001). The dynamic range in white matter was greatest for MWF (2.0%-27.5%), followed by MTR (14.4%-23.2%) and then ihMTR (1.2%-5.4%). The average scan-rescan coefficient of variation for white matter regions was 0.6% MTR, 0.3% ihMTR, and 0.7% MWF in metric units; however, when adjusted by the dynamic range, these became 6.3%, 6.1% and 2.8%, respectively. All three metrics varied with fiber direction: MWF and ihMTR were lower in white matter fibers perpendicular to B0 by 6% and 1%, respectively, compared with those parallel, whereas MTR was lower by 0.5% at about 40°, with the highest values at 90°. However, separating the apparent orientation dependence by white matter region revealed large dissimilarities in the trends, suggesting that real differences in myelination between regions are confounding the apparent orientation dependence measured using this method. CONCLUSION: The strong correlation between ihMTR and MWF suggests that these techniques are measuring the same myelination; however, the larger dynamic range of MWF may provide more power to detect small differences in myelin.

Nonaqueous magnetization following adiabatic and selective pulses in brain: T1 and cross-relaxation dynamics.

Inversion pulses are commonly employed in MRI for T 1 -weighted contrast and relaxation measurements. In the brain, it is often assumed that adiabatic pulses saturate the nonaqueous magnetization. We investigated this assumption using solid-state NMR to monitor the nonaqueous signal directly following adiabatic inversion and compared this with signals following hard and soft inversion pulses. The effects of the different preparations on relaxation dynamics were explored. Inversion recovery experiments were performed on ex vivo bovine and porcine brains using 360-MHz (8.4 T) and 200-MHz (4.7 T) NMR spectrometers, respectively, using broadband rectangular, adiabatic, and sinc inversion pulses as well as a long rectangular saturation pulse. Analogous human brain MRI experiments were performed at 3 T using single-slice echo-planar imaging. Relaxation data were fitted by mono- and biexponential decay models. Further fitting analysis was performed using only two inversion delay times. Adiabatic and sinc inversion left much of the nonaqueous magnetization along B 0 and resulted in biexponential relaxation. Saturation of both aqueous and nonaqueous magnetization components led to effectively monoexponential T 1 relaxation. Typical adiabatic inversion pulses do not, as has been widely assumed, saturate the nonaqueous proton magnetization in white matter. Unequal magnetization states in aqueous and nonaqueous 1 H reservoirs prepared by soft and adiabatic pulses result in biexponential T 1 relaxation. Both pools must be prepared in the same magnetization state (e.g., saturated or inverted) in order to observe consistent monoexponential relaxation.

A data-driven T2 relaxation analysis approach for myelin water imaging: Spectrum analysis for multiple exponentials via experimental condition oriented simulation (SAME-ECOS).

PURPOSE: The decomposition of multi-exponential decay data into a T2 spectrum poses substantial challenges for conventional fitting algorithms, including non-negative least squares (NNLS). Based on a combination of the resolution limit constraint and machine learning neural network algorithm, a data-driven and highly tailorable analysis method named spectrum analysis for multiple exponentials via experimental condition oriented simulation (SAME-ECOS) was proposed. THEORY AND METHODS: The theory of SAME-ECOS was derived. Then, a paradigm was presented to demonstrate the SAME-ECOS workflow, consisting of a series of calculation, simulation, and model training operations. The performance of the trained SAME-ECOS model was evaluated using simulations and six in vivo brain datasets. The code is available at https://github.com/hanwencat/SAME-ECOS. RESULTS: Using NNLS as the baseline, SAME-ECOS achieved over 15% higher overall cosine similarity scores in producing the T2 spectrum, and more than 10% lower mean absolute error in calculating the myelin water fraction (MWF), as well as demonstrated better robustness to noise in the simulation tests. Applying to in vivo data, MWF from SAME-ECOS and NNLS was highly correlated among all study participants. However, a distinct separation of the myelin water peak and the intra/extra-cellular water peak was only observed in the mean T2 spectra determined using SAME-ECOS. In terms of data processing speed, SAME-ECOS is approximately 30 times faster than NNLS, achieving a whole-brain analysis in 3 min. CONCLUSION: Compared with NNLS, the SAME-ECOS method yields much more reliable T2 spectra in a dramatically shorter time, increasing the feasibility of multi-component T2 decay analysis in clinical settings.

Characterization of multiple sclerosis neuroinflammation and neurodegeneration with relaxation and diffusion basis spectrum imaging.

BACKGROUND: Advanced magnetic resonance imaging (MRI) methods can provide more specific information about various microstructural tissue changes in multiple sclerosis (MS) brain. Quantitative measurement of T1 and T2 relaxation, and diffusion basis spectrum imaging (DBSI) yield metrics related to the pathology of neuroinflammation and neurodegeneration that occurs across the spectrum of MS. OBJECTIVE: To use relaxation and DBSI MRI metrics to describe measures of neuroinflammation, myelin and axons in different MS subtypes. METHODS: 103 participants (20 clinically isolated syndrome (CIS), 33 relapsing-remitting MS (RRMS), 30 secondary progressive MS and 20 primary progressive MS) underwent quantitative T1, T2, DBSI and conventional 3T MRI. Whole brain, normal-appearing white matter, lesion and corpus callosum MRI metrics were compared across MS subtypes. RESULTS: A gradation of MRI metric values was seen from CIS to RRMS to progressive MS. RRMS demonstrated large oedema-related differences, while progressive MS had the most extensive abnormalities in myelin and axonal measures. CONCLUSION: Relaxation and DBSI-derived MRI measures show differences between MS subtypes related to the severity and composition of underlying tissue damage. RRMS showed oedema, demyelination and axonal loss compared with CIS. Progressive MS had even more evidence of increased oedema, demyelination and axonal loss compared with CIS and RRMS.

Temperature dependence and histological correlation of inhomogeneous magnetization transfer and myelin water imaging in ex vivo brain.

PURPOSE: The promise of inhomogeneous magnetization transfer (ihMT) as a new myelin imaging method was studied in ex vivo human brain tissue and in relation to myelin water fraction (MWF). The temperature dependence of both methods was characterized, as well as their correspondence with a histological measure of myelin content. Unfiltered and filtered ihMT protocols were studied by adjusting the saturation scheme to preserve or attenuate signal from tissue with short dipolar relaxation time T1D. METHODS: ihMT ratio (ihMTR) and MWF maps were acquired at 7 T from formalin-fixed human brain samples at 22.5 °C, 30 °C and 37 °C. The impact of temperature on unfiltered ihMTR, filtered ihMTR and MWF was investigated and compared to myelin basic protein staining. RESULTS: Unfiltered ihMTR exhibited no temperature dependence, whereas filtered ihMTR increased with increasing temperature. MWF decreased at higher temperature, with an increasing prevalence of areas where the myelin water signal was unreliably determined, likely related to a reduction in T2 peak separability at higher temperatures ex vivo. MWF and ihMTR showed similar per-sample correlation with myelin staining at room temperature. At 37 °C, filtered ihMTR was more strongly correlated with myelin staining and had increased dynamic range compared to unfiltered ihMTR. CONCLUSIONS: Given the temperature dependence of filtered ihMT, increased dynamic range, and strong myelin specificity that persists at higher temperatures, we recommend carefully controlled temperatures close to 37 °C for filtered ihMT acquisitions. Unfiltered ihMT may also be useful, due to its independence from temperature, higher amplitude values, and sensitivity to short T1D components. Ex vivo myelin water imaging should be performed at room temperature, to avoid fitting issues found at higher temperatures.

Cervical cord myelin abnormality is associated with clinical disability in multiple sclerosis.

BACKGROUND: Myelin water imaging (MWI) was recently optimized to provide quantitative in vivo measurement of spinal cord myelin, which is critically involved in multiple sclerosis (MS) disability. OBJECTIVE: To assess cervical cord myelin measurements in relapsing-remitting multiple sclerosis (RRMS) and progressive multiple sclerosis (ProgMS) participants and evaluate the correlation between myelin measures and clinical disability. METHODS: We used MWI data from 35 RRMS, 30 ProgMS, and 28 healthy control (HC) participants collected at cord level C2/C3 on a 3 T magnetic resonance imaging (MRI) scanner. Myelin heterogeneity index (MHI), a measurement of myelin variability, was calculated for whole cervical cord, global white matter, dorsal column, lateral and ventral funiculi. Correlations were assessed between MHI and Expanded Disability Status Scale (EDSS), 9-Hole Peg Test (9HPT), timed 25-foot walk, and disease duration. RESULTS: In various regions of the cervical cord, ProgMS MHI was higher compared to HC (between 9.5% and 31%, p ⩽ 0.04) and RRMS (between 13% and 26%, p ⩽ 0.02), and ProgMS MHI was associated with EDSS (r = 0.42-0.52) and 9HPT (r = 0.45-0.52). CONCLUSION: Myelin abnormalities within clinically eloquent areas are related to clinical disability. MWI metrics have a potential role for monitoring subclinical disease progression and adjudicating treatment efficacy for new therapies targeting ProgMS.

Myelin water imaging data analysis in less than one minute.

PURPOSE: Based on a deep learning neural network (NN) algorithm, a super fast and easy to implement data analysis method was proposed for myelin water imaging (MWI) to calculate the myelin water fraction (MWF). METHODS: A NN was constructed and trained on MWI data acquired by a 32-echo 3D gradient and spin echo (GRASE) sequence. Ground truth labels were created by regularized non-negative least squares (NNLS) with stimulated echo corrections. Voxel-wise GRASE data from 5 brains (4 healthy, 1 multiple sclerosis (MS)) were used for NN training. The trained NN was tested on 2 healthy brains, 1 MS brain with segmented lesions, 1 healthy spinal cord, and 1 healthy brain acquired from a different scanner. RESULTS: Production of whole brain MWF maps in approximately 33 â€‹s can be achieved by a trained NN without graphics card acceleration. For all testing regions, no visual differences between NN and NNLS MWF maps were observed, and no obvious regional biases were found. Quantitatively, all voxels exhibited excellent agreement between NN and NNLS (all R2>0.98, p â€‹< â€‹0.001, mean absolute error <0.01). CONCLUSION: The time for accurate MWF calculation can be dramatically reduced to less than 1 â€‹min by the proposed NN, addressing one of the barriers facing future clinical feasibility of MWI.

Intra- and inter-site reproducibility of human brain single-voxel proton MRS at 3 T.

INTRODUCTION: Clinical trials that involve participants from multiple sites necessitate standardized and reliable quantitative MRI outcomes to detect significant group differences over time. Metabolite concentrations measured by proton MRS (1 H-MRS) provide valuable information about in vivo metabolism of the central nervous system, but can vary based on the acquisition and quantitation methods used by different MR sites. Therefore, we investigated the intra- and inter-site reproducibility of metabolite concentrations measured by 1 H-MRS on MRI scanners from a single manufacturer across six sites. METHODS: Five healthy controls were scanned twice within 24 h at six participating 3 T MR sites with large single-voxel PRESS (TE/TR/NSA = 36 ms/4000 ms/56) and anatomical images for voxel positioning and correction of partial volume relaxation. Absolute metabolite concentrations were calculated relative to the T1 and T2 relaxation corrected signal from water. Intra- and inter-site reproducibility was assessed using Bland-Altman plots and intra- and inter-site coefficient of variation (CoV) as well as intra- and inter-site intra-class correlation coefficient. RESULTS: The median intra-site CoVs for the five major metabolite concentrations ([NAA], [tCr], [Glu], [tCho] and [Ins]) were between 2.5 and 5.3%. Inter-site CoVs were also low, with the median CoVs for all metabolites between 3.7 and 6.4%. Metabolite concentrations were robust to small inconsistencies in voxel placement and site was not the driving factor in the variance of the measurement of any metabolite concentration. Between-subject differences accounted for the majority of the concentration variability for creatine, choline and myo-inositol (42-65% of the variance). CONCLUSION: A large single-voxel 1 H-MRS acquisition from a single manufacturer's MRI scanner is highly reproducible and reliable for multi-site clinical trials.

A 24-month advanced magnetic resonance imaging study of multiple sclerosis patients treated with alemtuzumab.

BACKGROUND: Tissue damage in both multiple sclerosis (MS) lesions and normal-appearing white matter (NAWM) are important contributors to disability and progression. Specific aspects of MS pathology can be measured using advanced imaging. Alemtuzumab is a humanised monoclonal antibody targeting CD52 developed for MS treatment. OBJECTIVE: To investigate changes over 2 years of advanced magnetic resonance (MR) metrics in lesions and NAWM of MS patients treated with alemtuzumab. METHODS: A total of 42 relapsing-remitting alemtuzumab-treated MS subjects were scanned for 2 years at 3 T. T1 relaxation, T2 relaxation, diffusion tensor, MR spectroscopy and volumetric sequences were performed. Mean T1 and myelin water fraction (MWF) were determined for stable lesions, new lesions and NAWM. Fractional anisotropy was calculated for the corpus callosum (CC) and N-acetylaspartate (NAA) concentration was determined from a large NAWM voxel. Brain parenchymal fraction (BPF), cortical thickness and CC area were also calculated. RESULTS: No change in any MR measurement was found in lesions or NAWM over 24 months. BPF, cortical thickness and CC area all showed decreases in the first year followed by stability in the second year. CONCLUSION: Advanced MR biomarkers of myelin (MWF) and neuron/axons (NAA) show no change in NAWM over 24 months in alemtuzumab-treated MS participants.

Global loss of myelin water over 5 years in multiple sclerosis normal-appearing white matter.

BACKGROUND: Reduced myelin water fraction (MWF, a marker for myelin), increased geometric mean T2 (ieGMT2, reflecting intra/extracellular water properties), and increased T1 (related to total water content) have been observed in cross-sectional studies of multiple sclerosis (MS) normal-appearing white matter (NAWM). OBJECTIVE: To assess longitudinal changes of magnetic resonance (MR) measures in relapsing-remitting MS (RRMS) brain NAWM. METHODS: A total of 11 subjects with RRMS and 4 controls were scanned on a 3T MRI at baseline and long-term follow-up (LTFU; 3.2-5.8 years) with a 32-echo T2 relaxation and an inversion recovery T1 sequence. For every voxel, MWF, ieGMT2, and T1 were obtained. Mean, peak height, and peak location from NAWM mask-based histograms were determined. RESULTS: In MS subjects, NAWM MWF mean decreased by 8% ( p = 0.0016). No longitudinal changes were measured in T1 or ieGMT2. There was no relationship between change in any MR metric and change in EDSS. Control white matter showed no differences over time in any metric. CONCLUSION: The decreases we observed in MWF suggest that changes in myelin integrity and loss of myelin may be occurring diffusely and over long time periods in the MS brain. The timescale of these changes indicates that chronic, progressive myelin damage is an evolving process occurring over many years.

Does hydration status affect MRI measures of brain volume or water content?

PURPOSE: To determine whether differences in hydration state, which could arise from routine clinical procedures such as overnight fasting, affect brain total water content (TWC) and brain volume measured with magnetic resonance imaging (MRI). MATERIALS AND METHODS: Twenty healthy volunteers were scanned with a 3T MR scanner four times: day 1, baseline scan; day 2, hydrated scan after consuming 3L of water over 12 hours; day 3, dehydrated scan after overnight fasting of 9 hours, followed by another scan 1 hour later for reproducibility. The following MRI data were collected: T2 relaxation (for TWC measurement), inversion recovery (for T1 measurement), and 3D T1 -weighted (for brain volumes). Body weight and urine specific gravity were also measured. TWC was calculated by fitting the T2 relaxation data with a nonnegative least-squares algorithm, with corrections for T1 relaxation and image signal inhomogeneity and normalization to ventricular cerebrospinal fluid. Brain volume changes were measured using SIENA. TWC means were calculated within 14 tissue regions. RESULTS: Despite indications of dehydration as demonstrated by increases in urine specific gravity (P = 0.03) and decreases in body weight (P = 0.001) between hydrated and dehydrated scans, there was no measurable change in TWC (within any brain region) or brain volume between hydration states. CONCLUSION: We demonstrate that within a range of physiologic conditions commonly encountered in routine clinical scans (no pretreatment with hydration, well hydrated before MRI, and overnight fasting), brain TWC and brain volumes are not substantially affected in a healthy control cohort. J. Magn. Reson. Imaging 2016;44:296-304.

High-resolution myelin water imaging in post-mortem multiple sclerosis spinal cord: A case report.

BACKGROUND: Loss of myelin in the spinal cord in multiple sclerosis (MS) is likely an important, and early, contributor to atrophy and associated disability. In vivo measurement of myelin is possible using myelin water fraction (MWF) imaging, but MWF has never been assessed in MS along the entire length of the spinal cord in vivo or in post-mortem tissue. OBJECTIVE: To assess the feasibility of measuring the distribution of MWF along the entire length of the spinal cord in post-mortem MS tissue using high-field MRI. METHODS: One formalin-fixed spinal cord from a female with secondary progressive MS (age: 78 years, disease duration: 25 years) was cut into 104 5-mm-thick cross sections along the entire length of the spinal cord from the cervico-medullary junction to the conus medullaris and imaged using a 64 echo T2 relaxation experiment at 7T. RESULTS: Myelin water maps showed cord anatomy in superb detail, white matter demonstrating a higher MWF than the grey matter. Anatomical variation in myelin distribution along cervical, thoracic and lumbar regions was observed. Lesions demonstrated myelin loss. CONCLUSION: Post-mortem myelin water imaging of formalin-fixed MS spinal cord is feasible.

Comparison of myelin water fraction from multiecho T2 decay curve and steady-state methods.

PURPOSE: Myelin water fraction is conventionally measured from the T2 decay curve. Recently, a steady-state approach entitled multicomponent-driven equilibrium single pulse observation of T1 /T2 (mcDESPOT) was employed for myelin water fraction mapping. However, no direct comparison between the established multiecho T2 relaxation method and mcDESPOT has been performed. METHODS: Gradient and spin echo (GRASE) acquired T2 decay curve and mcDESPOT measurements were acquired from 10 healthy volunteers using a 3T MRI. We compared myelin water fraction, transmit radio frequency field (B1 ), and T2 's of intra- and extracellular water obtained from both methods. RESULTS: For all brain regions examined, myelin water fractions from mcDESPOT were significantly higher than those from multiecho GRASE. B1 maps were qualitatively similar between GRASE and mcDESPOT, but multicomponent T2 times were significantly different. To investigate the effect of exchange, mcDESPOT data were analyzed with and without exchange. When exchange was turned off, intra- and extracellular T2 times from mcDESPOT were roughly consistent with GRASE results; however, myelin water fractions derived from mcDESPOT were still significantly higher than those derived from GRASE. CONCLUSION: Myelin water fraction values derived from mcDESPOT cannot be considered to be equivalent to those derived from T2 decay curve approaches.

How does magnetization transfer influence mcDESPOT results?

PURPOSE: A steady-state approach that was termed multicomponent driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) has recently been proposed for myelin water fraction (fM) mapping in brain development and demyelinating diseases. However, fMs estimated by mcDESPOT are significantly higher than myelin water fraction derived from multiecho spin echo T2-decay curve approaches. Magnetization transfer (MT), enhanced by the use of short, relatively high amplitude radiofrequency (RF) pulses in mcDESPOT, may artifactually influence fM maps. Our goal was to investigate the role of MT in mcDESPOT. METHODS: mcDESPOT data was collected twice from three healthy volunteers using short RF pulses with higher MT effect and long RF pulses with lower MT effect. MR parameters from 11 white and gray regions were compared using a paired student t-test. Whole slice difference images were also compared. RESULTS: MT effects had a substantial influence on the signal generated by the balanced steady-state free procession sequences used in mcDESPOT. However, these MT effects were not clearly evident in the fM values determined by the conventional two-pool mcDESPOT analysis. CONCLUSION: The signal generated from mcDESPOT is sensitive to MT, but the extracted myelin water fractions are relatively insensitive to changes of MT.

Pathological correlates of magnetic resonance imaging texture heterogeneity in multiple sclerosis.

OBJECTIVE: To analyze the texture of T2-weighted magnetic resonance imaging (MRI) of postmortem multiple sclerosis (MS) brain, and to determine whether and how MRI texture correlates with tissue pathology. METHODS: Ten brain samples from 3 subjects with MS were examined. Areas of complete, partial, or no loss of Luxol fast blue (myelin) and Bielschowsky (axons) staining were marked on histological images, and matched on corresponding MRI as lesions, diffusely abnormal white matter (DAWM), and normal-appearing white matter (NAWM). The number of CD45(+) cells (inflammation) was also counted. MRI texture was computed using polar Stockwell transform and compared to histology. RESULTS: Thirty-four lesions, 17 DAWM regions, and 36 NAWM regions were identified. After mixed effects modeling, MRI texture heterogeneity was greater in lesions than in DAWM (p < 0.001) and NAWM (p < 0.001), and was greater in DAWM than in NAWM (p < 0.001); the number of CD45+ cells was greater in both lesions (p < 0.001) and DAWM (p = 0.005) than in NAWM. In MRI, a gradient of texture heterogeneity was detected in lesions, with gradual tapering toward perilesional NAWM. Moreover, besides univariate correlation with histological markers, texture heterogeneity correlated independently with normalized myelin density (p < 0.01) when random effects were considered. Within sample, MRI texture correlated with myelin and axonal density in 7 of 10 samples (p < 0.01). INTERPRETATION: Texture analysis performed on routine clinical magnetic resonance images may be a potential measure of tissue integrity. Tissues with more severe myelin and axonal pathology are associated with greater texture heterogeneity.

Serum glial fibrillary acidic protein as a marker of brain MRI metrics in multiple sclerosis: A scoping review.

BACKGROUND AND PURPOSE: Magnetic resonance imaging (MRI) is heavily relied upon for the diagnosis and monitoring of multiple sclerosis (MS), a chronic, demyelinating disease of the central nervous system. Serum biomarkers may serve as an accessible tool for increasing sensitivity, improving accessibility, corroborating symptoms, and providing additional data to guide clinical management. This scoping review investigates the current understanding of how the serum biomarker glial fibrillary acidic protein (sGFAP) relates to brain MRI metrics. METHODS: We adhered to the Joanna Briggs Institute methodology for scoping reviews and the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. The databases Medline (Ovid), Embase (Ovid), CINAHL (Ebsco), and Web of Science (University of British Columbia institutional access) were searched on August 24, 2023 using a combination of medical subject headings and keyword terms for the topic of serum biomarkers in MS. RESULTS: A total of 9880 articles were retrieved in total of which 6271 unique titles and abstracts were screened. Twelve of the 259 resultant papers contained sGFAP data and proceeded to extraction. It was found that lesion MRI metrics generally had a positive relationship with sGFAP, while gray matter and white matter metrics, including normal-appearing white matter, were related negatively or not at all. CONCLUSIONS: These results highlight that while sGFAP may not be specific for MS, it may have utility for increasing sensitivity in postdiagnosis monitoring of MS progression.

The myelin water imaging transcriptome: myelin water fraction regionally varies with oligodendrocyte-specific gene expression.

Identifying sensitive and specific measures that can quantify myelin are instrumental in characterizing microstructural changes in neurological conditions. Neuroimaging transcriptomics is emerging as a valuable technique in this regard, offering insights into the molecular basis of promising candidates for myelin quantification, such as myelin water fraction (MWF). We aimed to demonstrate the utility of neuroimaging transcriptomics by validating MWF as a myelin measure. We utilized data from a normative MWF brain atlas, comprised of 50 healthy subjects (mean age = 25 years, range = 17-42 years) scanned at 3 Tesla. Magnetic resonance imaging data included myelin water imaging to extract MWF and T1 anatomical scans for image registration and segmentation. We investigated the inter-regional distributions of gene expression data from the Allen Human Brain Atlas in conjunction with inter-regional MWF distribution patterns. Pearson correlations were used to identify genes with expression profiles mirroring MWF. The Single Cell Type Atlas from the Human Protein Atlas was leveraged to classify genes into gene sets with high cell type specificity, and a control gene set with low cell type specificity. Then, we compared the Pearson correlation coefficients for each gene set to determine if cell type-specific gene expression signatures correlate with MWF. Pearson correlation coefficients between MWF and gene expression for oligodendrocytes and adipocytes were significantly higher than for the control gene set, whereas correlations between MWF and inhibitory/excitatory neurons were significantly lower. Our approach in integrating transcriptomics with neuroimaging measures supports an emerging technique for understanding and validating MRI-derived markers such as MWF.

Advanced Magnetic Resonance Imaging Biomarkers of the Injured Spinal Cord: A Comparative Study of Imaging and Histology in Human Traumatic Spinal Cord Injury.

A significant problem in the diagnosis and management of traumatic spinal cord injury (tSCI) is the heterogeneity of secondary injury and the prediction of neurological outcome. Imaging biomarkers specific to myelin loss and inflammation after tSCI would enable detailed assessment of the pathophysiological processes underpinning secondary damage to the cord. Such biomarkers could be used to biologically stratify injury severity and better inform prognosis for neurological recovery. While much work has been done to establish magnetic resonance imaging (MRI) biomarkers for SCI in animal models, the relationship between imaging findings and the underlying pathology has been difficult to discern in human tSCI because of the paucity of human spinal cord tissue. We utilized post-mortem spinal cords from individuals who had a tSCI to examine this relationship by performing ex vivo MRI scans before histological analysis. We investigated the correlation between the histological distribution of myelin loss and inflammatory cells in the injured spinal cord and a number of myelin and inflammation-sensitive MRI measures: myelin water fraction (MWF), inhomogeneous magnetization transfer ratio (ihMTR), and diffusion tensor and diffusion kurtosis imaging-derived fractional anisotropy (FA) and axial, radial, and mean diffusivity (AD, RD, MD). The histological features were analyzed by staining with Luxol Fast Blue (LFB) for myelin lipids and Class II major histocompatibility complex (Class II MHC) and CD68 for microglia and macrophages. Both MWF and ihMTR were strongly correlated with LFB staining for myelin, supporting the use of both as biomarkers for myelin loss after SCI. A decrease in ihMTR was also correlated with the presence of Class II MHC positive immune cells. FA and RD correlated with both Class II MHC and CD68 and may therefore be useful biomarkers for inflammation after tSCI. Our work demonstrates the utility of advanced MRI techniques sensitive to biological tissue damage after tSCI, which is an important step toward using these MRI techniques in the clinic to aid in decision-making.