Impaired White Matter Research Articles

Corticoefferent pathology distribution in amyotrophic lateral sclerosis: in vivo evidence from a meta-analysis of diffusion tensor imaging data

A sequential transaxonal disease spread of amyotrophic lateral sclerosis (ALS)-associated TDP-43 pathology in four stages has been defined by post-mortem data, which have been transferred to in vivo imaging by diffusion tensor imaging (DTI) studies. Here, we aimed to investigate whether DTI meta-data are consistent with this proposed pattern of progression in ALS. A systematic literature search using the search engines PubMed and Scopus yielded a total of 370 publications. Of these, 57 studies with cross-sectional data and 10 longitudinal studies of human whole-brain analyses of fractional anisotropy (FA) were included in the final data analysis. Statistical meta-analyses on coordinates of significant FA alterations were performed on a grand average alteration data set using a fixed-effect model. A widespread pattern of white matter impairment was identified from cross-sectional meta data (n = 2064 ALS patients vs. n = 1688 controls) and supported from longitudinal meta data (n = 266 ALS patients over 8 months). The results from cross-sectional meta-analyses corresponded to the brain regions and tract systems according to the sequential disease spread of ALS. Structural alterations in ALS patients vs. controls followed a power gradient, i.e., the most frequent alterations were observed along the corticospinal tract (CST, related to ALS stage 1), followed by frequent alterations along the corticorubral/-pontine tract (related to ALS stage 2), together with corticostriatal pathways (related to ALS stage 3), and, finally, alterations in the hippocampal regions adjacent to the proximal portion of the perforant path (related to ALS stage 4). The results from the DTI-based neuroimaging meta-analysis strongly support the model of the corticoefferent axonal disease progression in ALS and provides further in vivo evidence for the proposed staging scheme of ALS-associated pathology.

Diabetes Mellitus Impairs White Matter Repair and Long-Term Functional Deficits After Cerebral Ischemia.

Background and Purpose- Type 2 diabetes mellitus (T2DM) is a major comorbidity that exacerbates ischemic brain injury and worsens functional outcome after stroke. T2DM is known to aggravate white matter (WM) impairment, but the underlying mechanism is not completely understood. This study was designed to test the hypothesis that T2DM impedes poststroke WM recovery by suppressing both oligodendrogenesis and beneficial microglia/macrophage responses. Methods- Permanent distal middle cerebral artery occlusion was performed in wild-type, homozygous diabetic db/db, and heterozygous db/+ mice. The adhesive removal, open field, and Morris water maze tests were used to assess neurobehavioral outcomes. Neuronal tissue loss, WM damage, oligodendrogenesis, and microglia/macrophage responses were evaluated up to 35 days after stroke. The functional integrity of WM was measured by electrophysiology. Primary microglia-oligodendrocyte cocultures were used for additional mechanistic studies. Results- T2DM exacerbated structural damage and impaired conduction of compound action potentials in WM 35 days after stroke. The deterioration in WM integrity correlated with poor sensorimotor performance. Furthermore, T2DM impaired the proliferation of oligodendrocyte precursor cells and the generation of new myelinating oligodendrocytes. T2DM also promoted a shift of microglia/macrophage phenotype toward the proinflammatory modality. Coculture studies confirmed that microglia/macrophage polarization toward the proinflammatory phenotype under high glucose conditions suppressed oligodendrocyte precursor cell differentiation. Conclusions- Deterioration of WM integrity and impairments in oligodendrogenesis after stroke are associated with poor long-term functional outcomes in experimental diabetes mellitus. High glucose concentrations may shift microglia/macrophage polarization toward a proinflammatory phenotype, significantly impairing oligodendrocyte precursor cell differentiation and WM repair.

Radiomics Analysis of DTI Data to Assess Vision Outcome After Intravenous Methylprednisolone Therapy in Neuromyelitis Optic Neuritis.

Neuromyelitis optica-optic neuritis (NMO-ON) patients are routinely treated with intravenous methylprednisolone (IVMP). For the patients nonresponsive to IVMP, more effective but aggressive therapy of plasma exchange (PE) should be employed instead of IVMP in the first line. To assess the visual outcomes of NMO-ON patients after IVMP by radiomics analysis of whole brain diffusion tensor imaging (DTI) data. Retrospective. In all, 57 NMO-ON patients receiving IVMP therapy for 3 days. 3.0T; DTI images acquired by a single-shot echo planar image sequence; T1 images acquired by 3D fast spoiled gradient echo (3D-FSPGR) MRI. In all, 200 DTI measures were extracted from the DTI data and employed as features to construct a radiomics assessment model for visual outcomes of NMO-ON patients after IVMP. The assessment performance was evaluated by area under the receiver operating characteristic curve (AUC), classification accuracy (ACC), sensitivity, specificity, and positive and negative predicted values (PPV and NPV). The selected DTI measures would reveal the white matter impairments related to visual recovery of NMO-ON patients. The relationship between the selected DTI measures and the clinical visual characteristics were investigated by Pearson correlation, Spearman's rank correlation, and one-way analysis of variance analysis. The radiomics model obtained an ACC of 73.68% (P = 0.002), AUC of 0.7931, sensitivity of 0.6207, specificity of 0.8571, PPV of 0.8182, and NPV of 0.6857 in assessing visual outcomes of the NMO-ON patients after IVMP treatment. The selected DTI measures revealed white matter impairments related to the visual outcomes in the white matter tracts of vision-relevant regions, motor-related regions, and corpus callosum. The white matter impairments were found significantly correlated with the disease duration and the length of lesions in the optic nerve. Radiomics analysis of DTI data has great potential in assessing visual outcomes of NMO-ON patients after IVMP therapy. 2 Technical Efficacy: Stage 4 J. Magn. Reson. Imaging 2019;49:1365-1373.

Impaired white matter integrity between premotor cortex and basal ganglia in writer's cramp.

IntroductionWriter’s cramp (WC) as a focal hand dystonia is characterized by abnormal postures of the hand during writing. Impaired inhibition and maladaptive plasticity in circuits linking the basal ganglia and sensorimotor cortices have been described. In particular, a dysfunction of lateral premotor cortices has been associated with impaired motor control in WC. We applied diffusion tensor imaging to identify changes in white matter connectivity between premotor regions and important cortical and subcortical structures.MethodsWhole brain white matter tracts were reconstructed in 18 right‐handed WC patients and 18 matched controls, using probabilistic fiber tracking. We restricted our analyses to left‐hemispheric fibers between the middle frontal gyrus (MFG) and basal ganglia, thalamus, primary motor, and sensory cortex. Diffusion parameters (fractional anisotropy and linear anisotropy) were compared between both groups.ResultsA significant reduction in fractional anisotropy values was shown for patients (mean ± SD: 0.37 ± 0.02) vs. controls (0.39 ± 0.03) regarding fibers between the left‐sided MFG and the putamen (p < 0.05). The same applied for linear anisotropy values in this connection (p < 0.05).ConclusionsOur results suggest an impaired structural connectivity between the left‐hemispheric MFG and putamen with a loss of equally aligned fibers in WC patients. This could reflect a structural basis for functional findings interpreted as altered inhibition and plasticity, both within the premotor cortex and the basal ganglia, that at last lead to the clinical symptoms of WC.

Distinct Patterns of Interhemispheric Connectivity in Patients With Early- and Late-Onset Alzheimer's Disease.

Background: Early-onset Alzheimer’s disease (EOAD) presents a different clinical profile than late-onset Alzheimer’s disease (LOAD). Neuroimaging studies have demonstrated that patients with EOAD present more atrophy and functional disconnection than LOAD patients. However, it remains unknown whether the interhemispheric functional disconnection or its underlying structural impairment contributes to the different clinical profiles of EOAD and LOAD.Methods: According to the arbitrary cut-off age of 65, we included 22 EOAD patients, 27 LOAD patients and 38 healthy controls (further divided into 21 relatively young and 17 old controls). Participants underwent resting-state functional MRI, diffusion tensor imaging (DTI) and comprehensive neuropsychological assessments. We used voxel-mirrored homotopic connectivity (VMHC) to examine interhemispheric functional connectivity. Then, we calculated the diffusion index based on tract-based spatial statistics (TBSS). Two-sample t-tests were used to assess the interhemispheric connectivity differences between each patient group and its corresponding control group.Results: We found that the EOAD patients had lower VMHC in the hippocampus, parahippocampal gyrus (PHG), superior temporal gyrus (STG) and inferior parietal cortex (IPC) than did controls. Consistently, the EOAD patients exhibited white matter (WM) tract impairment in the posterior regions. On the other hand, the LOAD patients displayed increased VMHC and impaired WM tracts in the frontal region. Correlation analyses showed that VMHC in the IPC was related to executive function in the EOAD patients (r = −0.67, P < 0.05).Conclusion: In contrast to the LOAD patients, patients with EOAD exhibited more widely disrupted interhemispheric functional and structural connectivity, which overlapped well across brain regions. In addition, for the EOAD patients, decreased interhemispheric connectivity related to executive deficits. Our study suggested that different interhemispheric connectivity damage patterns may contribute to the distinct clinical profiles in EOAD and LOAD.

The impact of localized grey matter damage on neighboring connectivity: posterior cortical atrophy and the visual network.

Posterior cortical atrophy (PCA), a localized neurodegenerative syndrome involving the occipito-parietal cortices, can serve as a good model to elaborate on the consequence of a localized damage on the anatomical and functional connectivity within an affected system. Ten PCA patients and 14 aged-matched controls were enrolled. Structural connectivity was measured via Diffusion Tensor Imaging (DTI) and probabilistic tractography. The optic tracts and radiations and the splenial fibers were delineated and their microstructural properties were evaluated. Functional connectivity was measured by resting state functional MRI (rsfMRI). Voxel-based morphometry (VBM) was used to assess atrophy. Dorsal stream visual functions were tested and correlation between these behavioral data, volume measures, white matter integrity and connectivity were examined. Impaired white matter integrity was evident in patients' optic radiations and occipito-callosal fibers, in the segments located in close proximity to the occipital cortex, suggesting a localized damage. Degeneration did not proceed to the optic tracts, opposing trans-synaptic changes. rsfMRI revealed reduced connectivity within the visual network and between the visual and other related areas such as the frontal eye field. Correlations were found between grey matter volume and spatial perception abilities and between the integrity of the affected fibers and motion perception. White matter involvement in PCA seems to be grey matter dependent. Functional connectivity, on the other hand, showed a more diffuse pattern of damage. Correlations were found between the integrity of the affected fibers and patients' visual abilities suggesting that fiber integrity plays a role in determining behavioral manifestation.

Association of excessive social media use with abnormal white matter integrity of the corpus callosum

Borrowing from findings regarding other problematic behaviors, we posit that excessive social media use (ESMU) can relate to impaired inter-hemispheric connections. These are often reflected in impaired white matter integrity (decreased fractional anisotropy and increased mean diffusivity) of the corpus callosum. We test this idea with diffusion tensor imaging (DTI) data from 20 normal social media users with varying degrees of ESMU. The findings of a Regions of Interest analysis focusing on the corpus callosum indicate that ESMU is associated with increased mean diffusivity in the body and splenium sub-regions of the corpus callosum. Whole-brain Tract Based Spatial Statistics analysis revealed that ESMU is positively associated with mean diffusivity of left superior and inferior longitudinal fasciculi as well as left forceps minor; and that ESMU is positively associated with the fractional anisotropy of the right Corticospinal Tract. It is concluded that inter-hemispheric white matter deficits in the corpus callosum extended to forceps minor, as well as along the ventral semantic path can be associated with ESMU.

Altered white matter microstructure associated with mild and moderate depressive symptoms in young adults, a diffusion tensor imaging study.

In the context of growing evidence supporting disturbed neural connectivity in the pathogenesis of depressive symptoms, we used the diffusion tensor imaging technique to investigate white matter disruptions in previously undiagnosed and hence treatment-naive young adults with mild and moderate depressive symptoms screened by Beck's Depression Inventory test compared with age-matched and sex-matched healthy controls. This is the first diffusion tensor imaging study to assess minor forms of depression. We hypothesized that subthreshold depressive symptoms share the same neural disruptions as major depressive disorder (MDD). Each group included 47 participants with a mean age of 20.1±1.1 years. The exploratory region of interest method was used to assess integrity (fractional anisotropy and mean diffusivity) in 48 regions of the brain based on Mori atlas. Data were recruited from the Southwest University Longitudinal Imaging Multimodal Brain Data Repository. The following pathways showed significant microstructural changes by means of reduced fractional anisotropy in the group with depressive symptoms compared with normal participants: pontine crossing tract; genu of the corpus callosum; posterior limb of the internal capsule (bilaterally); and anterior, posterior, and superior corona radiata (bilaterally). None of the above regions, but the middle cerebellar peduncle and the right superior fronto-occipital fasciculus were shown to differ significantly in the mean diffusivity values between the two groups. On the basis of the current results, our findings provide evidence that the white matter impairments in the interhemispheric connections and frontal-subcortical neural circuits may play a key role in the pathogenesis of depression in young adults. The similarity of neural underpinnings in MDD and minor depressive disorder in this study further proves that these two mood disorders exist in a continuum, and milder depressive symptoms can herald a major episode. Besides the high prevalence and great burden of subthreshold forms of depression on personal and social aspects of life, there is lack of knowledge of them and most studies have mainly focused on MDD. This study provides a new avenue in addressing neuropathology of depression, mainly in subtle forms that are almost always overlooked.

Axonal chronic injury in treatment-na\xefve HIV+ adults with asymptomatic neurocognitive impairment and its relationship with clinical variables and cognitive status

BackgroundHIV is a neurotropic virus, and it can bring about neurodegeneration and may even result in cognitive impairments. The precise mechanism of HIV-associated white matter (WM) injury is unknown. The effects of multiple clinical contributors on WM impairments and the relationship between the WM alterations and cognitive performance merit further investigation.MethodsDiffusion tensor imaging (DTI) was performed in 20 antiretroviral-naïve HIV-positive asymptomatic neurocognitive impairment (ANI) adults and 20 healthy volunteers. Whole-brain analysis of DTI metrics between groups was conducted by employing tract-based spatial statistics (TBSS), including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD). DTI parameters were correlated with clinical variables (age, CD4+ cell count, CD4+/CD8+ ratio, plasma viral load and duration of HIV infection) and multiple cognitive tests by using multilinear regression analyses.ResultsDTI quantified diffusion alterations in the corpus callosum and corona radiata (MD increased significantly, P < 0.05) and chronic axonal injury in the corpus callosum, corona radiata, internal capsule, external capsule, posterior thalamic radiation, sagittal stratum, and superior longitudinal fasciculus (AD increased significantly, P < 0.05). The impairments in the corona radiata had significant correlations with the current CD4+/CD8+ ratios. Increased MD or AD values in multiple white matter structures showed significant associations with many cognitive domain tests.ConclusionsWM impairments are present in neurologically asymptomatic HIV+ adults, periventricular WM (corpus callosum and corona radiata) are preferential occult injuries, which is associated with axonal chronic damage rather than demyelination. Axonopathy may exist before myelin injury. DTI-TBSS is helpful to explore the WM microstructure abnormalities and provide a new perspective for the investigation of the pathomechanism of HIV-associated WM injury.

Nexilin Regulates Oligodendrocyte Progenitor Cell Migration and Remyelination and Is Negatively Regulated by Protease-Activated Receptor 1/Ras-Proximate-1 Signaling Following Subarachnoid Hemorrhage.

Progressive white matter (WM) impairments caused by subarachnoid hemorrhage (SAH) contribute to cognitive deficits and poor clinical prognoses; however, their pathogenetic mechanisms are poorly understood. We investigated the role of nexilin and oligodendrocyte progenitor cell (OPC)-mediated repair in a mouse model of experimental SAH generated via left endovascular perforation. Nexilin expression was enhanced by the elevated migration of OPCs after SAH. Knocking down nexilin by siRNA reduced OPC migration both in vitro and in vivo and abridged WM repair. In contrast, the protease-activated receptor 1 (PAR1), Ras-proximate-1 (RAP1) and phosphorylated RAP1 (pRAP1) levels in WM were elevated after SAH. The genetic inhibition of PAR1 reduced RAP1 and pRAP1 expression, further enhancing nexilin expression. When delivered at an early stage at a concentration of 25 µg/kg, thrombin receptor antagonist peptide along with PAR1 knockdown rescued the down-regulation of myelin basic protein and improved remyelination at the later stage of SAH. Our results suggest that nexilin is required for OPC migration and remyelination following SAH, as it negatively regulates PAR1/RAP1 signaling, thus providing a promising therapeutic target in WM repair and functional recovery.

White matter degeneration profile in the cognitive cortico-subcortical tracts in Parkinson's disease.

In Parkinson's disease cognitive impairment is an early nonmotor feature, but it is still unclear why some patients are able to maintain their cognitive performance at normal levels, as quantified by neuropsychological tests, whereas others cannot. The objectives of this study were to perform a cross-sectional study and analyze the white matter changes in the cognitive and motor bundles in patients with Parkinson's disease. Sixteen Parkinson's disease patients with normal cognitive performance, 19 with mild cognitive impairment (based on their performance of 1.5 standard deviations below the healthy population mean), and 16 healthy controls were compared with respect to their tractography patterns between the cortical cognitive / motor regions and subcortical structures, using high angular resolution diffusion imaging and constrained spherical deconvolution computation. Motor bundles showed decreased apparent fiber density in both PD groups, associated with a significant increase in diffusivity metrics, number of reconstructed streamlines, and track volumes, compared with healthy controls. By contrast, in the cognitive bundles, decreased fiber density in both Parkinson's groups was compounded by the absence of changes in diffusivity in patients with normal cognition, whereas patients with cognitive impairment had increased diffusivity metrics, lower numbers of reconstructed streamlines, and lower track volumes. Both PD groups showed similar patterns of white matter neurodegeneration in the motor bundles, whereas cognitive bundles showed a distinct pattern: Parkinson's patients with normal cognition had white matter diffusivity metrics similar to healthy controls, whereas in patients with cognitive impairment white matter showed a neurodegeneration pattern. © 2018 International Parkinson and Movement Disorder Society.

Pathological factors contributing to crossed cerebellar diaschisis in cerebral gliomas: a study combining perfusion, diffusion, and structural MR imaging.

To investigate imaging features of crossed cerebellar diaschisis (CCD) in cerebral gliomas, and its underlying pathophysiological mechanisms. Thirty-three pre-surgical patients with cerebral gliomas and 33 healthy controls underwent arterial spin-labeling, diffusion tensor imaging, and high-resolution T1-weighted imaging using MRI, in order to estimate cerebral blood flow (CBF), white matter integrity, and lesion volume, respectively. Asymmetry indices of CBF in the cerebellum were used for evaluating the level of CCD in the patients. These indices were correlated with clinical variables (lesion size and position, tumor histological grade, and CBF asymmetry) and diffusion tensor imaging parameters (fractional anisotropy and number of fibers in the cortico-ponto-cerebellar pathway and across the cerebral hemispheres), respectively. The patients showed decreased CBF in the cerebellar hemisphere contralateral to the supratentorial tumor, and increased CBF asymmetry in the cerebellum (both P < 0.05). CCD levels in high-grade gliomas were higher than those of low-grade gliomas (P < 0.05). CCD levels were negatively correlated with the size of the supratentorial lesions, and positively correlated with FA asymmetry in the cerebral fibers (both P < 0.05). CCD in cerebral gliomas was specifically associated with tumor histological grade, lesion size, and white matter impairments in the hemisphere ipsilateral to the tumor. The findings implicated that observing CCD might have potential for assisting grading diagnosis of cerebral gliomas.

Risk Factors Associated with Cortical Thickness and White Matter Hyperintensities in Dementia Free Okinawan Elderly.

Background:Cortical gray matter (GM) and white matter (WM) deterioration are signals of neurodegeneration and increased dementia risk; however, their specific etiologies in dementia-free aging is unclear.Objective:The objective of this study was to examine potentially modifiable risk factors of GM and WM degeneration in a well-characterized cohort of dementia-free elderly.Methods:96 Okinawan elderly participants (age 83.6) from the Keys to Optimal Cognitive Aging Project (KOCOA) underwent MRI and cognitive evaluation. Serum markers of inflammation (interleukin-6 (IL-6), high sensitivity C-reactive protein), cerebrovascular disease (systolic blood pressure (SBP) 140+, hemoglobin A1C (HgbA1C), total cholesterol), and essential minerals (copper (Cu), magnesium, and calcium) were examined in relation to mean cortical thickness (MCT) and white matter hyperintensities (WMH), adjusting for age and gender. Voxel-based morphometry (VBM) analyses identified relationships between regional GM density and the above markers.Results:Decreased MCT was associated with SBP 140 + (p = 0.029) and increased serum IL-6 (p = 0.036), HgbA1C (p = 0.002), and Cu (p = 0.025). In VBM analyses, increased IL-6, HgbA1C, and Cu were associated with decreased GM density in temporal lobe regions. HgbA1C (p = 0.004) was associated with greater WMH volume.Conclusions:Peripheral markers of Cu, CVD risk, and inflammation are associated with MRI-markers of decreased brain health in dementia-free Okinawan elderly, with regional cortical thinning in areas involved in early accumulation of Alzheimer’s disease pathology. Results identify potentially modifiable biomarkers as targets in the prevention of dementia in older individuals.

F206. A TRANSLATIONAL STUDY OF BEHAVIOR, BRAIN STRUCTURE AND GENE PATHWAY IN ERBB4 KNOCKOUT MICE AND FIRST-EPISODE TREATMENT-NAïVE PATIENTS WITH SCHIZOPHRENIA

BackgroundThe current study was to explore how disruption of specific molecular circuits in the cerebral cortex may cause large-scale brain structure deficits and behavior changes via a translational study in conditional Erbb4 mutant mice and patients with schizophrenia.MethodsWe conducted prepulse inhibition (PPI) and brain structural and diffusion magnetic resonance imaging (MRI) scans in 27 mice with ErbB4 knockout in parvalbumin (PV) interneurons and 23 age, sex-matched controls. Real-time quantitative polymerase chain reaction was used to assess the levels of five GABA-related transcripts in brain regions. We also measured structural and diffusion MRI and cumulative contribution of risk alleles in the GABA pathway genes using polygenic risk scores (PRS) in first-episode treatment-naïve schizophrenic patients (N=117) and age, sex-matched healthy controls (N=86).ResultsErbB4 knockout mice displayed behavioral deficit of PPI, as well as gray and white matter impairment in right sensorimotor cortical-striatal networks. We found significant correlations between gray matter volumes (GMVs) of the somatosensory cortex and PPI as well as GAD1 mRNA expression in controls but not in knockout mice. These findings were confirmed in a human sample where we observed significantly decreased gray and white matter impairment in sensorimotor cortical-striatal networks in schizophrenics. The PRS of GABA-pathway genes also displayed a negative correlation with the GMVs of the somatosensory cortex in patients.DiscussionOur study identified ErbB4 ablation induced prepulse inhibition deficits and GABAergic dysregulation in sensorimotor cortical-lateral striatal networks. We propose that ErbB4 signaling participates in sensorimotor gating dysfunction in schizophrenia by getting involved in somatosensory cortex deficits and GABAergic dysfunction.

Longitudinal microstructural changes of cerebral white matter and their association with mobility performance in older persons.

Mobility impairment in older persons is associated with brain white matter hyperintensities (WMH), a common finding in magnetic resonance images and one established imaging biomarker of small vessel disease. The contribution of possible microstructural abnormalities within normal-appearing white matter (NAWM) to mobility, however, remains unclear. We used diffusion tensor imaging (DTI) measures, i.e. fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD), to assess microstructural changes within supratentorial NAWM and WMH sub-compartments, and to investigate their association with changes in mobility performance, i.e. Tinetti assessment and the 2.5-meters walk time test. We analyzed baseline (N = 86, age ≥75 years) and 4-year (N = 41) follow-up data. Results from cross-sectional analysis on baseline data showed significant correlation between WMH volume and NAWM-FA (r = -0.33, p = 0.002), NAWM-AD (r = 0.32, p = 0.003) and NAWM-RD (r = 0.39, p = 0.0002). Our longitudinal analysis showed that after 4-years, FA and AD decreased and RD increased within NAWM. In regional tract-based analysis decrease in NAWM-FA and increase in NAWM-RD within the genu of the corpus callosum correlated with slower walk time independent of age, gender and WMH burden. In conclusion, global DTI indices of microstructural integrity indicate that significant changes occur in the supratentorial NAWM over four years. The observed changes likely reflect white matter deterioration resulting from aging as well as accrual of cerebrovascular injury associated with small vessel disease. The observed association between mobility scores and regional measures of NAWM microstructural integrity within the corpus callosum suggests that subtle changes within this structure may contribute to mobility impairment.

White Matter Abnormalities and Correlation With Severity in Normal Tension Glaucoma: A Whole Brain Atlas-Based Diffusion Tensor Study.

To detect injury of whole brain white matter (WM) in normal tension glaucoma (NTG) patients by using diffusion tensor imaging (DTI) and to analyze the correlations between DTI parameters and glaucoma indices. Twenty mild, 17 moderate, and 18 severe NTG patients as well as 25 normal subjects were enrolled in this study. Atlas-based diffusion tensor analysis was performed to measure the fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD). One-way analyses of variance were used for comparisons of DTI parameters between NTG subgroups and normal control (NC) group. The relationships between DTI parameters and glaucoma indices were also assessed by Pearson's correlation and "broken-stick" analyses. As compared with NC subjects, significantly decreased FA and AD and increased MD and RD were observed in the bilateral posterior thalamic radiation, bilateral sagittal stratum, bilateral cingulum-hippocampus, and bilateral fornix/stria terminalis in NTG patients. The DTI parameters of these WM regions correlated with the mean deviation of visual field (MDVF) and retinal nerve fiber layer (RNFL) thickness. Additionally, there was a tipping point between MDVF and DTI parameters as well as between MDVF and RNFL thickness. Atlas-based DTI analysis was capable of indicating WM damage in the four regions associated with visual and visual-related functions in NTG patients, and it could also be used for investigating disease progression and pathologic changes. In addition, WM impairment and RNFL thinning occurred before patients showed detectable visual field loss.

Microglial activation, white matter tract damage, and disability in MS

ObjectiveTo investigate the relationship of in vivo microglial activation to clinical and MRI parameters in MS.MethodsPatients with secondary progressive MS (n = 10) or relapsing-remitting MS (n = 10) and age-matched healthy controls (n = 17) were studied. Microglial activation was measured using PET and radioligand [11C](R)-PK11195. Clinical assessment and structural and quantitative MRI including diffusion tensor imaging (DTI) were performed for comparison.Results[11C](R)-PK11195 binding was significantly higher in the normal-appearing white matter (NAWM) of patients with secondary progressive vs relapsing MS and healthy controls, in the thalami of patients with secondary progressive MS vs controls, and in the perilesional area among the progressive compared with relapsing patients. Higher binding in the NAWM was associated with higher clinical disability and reduced white matter (WM) structural integrity, as shown by lower fractional anisotropy, higher mean diffusivity, and increased WM lesion load. Increasing age contributed to higher microglial activation in the NAWM among patients with MS but not in healthy controls.ConclusionsPET can be used to quantitate microglial activation, which associates with MS progression. This study demonstrates that increased microglial activity in the NAWM correlates closely with impaired WM structural integrity and thus offers one rational pathologic correlate to diffusion tensor imaging (DTI) parameters.

Association between abnormal serum myelin-specific protein levels and white matter integrity in first-episode and drug-naïve patients with major depressive disorder

BackgroundAlthough the structural abnormalities of white matter (WM) have been described in patients with major depressive disorder (MDD), the neuropathological changes remain unclear. The current study aimed to investigate the myelin oligodendrocyte glycoprotein (MOG) and myelin-associated glycoprotein (MAG) levels and their correlations with WM integrity in first-episode, drug-naïve MDD patients. MethodsWe obtained diffusion tensor images of 102 first-episode, drug-naïve MDD patients and 81 age- and sex-matched controls. Serum MOG and MAG levels of all participants were measured and compared between the two groups. The correlations between WM integrity and MOG and MAG levels were examined. ResultsMOG and MAG serum levels were significantly higher in MDD patients than in controls. Patients with MDD also showed decreased fractional anisotropy (FA) and axial diffusivity in the WM of the bilateral thalamus, right hippocampus, right temporal lobe, and left pulvinar. At the whole-brain level, no regions showed any correlations of diffusivity parameters with MOG or MAG levels in healthy subjects. However, we observed two-way correlations between the MOG and MAG levels and the FA and mean diffusivity values in the WM of the left middle frontal lobe, right inferior parietal lobe, and right supplementary motor area in MDD patients. LimitationsFurther investigation with a larger sample size and longitudinal studies are required to better understand the neuropathology of WM integrity in MDD. ConclusionsOur findings represent the first evidence of a relationship between abnormal serum myelin-specific protein levels and impaired WM integrity, which may help to better understand the neurobiological mechanisms of MDD.

Reduced white matter connectivity associated with auditory verbal hallucinations in first-episode and chronic schizophrenia: A diffusion tensor imaging study

This study aims to explore whether auditory verbal hallucinations (AVH) in schizophrenia are associated with the white matter abnormalities in tracts connecting language, auditory and memory/limbic networks in first-episode and chronic schizophrenia patients. 21 first-episode (FE-AVH) and 12 chronic (chronic-AVH group) patients who suffered from auditory verbal hallucinations and 26 healthy controls (HC group) were enrolled. Diffusion tensor imaging with tract-based spatial statistics was performed to assess the white matter changes between the two patient groups and HC group. Decreased fractional anisotropy and increased radial diffusivity were found in the patient groups compared to the HC group in multiple white matter tracts including the corpus callosum, superior longitudinal fasciculus, inferior fronto-occipital fasciculus, uncinate fasciculus, cingulum, external capsule and anterior limb of the internal capsule. The chronic-AVH group showed more widespread white matter impairment than the FE-AVH group. Furthermore, increased axial diffusivity was also observed in some discrete regions of the chronic-AVH group. Auditory verbal hallucinations in schizophrenia are accompanied by white matter abnormalities in tracts connecting the language, auditory and memory/limbic networks. Chronic-AVH schizophrenia patients may present with more severe neurodegeneration relative to first-episode patients.

Abstract TMP27: Tgfalpha Protects Oligodendrocytes Against Ischemic Injury and Promotes White Matter Integrity After Stroke

Introduction: The loss of white matter integrity after ischemic stroke contributes to long-term sensorimotor and cognitive deficits. Elucidating the mechanisms for white matter protection or recovery is therefore important to improve stroke outcomes. This study investigates the function of TGFα, a member of the epidermal growth factor family, in white matter recovery after stroke and elucidate the mechanisms of action. Methods: Cerebral ischemia was induced by transient (60 min) middle cerebral artery occlusion (tMCAO) in wild type and TGFα knockout mice. The spatiotemporal pattern of TGFα expression was evaluated by immunofluorescent staining at 1, 3, 5, 14, 21 and 35 days after tMCAO. Sensorimotor (rota-rod test, adhesive-remove test and open field test) and cognitive (Morris water-maze test) functions were assessed up to 35 days after stroke. White matter injury was quantified by MBP (myelin basic protein) and SMI32 (recognizes damaged non-phosphorylated neurofilament proteins) staining. The direct effect of TGFα on oligodendrocytes were evaluated in vitro using primary cultures. Live/dead cell staining and LDH (lactate dehydrogenase) assay were used to assess oligodendrocytes death after 90 min oxygen and glucose deprivation (OGD). Result: Cerebral ischemic induced an abrupt and transient increase of TGFα in the brain. The expression of TGFα was mainly increased in microglia and neurons. TGFα deficiency resulted in exacerbation in sensorimotor and cognitive deficits up to 35 days after tMCAO. MAP2 (microtubule-associated protein 2) staining at 3 days and 35 days showed lager tissue loss in TGFα knockout mice as compared with wild type stroke mice. Importantly. TGFα knockout mice also exhibited impaired white matter integrity, as revealed by the loss of MBP staining and elevation in SMI32 staining, at 35 days after stroke. Correlation analysis demonstrated positive correlation between white matter integrity and functional outcomes after stroke in TGFα knockout mice and wild type mice. In vitro study confirmed that TGFα (5, 10 or 20 ng/ml) protected oligodendrocyte precursor cells and oligodendrocytes against OGD. Conclusion: TGFα is important for maintaining white matter integrity and improving neurological recovery after stroke.