Normal-appearing White Matter Of Patients Research Articles

Enhancing T1 signal of normal-appearing white matter with divided subtracted inversion recovery: A pilot study in mild traumatic brain injury.

Magnetic resonance imaging (MRI) and cognitive profiles in patients with mild traumatic brain injury (mTBI) are often discordant. Conventional MRI seldom captures the full extent of pathological changes in the normal-appearing white matter (NAWM). The divided subtracted inversion recovery (dSIR) technique may enhance T1 differences in NAWM, making them easily visible. We aimed to implement dSIR on a clinical scanner and tested results in mTBI patients. To produce dSIR images, Inversion Recovery-Turbo Spin Echo sequences were modified using six different inversion times (TI) on a 3-T scanner in healthy participants and patients with mTBI. The multiple TIs determined normal white (TIshort) and gray matter (TIlong) nulling points in healthy subjects, which were used to create dSIR images. In one patient, the protocol was repeated at 3 months to identify changes after rehabilitation. Diffusion tensor imaging (DTI)-derived mean diffusivity (MD) and fractional anisotropy (FA) maps were aligned to dSIR images to ensure that signal was not artefactual. Ten healthy participants (five females; age 24 ± 3 [95% CI: 21, 26] years) were included. TIshort and TIlong were set at 450 and 750 ms, respectively. In both patients (one male, age 17 years; one female, age 14 years), dSIR images revealed areas with increased T1 in the NAWM not visible on conventional MRI. dSIR-based hyperintensities corresponded to elevated MD and reduced FA. Substantial changes were found at follow-up with improvement in DTI-based parameters. dSIR images enhance subtle changes in the NAWM of patients with mTBI by amplifying their intrinsic T1 signal.

Ultra-High Contrast MRI: Using Divided Subtracted Inversion Recovery (dSIR) and Divided Echo Subtraction (dES) Sequences to Study the Brain and Musculoskeletal System.

Divided and subtracted MRI is a novel imaging processing technique, where the difference of two images is divided by their sum. When the sequence parameters are chosen properly, this results in images with a high T1 or T2 weighting over a small range of tissues with specific T1 and T2 values. In the T1 domain, we describe the implementation of the divided Subtracted Inversion Recovery Sequence (dSIR), which is used to image very small changes in T1 from normal in white matter. dSIR has shown widespread changes in otherwise normal-appearing white matter in patients suffering from mild traumatic brain injury (mTBI), substance abuse, and ischemic leukoencephalopathy. It can also be targeted to measure small changes in T1 from normal in other tissues. In the T2 domain, we describe the divided echo subtraction (dES) sequence that is used to image musculoskeletal tissues with a very short T2*. These tissues include fascia, tendons, and aponeuroses. In this manuscript, we explain how this contrast is generated, review how these techniques are used in our research, and discuss the current challenges and limitations of this technique.

Diffusion Tensor Imaging for Interpreting Fractional Anisotropy and Mean Diffusivity in Normal-appearing White Matter of Patients with HIV-associated Neurocognitive Disorders: A Case-control Study

Introduction: {Human Immunodeficiency Virus (HIV)-associated Neurocognitive Disorder (HAND)} affects the everyday functioning of patients. It is usually difficult to diagnose HAND in the outpatient setting as detailed neuropsychological performance testing, such as the International HIV Dementia Scale (IHDS), is required. Neuroimaging techniques hold great promise in the early diagnosis and management of HAND, but there is a paucity of studies on the evaluation of HAND using Diffusion Tensor Imaging (DTI) in the Indian population. Aim: To investigate DTI and interpret Fractional Anisotropy (FA) and Mean Diffusivity (MD) values in the White Matter (WM) of patients with HAND and compare them with age and sex- matched controls. Materials and Methods: A case-control study was conducted at the Department of Radiodiagnosis, ABVIMS and Dr. RML Hospital, New Delhi, India, from January 2021 to May 2022. Thirty subjects (15 cases and 15 controls) were included. HIV-positive patients underwent the IHDS to assess cognitive impairment. Magnetic Resonance Imaging (MRI) examination was performed at three tesla using conventional sequences, and DTI was applied. Maps of FA and MD values were generated. Mean FA and MD values of normal-appearing white matter tracts between cases and controls were compared using a t-test. Spearman's correlation test was applied to assess the correlation between IHDS scores and DTI parameters. Results: The majority of cases in the study were in the age group of 31-40 years, and the mean age of cases was 41.27±11.16 years. The present study revealed significantly lower FA values compared to controls in bilateral Frontal WM, Parieto-occipital WM, genu of the Corpus Callosum (CC), right hippocampal WM, and right corona radiata. The mean MD of bilateral Frontal WM, Parieto-occipital WM, corona radiata, and Hippocampal WM was significantly increased in cases compared to healthy controls. A significant association was found between the IHDS score and FA values of the genu of the CC (rho= 0.7), right corona radiata (rho= 0.7), right Hippocampal WM (rho= 0.9), and MD of the left Parieto-occipital WM (rho= -0.6), and left hippocampal WM (rho= -0.5). Conclusion: Diffusion tensor MR imaging can detect abnormalities that are missed by routine MR imaging. DTI provides a valuable marker to monitor HIV-associated Central Nervous System (CNS) injury, which can lead to neurocognitive impairment.

Impaired oxygen extraction and adaptation of intracellular energy metabolism in cerebral small vessel disease.

We aimed to investigate whether combined phosphorous (31P) magnetic resonance spectroscopic imaging (MRSI) and quantitative mapping are able to detect alterations of the cerebral oxygen extraction fraction (OEF) and intracellular pH (pHi) as markers the of cellular energy metabolism in cerebral small vessel disease (SVD). 32 patients with SVD and 17 age-matched healthy control subjects were examined with 3-dimensional31P MRSI and oxygenation-sensitive quantitative mapping (1/ =1/T2* - 1/T2) at 3 Tesla (T). PHiwas measured within the white matter hyperintensities (WMH) in SVD patients. Quantitative values were averaged across the entire white matter (WM).Furthermore, values were extracted from normal-appearing WM (NAWM) and the WMH and compared between patients and controls. Quantitative values were significantly increased across the entire WM and in the NAWM in patients compared to control subjects (149.51±16.94vs. 138.19±12.66ms and 147.45±18.14vs. 137.99±12.19ms, p<0.05).WM values correlated significantly with the WMH load (ρ=0.441, p=0.006). Increased was significantly associated with more alkaline pHi(ρ=0.299, p<0.05). Both and pHi were significantly positively correlated with vascular pulsatility in the distal carotid arteries (ρ=0.596, p=0.001 and ρ=0.452, p=0.016). This exploratory study found evidence of impaired cerebral OEF in SVD, which is associated with intracellular alkalosis as an adaptive mechanism. The employed techniques provide new insights into the pathophysiology of SVD with regard to disease-related consequences on the cellular metabolic state.

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.

Correlation between functional MRI techniques and early disability in ambulatory patients with relapsing\u2013remitting MS

BackgroundMultiple sclerosis (MS) is a common neurological disorder which can lead to an occasional damage to the central nervous system. Conventional magnetic resonance imaging (cMRI) is an important modality in the diagnosis of MS; however, correlation between cMRI findings and clinical impairment is weak. Non-conventional MRI techniques including apparent diffusion coefficient (ADC) and magnetic resonance spectroscopy (MRS) investigate the metabolic changes over the course of MS and overcome the limits of cMRI.A total of 80 patients with MS and 20 age and sex-matched healthy control subjects were enrolled in this cross-sectional study. Ambulatory patients with relapsing–remitting MS (RRMS) were recruited. Expanded Disability Status Scale (EDSS) was used to assess the disability and the patients were categorized into three groups “no disability”, “minimal disability” and “moderate disability”. All patients underwent cMRI techniques. ADC was measured in MS plaques and in normal appearing white matter (NAWM) adjacent and around the plaque. All metabolites concentrations were expressed as ratios including N-acetyl-aspartate/creatine (NAA/Cr), choline/N-acetyl-aspartate (Cho/NAA) and choline/creatine (Cho/Cr). ADC and metabolite concentrations were measured in the normal white matter of 20 healthy control subjects.ResultsThe study was carried on 80 MS patients [36 males (45%) and 44 females (55%)] and 20 healthy control [8 males (40%) and 12 females (60%)]. The ADC values and MRS parameters in NAWM of patients with MS were significantly different from those of the control group. The number of the plaques on T2 images and black holes were significantly higher at “Minimal disability” group. Most of the enhanced plaques were at the “Moderate disability” group with P value < 0.001. The mean of ADC in the group 1, 2 and 3 of disability was 1.12 ± 0.19, 1.50 ± 0.35, 1.51 ± 0.36, respectively, with P value < 0. 001. In the group 1, 2 and 3 of disability, the mean of NAA/Cr ratio at the plaque was 1.34 ± 0.44, 1.59 ± 0.51 and 1.11 ± 0.15, respectively, with P value equal 0.001.ConclusionThe non-conventional quantitative MRI techniques are useful tools for detection of early disability in MS patients.

Investigating Microstructural Changes in White Matter in Multiple Sclerosis: A Systematic Review and Meta-Analysis of Neurite Orientation Dispersion and Density Imaging.

Multiple sclerosis (MS) is characterised by widespread damage of the central nervous system that includes alterations in normal-appearing white matter (NAWM) and demyelinating white matter (WM) lesions. Neurite orientation dispersion and density imaging (NODDI) has been proposed to provide a precise characterisation of WM microstructures. NODDI maps can be calculated for the Neurite Density Index (NDI) and Orientation Dispersion Index (ODI), which estimate orientation dispersion and neurite density. Although NODDI has not been widely applied in MS, this technique is promising in investigating the complexity of MS pathology, as it is more specific than diffusion tensor imaging (DTI) in capturing microstructural alterations. We conducted a meta-analysis of studies using NODDI metrics to assess brain microstructural changes and neuroaxonal pathology in WM lesions and NAWM in patients with MS. Three reviewers conducted a literature search of four electronic databases. We performed a random-effect meta-analysis and the extent of between-study heterogeneity was assessed with the I2 statistic. Funnel plots and Egger’s tests were used to assess publication bias. We identified seven studies analysing 374 participants (202 MS and 172 controls). The NDI in WM lesions and NAWM were significantly reduced compared to healthy WM and the standardised mean difference of each was −3.08 (95%CI −4.22 to (−1.95), p ≤ 0.00001, I2 = 88%) and −0.70 (95%CI −0.99 to (−0.40), p ≤ 0.00001, I2 = 35%), respectively. There was no statistically significant difference of the ODI in MS WM lesions and NAWM compared to healthy controls. This systematic review and meta-analysis confirmed that the NDI is significantly reduced in MS lesions and NAWM than in WM from healthy participants, corresponding to reduced intracellular signal fraction, which may reflect underlying damage or loss of neurites.

Fingolimod treatment reverses signs of diffuse white matter damage in multiple sclerosis: A pilot study

BackgroundIn multiple sclerosis (MS) diffuse normal appearing white matter (NAWM) damage may drive chronic worsening independent of relapse activity. Diffusion tensor imaging (DTI) is a nonconventional MRI technique that can be used to assess microstructural alterations in myelin and axons. The aim of our study was to investigate the effect of six months fingolimod treatment on the integrity of entire and segmented NAWM in patients with relapsing-remitting multiple sclerosis (RRMS). MethodsTen RRMS patients initiating fingolimod treatment were included in the study. Patients underwent 3 T MRI including diffusion tensor sequences at baseline before the initiation of treatment and at six months. The mean values for fractional anisotropy (FA), and mean, radial and axial diffusivities (MD, RD and AD) were calculated within the whole NAWM and in six segmented sub-regions of NAWM (frontal, parietal, temporal, occipital, cingulate and deep NAWM). Clinical characteristics, Expanded Disability Status Scale (EDSS) and volumetric MRI data were also evaluated. ResultsIn the cingulate NAWM FA was increased and RD was decreased significantly at six months compared to baseline (0.462 vs. 0.472, P = 0.027 and 0.000646 vs. 0.000634, P = 0.041, respectively), indicating improvements in myelin and axonal integrity following fingolimod treatment, whereas there were no alterations in cingulate MD or AD. Cingulate and temporal FA and RD correlated with T2 lesion volume percentage of cingulate and temporal areas. EDSS change correlated with change of the whole NAWM AD. ConclusionsIncreased FA and decreased RD in the cingulate NAWM might suggest microstructural fingolimod-induced improvements in the normal appearing cingulate white matter. Our results support the concept that DTI can be used as a marker of diffuse neuronal damage also in interventional settings.

Myelin and Axonal Damage in Normal-Appearing White Matter in Patients with Moyamoya Disease.

Although chronic ischemia is known to induce myelin and axonal damage in animal models, knowledge regarding patients with Moyamoya disease is limited. We aimed to investigate the presence of myelin and axonal damage in Moyamoya disease and their relationship with cognitive performance. Eighteen patients with Moyamoya disease (16-55 years of age) and 18 age- and sex-matched healthy controls were evaluated with myelin-sensitive MR imaging based on magnetization transfer saturation imaging and 2-shell diffusion MR imaging. The myelin volume fraction, which reflects the amount of myelin sheath; the g-ratio, which represents the ratio of the inner (axon) to the outer (axon plus myelin) diameter of the fiber; and the axon volume fraction, which reflects axonal components, were calculated and compared between the patients and controls. In the patients with Moyamoya disease, the relationship between these parameters and cognitive task-measuring performance speed was also evaluated. Compared with the healthy controls, the patients with Moyamoya disease showed a significant decrease in the myelin and axon volume fractions (P < .05) in many WM regions, while the increases in the g-ratio values were not statistically significant. Correlations with cognitive performance were most frequently observed with the axon volume fraction (r = 0.52-0.54; P < .03 in the right middle and posterior cerebral artery areas) and were the strongest with the g-ratio values in the right posterior cerebral artery region (r = 0.64; P = .004). Myelin-sensitive MR imaging and diffusion MR imaging revealed that myelin and axonal damage exist in patients with Moyamoya disease. The relationship with cognitive performance might be stronger with axonal damage than with myelin damage.

Individual Mapping of Innate Immune Cell Activation Is a Candidate Marker of Patient-Specific Trajectories of Worsening Disability in Multiple Sclerosis.

Our objective was to develop a novel approach to generate individual maps of white matter (WM) innate immune cell activation using 18F-DPA-714 translocator protein PET and to explore the relationship between these maps and individual trajectories of worsening disability in patients with multiple sclerosis (MS). Methods: Patients with MS (n = 37), whose trajectories of worsening disability over the 2 y preceding study entry were calculated, and healthy controls (n = 19) underwent MRI and 18F-DPA-714 PET. A threshold for significant activation of 18F-DPA-714 binding was calculated with a voxelwise randomized permutation-based comparison between patients and controls and used to classify each WM voxel in all subjects as characterized by a significant activation of innate immune cells (DPA+) or not. Individual maps of innate immune cell activation in the WM were used to calculate the extent of activation in WM regions of interests and to classify each WM lesion as DPA-active, DPA-inactive, or unclassified. Results: Compared with the WM of healthy controls, patients with MS had a significantly higher percentage of DPA+ voxels in the normal-appearing WM (NAWM) (NAWM in patients, 24.6% ± 1.4%; WM in controls, 14.6% ± 2.0%; P < 0.001). In patients with MS, the percentage of DPA+ voxels increased significantly from the NAWM to the perilesional areas, T2 hyperintense lesions, and T1 hypointense lesions (38.1% ± 2.6%, 45.0% ± 2.6%, 51.8% ± 2.6%, respectively; P < 0.001). Among the 1,379 T2 lesions identified, 512 were defined as DPA-active and 258 as DPA-inactive. A higher number of lesions classified as DPA-active (odds ratio, 1.13; P = 0.009), a higher percentage of DPA+ voxels in the NAWM (odds ratio, 1.16; P = 0.009), and a higher percentage of DPA+ voxels in T1 spin-echo lesions (odds ratio, 1.06; P = 0.036) were significantly associated with a retrospectively more severe clinical trajectory in patients with MS. Conclusion: A more severe trajectory of disability worsening in MS is associated with innate immune cell activation inside and around WM lesions. 18F-DPA-714 PET may provide a promising biomarker to identify patients at risk of a severe clinical trajectory.

Whole-Brain Myelin Imaging Using 3D Double-Echo Sliding Inversion Recovery Ultrashort Echo Time (DESIRE UTE) MRI.

Background Signal contamination from long T2 water is a major challenge in direct imaging of myelin with MRI. Nulling of the unwanted long T2 signals can be achieved with an inversion recovery (IR) preparation pulse to null long T2 white matter within the brain. The remaining ultrashort T2 signal from myelin can be detected with an ultrashort echo time (UTE) sequence. Purpose To develop patient-specific whole-brain myelin imaging with a three-dimensional double-echo sliding inversion recovery (DESIRE) UTE sequence. Materials and Methods The DESIRE UTE sequence generates a series of IR images with different inversion times during a single scan. The optimal inversion time for nulling long T2 signal is determined by finding minimal signal on the second echo. Myelin images are generated by subtracting the second echo image from the first UTE image. To validate this method, a prospective study was performed in phantoms, cadaveric brain specimens, healthy volunteers, and patients with multiple sclerosis (MS). A total of 20 healthy volunteers (mean age, 40 years ± 13 [standard deviation], 10 women) and 20 patients with MS (mean age, 58 years ± 8; 15 women) who underwent MRI between November 2017 and February 2019 were prospectively included. Analysis of variance was performed to evaluate the signal difference between MS lesions and normal-appearing white matter in patients with MS. Results High signal intensity and corresponding T2* and T1 of the extracted myelin vesicles provided evidence for direct imaging of ultrashort-T2 myelin protons using the UTE sequence. Gadobenate dimeglumine phantoms with a wide range of T1 values were selectively suppressed with DESIRE UTE. In the ex vivo brain study of MS lesions, signal loss was observed in MS lesions and was conformed with histologic analysis. In the human study, there was a significant reduction in normalized signal intensity in MS lesions compared with that in normal-appearing white matter (0.19 ± 0.10 vs 0.76 ± 0.11, respectively; P < .001). Conclusion The double-echo sliding inversion recovery ultrashort echo time sequence can generate whole-brain myelin images specifically with a clinical 3-T scanner. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Port in this issue.

Reduced Myelin Signal in Normal-appearing White Matter in Neuromyelitis Optica Measured by 7T Magnetic Resonance Imaging

Whether the integrity of normal-appearing white matter (NAWM) is preserved in neuromyelitis optica spectrum disorders (NMOSD) is open to debate. To examine whether the tissue integrity of NAWM in NMOSD is compromised compared to that in healthy controls and patients with multiple sclerosis (MS), we prospectively enrolled 14 patients with NMOSD, 12 patients with MS, and 10 controls for clinical functional assessments and quantitative imaging, including T1 relaxation time (T1) and magnetization transfer ratio (MTR) at 7 Tesla. Cognitive performance on the Paced Auditory Serial Addition Test with a 3-second interstimulus interval (PASAT-3) was significantly lower in the NMOSD compared to the MS group (mean number of correct answers, 34.1 vs. 47.6; p = 0.006), but there were no differences in disease duration or disability. Histograms of T1 and MTR maps of NAWM demonstrated a decreased peak height in patients with NMOSD compared to the healthy controls, but not compared to patients with MS. Using 7T quantitative magnetic resonance imaging (MRI), this study showed that the NAWM in patients with NMOSD is abnormal, with reduced myelin signal; this was not previously observed using MRI at a lower field strength.

Axonal water fraction as marker of white matter injury in primary-progressive multiple sclerosis: a longitudinal study.

Diffuse white matter (WM) injury is prominent in primary-progressive multiple sclerosis (PP-MS) pathology and is a potential biomarker of disease progression. Diffusion kurtosis imaging allows the quantification of non-Gaussian water diffusion, providing metrics with high WM pathological specificity. The aim of this study was to characterize the pathological changes occurring in the normal-appearing WM of patients with PP-MS at baseline and at 1-year follow-up and to assess their impact on disability and short-term disease progression. A total of 26 patients with PP-MS and 20 healthy controls were prospectively enrolled. Diffusion kurtosis imaging single-shot echo-planar imaging (EPI) was acquired on a 3-T scanner (Philips Achieva, Best, The Netherlands) (voxel size, 2×2×2mm3 , 30 directions for each b-value=1000, 2000s/mm2 and one b=0s/mm2 ). A two-compartment biophysical model of WM tract integrity was used to derive spatial maps of axonal water fraction (AWF), intra-axonal diffusivity, extra-axonal axial and radial diffusivities (De,axial , De,radial ) and tortuosity from the following WM tracts: corpus callosum (CC), corticospinal tract (CST) and posterior thalamic radiation (PTR). At baseline, patients with PP-MS showed a widespread decrease of AWF, tortuosity and De,axial and an increase of De,radial in CC, CST and PTR (P ranging from 0.001 to 0.036). At 1-year follow-up, a significant AWF decrease was detected in the body of CC (P=0.048), PTR (P=0.008) and CST (P=0.044). Baseline AWF values in CST significantly discriminated progressed from non-progressed patients (P=0.021; area under the curve, 0.854). Based on its change over time and its relationship with disease progression, among the analyzed metrics, AWF seems the most sensitive metric of WM tissue damage in PP-MS and therefore it could be considered as a marker for monitoring disease progression.

Common Patterns of Regional Brain Injury Detectable by Diffusion Tensor Imaging in Otherwise Normal-Appearing White Matter in Patients with Early Moderate to Severe Traumatic Brain Injury.

Traumatic brain injury (TBI) alters the lives of millions of people every year. Although mortality rates have improved, attributed to better pre-hospital care and reduction of secondary injury in the critical care setting, improvements in functional outcomes post-TBI have been difficult to achieve. Diffusion-tensor imaging (DTI) allows detailed measurement of microstructural damage in regional brain tissue post-TBI, thus improving our understanding of the extent and severity of TBI. Twenty subjects were recruited from a neurological intensive care unit and compared to 18 healthy control subjects. Magnetic resonance imaging (MRI) scanning was performed on a 3.0-Tesla Siemens TIM Trio Scanner (Siemens Medical Solutions, Erlangen, Germany) including T1- and T2-weighted sequences and DTI. Images were processed using DTIStudio software. SAS (SAS Institute Inc., Cary, NC) was used for statistical analysis of group differences in 14 brain regions (25 regions of interests [ROIs]). Seventeen TBI subjects completed scanning. TBI and control subjects did not differ in age or sex. All TBI subjects had visible lesions on structural MRI. TBI subjects had seven brain regions (nine ROIs) that showed significant group differences on DTI metrics (fractional anisotropy, radial diffusion, or mean diffusion) compared to noninjured subjects, including the corpus callosum (genu and splenium), superior longitudinal fasciculus, internal capsule, right retrolenticular internal capsule, posterior corona radiata, and thalamus. However, 16 ROIs showed relatively normal DTI measures. Quantitative DTI demonstrates multiple areas of microstructual injury in specific normal-appearing white matter brain regions. DTI may be useful for assessing the extent of brain injury in patients with early moderate to severe TBI.

Quantifying the Susceptibility Variation of Normal-Appearing White Matter in Multiple Sclerosis by Quantitative Susceptibility Mapping.

The purpose of this study is to evaluate the magnetic susceptibility of normal-appearing white matter (NAWM) in patients with multiple sclerosis (MS) using quantitative susceptibility mapping. Ninety-four patients with relapse-remitting MS (RRMS) (37 with gadolinium-enhancing lesions and 57 with only gadolinium-nonenhancing lesions) and 55 healthy control subjects were included in this retrospective study. The susceptibility values of NAWM relative to CSF in patients with MS were compared with those of white matter (WM) in healthy control subjects and were correlated with the patient status of gadolinium-enhancing lesions, disease duration, and expanded disability status scale scores. All 37 patients with RRMS and gadolinium-enhancing lesions also had gadolinium-nonenhancing lesions. Susceptibility values of NAWM in patients with MS and only gadolinium-nonenhancing lesions (-18.29 ± 8.03 parts per billion [ppb]) were higher than those for WM in healthy control subjects (-25.81 ± 6.02 ppb; p < 0.001) and NAWM in patients with gadolinium-enhancing lesions (-25.64 ± 6.55 ppb; p < 0.001). Susceptibility values of NAWM in patients with MS with gadolinium-enhancing lesions were similar to those for WM in healthy control subjects (p = 0.91). This trend was dependent on neither NAWM region nor disease duration when the data were controlled for age. NAWM susceptibility was not correlated with either disease duration or expanded disability status scale (p > 0.05). In patients with RRMS and gadolinium-nonenhancing lesions, the susceptibility values of NAWM decrease when gadolinium-enhancing lesions appear, approaching values similar to those of WM in healthy control subjects, suggesting that NAWM may contribute to the iron accumulation observed in early active MS lesions.

Blood-brain barrier permeability of normal-appearing white matter in patients with vestibular schwannoma: A new hybrid approach for analysis of T 1 -W DCE-MRI

Blood-brain barrier permeability of normal-appearing white matter in patients with vestibular schwannoma: A new hybrid approach for analysis of <i>T</i> ₁ -W DCE-MRI

Loss of 'homeostatic' microglia and patterns of their activation in active multiple sclerosis.

Microglia and macrophages accumulate at the sites of active demyelination and neurodegeneration in the multiple sclerosis brain and are thought to play a central role in the disease process. We used recently described markers to characterize the origin and functional states of microglia/macrophages in acute, relapsing and progressive multiple sclerosis. We found microglia activation in normal white matter of controls and that the degree of activation increased with age. This microglia activation was more pronounced in the normal-appearing white matter of patients in comparison to controls and increased with disease duration. In contrast to controls, the normal-appearing white matter of patients with multiple sclerosis showed a significant reduction of P2RY12, a marker expressed in homeostatic microglia in rodents, which was completely lost in active and slowly expanding lesions. Early stages of demyelination and neurodegeneration in active lesions contained microglia with a pro-inflammatory phenotype, which expressed molecules involved in phagocytosis, oxidative injury, antigen presentation and T cell co-stimulation. In later stages, the microglia and macrophages in active lesions changed to a phenotype that was intermediate between pro- and anti-inflammatory activation. In inactive lesions, the density of microglia/macrophages was significantly reduced and microglia in part converted to a P2RY12+ phenotype. Analysis of TMEM119, which is expressed on microglia but not on recruited macrophages, demonstrated that on average 45% of the macrophage-like cells in active lesions were derived from the resident microglia pool. Our study demonstrates the loss of the homeostatic microglial signature in active multiple sclerosis with restoration associated with disease inactivity.

Diffusion tensor imaging of normal-appearing white matter in patients with neuromyelitis optica spectrum disorder and multiple sclerosis.

The occult changes in normal-appearing white matter (NAWM) were investigated and compared amongst patients with neuromyelitis optica spectrum disorder (NMOSD), patients with multiple sclerosis (MS) and healthy controls (HCs) by applying tract-based spatial statistics to diffusion tensor imaging (DTI) data. Diffusion tensor imaging was performed with a 3-T scanner in 93 patients with NMOSD, 53 patients with MS and 43 HCs. Voxel-wise statistical analyses of the DTI data were performed using tract-based spatial statistics. Compared to HCs, patients with NMOSD had significantly lower mean global fractional anisotropy, higher mean diffusivity and radial diffusivity, and no significant differences in axial diffusivity in their NAWM. Patients with MS demonstrated significantly lower mean global fractional anisotropy and higher mean diffusivity, axial diffusivity and radial diffusivity in the NAWM than did patients with NMOSD and HCs. Compared to patients with NMOSD, patients with MS had NAWM damage that was more extensive, particularly in the inferior cerebellar peduncle, external capsule, cingulum, superior fronto-occipital fasciculus and uncinate fasciculus. Using DTI, widespread occult damage was demonstrated in the NAWM of patients with NMOSD. However, the NAWM was less affected in patients with NMOSD than it was in patients with MS; specifically, the axonal injuries and diffusion abnormalities in the association fibers were more severe in patients with MS than they were in patients with NMOSD.

Metabolic changes in normal appearing white matter in multiple sclerosis patients using multivoxel magnetic resonance spectroscopy imaging.

Demyelination and axonal degeneration caused by multiple sclerosis (MS) exist in the white matter and not only in the lesion area. Magnetic resonance spectroscopy (MRS) could provide a unique insight into metabolic changes in the normal appearing white matter (NAWM). To evaluate the subtle axonal degeneration and delineate the spatial distribution of metabolite abnormalities in the NAWM in patients with MS. A total of 17 clinically definite relapsing-remitting MS (RRMS) patients and 21 healthy controls were enrolled in this study. 2D 1H magnetic resonance spectroscopic imaging (MRSI) performed at 3 Tesla was used to measure metabolite concentrations in the frontal-parietal-occipital NAWM. Ratios of N-acetyl-aspartate (NAA) and choline (Cho) to creatine (Cr) and Cho to NAA were calculated in each voxel. MS patients showed decreased NAA/Cr and increased Cho/NAA ratios in the NAWM compared to healthy controls. In the parietal NAWM, the extent of NAA/Cr decrease was significantly higher than that in the frontal and parietal-occipital NAWM. Decreased NAA in the NAWM would provide useful metabolic information for evaluation of disease progression in MS. The high extent of NAA decrease in the parietal NAWM helps improve the accuracy of the prediction.

11C-PBR28 and 18F-PBR111 Detect White Matter Inflammatory Heterogeneity in Multiple Sclerosis.

The objective of this study was to assess microglial activation in lesions and in normal-appearing white matter (NAWM) of multiple sclerosis (MS) patients using PET. Methods: Thirty-four MS patients (7 with secondary progressive MS [SPMS], 27 with relapsing remitting MS [RRMS]) and 30 healthy volunteers, genetically stratified for translocator protein (TSPO) binding status, underwent PET scanning with TSPO radioligands (11C-PBR28 or 18F-PBR111). Regional TSPO availability was measured as a distribution volume ratio (DVR) relative to the caudate (a pseudoreference region). White matter lesions (WMLs) were classified as "active" (DVR highest in the lesion), "peripherally active" (perilesional DVR highest), "inactive" (DVR highest in surrounding NAWM), or "undifferentiated" (similar DVR across lesion, perilesional and NAWM volumes). Results: The mean DVR in NAWM of patients was greater than that of the healthy volunteer white matter for both radioligands. Uptake for individual WML in patients was heterogeneous, but the median WML DVR and NAWM DVR for individual patients were strongly correlated (ρ = 0.94, P = 4 × 10-11). A higher proportion of lesions were inactive in patients with SPMS (35%) than RRMS (23%), but active lesions were found in all patients, including those on highly efficacious treatments. Conclusion: TSPO radioligand uptake was increased in the brains of MS patients relative to healthy controls with 2 TSPO radiotracers. WML showed heterogeneous patterns of uptake. Active lesions were found in patients with both RRMS and SPMS. Their independent prognostic significance needs further investigation.