An approach to evaluation of the point-spread function for 23 Na magnetic resonance imaging.

Despite the technical challenges that require lengthy acquisitions to overcome poor signal-to-noise ratio (SNR), sodium (23 Na) magnetic resonance imaging (MRI) is an intriguing area of research due to its essential role in human metabolism. Low SNR images can impact the measurement of the point-spread function (PSF) by adding uncertainty into the resulting quantities. Here, we present methods to calculate the PSF by using the modulation transfer function (MTF), and a 3D-printed line-pair phantom in the context of 23 Na MRI. A simulation study investigated the effect of noise on the resulting MTF curves, which were derived by direct modulation (DM) and a method utilizing Fourier harmonics (FHs). Experimental data utilized a line-pair phantom with nine spatial frequencies, filled with different concentrations (15, 30, and 60 mM) of sodium in 3% agar. MTF curves were calculated using both methods from data acquired from density-adapted 3D radial projections (DA-3DRP) and Fermat looped orthogonally encoded trajectories (FLORET). Simulations indicated that the DM method increased variability in the MTF curves at all tested noise levels over the FH method. For the experimental data, the FH method resulted in PSFs with a narrower full width half maximum with reduced variability, although the improvement in variability was not as pronounced as predicted by simulations. The DA-3DRP data indicated an improvement in the PSF over FLORET. It was concluded that a 3D-printed line-pair phantom represents a convenient method to measure the PSF experimentally. The MTFs from the noisy images in 23 Na MRI have reduced variability from a FH method over DM.

Multimodal Imaging of Retired Professional Contact Sport Athletes Does Not Provide Evidence of Structural and Functional Brain Damage.

BACKGROUND: Long-term consequences of playing professional football and hockey on brain function and structural neuronal integrity are unknown. OBJECTIVES: To investigate multimodal metabolic and structural brain magnetic resonance imaging (MRI) differences in retired professional contact sport athletes compared with noncontact sport athletes. METHODS: Twenty-one male contact sport athletes and 21 age-matched noncontact sport athletes were scanned on a 3 tesla (3T) MRI using a multimodal imaging approach. The MRI outcomes included presence, number, and volume of focal white matter signal abnormalities, volumes of global and regional tissue-specific brain structures, diffusion-tensor imaging tract-based spatial statistics measures of mean diffusivity and fractional anisotropy, quantitative susceptibility mapping of deep gray matter, presence, number, and volume of cerebral microbleeds, MR spectroscopy N-acetyl-aspartate, glutamate, and glutamine concentrations relative to creatine and phosphor creatine of the corpus callosum, and perfusion-weighted imaging mean transit time, cerebral blood flow, and cerebral blood volume outcomes. Subjects were also classified as having mild cognitive impairment. RESULTS: No significant differences were found for structural or functional MRI measures between contact sport athletes and noncontact sport athletes. CONCLUSIONS: This multimodal imaging study did not show any microstructural, metabolic brain tissue injury differences in retired contact versus non-contact sport athletes.

Changes of deep gray matter magnetic susceptibility over 2 years in multiple sclerosis and healthy control brain.

In multiple sclerosis, pathological changes of both tissue iron and myelin occur, yet these factors have not been characterized in a longitudinal fashion using the novel iron- and myelin-sensitive quantitative susceptibility mapping (QSM) MRI technique. We investigated disease-relevant tissue changes associated with myelin loss and iron accumulation in multiple sclerosis deep gray matter (DGM) over two years. One-hundred twenty (120) multiple sclerosis patients and 40 age- and sex-matched healthy controls were included in this prospective study. Written informed consent and local IRB approval were obtained from all participants. Clinical testing and QSM were performed both at baseline and at follow-up. Brain magnetic susceptibility was measured in major DGM structures. Temporal (baseline vs. follow-up) and cross-sectional (multiple sclerosis vs. controls) differences were studied using mixed factorial ANOVA analysis and appropriate t-tests. At either time-point, multiple sclerosis patients had significantly higher susceptibility in the caudate and globus pallidus and lower susceptibility in the thalamus. Over two years, susceptibility increased significantly in the caudate of both controls and multiple sclerosis patients. Inverse thalamic findings among MS patients suggest a multi-phase pathology explained by simultaneous myelin loss and/or iron accumulation followed by iron depletion and/or calcium deposition at later stages.

Effect of teriflunomide on cortex-basal ganglia-thalamus (CxBGTh) circuit glutamatergic dysregulation in the Theiler's Murine Encephalomyelitis Virus mouse model of multiple sclerosis.

BACKGROUND: Pathology of gray matter is associated with development of physical and cognitive disability in patients with multiple sclerosis. In particular, glutamatergic dysregulation in the cortex-basal ganglia-thalamus (CxBGTh) circuit could be associated with decline in these behaviors. OBJECTIVES: To investigate the effect of an immunomodulatory therapy (teriflunomide, Aubagio®) on changes of the CxBGTh loop in the Theiler's Murine Encephalomyelitis Virus, (TMEV) mouse model of MS. METHODS: Forty-eight (48) mice were infected with TMEV, treated with teriflunomide (24) or control vehicle (24) and followed for 39 weeks. Mice were examined with MRS and volumetric MRI scans (0, 8, 26, and 39 weeks) in the cortex, basal ganglia and thalamus, using a 9.4T scanner, and with behavioral tests (0, 4, 8, 12, 17, 26, and 39 weeks). Within conditions, MRI measures were compared between two time points by paired samples t-test and across multiple time points by repeated measures ANOVA (rmANOVA), and between conditions by independent samples t-test and rmANOVA, respectively. Data were considered as significant at the p<0.01 level and as a trend at p<0.05 level. RESULTS: In the thalamus, the teriflunomide arm exhibited trends toward decreased glutamate levels at 8 and 26 weeks compared to the control arm (p = 0.039 and p = 0.026), while the control arm exhibited a trend toward increased glutamate between 0 to 8 weeks (p = 0.045). In the basal ganglia, the teriflunomide arm exhibited a trend toward decreased glutamate earlier than the control arm, from 0 to 8 weeks (p = 0.011), resulting in decreased glutamate compared to the control arm at 8 weeks (p = 0.016). CONCLUSIONS: Teriflunomide may reduce possible excitotoxicity in the thalamus and basal ganglia by lowering glutamate levels.

Methods for the computation of templates from quantitative magnetic susceptibility maps (QSM): Toward improved atlas- and voxel-based analyses (VBA).

PURPOSE: To develop and assess a method for the creation of templates for voxel-based analysis (VBA) and atlas-based approaches using quantitative magnetic susceptibility mapping (QSM). MATERIALS AND METHODS: We studied four strategies for the creation of magnetic susceptibility brain templates, derived as successive extensions of the conventional template generation (CONV) based on only T1 -weighted (T1 w) images. One method that used only T1 w images involved a minor improvement of CONV (U-CONV). One method used only magnetic susceptibility maps as input for template generation (DIRECT), and the other two used a linear combination of susceptibility and T1 w images (HYBRID) and an algorithm that directly used both image modalities (MULTI), respectively. The strategies were evaluated in a group of N = 10 healthy human subjects and semiquantitatively assessed by three experienced raters. Template quality was compared statistically via worth estimates (WEs) obtained with a log-linear Bradley-Terry model. RESULTS: The overall quality of the templates was better for strategies including both susceptibility and T1 w contrast (MULTI: WE = 0.62; HYBRID: WE = 0.21), but the best method depended on the anatomical region of interest. While methods using only one modality resulted in lower WEs, lowest overall WEs were obtained when only T1 w images were used (DIRECT: WE = 0.12; U-CONV: WE = 0.05). CONCLUSION: Template generation strategies that employ only magnetic susceptibility contrast or both magnetic susceptibility and T1 w contrast produce templates with the highest quality. The optimal approach depends on the anatomical structures of interest. The established approach of using only T1 w images (CONV) results in reduced image quality compared to all other approaches studied. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2017;46:1474-1484.

An improved FSL-FIRST pipeline for subcortical gray matter segmentation to study abnormal brain anatomy using quantitative susceptibility mapping (QSM).

Accurate and robust segmentation of subcortical gray matter (SGM) nuclei is required in many neuroimaging applications. FMRIB's Integrated Registration and Segmentation Tool (FIRST) is one of the most popular software tools for automated subcortical segmentation based on T1-weighted (T1w) images. In this work, we demonstrate that FIRST tends to produce inaccurate SGM segmentation results in the case of abnormal brain anatomy, such as present in atrophied brains, due to a poor spatial match of the subcortical structures with the training data in the MNI space as well as due to insufficient contrast of SGM structures on T1w images. Consequently, such deviations from the average brain anatomy may introduce analysis bias in clinical studies, which may not always be obvious and potentially remain unidentified. To improve the segmentation of subcortical nuclei, we propose to use FIRST in combination with a special Hybrid image Contrast (HC) and Non-Linear (nl) registration module (HC-nlFIRST), where the hybrid image contrast is derived from T1w images and magnetic susceptibility maps to create subcortical contrast that is similar to that in the Montreal Neurological Institute (MNI) template. In our approach, a nonlinear registration replaces FIRST's default linear registration, yielding a more accurate alignment of the input data to the MNI template. We evaluated our method on 82 subjects with particularly abnormal brain anatomy, selected from a database of >2000 clinical cases. Qualitative and quantitative analyses revealed that HC-nlFIRST provides improved segmentation compared to the default FIRST method.

Leptomeningeal contrast enhancement is associated with progression of cortical atrophy in MS: A retrospective, pilot, observational longitudinal study.

BACKGROUND: Leptomeningeal contrast enhancement (LM CE) has been recently described in multiple sclerosis (MS) patients as a potential in vivo marker of cortical pathology. OBJECTIVES: To investigate the association of LM CE and development of cortical atrophy in 50 MS patients (27 relapsing-remitting (RR) and 23 secondary-progressive (SP)) followed for 5 years. METHODS: The presence and number of LM CE foci were assessed only at the 5-year follow-up using three-dimensional (3D) fluid-attenuated inversion recovery magnetic resonance imaging (MRI) sequence obtained 10 minutes after single dose of gadolinium injection on 3T scanner. The percentage change in whole brain, cortical and deep gray matter (GM) volumes, and lesion volume (LV) was measured between baseline and the 5-year follow-up. RESULTS: In total, 25 (50%) of MS patients had LM CE at the 5-year follow-up. Significantly more SPMS patients (12, 85.7%) had multiple LM CE foci, compared to those with RRMS (2, 18.2%) ( p = 0.001). MS patients with LM CE showed significantly greater percentage decrease in total GM (-3.6% vs -2%, d = 0.80, p = 0.006) and cortical (-3.4% vs -1.8%, d = 0.84, p = 0.007) volumes and greater percentage increase in ventricular cerebrospinal fluid (vCSF) volume (22.8% vs 9.9%, d = 0.90, p = 0.003) over the follow-up, compared to those without. CONCLUSION: In this retrospective, pilot, observational longitudinal study, the presence of LM CE was associated with progression of cortical atrophy over 5 years.

Differential effects on glial activation by a direct versus an indirect thrombin inhibitor.

Thrombin is a potent regulator of brain function in health and disease, modulating glial activation and brain inflammation. Thrombin inhibitors, several of which are in clinical use as anti-coagulants, can reduce thrombin-dependent neuroinflammation in pathological conditions. However, their effects in a healthy CNS are largely unknown. In adult healthy mice, we compared the effects of treatment by the direct thrombin inhibitor dabigatran etexilate (DE), to those of warfarin, which acts by preventing vitamin K recycling essential for coagulation. After 4weeks, warfarin increased both astrocyte GFAP and microglia Iba-1 staining throughout the CNS; whereas DE reduced expression of both markers. Warfarin, but not DE, reduced sulfatide levels; and warfarin showed longer lasting changes in cerebellar gene expression. DE also reduced glial activation in a mouse model of Alzheimer's disease, although no changes in amyloid plaque burden were observed. These results suggest that treatment with direct thrombin inhibitors may be preferable to those agents which reduce vitamin K levels and have the potential to increase glial activation.

Cerebral Microbleeds in Multiple Sclerosis Evaluated on Susceptibility-weighted Images and Quantitative Susceptibility Maps: A Case-Control Study.

Purpose To assess cerebral microbleed (CMB) prevalence in patients with multiple sclerosis (MS) and clinically isolated syndrome (CIS) and associations with clinical outcomes. Materials and Methods CMBs are associated with aging and neurodegenerative disorders. The prevalence of CMBs has not previously been well established. In this study, 445 patients with MS (266 with relapsing-remitting MS, 138 with secondary progressive MS, and 41 with primary progressive MS), 45 patients with CIS, 51 patients with other neurological diseases, and 177 healthy control subjects (HCs) underwent 3-T magnetic resonance (MR) imaging and clinical examinations. A subset of 168 patients with MS and 50 HCs underwent neuropsychological testing. Number of CMBs was assessed on susceptibility-weighted minimum intensity projections by using the Microbleed Anatomic Rating Scale; volume was calculated by using quantitative susceptibility maps. Differences between groups were analyzed with the χ2 test, Fisher exact test, Student t test, and analysis of variance; associations of CMBs with clinical and other MR imaging outcomes were explored with correlation and regression analyses. Because CMB frequency increases with age, prevalence was investigated in participants at least 50 years of age and younger than 50 years. Results Significantly more patients with MS than HCs had CMBs (19.8% vs 7.4%, respectively; P = .01) in the group at least 50 years old. A trend toward greater presence of CMBs was found in patients with MS (P = .016) and patients with CIS who were younger than 50 years (P = .039) compared with HCs. In regression analysis adjusted for age, hypertension, and normalized brain volume, increased number of CMBs was significantly associated with increased physical disability in the MS population (R2 = 0.23, P < .0001). In correlation analysis, increased number of CMBs was significantly associated with deteriorated auditory and verbal learning and memory (P = .006) and visual information processing speed trends (P = .049) in patients with MS. Conclusion Monitoring CMBs may be relevant in patients with MS and CIS at higher risk for developing cognitive and physical disability. © RSNA, 2016 Online supplemental material is available for this article.

Membrane Cholesterol Modulates Superwarfarin Toxicity.

Superwarfarins are modified analogs of warfarin with additional lipophilic aromatic rings, up to 100-fold greater potency, and longer biological half-lives. We hypothesized that increased hydrophobicity allowed interactions with amphiphilic membranes and modulation of biological responses. We find that superwarfarins brodifacoum and difenacoum increase lactate production and cell death in neuroblastoma cells. In contrast, neither causes changes in glioma cells that have higher cholesterol content. After choleterol depletion, lactate production was increased and cell viability was reduced. Drug-membrane interactions were examined by surface X-ray scattering using Langmuir monolayers of dipalmitoylphosphatidylcholine and/or cholesterol. Specular X-ray reflectivity data revealed that superwarfarins, but not warfarin, intercalate between dipalmitoylphosphatidylcholine molecules, whereas grazing incidence X-ray diffraction demonstrated changes in lateral crystalline order of the film. Neither agent showed significant interactions with monolayers containing >20% cholesterol. These findings demonstrate an affinity of superwarfarins to biomembranes and suggest that cellular responses to these agents are regulated by cholesterol content.

Imaging Chronic Traumatic Encephalopathy: A Biomedical Engineering Perspective.

A disease initially associated with boxers ninety years ago, chronic traumatic encephalopathy (CTE) is now recognized as a significant risk to boxers, American football players, ice hockey players, military personnel or anyone to whom recurrent head injuries are a distinct possibility. Diagnosis is currently confirmed at autopsy, although CTE's presumed sufferers have symptoms of depression, suicidal thoughts, mood and personality changes, and loss of memory. CTE sufferers also complain of losing cognitive ability, dysfunction in everyday activities, inability to keep regular employment, violent tendencies and marital strife. Dementia may develop over the long term. Unfortunately, there is no clear consensus in regards to pathology, with both number and severity of head injuries being linked to disease progression. Despite the slow advancement of this disease, there are no clinical methods to diagnose or monitor prognosis in presumed patients, limiting clinicians' efforts to symptom management. The lack of diagnostic tools fuels the need for biomedical engineers to develop techniques for in vivo detection of CTE. This review examines efforts made with various magnetic resonance and nuclear imaging techniques, with a view towards improving the sensitivity and specificity of diagnostic imaging for CTE.

Lanthionine ketimine ester provides benefit in a mouse model of multiple sclerosis.

Lanthionine ketimine (LK) is a natural sulfur amino acid metabolite which binds to collapsin response mediator protein-2 (CRMP2), an abundant brain protein that interacts with multiple partners to regulate microtubule dynamics, neurite growth and retraction, axonal transport, and neurotransmitter release. LK ethyl-ester (LKE) is a cell-permeable synthetic derivative that promotes neurogenesis, suppresses nitric oxide production from microglia, and reduces neurotoxicity of microglia-conditioned medium. These properties led us to test the effects of LKE in experimental autoimmune encephalomyelitis (EAE), a commonly used mouse model of multiple sclerosis. Female C57Bl/6 mice were immunized with myelin oligodendrocyte glycoprotein peptide 35-55 to develop a chronic disease. LKE was provided in the chow at 100 ppm, ad libitum beginning when the mice reached moderate clinical signs. Over the following 4 weeks the LKE-treated mice showed a significant reduction in clinical signs compared to vehicle-treated mice. LKE dose dependently reduced IFNγ production from splenic T cells, but had no effect on IL-17 production suggesting protective effects were mediated within the CNS. Electron microscopy revealed that, compared to sham mice, EAE mice had significant neurodegeneration in both the optic nerve and spinal cord, which was reduced in the LKE-treated mice. In contrast only minimal disruption of myelin was observed at this time point. In the optic nerve, measurements of axon caliber and myelin thickness showed little changes between sham and EAE mice, however, treatment with LKE increased the percentage of axons with thicker myelin and with larger axon calibers. In the spinal cord, only smaller effects of LKE on myelin thickness were observed. The effects of LKE were associated with a reduced relative level of phosphorylated CRMP2 to CRMP2. Together, these results demonstrate that LKE reduces neurodegeneration in a chronic EAE model of MS, which could have translation potential for treatment of progressive forms of MS.

A single-nucleotide polymorphism in serine-threonine kinase 11, the gene encoding liver kinase B1, is a risk factor for multiple sclerosis.

We identified a family in which five siblings were diagnosed with multiple sclerosis (MS) or clinically isolated syndrome. Several women in the maternal lineage have comorbidities typically associated with Peutz Jeghers Syndrome, a rare autosomal-dominant disease caused by mutations in the serine-threonine-kinase 11 (STK11) gene, which encodes liver kinase B1. Sequence analysis of DNA from one sibling identified a single-nucleotide polymorphism (SNP) within STK11 intron 5. This SNP (dbSNP ID: rs9282860) was identified by TaqMan polymerase chain reaction (PCR) assays in DNA samples available from two other siblings. Further screening was carried out in samples from 654 relapsing-remitting MS patients, 100 primary progressive MS patients, and 661 controls. The STK11-SNP has increased frequency in all female patients versus controls (odds ratio = 1.66, 95% CI = 1.05, 2.64, p = .032). The STK11-SNP was not associated with disease duration or onset; however, it was significantly associated with reduced severity (assessed by MS severity scores), with the lowest scores in patients who also harbored the HLA-DRB1*1501 allele. In vitro studies showed that peripheral blood mononuclear cells from members of the family were more sensitive to the mitochondrial inhibitor metformin than cells from MS patients with the major STK11 allele. The increased association of SNP rs9282860 in women with MS defines this variant as a genetic risk factor. The lower disease severity observed in the context of HLA-DRB1*1501 combined with limited in vitro studies raises the provocative possibility that cells harboring the STK11-SNP could be targeted by drugs which increase metabolic stress.

Diffusion tensor imaging alterations in patients with postconcussion syndrome undergoing exercise treatment: a pilot longitudinal study.

PURPOSE: To investigate diffusion tensor imaging characteristics in patients with postconcussion syndrome (PCS) who received exercise (n = 4) and placebo stretching (n = 4) treatments compared with a group of healthy controls (n = 15). METHODS: Subjects diagnosed with PCS obtained a diffusion tensor imaging magnetic resonance image at pretreatment (baseline) and approximately 8 weeks later (follow-up). Analyses included a groupwise comparison using tract-based spatial statistics and a z-score map that investigated localized regional anomalies compared with the healthy control group projected onto the tract-based spatial statistics skeleton. RESULTS: The tract-based spatial statistics analysis detected groupwise differences in the genu of the corpus callosum at both time points with decreased fractional anisotropy and increased radial diffusivity and mean diffusivity values. In contrast, the z-score analysis was more sensitive to heterogeneous changes in fractional anisotropy, with both low- and high-localized areas across various white matter regions, the most prevalent being the corpus callosum, anterior and superior corona radiata, and internal and external capsules. The mean number of voxels different in patients with PCS versus healthy controls was greater in all cases (baseline lower: P < .03 and higher: P < .0001; follow-up lower: P < .0001 and higher: P < .0001). The volume and location of these abnormal regions changed between the 2 diffusion tensor imaging scans, but these did not correlate with the mitigation of symptoms in the patients with PCS. CONCLUSIONS: Diffusion tensor imaging revealed spatially varying and heterogeneous localized irregularities in patients with PCS that persisted even as patient symptoms decreased and prognosis improved.

The blood-brain barrier-permeable catechol-O-methyltransferase inhibitor dinitrocatechol suppresses experimental autoimmune encephalomyelitis.

Reduced levels of noradrenaline (NA) in CNS of multiple sclerosis patients could be due to metabolism by catechol-O-methyltransferase (COMT). In mice immunized with myelin oligodendrocyte glycoprotein peptide, the BBB-permeable COMT inhibitor dinitrocatechol (DNC) reduced clinical signs, while entacapone, a non-BBB-permeable inhibitor, had no effect. Spinal cord NA levels were slightly increased by DNC, and there was an inverse correlation between NA levels and average clinical signs. Spinal cord COMT mRNA levels were not increased during EAE, but were found increased in the frontal cortex of MS patients. These results suggest that COMT inhibitors could provide benefit to MS patients.

Masking level differences--a diffusion tensor imaging and functional MRI study.

In our previous study we investigated Masking Level Differences (MLD) using functional Magnetic Resonance Imaging (fMRI), but were unable to confirm neural correlations for the MLD within the auditory cortex and inferior colliculus. Here we have duplicated conditions from our previous study, but have included more participants and changed the study site to a new location with a newer scanner and presentation system. Additionally, Diffusion Tensor Imaging (DTI) is included to allow investigation of fiber tracts that may be involved with MLDs. Twenty participants were included and underwent audiometric testing and MRI scanning. The current study revealed regions of increased and decreased activity within the auditory cortex when comparing the combined noise and signal of the dichotic MLD stimuli (N0Sπ and NπS0) with N0S0. Furthermore, we found evidence of inferior colliculus involvement. Our DTI findings show strong correlations between DTI measures within the brainstem and signal detection threshold levels. Patterns of correlation when the signal was presented only to the right ear showed an extensive network in the left hemisphere; however, the opposite was not true for the signal presented only to the left ear. Our current study was able to confirm what we had previously hypothesized using fMRI, while extending our investigation of MLDs to include the characteristics of connecting neural pathways.

Effects of peptide fraction and counter ion on the development of clinical signs in experimental autoimmune encephalomyelitis.

The most commonly used immunogen to induce experimental autoimmune encephalomyelitis is MOG35-55 , a 21-residue peptide derived from myelin oligodendrocyte glycoprotein (MOG). In most studies, mice exhibit a chronic disease; however, in some studies mice show a transient disease. One variable that is not often controlled for is the peptide fraction of the purified MOG material, which can vary from less than 50% to over 90%, with the remainder of mass primarily comprised of the counter ion used for peptide purification. We compared the development of clinical signs in female C57Bl6 mice immunized with two commercially available MOG35-55 peptides of similar purity but different peptide fraction (MOG-A being 45%; MOG-B being 72%). A single immunization with MOG-A induced a chronic disease course with some recovery at later stages, whereas immunization with MOG-B induced a similar course of disease but with significantly lower average clinical scores despite a higher peptide content. The addition of a booster immunization significantly increased clinical severity with both preparations, and significantly reduced the average day of onset using MOG-A. To determine if the counter ion could influence disease, we compared MOG-B-containing trifluoroacetate with MOG-B-containing acetate. Although disease incidence and severity were similar, the average day of disease onset occurred approximately 5 days earlier with the use of MOG-B-containing trifluoroacetate. These results demonstrate that differences in peptide fraction influence the course of encephalomyelitis disease, which may be due in part to the levels of counter ions present in the purified material. These findings underscore the fact that a knowledge of peptide fraction is as critical as knowledge of peptide purity when using peptides from different sources.

Tract-based spatial statistics analysis of diffusion-tensor imaging data in pediatric- and adult-onset multiple sclerosis.

BACKGROUND: White matter (WM) microstructure may vary significantly in pediatric-onset (PO) and adult-onset (AO) patients with multiple sclerosis (MS), a difference that could be explained by the effects of an inherent plasticity in the affected pediatric brains early in the disease, and a phenomenon that does not occur later in life. This hypothesis would support the observation that disease progression is much slower in POMS compared to AOMS patients. OBJECTIVES: To examine WM microstructure in the brain of adults with POMS and AOMS, using tract based spatial statistics (TBSS) analysis of diffusion-tensor imaging (DTI). METHODS: Adults with relapsing-remitting (RR) POMS, who were diagnosed before age of 18 years (n = 16), were compared with age-matched (AOA, n = 23) and disease duration-matched (AOD, n = 22) RR patients who developed MS after the age of 18 years. Scans were analyzed using the FSL software package (Oxford, UK) and statistics were performed using TBSS to evaluate WM microstructure between groups based on the mean fractional anisotropy (FA) values obtained from the DTI. RESULTS: Widespread cortical and deep WM area differences characterized by increased FA values were seen in the AOAMS compared with POMS group (P < 0.05, TFCE corrected). Significantly increased FA values of posterior WM areas were detected in the AODMS compared with POMS group (P < 0.05, TFCE corrected). CONCLUSION: Increased FA values in WM areas of the AOMS compared with the POMS patients suggest that diffuse WM microstructure changes are more attributable to age of onset than a simple function of disease duration and age.

Dimethyl fumarate regulates histone deacetylase expression in astrocytes.

We previously showed that dimethyl fumarate (DMF) reduces inflammatory activation in astrocytes, involving activation of transcription factor Nrf2. However, the pathways causing Nrf2 activation were not examined. We now show that DMF modifies expression of histone deacetylases (HDACs) in primary rat astrocytes. After 4h incubation, levels of HDAC1, 2, and 4 mRNAs were increased by DMF; however, after 24h, levels returned to or were below control values. At that time, HDAC protein levels and overall activity were also reduced by DMF. Stimulation of astrocytes with pro-inflammatory cytokines significantly increased HDAC mRNA levels after 24h, although protein levels were not increased at that time point. In the presence of cytokines, DMF reduced HDAC mRNAs, proteins, and activity. Proteomic analysis of DMF-treated astrocytes identified 8 proteins in which lysine acetylation was increased by DMF, including histones H2a.1 and H3.3. A role for HDACs in mediating DMF actions is suggested by findings that the selective HDAC inhibitor SAHA increased nuclear Nrf2:DNA binding activity, reduced inflammatory activation of astrocytes which was reversed by a selective inhibitor of the Nrf2 target gene heme-oxygenase 1. These data show that DMF regulates astrocyte HDAC expression, which could contribute to Nrf2 activation, suppression of inflammatory responses and cause long-lasting changes in gene expression.

Development of amyloid burden in African Green monkeys.

The vervet is an old world monkey increasingly being used as a model for human diseases. In addition to plaques and tangles, an additional hallmark of Alzheimer's disease is damage to neurons that synthesize noradrenaline (NA). We characterized amyloid burden in the posterior temporal lobe of young and aged vervets, and compared that with changes in NA levels and astrocyte activation. Total amyloid beta (Aß)40 and Aß42 levels were increased in the aged group, as were numbers of amyloid plaques detected using antibody 6E10. Low levels of Aß42 were detected in 1 of 5 younger animals, although diffusely stained plaques were observed in 4 of these. Increased glial fibrillary acidic protein staining and messenger RNA levels were significantly correlated with increased age, as were cortical NA levels. Levels of Aß42 and Aß40, and the number of 6E10-positive plaques, were correlated with NA levels. Interestingly messenger RNA levels of glial derived neurotrophic factor, important for noradrenergic neuronal survival, were reduced with age. These findings suggest that amyloid pathology in aged vervets is associated with astrocyte activation and higher NA levels.