Normal-appearing Gray Matter Research Articles

Quantifying the Metabolic Signature of Multiple Sclerosis by in vivo Proton Magnetic Resonance Spectroscopy: Current Challenges and Future Outlook in the Translation From Proton Signal to Diagnostic Biomarker.

Proton magnetic resonance spectroscopy (1H-MRS) offers a growing variety of methods for querying potential diagnostic biomarkers of multiple sclerosis in living central nervous system tissue. For the past three decades, 1H-MRS has enabled the acquisition of a rich dataset suggestive of numerous metabolic alterations in lesions, normal-appearing white matter, gray matter, and spinal cord of individuals with multiple sclerosis, but this body of information is not free of seeming internal contradiction. The use of 1H-MRS signals as diagnostic biomarkers depends on reproducible and generalizable sensitivity and specificity to disease state that can be confounded by a multitude of influences, including experiment group classification and demographics; acquisition sequence; spectral quality and quantifiability; the contribution of macromolecules and lipids to the spectroscopic baseline; spectral quantification pipeline; voxel tissue and lesion composition; T1 and T2 relaxation; B1 field characteristics; and other features of study design, spectral acquisition and processing, and metabolite quantification about which the experimenter may possess imperfect or incomplete information. The direct comparison of 1H-MRS data from individuals with and without multiple sclerosis poses a special challenge in this regard, as several lines of evidence suggest that experimental cohorts may differ significantly in some of these parameters. We review the existing findings of in vivo 1H-MRS on central nervous system metabolic abnormalities in multiple sclerosis and its subtypes within the context of study design, spectral acquisition and processing, and metabolite quantification and offer an outlook on technical considerations, including the growing use of machine learning, by future investigations into diagnostic biomarkers of multiple sclerosis measurable by 1H-MRS.

Normal-Appearing Cerebellar Damage in Neuromyelitis Optica Spectrum Disorder.

The cerebellum plays an important role in motor and cognitive functions. However, whether and how the normal-appearing cerebellum is impaired in patients with neuromyelitis optica spectrum disorders remain unknown. We aimed to identify the occult structural damage of the cerebellum in neuromyelitis optica spectrum disorder and its possible causes at the level of substructures. Normal-appearing gray matter volume of the cerebellar lobules and nuclei and normal-appearing white matter volume of the cerebellar peduncles were compared between patients with neuromyelitis optica spectrum disorder and healthy controls. The cerebellar damage of patients with neuromyelitis optica spectrum disorder in the hemispheric lobule VI, vermis lobule VI, and all cerebellar nuclei and peduncles was related only to spinal lesions; and cerebellar damage in the hemispheric lobules VIII and X was related only to the aquaporin-4 antibody. The mixed cerebellar damage in the hemispheric lobules V and IX and vermis lobule Crus I was related mainly to spinal lesions; and mixed cerebellar damage in the hemispheric lobule VIIb was related mainly to the aquaporin-4 antibody. Other cerebellar substructures showed no significant cerebellar damage. We have shown that the damage in cerebellar normal-appearing white matter and normal-appearing gray matter is associated with aquaporin-4-mediated primary damage or axonal degeneration secondary to spinal lesions or both. The etiologic classifications of substructure-specific occult cerebellar damage may facilitate developing neuroimaging markers for assessing the severity and the results of therapy of neuromyelitis optica spectrum disorder occult cerebellar damage.

Diffusion tensor imaging of the normal-appearing deep gray matter in primary and secondary progressive multiple sclerosis.

Despite strongly overlapping patterns of clinical and histopathologic findings in primary and secondary progressive multiple sclerosis, differences concerning motor symptoms, central nervous system inflammation, atrophy, and demyelination that cannot be accounted for by lesion load alone remain to be elucidated. To evaluate the normal-appearing deep gray matter in patients with primary and secondary progressive multiple sclerosis, diffusion tensor imaging was used in this study. In 14 multiple sclerosis patients with primary and secondary progressive multiple sclerosis, axial echo-planar single-shot diffusion tensor imaging sequences with 32 diffusion-encoding directions and axial FLAIR sequences were acquired on a 3T system using an eight-channel SENSE head coil. FLAIR hyperintense multiple sclerosis lesions were outlined semi-automatically and normal-appearing deep gray matter was outlined manually (caudate nucleus, globus pallidus, putamen, thalamus, substantia nigra, and red nucleus). Fractional anisotropy and mean diffusivity values within the normal-appearing deep gray matter for the two groups were compared. Interhemispheric differences in mean diffusivity values (but not in fractional anisotropy), were significantly higher in primary progressive multiple sclerosis than in secondary progressive multiple sclerosis for the substantia nigra ( P = 0.04) and the putamen ( P = 0.021). Volumes, mean diffusivity, or fractional anisotropy of the remaining normal-appearing deep gray matter did not differ significantly. This study showed a higher interhemispheric difference in the mean diffusivity in the substantia nigra and putamen in patients with primary progressive multiple sclerosis than in those with secondary progressive multiple sclerosis. These changes may represent edema, as well as axonal and myelin loss that can affect the normal-appearing deep gray matter of the two hemispheres differently and may point to differences in the laterality of motor symptoms.

Transcriptional profiling of human microglia reveals grey\u2013white matter heterogeneity and multiple sclerosis-associated changes

Here we report the transcriptional profile of human microglia, isolated from normal-appearing grey matter (GM) and white matter (WM) of multiple sclerosis (MS) and non-neurological control donors, to find possible early changes related to MS pathology. Microglia show a clear region-specific profile, indicated by higher expression of type-I interferon genes in GM and higher expression of NF-κB pathway genes in WM. Transcriptional changes in MS microglia also differ between GM and WM. MS WM microglia show increased lipid metabolism gene expression, which relates to MS pathology since active MS lesion-derived microglial nuclei show similar altered gene expression. Microglia from MS GM show increased expression of genes associated with glycolysis and iron homeostasis, possibly reflecting microglia reacting to iron depositions. Except for ADGRG1/GPR56, expression of homeostatic genes, such as P2RY12 and TMEM119, is unaltered in normal-appearing MS tissue, demonstrating overall preservation of microglia homeostatic functions in the initiation phase of MS.

Higher EBV response is associated with more severe gray matter and lesion pathology in relapsing multiple sclerosis patients: A case-controlled magnetization transfer ratio study

Background: Epstein–Barr virus (EBV) infection has been associated with higher clinical activity and risk of multiple sclerosis (MS). Objective: To evaluate associations between EBV-specific humoral response and magnetization transfer ratio (MTR)-derived measure in MS patients and healthy controls (HCs). Methods: The study included 101 MS patients (69 relapsing-remitting multiple sclerosis (RRMS) and 32 secondary-progressive multiple sclerosis (SPMS)) and 41 HCs who underwent clinical, serological, and magnetic resonance imaging (MRI) investigations. MTR values of T1 or T2 lesion volume (LV), normal-appearing (NA) brain tissue (NABT), gray matter (NAGM), and white matter (NAWM) were obtained. Enzyme-linked immunosorbent assay was used to quantify EBV antibody levels. Partial correlations corrected for MRI strength were used, and Benjamini–Hochberg–adjusted p-values < 0.05 were considered significant. Results: MS patients had significantly higher anti-EBV nuclear antigen-1 (EBNA-1) titer when compared to HCs (107.9 U/mL vs 27.8 U/mL, p < 0.001). Within the MS group, higher serum anti-EBNA-1 titer was significantly correlated with lower T1-LV MTR (r = –0.287, p = 0.035). Within the RRMS group, higher serum anti-EBNA-1 titer was associated with T1-LV MTR (r = –0.524, p = 0.001) and NAGM MTR (r = –0.308, p = 0.043). These associations were not present in HCs or SPMS patients. Conclusion: Greater EBV humoral response is associated with lower GM MTR changes and focal destructive lesion pathology in RRMS patients.

Microglia pre-activation and neurodegeneration precipitate neuroinflammation without exacerbating tissue injury in experimental autoimmune encephalomyelitis

Human inflammatory or neurodegenerative diseases, such as progressive multiple sclerosis (MS), occur on a background of age-related microglia activation and iron accumulation as well as pre-existing neurodegeneration. Most experimental models for CNS diseases, however, are induced in rodents, which are naturally characterized by a homeostatic microglia phenotype, low cellular iron load and absence of neurodegeneration. Here, we show that naïve LEWzizi rats – Lewis rats with a zitter rat background – show a spontaneous phenotype partly mimicking the changes seen in human aging and particularly in the normal-appearing white and grey matter of patients with progressive MS. Using this model system, we further aimed to investigate (i) whether the acute monophasic MS model experimental autoimmune encephalomyelitis (EAE) transforms into chronic progressive disease and (ii) whether EAE-induced neuroinflammation and tissue damage aggravate on the LEWzizi background. We found that the pre-existing LEWzizi-specific pathology precipitated EAE-related neuroinflammation into forebrain areas, which are devoid of EAE lesions in normal Lewis rats. However, EAE-related tissue damage was neither modified by the LEWzizi-specific pathology nor did EAE-induced neuroinflammation modify the LEWzizi-related pathological process. Our data indicate that the interaction between pre-activated microglia and CD4+ autoreactive T cells during the induction and propagation of tissue damage in the CNS is limited.

Corticohippocampal Dysfunction In The OBiden Mouse Model Of Primary Oligodendrogliopathy

Despite concerted efforts over decades, the etiology of multiple sclerosis (MS) remains unclear. Autoimmunity, environmental-challenges, molecular mimicry and viral hypotheses have proven equivocal because early-stage disease is typically presymptomatic. Indeed, most animal models of MS also lack defined etiologies. We have developed a novel adult-onset oligodendrogliopathy using a delineated metabolic stress etiology in myelinating cells, and our central question is, “how much of the pathobiology of MS can be recapitulated in this model?” The analyses described herein demonstrate that innate immune activation, glial scarring, cortical and hippocampal damage with accompanying electrophysiological, behavioral and memory deficits naturally emerge from disease progression. Molecular analyses reveal neurofilament changes in normal-appearing gray matter that parallel those in cortical samples from MS patients with progressive disease. Finally, axon initial segments of deep layer pyramidal neurons are perturbed in entorhinal/frontal cortex and hippocampus from OBiden mice, and computational modeling provides insight into vulnerabilities of action potential generation during demyelination and early remyelination. We integrate these findings into a working model of corticohippocampal circuit dysfunction to predict how myelin damage might eventually lead to cognitive decline.

Single scan quantitative gradient recalled echo MRI for evaluation of tissue damage in lesions and normal appearing gray and white matter in multiple sclerosis.

Multiple sclerosis (MS) is a chronic disease affecting the human central nervous system (CNS) and leading to neurologic disability. Although conventional MRI techniques can readily detect focal white matter (WM) lesions, it remains challenging to quantify tissue damage in normal-appearing gray matter (GM) and WM. To demonstrate that a new MRI biomarker, R2t*, can provide quantitative analysis of tissue damage across the brain in MS patients in a single scan. Prospective. Forty-four MS patients and 19 healthy controls (HC). 3T, quantitative gradient-recalled-echo (qGRE), Magnetization-prepared rapid gradient-echo, fluid-attenuated inversion recovery. Severity of tissue damage was assessed by reduced R2t*. Tissue atrophy was assessed by cortical thickness and cervical spinal cord cross-sectional area (CSA). Multiple Sclerosis Functional Composite was used for clinical assessment. R2t* in cortical GM was more sensitive to MS damage than cortical atrophy. Using more than two standard deviations (SD) reduction versus age-matched HC as the cutoff, 48% of MS patients showed lower R2t*, versus only 9% with lower cortical thickness. Significant correlations between severities of tissue injury were identified among 1) upper cervical cord and several cortical regions, including motor cortex (P < 0.001), and 2) adjacent regions of GM and subcortical WM (P < 0.001). R2t*-defined tissue cellular damage in cortical GM was greater relative to adjacent WM. Reductions in cortical R2t* correlated with cognitive impairment (P < 0.01). Motor-related clinical signs correlated most with cervical cord CSA (P < 0.001). Reductions in R2t* within cortical GM was more sensitive to tissue damage than atrophy, potentially allowing a reduced sample size in clinical trials. R2t* together with structural morphometry suggested topographic patterns of regions showing correlated tissue damage throughout the brain and the cervical spinal cord of MS patients. 2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2019;49:487-498.

Investigation of grey matter abnormalities in multiple sclerosis patients by combined use of double inversion recovery sequences and diffusion tensor MRI at 3.0 Tesla

To investigate the grey matter abnormalities in multiple sclerosis (MS) patients by combined use of double inversion recovery (DIR) sequences and diffusion tensor (DTI) magnetic resonance imaging (MRI) at 3 T. Twenty relapsing-remitting MS (RRMS) patients and 20 healthy control were enrolled in this study. All participants underwent DIR and DTI MRI and completed the Mini-Mental State Examination (MMSE) and Expanded Disability Status Scale (EDSS). The cortical lesions and normal-appearing grey matter (NAGM) of the patient group, as well as the NAGM of the control group were quantitatively analysed using the DIR and DTI images. The average NAGM mean diffusion (MD) and fractional anisotropy (FA) values of the patient group and control group were measured and compared. The correlation between NAGM MD and FA values and the number of cortical lesions, cognitive impairment, as well as the degree of nerve damage were analysed. The NAGM of the patient group had average MD and FA values that were significantly different compared with the control group. In addition, the NAGM FA values of the MS patients were negatively correlated with the MMSE score, but positively correlated with the EDSS score. The NAGM MD values of the MS patients were also negatively correlated with the MMSE score, but positively correlated with the EDSS score. The NAGM of MS patients has microstructural damages. The extent of such damage was correlated with the number of cortical lesions. The severity of the damage also correlated with increased severity of cognitive impairment and neural defects.

Quantitative susceptibility map analysis in preterm neonates with germinal matrix-intraventricular hemorrhage.

Germinal matrix-intraventricular hemorrhage (GMH-IVH) is a common form of intracranial hemorrhage occurring in preterm neonates that may affect normal brain development. Although the primary lesion is easily identified on MRI by the presence of blood products, its exact extent may not be recognizable with conventional sequences. Quantitative susceptibility mapping (QSM) quantify the spatial distribution of magnetic susceptibility within biological tissues, including blood degradation products. To evaluate magnetic susceptibility of normal-appearing white (WM) and gray matter regions in preterm neonates with and without GMH-IVH. Retrospective case-control. A total of 127 preterm neonates studied at term equivalent age: 20 had mild GMH-IVH (average gestational age 28.7 ± 2.1 weeks), 15 had severe GMH-IVH (average gestational age 29.3 ± 1.8 weeks), and 92 had normal brain MRI (average gestational age 29.8 ± 1.8 weeks). QSM at 1.5 Tesla. QSM analysis was performed for each brain hemisphere with a region of interest-based approach including five WM regions (centrum semiovale, frontal, parietal, temporal, and cerebellum), and a subcortical gray matter region (basal ganglia/thalami). Changes in magnetic susceptibility were explored using a one-way analysis of covariance, according to GMH-IVH severity (P < 0.05). In preterm neonates with normal brain MRI, all white and subcortical gray matter regions had negative magnetic susceptibility values (diamagnetic). Neonates with severe GMH-IVH showed higher positive magnetic susceptibility values (i.e. paramagnetic) in the centrum semiovale (0.0019 versus -0.0014 ppm; P < 0.001), temporal WM (0.0011 versus -0.0012 ppm; P = 0.037), and parietal WM (0.0005 versus -0.0001 ppm; P = 0.002) compared with controls. No differences in magnetic susceptibility were observed between neonates with mild GMH-IVH and controls (P = 0.236). Paramagnetic susceptibility changes occur in several normal-appearing WM regions of neonates with severe GMH-IVH, likely related to the accumulation of hemosiderin/ferritin iron secondary to diffusion of extracellular hemoglobin from the ventricle into the periventricular WM. 4 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:1199-1207.

Characterizing Microstructural Tissue Properties in Multiple Sclerosis with Diffusion MRI at 7 T and 3 T: The Impact of the Experimental Design

The recent introduction of advanced magnetic resonance (MR) imaging techniques to characterize focal and global degeneration in multiple sclerosis (MS), like the Composite Hindered and Restricted Model of Diffusion, or CHARMED, diffusional kurtosis imaging (DKI) and Neurite Orientation Dispersion and Density Imaging (NODDI) made available new tools to image axonal pathology non-invasively in vivo. These methods already showed greater sensitivity and specificity compared to conventional diffusion tensor-based metrics (e.g., fractional anisotropy), overcoming some of its limitations.While previous studies uncovered global and focal axonal degeneration in MS patients compared to healthy controls, here our aim is to investigate and compare different diffusion MRI acquisition protocols in their ability to highlight microstructural differences between MS and control tissue over several much used models. For comparison, we contrasted the ability of fractional anisotropy measurements to uncover differences between lesion, normal-appearing white matter (WM), gray matter and healthy tissue under the same imaging protocols. We show that: (1) focal and diffuse differences in several microstructural parameters are observed under clinical settings; (2) advanced models (CHARMED, DKI and NODDI) have increased specificity and sensitivity to neurodegeneration when compared to fractional anisotropy measurements; and (3) both high (3 T) and ultra-high fields (7 T) are viable options for imaging tissue change in MS lesions and normal appearing WM, while higher b-values are less beneficial under the tested short-time (10 min acquisition) conditions.

DTI metrics reflecting microstructural changes of normal appearing deep grey matter in multiple sclerosis

PurposeTo evaluate the role of apparent diffusion coefficient (ADC) and fractional anisotropy (FA) in detecting microstructural changes of normal-appearing deep grey matter (NDGM) in multiple sclerosis (MS). Patient and methodsWe examined 40 patients with MS and 20 healthy volunteers using DTI to correlate average ADC and FA of the thalami, lentiform and caudate nuclei between the two groups. Receiver operating characteristic analysis was used to test the diagnostic performance of ADC and FA in detecting NDGM involvement in multiple sclerosis. ResultsBetween the two study groups, there was statistically significant difference of ADC of thalami, lentiform, caudate nuclei, and FA of the thalami (p < .05). No statistically significant difference of FA of lentiform (p = .2) and caudate (p = .06) nuclei. For detection of microstructural changes of NDGM, ADC cut off values were 0.762 × 10−3 mm2/s for thalamus (90% sensitivity and 66% specificity), 0.529 × 10−3 mm2/s for lentiform (86% sensitivity and 60% specificity) and 0.784 × 10−3 mm2/s for caudate nuclei (83% sensitivity and 67% specificity). ConclusionADC has better diagnostic performance and is more accurate than FA as a measure to detect microstructural changes of NDGM.

Long-term disability progression in primary progressive multiple sclerosis: a 15-year study.

Prognostic markers of primary progressive multiple sclerosis evolution are needed. We investigated the added value of magnetic resonance imaging measures of brain and cervical cord damage in predicting long-term clinical worsening of primary progressive multiple sclerosis compared to simple clinical assessment. In 54 patients, conventional and diffusion tensor brain scans and cervical cord T1-weighted scans were acquired at baseline and after 15 months. Clinical evaluation was performed after 5 and 15 years in 49 patients. Lesion load, brain and cord atrophy, mean diffusivity and fractional anisotropy values from the brain normal-appearing white matter and grey matter were obtained. Using linear regression models, we screened the clinical and imaging variables as independent predictors of 15-year disability change (measured on the expanded disability status scale). At 15 years, 90% of the patients had disability progression. Integrating clinical and imaging variables at 15 months predicted disability changes at 15 years better than clinical factors at 5 years (R2 = 61% versus R2 = 57%). The model predicted long-term disability change with a precision within one point in 38 of 49 patients (77.6%). Integration of clinical and imaging measures allows identification of primary progressive multiple sclerosis patients at risk of long-term disease progression 4 years earlier than when using clinical assessment alone.

Analysis of brain and spinal cord lesions to occult brain damage in seropositive and seronegative neuromyelitis optica

ObjectivesAccording to aquaporin-4 antibody (AQP4-Ab), neuromyelitis optica (NMO) can be divided into seropositive and seronegative subgroups. The purpose of this study was to a) compare the distribution of spinal cord and brain magnetic resonance imaging (MRI) lesions between seropositive and seronegative NMO patients; b) explore occult brain damage in seropositive and seronegative NMO patients; and c) explore the contribution of visible lesions to occult grey and white matter damage in seropositive and seronegative NMO patients. Materials and methodsTwenty-two AQP4-Ab seropositive and 14 seronegative NMO patients and 30 healthy controls were included in the study. Two neuroradiologists independently measured the brain lesion volume (BLV) and the length of spinal cord lesion (LSCL) and recorded the region of brain lesions. The normal-appearing grey matter volume (NAGM-GMV) and white matter fractional anisotropy (NAWM-FA) were calculated for each subject to evaluate occult brain damage. ResultsThe seropositive patients displayed more extensive damage in the spinal cord than the seronegative patients, and the seronegative group had a higher proportion of patients with brainstem lesions (28.57%) than the seropositive group (4.55%, P=0.064). Both NMO subgroups exhibited reduced NAGM-GMV and NAWM-FA compared with the healthy controls. NAGM-GMV was negatively correlated with LSCL in the seropositive group (rs=−0.444, P=0.044) and with BLV in the seronegative group (rs=−0.768, P=0.002). NAWM-FA was also negatively correlated with BLV in the seropositive group (rs=−0.682, P<0.001). ConclusionOur findings suggest that the occult brain damage in these two NMO subgroups may be due to different mechanisms, which need to be further clarified.

Cortical Remyelination Is Heterogeneous in Multiple Sclerosis.

Cortical lesions (CLs) are an important component of multiple sclerosis (MS) pathology; they correlate better with physical disability and cognitive impairment than white matter lesions (WMLs). Because remyelination can be extensive in CLs, we quantified remyelination in gray matter (GM) and white matter (WM), addressing oligodendrocyte (OGD) maturation state and clinical relevance of remyelination. Brain tissue samples from 21 chronic MS patients were immunohistochemically stained for myelin proteolipid protein, Olig2, which is strongly expressed in OGD precursor cells (OPCs), but weakly expressed in mature OGDs and other OGD markers. Sections were scored for the presence of normal-appearing WM and GM, de- and remyelination, and OPC and OGD cell counts. Remyelination was significantly more extensive in CLs than in WMLs with a trend toward more GM remyelination in primary progressive MS (PPMS) vs relapse-onset MS patients. More OPCs were found in remyelinated and nonremyelinated CLs vs remyelinated WMLs and nonremyelinated WMLs. Thus, there is more remyelination in the GM than in the WM in MS patient brains, with a trend toward more remyelination in those with PPMS. There does not seem to be a significant OPC recruitment failure in the GM, which casts new light on the process of remyelination failure.

Evaluation of the Effect of Fingolimod Treatment on Microglial Activation Using Serial PET Imaging in Multiple Sclerosis.

Traditionally, multiple sclerosis (MS) has been considered a white matter disease with focal inflammatory lesions. It is, however, becoming clear that significant pathology, such as microglial activation, also takes place outside the plaque areas, that is, in areas of normal-appearing white matter (NAWM) and gray matter (GM). Microglial activation can be detected in vivo using 18-kDa translocator protein (TSPO)-binding radioligands and PET. It is unknown whether fingolimod affects microglial activation in MS. The aim of this study was to investigate whether serial PET can be used to evaluate the effect of fingolimod treatment on microglial activation. Methods: Ten relapsing-remitting MS patients were studied using the TSPO radioligand 11C-(R)-PK11195. Imaging was performed at baseline and after 8 and 24 wk of fingolimod treatment. Eight healthy individuals were imaged for comparison. Microglial activation was evaluated as distribution volume ratio of 11C-(R)-PK11195. Results: The patients had MS for an average of 7.9 ± 4.3 y (mean ± SD), their total relapses averaged 4 ± 2.4, and their Expanded Disability Status Scale was 2.7 ± 0.5. The patients were switched to fingolimod because of safety reasons or therapy escalation. The mean washout period before the initiation of fingolimod was 2.3 ± 1.1 mo. The patients were clinically stable on fingolimod. At baseline, microglial activation was significantly higher in the combined NAWM and GM areas of MS patients than in healthy controls (P = 0.021). 11C-(R)-PK11195 binding was reduced (-12.31%) within the combined T2 lesion area after 6 mo of fingolimod treatment (P = 0.040) but not in the areas of NAWM or GM. Conclusion: Fingolimod treatment reduced microglial/macrophage activation at the site of focal inflammatory lesions, presumably by preventing leukocyte trafficking from the periphery. It did not affect the widespread, diffuse microglial activation in the NAWM and GM. The study opens new vistas for designing future therapeutic studies in MS that use the evaluation of microglial activation as an imaging outcome measure.

A theoretical framework for determining cerebral vascular function and heterogeneity from dynamic susceptibility contrast MRI

Mapping the complex heterogeneity of vascular tissue in the brain is important for understanding cerebrovascular disease. In this translational study, we build on previous work using vessel architectural imaging (VAI) and present a theoretical framework for determining cerebral vascular function and heterogeneity from dynamic susceptibility contrast magnetic resonance imaging (MRI). Our tissue model covers realistic structural architectures for vessel branching and orientations, as well as a range of hemodynamic scenarios for blood flow, capillary transit times and oxygenation. In a typical image voxel, our findings show that the apparent MRI relaxation rates are independent of the mean vessel orientation and that the vortex area, a VAI-based parameter, is determined by the relative oxygen saturation level and the vessel branching of the tissue. Finally, in both simulated and patient data, we show that the relative distributions of the vortex area parameter as a function of capillary transit times show unique characteristics in normal-appearing white and gray matter tissue, whereas tumour-voxels in comparison display a heterogeneous distribution. Collectively, our study presents a comprehensive framework that may serve as a roadmap for in vivo and per-voxel determination of vascular status and heterogeneity in cerebral tissue.

Radiation-induced abnormal cortical thickness in patients with nasopharyngeal carcinoma after radiotherapy

Conventional MRI studies showed that radiation-induced brain necrosis in patients with nasopharyngeal carcinoma (NPC) in years after radiotherapy (RT) could involve brain gray matter (GM) and impair brain function. However, it is still unclear the radiation-induced brain morphological changes in NPC patients with normal-appearing GM in the early period after RT. In this study, we acquired high-resolution brain structural MRI data from three groups of patients, 22 before radiotherapy (pre-RT) NPC patients with newly diagnosed but not yet medically treated, 22 NPC patients in the early-delayed stage after radiotherapy (post-RT-ED), and 20 NPC patients in the late-delayed stage after radiotherapy (post-RT-LD), and then analyzed the radiation-induced cortical thickness alteration in NPC patients after RT. Using a vertex-wise surface-based morphometry (SBM) approach, we detected significantly decreased cortical thickness in the precentral gyrus (PreCG) in the post-RT-ED group compared to the pre-RT group. And the post-RT-LD group showed significantly increased cortical thickness in widespread brain regions, including the bilateral inferior parietal, left isthmus of the cingulate, left bank of the superior temporal sulcus and left lateral occipital regions, compared to the pre-RT group, and in the bilateral PreCG compared to the post-RT-ED group. Similar analysis with ROI-wise SBM method also found the consistent results. These results indicated that radiation-induced brain injury mainly occurred in the post-RT-LD group and the cortical thickness alterations after RT were dynamic in different periods. Our findings may reflect the pathogenesis of radiation-induced brain injury in NPC patients with normal-appearing GM and an early intervention is necessary for protecting GM during RT.

New rapid, accurate T2 quantification detects pathology in normal-appearing brain regions of relapsing-remitting MS patients.

IntroductionQuantitative T2 mapping may provide an objective biomarker for occult nervous tissue pathology in relapsing-remitting multiple sclerosis (RRMS). We applied a novel echo modulation curve (EMC) algorithm to identify T2 changes in normal-appearing brain regions of subjects with RRMS (N = 27) compared to age-matched controls (N = 38).MethodsThe EMC algorithm uses Bloch simulations to model T2 decay curves in multi-spin-echo MRI sequences, independent of scanner, and scan-settings. T2 values were extracted from normal-appearing white and gray matter brain regions using both expert manual regions-of-interest and user-independent FreeSurfer segmentation.ResultsCompared to conventional exponential T2 modeling, EMC fitting provided more accurate estimations of T2 with less variance across scans, MRI systems, and healthy individuals. Thalamic T2 was increased 8.5% in RRMS subjects (p < 0.001) and could be used to discriminate RRMS from healthy controls well (AUC = 0.913). Manual segmentation detected both statistically significant increases (corpus callosum & temporal stem) and decreases (posterior limb internal capsule) in T2 associated with RRMS diagnosis (all p < 0.05). In healthy controls, we also observed statistically significant T2 differences for different white and gray matter structures.ConclusionsThe EMC algorithm precisely characterizes T2 values, and is able to detect subtle T2 changes in normal-appearing brain regions of RRMS patients. These presumably capture both axon and myelin changes from inflammation and neurodegeneration. Further, T2 variations between different brain regions of healthy controls may correlate with distinct nervous tissue environments that differ from one another at a mesoscopic length-scale.

P.1.i.046 - Magnetic resonance spectroscopy as a marker of neuronal activity within normal-appearing grey matter in patients with multiple sclerosis before treatment

To present diffusion and perfusion magnetic resonance imaging (MRI) characteristics of focal nodular hyperplasia (FNH) of the liver.Thirty-five patients with 52 FNHs (21 were pathologically-confirmed) underwent MRI at 1.5-T device. MR diffusion [diffusion-weighted imaging (DWI)] was performed using a free-breathing single-shot, spin-echo, echo-planar sequence with b gradient factor value of 500 s/mm². MR perfusion [perfusion-weighted imaging (PWI)] consisted of a 3D free-breathing LAVA sequence repeated up to 5 minutes after injection of 7 mL Gd-BOPTA (MultiHance, Bracco, Italy) and 20 mL saline flush at a flow rate of 4 mL/s. Apparent diffusion coefficient (ADC) and time-signal intensity curve (TSIC) were obtained for both normal liver and each FNH by two reviewers in conference; maximum enhancement (ME) percentage, time to peak enhancement (TTP), and maximal slope (MS) were also calculated.On DWI mean ADC value was 1.624×10− 3 mm2/s for normal liver and 1.629×10− 3 mm2/s for FNH. ADC value for each FNH and the normal liver was not statistically different (P= .936). On PWI, TSIC-Type 1 (quick and marked enhancement and quick decay followed by slowly decaying) was observed in all 52 FNHs, and TSIC-Type 2 (fast enhancement followed by slowly decaying plateau) in all normal livers. The mean ME, TTP and MS values were significantly different for FNH and normal liver (P= .005).FNHs of the liver showed typical diffusion and perfusion MRI characteristics in all cases. On the ADC map, we could get similar value between the FNHs and the background parenchyma. On the perfusion imaging, FNHs showed a different pattern distinguished from the background liver.