Evaluation of microglia activation related markers following a clinical course of TBS: A non-human primate study.

While the applicability and popularity of theta burst stimulation (TBS) paradigms remain, current knowledge of their neurobiological effects is still limited, especially with respect to their impact on glial cells and neuroinflammatory processes. We used a multimodal imaging approach to assess the effects of a clinical course of TBS on markers for microglia activation and tissue injury as an indirect assessment of neuroinflammatory processes. Healthy non-human primates received continuous TBS (cTBS), intermittent TBS (iTBS), or sham stimulation over the motor cortex at 90% of resting motor threshold. Stimulation was delivered to the awake subjects 5 times a week for 3-4 weeks. Translocator protein (TSPO) expression was evaluated using Positron Emission Tomography and [11C]PBR28, and myo-inositol (mI) and N-acetyl-aspartate (NAA) concentrations were assessed with Magnetic Resonance Spectroscopy. Animals were then euthanized, and immunofluorescence staining was performed using antibodies against TSPO. Paired t-tests showed no significant changes in [11C]PBR28 measurements after stimulation. Similarly, no significant changes in mI and NAA concentrations were found. Post-mortem TSPO evaluation showed comparable mean immunofluorescence intensity after active TBS and sham delivery. The current study suggests that in healthy brains a clinical course of TBS, as evaluated with in-vivo imaging techniques (PET and MRS), did not measurably modulate the expression of glia related markers and metabolite associated with neural viability.

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.

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.

Myelin and Physical Activity in Older Adults With Cerebral Small Vessel Disease and Mild Cognitive Impairment.

BACKGROUND: Myelin loss is a feature of cerebral small vessel disease (cSVD). Although physical activity levels may exert protective effects over cSVD pathology, its specific relationship with myelin content in people living with the cSVD is unknown. Thus, we investigated whether physical activity levels are associated with myelin in community-dwelling older adults with cSVD and mild cognitive impairment. METHODS: Cross-sectional data from 102 individuals with cSVD and mild cognitive impairment were analyzed (mean age [SD] = 74.7 years [5.5], 63.7% female). Myelin was measured using a magnetic resonance gradient and spin echo sequence. Physical activity was estimated using the Physical Activity Scale for the Elderly. Hierarchical regression models adjusting for total intracranial volume, age, sex, body mass index, and education were conducted to determine the associations between myelin content and physical activity. Significant models were further adjusted for white matter hyperintensity volume. RESULTS: In adjusted models, greater physical activity was linked to higher myelin content in the whole-brain white matter (R2change = .04, p = .048). Greater physical activity was also associated with myelin content in the sagittal stratum (R2change = .08, p = .004), anterior corona radiata (R2change = .04, p = .049), and genu of the corpus callosum (R2change = .05, p = .018). Adjusting for white matter hyperintensity volume did not change any of these associations. CONCLUSIONS: Physical activity may be a strategy to maintain myelin in older adults with cSVD and mild cognitive impairment. Future randomized controlled trials of exercise are needed to determine whether exercise increases myelin content.

Myelin heterogeneity for assessing normal appearing white matter myelin damage in multiple sclerosis.

BACKGROUND AND PURPOSE: Conventional MRI measures of multiple sclerosis (MS) disease severity, such as lesion volume and brain atrophy, do not provide information about microstructural tissue changes, which may be driving physical and cognitive progression. Myelin damage in normal-appearing white matter (NAWM) is likely an important contributor to MS disability. Myelin water fraction (MWF) provides quantitative measurements of myelin. Mean MWF reflects average myelin content, while MWF standard deviation (SD) describes variation in myelin within regions. The myelin heterogeneity index (MHI = SD/mean MWF) is a composite metric of myelin content and myelin variability. We investigated how mean MWF, SD, and MHI compare in differentiating MS from controls and their associations with physical and cognitive disability. METHODS: Myelin water imaging data were acquired from 91 MS participants and 31 healthy controls (HC). Segmented whole-brain NAWM and corpus callosum (CC) NAWM, mean MWF, SD, and MHI were compared between groups. Associations of mean MWF, SD, and MHI with Expanded Disability Status Scale and Symbol Digit Modalities Test were assessed. RESULTS: NAWM and CC MHI had the highest area under the curve: .78 (95% confidence interval [CI]: .69, .86) and .84 (95% CI: .76, .91), respectively, distinguishing MS from HC. CONCLUSIONS: Mean MWF, SD, and MHI provide complementary information when assessing regional and global NAWM abnormalities in MS and associations with clinical outcome measures. Examining all three metrics (mean MWF, SD, and MHI) enables a more detailed interpretation of results, depending on whether regions of interest include areas that are more heterogeneous, earlier in the demyelination process, or uniformly injured.

Comparing myelin-sensitive magnetic resonance imaging measures and resulting g-ratios in healthy and multiple sclerosis brains.

The myelin concentration and the degree of myelination of nerve fibers can provide valuable information on the integrity of human brain tissue. Magnetic resonance imaging (MRI) of myelin-sensitive parameters can help to non-invasively evaluate demyelinating diseases such as multiple sclerosis (MS). Several different myelin-sensitive MRI methods have been proposed to determine measures of the degree of myelination, in particular the g-ratio. However, variability in underlying physical principles and different biological models influence measured myelin concentrations, and consequently g-ratio values. We therefore investigated similarities and differences between five different myelin-sensitive MRI measures and their effects on g-ratio mapping in the brains of both MS patients and healthy volunteers. We compared two different estimates of the myelin water fraction (MWF) as well as the inhomogeneous magnetization transfer ratio (ihMTR), magnetization transfer saturation (MTsat), and macromolecular tissue volume (MTV) in 13 patients with MS and 14 healthy controls. In combination with diffusion-weighted imaging, we derived g-ratio parameter maps for each of the five different myelin measures. The g-ratio values calculated from different myelin measures varied strongly, especially in MS lesions. While, compared to normal-appearing white matter, MTsat and one estimate of the MWF resulted in higher g-ratio values within lesions, ihMTR, MTV, and the second MWF estimate resulted in lower lesion g-ratio values. As myelin-sensitive measures provide rough estimates of myelin content rather than absolute myelin concentrations, resulting g-ratio values strongly depend on the utilized myelin measure and model used for g-ratio mapping. When comparing g-ratio values, it is, thus, important to utilize the same MRI methods and models or to consider methodological differences. Particular caution is necessary in pathological tissue such as MS lesions.

A pilot study comparing myelin measurements from myelin water imaging and 11C-PIB PET in multiple sclerosis.

MRI-based myelin water fraction (MWF) and PET-based Pittsburgh compound B (PiB) imaging both have potential to measure myelin in multiple sclerosis (MS). We characterised the differences in MWF and PiB binding in MS lesions relative to normal-appearing white matter and assessed the correlation between MWF and PiB binding in 11 MS participants and 3 healthy controls within 14 white matter regions of interest. Both PiB binding and MWF were reduced in MS lesions relative to NAWM, and a modest within subject correlation between MWF and PiB binding was found. This pilot study shows that MWF and PET-PiB provide different information about myelin loss in MS.

Myelin Content and Gait Impairment in Older Adults with Cerebral Small Vessel Disease and Mild Cognitive Impairment.

We investigated whether myelin is associated with gait parameters in older adults with cerebral small vessel disease (cSVD). Cross-sectional data from sixty-four participants with cSVD and mild cognitive impairment were analyzed. Myelin was assessed via MRI multi-echo gradient and spin echo T2 relaxation sequence, indexed as myelin water fraction (MWF). Gait was assessed using an electronic walkway. Hierarchical regression models adjusting for total intracranial volume, age, sex, Mini-Mental State Examination, and body mass index were conducted to determine associations between MWF and gait parameters. Significant models were further adjusted for white matter hyperintensities. Sixty-four participants were included (mean [SD], age = 75.2y [5.4], 62.5% female). In adjusted models, lower MWF in the cingulum (p = 0.015), superior longitudinal fasciculus (p = 0.034), posterior corona radiata (p = 0.039), and body of the corpus callosum (p = 0.040) was associated with higher cycle time variability. White matter hyperintensities weakened these associations. Lower myelin in specific white matter tracts may contribute to higher gait variability, increasing the overall risk of mobility impairment.

Myelin water imaging in relapsing multiple sclerosis treated with ocrelizumab and interferon beta-1a.

BACKGROUND: Myelin water imaging is a magnetic resonance imaging (MRI) technique that quantifies myelin damage and repair in multiple sclerosis (MS) via the myelin water fraction (MWF). OBJECTIVE: In this substudy of a phase 3 therapeutic trial, OPERA II, MWF was assessed in relapsing MS participants assigned to interferon beta-1a (IFNb-1a) or ocrelizumab (OCR) during a two-year double-blind period (DBP) followed by a two-year open label extension (OLE) with ocrelizumab treatment. METHODS: MWF in normal appearing white matter (NAWM), including both whole brain NAWM and 5 white matter structures, and chronic lesions, was assessed in 29 OCR and 26 IFNb-1a treated participants at weeks 0, 24, 48 and 96 (DBP), and weeks 144 and 192 (OLE), and in white matter for 23 healthy control participants at weeks 0, 48 and 96. RESULTS: Linear mixed-effects models of data from baseline to week 96 showed a difference in the change in MWF over time favouring ocrelizumab in all NAWM regions. At week 192, lesion MWF was lower for participants originally randomised to IFNb-1a compared to those originally randomised to OCR. Controls showed no change in MWF over 96 weeks in any region. CONCLUSION: Ocrelizumab appears to protect against demyelination in MS NAWM and chronic lesions and may allow for a more permissive micro environment for remyelination to occur in focal and diffusely damaged tissue.

In vivo myelin imaging and tissue microstructure in white matter hyperintensities and perilesional white matter.

White matter hyperintensities negatively impact white matter structure and relate to cognitive decline in aging. Diffusion tensor imaging detects changes to white matter microstructure, both within the white matter hyperintensity and extending into surrounding (perilesional) normal-appearing white matter. However, diffusion tensor imaging markers are not specific to tissue components, complicating the interpretation of previous microstructural findings. Myelin water imaging is a novel imaging technique that provides specific markers of myelin content (myelin water fraction) and interstitial fluid (geometric mean T2). Here we combined diffusion tensor imaging and myelin water imaging to examine tissue characteristics in white matter hyperintensities and perilesional white matter in 80 individuals (47 older adults and 33 individuals with chronic stroke). To measure perilesional normal-appearing white matter, white matter hyperintensity masks were dilated in 2 mm segments up to 10 mm in distance from the white matter hyperintensity. Fractional anisotropy, mean diffusivity, myelin water fraction, and geometric mean T2 were extracted from white matter hyperintensities and perilesional white matter. We observed a spatial gradient of higher mean diffusivity and geometric mean T2, and lower fractional anisotropy, in the white matter hyperintensity and perilesional white matter. In the chronic stroke group, myelin water fraction was reduced in the white matter hyperintensity but did not show a spatial gradient in perilesional white matter. Across the entire sample, white matter metrics within the white matter hyperintensity related to whole-brain white matter hyperintensity volume; with increasing white matter hyperintensity volume there was increased mean diffusivity and geometric mean T2, and decreased myelin water fraction in the white matter hyperintensity. Normal-appearing white matter adjacent to white matter hyperintensities exhibits characteristics of a transitional stage between healthy white matter and white matter hyperintensities. This effect was observed in markers sensitive to interstitial fluid, but not in myelin water fraction, the specific marker of myelin concentration. Within the white matter hyperintensity, interstitial fluid was higher and myelin concentration was lower in individuals with more severe cerebrovascular disease. Our data suggests white matter hyperintensities have penumbra-like effects in perilesional white matter that specifically reflect increased interstitial fluid, with no changes to myelin concentration. In contrast, within the white matter hyperintensity there are varying levels of demyelination, which vary based on the severity of cerebrovascular disease. Diffusion tensor imaging and myelin imaging may be useful clinical markers to predict white matter hyperintensity formation, and to stage neuronal damage within white matter hyperintensities.

Serum neurofilament light chain correlates with myelin and axonal magnetic resonance imaging markers in multiple sclerosis.

BACKGROUND: Neurofilaments are cytoskeletal proteins that are detectable in the blood after neuroaxonal injury. Multiple sclerosis (MS) disease progression, greater lesion volume, and brain atrophy are associated with higher levels of serum neurofilament light chain (NfL), but few studies have examined the relationship between NfL and advanced magnetic resonance imaging (MRI) measures related to myelin and axons. We assessed the relationship between serum NfL and brain MRI measures in a diverse group of MS participants. METHODS AND MATERIALS: 103 participants (20 clinically isolated syndrome, 33 relapsing-remitting, 30 secondary progressive, 20 primary progressive) underwent 3T MRI to obtain myelin water fraction (MWF), geometric mean T2 (GMT2), water content, T1; high angular resolution diffusion imaging (HARDI)-derived axial diffusivity (AD), radial diffusivity (RD), fractional anisotropy (FA); diffusion basis spectrum imaging (DBSI)-derived AD, RD, FA; restricted, hindered, water and fiber fractions; and volume measurements of normalized brain, lesion, thalamic, deep gray matter (GM), and cortical thickness. Multiple linear regressions assessed the strength of association between serum NfL (dependent variable) and each MRI measure in whole brain (WB), normal appearing white matter (NAWM) and T2 lesions (independent variables), while controlling for age, expanded disability status scale, and disease duration. RESULTS: Serum NfL levels were significantly associated with metrics of axonal damage (FA: R2WB-HARDI = 0.29, R2NAWM-HARDI = 0.31, R2NAWM-DBSI = 0.30, R2Lesion-DBSI = 0.31; AD: R2WB-HARDI=0.31), myelin damage (MWF: R2WB = 0.29, R2NAWM = 0.30, RD: R2WB-HARDI = 0.32, R2NAWM-HARDI = 0.34, R2Lesion-DBSI = 0.30), edema and inflammation (T1: R2Lesion = 0.32; GMT2: R2WB = 0.31, R2Lesion = 0.31), and cellularity (restricted fraction R2WB = 0.30, R2NAWM = 0.32) across the entire MS cohort. Higher serum NfL levels were associated with significantly higher T2 lesion volume (R2 = 0.35), lower brain structure volumes (thalamus R2 = 0.31; deep GM R2 = 0.33; normalized brain R2 = 0.31), and smaller cortical thickness R2 = 0.31). CONCLUSION: The association between NfL and myelin MRI markers suggest that elevated serum NfL is a useful biomarker that reflects not only acute axonal damage, but also damage to myelin and inflammation, likely due to the known synergistic myelin-axon coupling relationship.

Cervical Spinal Cord Atrophy can be Accurately Quantified Using Head Images.

BACKGROUND: Spinal cord atrophy provides a clinically relevant metric for monitoring MS. However, the spinal cord is imaged far less frequently than brain due to artefacts and acquisition time, whereas MRI of the brain is routinely performed. OBJECTIVE: To validate spinal cord cross-sectional area measurements from routine 3DT1 whole-brain MRI versus those from dedicated cord MRI in healthy controls and people with MS. METHODS: We calculated cross-sectional area at C1 and C2/3 using T2*-weighted spinal cord images and 3DT1 brain images, for 28 healthy controls and 73 people with MS. Correlations for both groups were assessed between: (1) C1 and C2/3 using cord images; (2) C1 from brain and C1 from cord; and (3) C1 from brain and C2/3 from cord. RESULTS AND CONCLUSION: C1 and C2/3 from cord were strongly correlated in controls (r = 0.94, p<0.0001) and MS (r = 0.85, p<0.0001). There was strong agreement between C1 from brain and C2/3 from cord in controls (r = 0.84, p<0.0001) and MS (r = 0.81, p<0.0001). This supports the use of C1 cross-sectional area calculated from brain imaging as a surrogate for the traditional C2/3 cross-sectional area measure for spinal cord atrophy.

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.

Diffusely abnormal white matter in multiple sclerosis.

MRI enables detailed in vivo depiction of multiple sclerosis (MS) pathology. Localized areas of MS damage, commonly referred to as lesions, or plaques, have been a focus of clinical and research MRI studies for over four decades. A nonplaque MRI abnormality which is present in at least 25% of MS patients but has received far less attention is diffusely abnormal white matter (DAWM). DAWM has poorly defined boundaries and a signal intensity that is between normal-appearing white matter and classic lesions on proton density and T2 -weighted images. All clinical phenotypes of MS demonstrate DAWM, including clinically isolated syndrome, where DAWM is associated with higher lesion volume, reduced brain volume, and earlier conversion to MS. Advanced MRI metric abnormalities in DAWM tend to be greater than those in NAWM, but not as severe as focal lesions, with myelin, axons, and water-related changes commonly reported. Histological studies demonstrate a primary lipid abnormality in DAWM, with some axonal damage and lesser involvement of myelin proteins. This review provides an overview of DAWM identification, summarizes in vivo and postmortem observations, and comments on potential pathophysiological mechanisms, which may underlie DAWM in MS. Given the prevalence and potential clinical impact of DAWM, the number of imaging studies focusing on DAWM is insufficient. Characterization of DAWM significance and microstructure would benefit from larger longitudinal and additional quantitative imaging efforts. Revisiting data from previous studies that included proton density and T2 imaging would enable retrospective DAWM identification and analysis.

Elevated levels of serum CD5 antigen-like protein distinguish secondary progressive multiple sclerosis from other disease subtypes.

CD5 antigen-like (CD5L) protein is a macrophage-secreted protein with roles in immunomodulation and lipid homeostasis. We compared serum CD5L levels in healthy controls to individuals diagnosed with clinically isolated syndrome, relapsing remitting (RR), secondary progressive (SP), and primary progressive (PP) multiple sclerosis (MS). CD5L was increased in SPMS relative to controls, RRMS, and PPMS. SPMS CD5L was associated with longer disease duration independent of age, sex, or disease severity. The positive relationship between CD5L and disease duration in SPMS suggests a chronic peripheral inflammatory profile compared to other subtypes, particularly PPMS, warranting investigation of functional roles for CD5L in MS.

Water content changes in new multiple sclerosis lesions have a minimal effect on the determination of myelin water fraction values.

BACKGROUND AND PURPOSE: Myelin water fraction (MWF) is a histopathologically validated in vivo myelin marker. As MWF is the proportion of water with a short T2 relative to the total water, increases in water from edema and inflammation may confound MWF determination in multiple sclerosis (MS) lesions. Total water content (TWC) measurement enables calculation of absolute myelin water content (MWC) and can be used to distinguish edema/inflammation from demyelination. We assessed what influence changes in total water might have on MWF by calculating MWC values in new MS lesions. METHODS: 3T 32-echo T2 relaxation data were collected monthly for 6 months from six relapsing-remitting MS participants. TWC was determined and multiplied with MWF images to calculate corrected MWC images. The effect of this water content correction was examined in 20 new lesions by comparing mean MWF and MWC over time. RESULTS: On average, at lesion first appearance, lesion TWC increased by 6.4% (p = .003; range: -1% to +21%), MWF decreased by 24% (p = .006; range: -70% to +12%), and MWC decreased by 20% (p = .026; range: -68% to +21%), relative to prelesion values. Average TWC in lesions then gradually decreased, whereas MWF and MWC remained low. The shape of the MWF and MWC lesion evolution curves was nearly identical, differing only by an offset. CONCLUSION: MWF mirrors MWC and is able to monitor myelin in new lesions. Even after taking into account water content increases, MWC still decreased at lesion first appearance attributed to demyelination.

Nonlesional diffusely abnormal appearing white matter in clinically isolated syndrome: Prevalence, association with clinical and MRI features, and risk for conversion to multiple sclerosis.

BACKGROUND AND PURPOSE: While diffusely abnormal white matter (DAWM) is a nonlesional MRI abnormality identified in ∼25% of patients with multiple sclerosis (MS), it has yet to be investigated in patients at an earlier disease stage, namely clinically isolated syndrome (CIS). The goals of this study were to (1) determine the prevalence of DAWM in patients with a CIS suggestive of MS, (2) evaluate the association between DAWM and demographic, clinical, and MRI features, and (3) evaluate the prognostic significance of DAWM on conversion from CIS to MS. METHODS: One hundred and forty-two CIS participants were categorized into DAWM and non-DAWM groups at baseline and followed for up to 24 months or until MS diagnosis. The primary outcome was conversion to MS (2005 McDonald criteria) within 6 months. RESULTS: DAWM was present in 27.5% of participants, and was positively associated with brainstem symptom onset, receiving corticosteroids, dissemination in space, and T2 lesion volume. DAWM was associated with an increased risk of conversion to MS over 6 months after adjustment for age and disability (hazard ratio [HR] = 2.24, p = 0.004). This association remained at a trend-level after adjustment for high-risk imaging features (HR = 1.68, p = 0.10). CONCLUSIONS: DAWM is present in a similar proportion of patients with CIS and clinically definite MS, and it is associated with increased risk of conversion to MS over 6 months.

Cortical N-acetylaspartate concentrations are impacted in chronic stroke but do not relate to motor impairment: A magnetic resonance spectroscopy study.

Magnetic resonance spectroscopy (MRS) measures cerebral metabolite concentrations, which can inform our understanding of the neurobiological processes associated with stroke recovery. Here, we investigated whether metabolite concentrations in primary motor and somatosensory cortices (sensorimotor cortex) are impacted by stroke and relate to upper-extremity motor impairment in 45 individuals with chronic stroke. Cerebral metabolite estimates were adjusted for cerebrospinal fluid and brain tissue composition in the MRS voxel. Upper-extremity motor impairment was indexed with the Fugl-Meyer (FM) scale. N-acetylaspartate (NAA) concentration was reduced bilaterally in stroke participants with right hemisphere lesions (n = 23), relative to right-handed healthy older adults (n = 15; p = .006). Within the entire stroke sample (n = 45) NAA and glutamate/glutamine (GLX) were lower in the ipsilesional sensorimotor cortex, relative to the contralesional cortex (NAA: p < .001; GLX: p = .003). Lower ipsilesional NAA was related to greater extent of corticospinal tract (CST) injury, quantified by a weighted CST lesion load (p = .006). Cortical NAA and GLX concentrations did not relate to the severity of chronic upper-extremity impairment (p > .05), including after a sensitivity analysis imputing missing metabolite data for individuals with large cortical lesions (n = 5). Our results suggest that NAA, a marker of neuronal integrity, is sensitive to stroke-related cortical damage and may provide mechanistic insights into cellular processes of cortical adaptation to stroke. However, cortical MRS metabolites may have limited clinical utility as prospective biomarkers of upper-extremity outcomes in chronic stroke.

Myelin water fraction decrease in individuals with chronic mild traumatic brain injury and persistent symptoms.

The diffuse and continually evolving secondary changes after mild traumatic brain injury (mTBI) make it challenging to assess alterations in brain-behaviour relationships. In this study we used myelin water imaging to evaluate changes in myelin water fraction (MWF) in individuals with chronic mTBI and persistent symptoms and measured their cognitive status using the NIH Toolbox Cognitive Battery. Fifteen adults with mTBI with persistent symptoms and twelve age, gender and education matched healthy controls took part in this study. We found a significant decrease in global white matter MWF in patients compared to the healthy controls. Significantly lower MWF was evident in most white matter region of interest (ROIs) examined including the corpus callosum (separated into genu, body and splenium), minor forceps, right anterior thalamic radiation, left inferior longitudinal fasciculus; and right and left superior longitudinal fasciculus and corticospinal tract. Although patients showed lower cognitive functioning, no significant correlations were found between MWF and cognitive measures. These results suggest that individuals with chronic mTBI who have persistent symptoms have reduced MWF.

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.