Brain White Matter In Patients Research Articles

Differences between Tuberous Sclerosis Complex Patients with and without Epilepsy: The Results of a Quantitative Diffusion Tensor Imaging Study.

Tuberous sclerosis complex (TSC) is a neurocutaneous disease with a high incidence of epilepsy and damaging effects on cognitive development. To understand the mechanisms leading to abnormal cognitive development, diffusion tensor imaging (DTI) techniques have begun to be used in recent years. The present study is the first to investigate differences in the microstructure and integrity of white matter tracts in adult patients with TSC and with and without epilepsy. A total of 37 patients with TSC (18 with epilepsy, median age 36 years; 19 without epilepsy, median age 35 years) without intellectual disability and autism spectrum disorder were included in the study. The control group (median age 34 years) comprised 37 individuals without psychiatric or neurodevelopmental disorders and neurological and cardiovascular diseases, diabetes, or addictions. A magnetic resonance imaging (MRI) DTI sequence was applied. There were differences in the average values of DTI parameters between patients with TSC and epilepsy and patients with TSC but without epilepsy in five white matter bands. When comparing the average values of DTI parameters between patients with TSC and epilepsy and healthy controls, we found differences in 15 of 20 analysed white matter fibres. White matter tracts in patients with TSC and epilepsy had more abnormalities than in patients with TSC but without epilepsy. The former group presented abnormalities in longer white matter fibres, especially in the left hemisphere. However, the latter group presented abnormalities in more medial and shorter white matter fibres. This DTI study documents the changes in the brain white matter of patients with TSC associated with the presence of epilepsy.

Widespread intra-axonal signal fraction abnormalities in bipolar disorder from multicompartment diffusion MRI: Sensitivity to diagnosis, association with clinical features and pharmacologic treatment.

Despite diffusion tensor imaging (DTI) evidence for widespread fractional anisotropy (FA) reductions in the brain white matter of patients with bipolar disorder, questions remain regarding the specificity and sensitivity of FA abnormalities as opposed to other diffusion metrics in the disorder. We conducted a whole-brain voxel-based multicompartment diffusion MRI study on 316 participants (i.e., 158 patients and 158 matched healthy controls) employing four diffusion metrics: the mean diffusivity (MD) and FA estimated from DTI, and the intra-axonal signal fraction (IASF) and microscopic axonal parallel diffusivity (Dpar) derived from the spherical mean technique. Our findings provide novel evidence about widespread abnormalities in other diffusion metrics in BD. An extensive overlap between the FA and IASF results suggests that the lower FA in patients may be caused by a reduced intra-axonal volume fraction or a higher macromolecular content in the intra-axonal water. We also found a diffuse alteration in MD involving white and grey matter tissue and more localised changes in Dpar. A Machine Learning analysis revealed that FA, followed by IASF, were the most helpful metric for the automatic diagnosis of BD patients, reaching an accuracy of 72%. Number of mood episodes, age of onset/duration of illness, psychotic symptoms, and current treatment with lithium, antipsychotics, antidepressants, and antiepileptics were all significantly associated with microstructure abnormalities. Lithium treatment was associated with less microstructure abnormality.

Assessment of normal-appearing brain white matter in patients with optic neuritis and multiple sclerosis by magnetic resonance spectroscopy

Background Multiple sclerosis (MS) is an inflammatory, demyelinating, and neurodegenerative disease of the central nervous system, characterized pathologically by disseminated areas of demyelination and variable degrees of axonal loss and glial scarring. Typical optic neuritis may be associated with MS and is the most common type of optic neuritis. Nonconventional MRI such as magnetic resonance spectroscopy (MRS) has been used to enhance our knowledge of the pathophysiology of MS. Objectives To evaluate metabolic changes of brain normal-appearing white matter among patients either presented with optic neuritis alone or those already diagnosed as having MS. Patients and methods This is a cross-sectional study that was carried out on 30 patients with MS and 30 patients with typical optic neuritis attending neurology MS clinic of Al Azhar University Hospitals. All patients were subjected to the following: detailed history talking, assessment of disease severity by the Expanded Disability Status Scale, routine laboratory investigations, radiological evaluation (MS protocol), and MRS. Results The results of the study revealed significant metabolic changes by MRS in patients with optic neuritis and MS. Conclusion MRS provides advanced insights into the pathogenesis of optic neuritis and MS by obtaining information on the microenvironment within the brain. This enhances the understanding of the mechanisms involved in disease progression. MRS opens a window to detect early conversion of patient of the typical optic neuritis into MS.

Micro-structural white matter abnormalities and cognitive impairment in asymptomatic carotid plaque patients: A DTI study using TBSS analysis

BackgroundIt has been shown that symptomatic or severe carotid atherosclerosis is closely related to cognitive impairment and brain white matter damage. However, there is still a lack of effective and non-invasive imaging biomarkers to identify early high-risk cerebrovascular diseases. Therefore, the purpose of this study is to explore the integrity of brain white matter and cognitive impairment in patients with asymptomatic carotid plaques by using imaging technology. MethodsAll subjects were from a project of Stroke Risk Screening and Prevention and were defined as stroke high-risk patients (with three or more stroke risk factors). Tract-based spatial statistics (TBSS) based on diffusion tensor imaging (DTI) was used to analyze the whole brain white matter abnormalities in 61 patients with carotid artery plaque and in 40 healthy controls. At the same time, the general clinical data between the two groups were compared, such as age, gender, smoking, hypertension and cognitive function scores etc. Furthermore, the plaque group was divided into the have-hyperintensities group and the no-hyperintensities group to compare their microstructure of white matter injuries. ResultsThe cognitive scores of plaque group were significantly lower than that of control group. We found that when plaque group and control group were compared, no white matter fiber tracts with difference was found in FA, MD, AD and RD. However, the decrease of FA and the increase of RD were found in some white matter regions (P < 0.05) when comparing the have-hyperintensities group and the no-hyperintensities group. These white matter regions included anterior thalamic radiation, corticospinal tract, cingulum (cingulate gyrus), forceps minor, inferior fronto-occipital fasciculus, superior longitudinal fasciculus, uncinate fasciculus. What’s more, there were significant differences in blood pressure between the two groups. ConclusionThe cognitive function of patients with early high-risk cerebrovascular diseases (asymptomatic carotid plaques) has a downward trend. TBSS based on DTI can help to find out the actual damage of brain white matter in patients with early carotid plaque, and reflect the early pathological changes from the micro level.

Abnormal brain white matter in patients with hemifacial spasm: a diffusion tensor imaging study.

Refractory hemifacial contraction and comorbid emotional disorders are major annoyance suffered by patients with hemifacial spasm (HFS). It is currently unknown how whiter matter (WM) abnormalities in the brain contribute to HFS. To investigate WM alterations in HFS, 26 patients and 29 matched healthy controls were ultimately recruited in this experiment. The whole brain diffusion tensor imaging (DTI) was acquired at 3.0 Tesla scanner. Tract-based spatial statistics (TBSS) analysis was applied to investigate the differences of DTI metrics (fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) axial diffusivity (AD)) between HFS patients and controls throughout brain WM. The relationship between the severity of facial spasm and affective disturbance in HFS patients, and WM abnormalities was examined using spearman correlation analyses. TBSS method showed structural alterations in the genu and body of corpus callosum; bilateral inferior longitudinal fasciculus (ILF) and inferior frontal-occipital fasciculus (IFOF); left superior longitudinal fasciculus, anterior, posterior, and superior portion of corona radiata; left posterior limb of the internal capsule; and left posterior thalamic radiation in HFS patients compared with healthy subjects. In addition, the overlapped region of decreased FA together with increased RD and MD was merely localized in the right ILF and IFOF in the HFS group, and abnormality of RD value in this region was positively correlated with the patients' spasm score. The present study indicate extensive disruptions of WM integrity, especially the RD changes in right ILF and IFOF, which may provide alternative imaging clues for evaluating the characteristics of HFS.

Molecular signature of different lesion types in the brain white matter of patients with progressive multiple sclerosis

To identify pathogenetic markers and potential drivers of different lesion types in the white matter (WM) of patients with progressive multiple sclerosis (PMS), we sequenced RNA from 73 different WM areas. Compared to 25 WM controls, 6713 out of 18,609 genes were significantly differentially expressed in MS tissues (FDR < 0.05). A computational systems medicine analysis was performed to describe the MS lesion endophenotypes. The cellular source of specific molecules was examined by RNAscope, immunohistochemistry, and immunofluorescence. To examine common lesion specific mechanisms, we performed de novo network enrichment based on shared differentially expressed genes (DEGs), and found TGFβ-R2 as a central hub. RNAscope revealed astrocytes as the cellular source of TGFβ-R2 in remyelinating lesions. Since lesion-specific unique DEGs were more common than shared signatures, we examined lesion-specific pathways and de novo networks enriched with unique DEGs. Such network analysis indicated classic inflammatory responses in active lesions; catabolic and heat shock protein responses in inactive lesions; neuronal/axonal specific processes in chronic active lesions. In remyelinating lesions, de novo analyses identified axonal transport responses and adaptive immune markers, which was also supported by the most heterogeneous immunoglobulin gene expression. The signature of the normal-appearing white matter (NAWM) was more similar to control WM than to lesions: only 465 DEGs differentiated NAWM from controls, and 16 were unique. The upregulated marker CD26/DPP4 was expressed by microglia in the NAWM but by mononuclear cells in active lesions, which may indicate a special subset of microglia before the lesion develops, but also emphasizes that omics related to MS lesions should be interpreted in the context of different lesions types. While chronic active lesions were the most distinct from control WM based on the highest number of unique DEGs (n = 2213), remyelinating lesions had the highest gene expression levels, and the most different molecular map from chronic active lesions. This may suggest that these two lesion types represent two ends of the spectrum of lesion evolution in PMS. The profound changes in chronic active lesions, the predominance of synaptic/neural/axonal signatures coupled with minor inflammation may indicate end-stage irreversible molecular events responsible for this less treatable phase.

Abnormal brain white matter in patients with right trigeminal neuralgia: a diffusion tensor imaging study

BackgroundIdiopathic or classical trigeminal neuralgia (TN) is a chronic painful condition characterized by intermittent pain attacks. Enough evidence demonstrates classical TN is related to neurovascular compression (NVC) at the trigeminal root entry zone (REZ), but white matter change secondary to TN are not totally known.MethodsVisual Analogue Scale (VAS) and diffusion tensor imaging were performed on 29 patients with right TN and 35 healthy individuals. Voxel-wise analyses were performed with TBSS using multiple diffusion metrics, including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD). Group differences in these parameters were compared between right TN patients and controls using TBSS and correlations between the white matter change and disease duration and VAS in right TN patients were assessed. Multiple comparison correction were applied to test significant correlations.ResultsThe right TN patients showed significantly lower FA and higher RD in most left white matter (P < 0.05, FWE corrected). Moreover, negative correlations were observed between disease duration and the FA values of left corona radiata, genu of corpus callosum, left external capsule and left cerebral peduncle, and between VAS and the FA values of left corona radiata, left external capsule and left cerebral peduncle (P < 0.05). Positive correlations were observed for disease duration and the RD values of left corona radiata, right external capsule, left fornix cerebri and left cerebral peduncle, and for VAS and the RD values of left corona radiata and left external capsule (P < 0.05). However, once Bonferroni corrections were applied, these correlations were not statistically significant.ConclusionThese findings suggest that TN selectively impairs widespread white matter, especially contralateral hemisphere, which may be the hallmark of disease severity in TN patients.

Pain-related white matter tract abnormalities in mild traumatic brain injury patients with persistent headache.

BackgroundThe occurrence of debilitating chronic persistent (24/7) headache after mild traumatic brain injury represents a central neuropathic pain state. Previous studies suggest that this chronic headache state can be attributed to altered supraspinal modulatory functional connectivity in both resting and evoked pain states. Abnormalities in the myelin sheaths along the supraspinal superior longitudinal fasciculus and anterior thalamic radiation are frequently associated with alteration in pain modulation related to functional connectivity deficit with the prefrontal cortex. This study assessed the correlated axonal injury-related white matter tract abnormality underlying these previously observed prefrontal functional connectivity deficits by comparing the fractional anisotropy, axial diffusivity, and radial diffusivity of brain white matter in patients with mild traumatic brain injury-related headache to healthy controls.ResultDiffusion tensor imaging data from patients (N = 12, average age ± SD = 35.0 ± 8.0 years old, 10 male) with mild traumatic brain injury-headache were compared with images acquired from healthy controls. The mild traumatic brain injury cohort demonstrated two areas of significant (P < 0.01, F value >16, cluster size >50 voxels) white matter tract abnormalities closely related to pain affective and modulatory functions in (1) the left superior longitudinal fasciculus which connects the prefrontal cortices with the parietal cortices and (2) the right anterior thalamic radiation connecting the prefrontal cortices with the anterior cingulate cortex. In addition, a significant (P < 0.01) decrease in axial diffusivity and increase in radial diffusivity at the superior longitudinal fasciculus cluster were noted in the mild traumatic brain injury cohort.ConclusionThe identified white matter tract abnormalities may represent a state of Wallerian degeneration which correlates with the functional connectivity deficit in pain modulation and can contribute to the development of the chronic persistent headache in the patients with mild traumatic brain injury.

Metformin‐induced mitochondrial function and ABCD2 up‐regulation in X‐linked adrenoleukodystrophy involves AMP‐activated protein kinase

X-linked adrenoleukodystrophy (X-ALD) is a progressive neurometabolic disease caused by mutations/deletions in the Abcd1 gene. Similar mutations/deletions in the Abcd1 gene often result in diagonally opposing phenotypes of mild adrenomyeloneuropathy and severe neuroinflammatory cerebral adrenoleukodystrophy (ALD), which suggests involvement of downstream modifier genes. We recently documented the first evidence of loss of AMP-activated protein kinase α1 (AMPKα1) in ALD patient-derived cells. Here, we report the novel loss of AMPKα1 in postmortem brain white matter of patients with ALD phenotype. Pharmacological activation of AMPK can rescue the mitochondrial dysfunction and inhibit the pro-inflammatory response. The FDA approved anti-diabetic drug Metformin, a well-known AMPK activator, induces mitochondrial biogenesis and is documented for its anti-inflammatory role. We observed a dose-dependent activation of AMPKα1 in metformin-treated X-ALD patient-derived fibroblasts. Metformin also induced mitochondrial oxidative phosphorylation and ATP levels in X-ALD patient-derived fibroblasts. Metformin treatment decreased very long chain fatty acid levels and pro-inflammatory cytokine gene expressions in X-ALD patient-derived cells. Abcd2 [adrenoleukodystrophy protein-related protein] levels were increased in metformin-treated X-ALD patient-derived fibroblasts and Abcd1-KO mice primary mixed glial cells. Abcd2 induction was AMPKα1-dependent since metformin failed to induce Abcd2 levels in AMPKα1-KO mice-derived primary mixed glial cells. In vivo metformin (100mg/Kg) in drinking water for 60days induced Abcd2 levels and mitochondrial oxidative phosphorylation protein levels in the brain and spinal cord of Abcd1-KO mice. Taken together, these results provide proof-of-principle for therapeutic potential of metformin as a useful strategy for correcting the metabolic and inflammatory derangements in X-ALD by targeting AMPK. There is no effective therapy for inherited peroxisomal disorder X-linked adrenoleukodystrophy (X-ALD). We document the therapeutic potential of FDA approved drug, Metformin, for X-ALD by targeting AMPK. Metformin induced peroxisomal Abcd2 levels invitro and invivo. Metformin lowered VLCFA levels, improved mitochondrial function and ameliorated inflammatory gene expression in X-ALD patient-derived cells. Metformin-induced Abcd2 levels were dependent on AMPKα1, a metabolic and anti-inflammatory gene, recently documented by our laboratory to play a putative role in X-ALD pathology. Read the Editorial Highlight for this article on page 10.

Diffusion tensor imaging: Tract based spatial statistics study in essential tremor

IntroductionEssential tremor (ET) is a common movement disorder with motor and non-motor symptoms. We aimed to investigate the neurodegenerative changes in the brain white matter of patients with ET using Diffusion Tensor Imaging (DTI). MethodsClinical and MRI data from 20 patients (5 women and 15 men; age-38.2 ± 16.5 yrs) with ET and 17 controls (3 women and 14 men; age-40.7 ± 16.5 yrs) were collected prospectively. The DTI data were analyzed using tract based spatial statistics (TBSS) software for tract wise analysis. Further region of interest (ROI) analysis was carried out in the genu of corpus callosum, anterior limb of internal capsule (ALIC), corticospinal tract (CS), and cerebellar peduncles. Effect of tremor severity, disease duration and age of onset on DTI metrics was also studied. ResultsPatients with ET in comparison to controls showed significant (Pcorrected < 0.05) increase of mean diffusivityand radial diffusivity in right frontoparietal white matter. Axial diffusivity increase was seen in bilateral cerebral hemispheres, thalamus, brainstem and cerebellar hemisphere white matter. No significant change in fractional anisotropy of the white matter was seen. ROI analysis also revealed abnormalities in the ALIC and cerebellar peduncles. There was no correlation between the severity of white matter changes and clinical tremor severity score as well as disease duration. ConclusionsThis study provides in vivo evidence for axonal disintegration of the cerebral and cerebellar white matter fibres in patients with ET.

MR diffusion tensor imaging voxel-based analysis of whole brain white matter in patients with amnestic-type mild cognitive impairment and mild Alzheimer disease

Objective To evaluate the microstructural integrity of white matter (WM) in patients with amnestic mild cognitive impairment (aMCI) and mild Alzheimer's disease (AD) using voxel-based analysis (VBA), and investigate the relationship between WM abnormalities and gray matter(GM) atrophy.Methods Thirty-three cases with aMCI, 32 cases with mild AD and 31 normal aging volunteers as control subjects were scanned on a 3.0 T MR system using diffusion tensor imaging (DTI) and three-dimensional spoiled gradient-recalled(3DSPGR) sequences. Fractional anisotropy (FA) maps and morphological images were preprocessed by SPM5 and voxel-based comparisons between the 2 patient groups and the control group were performed by t test. Results Relative to the control group, patients with aMCI showed significantly reduced FA value in bilateral frontal, temporal and left occipital WM, left anterior part of cingulum, left inferior parietal lobule, and the W M adjacent to the triangular part of the right lateral ventricle(k≥20 voxels).In mild AD,significantly reduced FA value was found in bilateral hippocampal,inferior parietal lobular,frontal,temporal,and occipital WM,bilateral corpus callosum,anterior part of cingulums,the WM adjacent to the triaangular part of the bilateral lateral ventricles,left temporal stem,left thalamus,right precuneus(k≥20 voxels).Significantly reduced GM volume was found in left hippocampus,parahippocampal gyrus,lingual gyrus and superior temporal gyrus,bilateral insulae and middle temporal gyri in aMCl group whencompared with control group(k≥50 voxels).In mild AD,significantly reduced GM volume was found in bilateral hippoeampi,parahippocampal gyri,amygdalae,thalami,temporal,parietal,frontal,occipital cortex(k≥50 voxels).The pattern of areas with reduced FA differs;from that of the GM volumetric reduction.No areas with significantlv reduced FA was detected in aMCl compared with mild AD. There was no significant correlation between FA value of WM in patient groups and Mini-Mental State Examination(MMSE)scores.Conclusions Voxel-based MRI DTI analysis of whole brain white matter can objectively reveal widespread white matter abnormalities in early-stage AD.The difierence between WM FA reduction pattern and GM volumetric reduction pattern indicates that the pathological WM changes in earlyslage AD were caused by multiple mechanisms. FA did not vary significantly in patients pr0gressing from aMCI to mild AD and can hardly reflect the severitv of cognitive function damage in these patients. Key words: Cognition disorders; Alzheimer disease; Magnetic resonance imaging

Microstructural Brain Abnormalities in Patients with Obsessive-Compulsive Disorder: Diffusion-Tensor MR Imaging Study at 3.0 T

To use diffusion-tensor (DT) magnetic resonance (MR) imaging to explore the integrity and connectivity of brain white matter in patients with obsessive-compulsive disorder (OCD) and to correlate DT parameters with clinical measures. This study was approved by the local ethical committee, and written informed consent was obtained from all participants. DT imaging was performed by using a 3.0-T MR imager in 23 patients with OCD and 23 healthy control subjects matched for age, sex, education level, and handedness. By using voxel-based analysis, fractional anisotropy (FA) and axial and radial diffusivities were compared between patients and control subjects with a two-sample t test and were tested for correlation with symptom severity, as measured by using the Yale-Brown Obsessive-Compulsive Scale and obsessive-compulsive subscale scores, and with illness duration, as measured by using simple regression in statistical parametric mapping program. Compared with control subjects, OCD patients demonstrated significantly increased FA in the genu and body of corpus callosum and white matter of right superior frontal gyrus and corpus callosum; no areas of significantly decreased FA were found. For areas of increased FA, axial diffusivity was higher than that in control subjects, while radial diffusivity was not significantly different. The FA values in the white matter of left middle temporal gyrus in OCD patients correlated positively with clinical measures (r = 0.542, P < .001). OCD is associated with axonal microstructural abnormalities within the white matter, which may indicate impaired axonal integrity and increased connectivity. The positive correlation between DT abnormalities and symptom severity suggests that DT imaging may be of clinical value in measuring and following disability in OCD patients.

Evidence of Nitrosative Damage in the Brain White Matter of Patients with Multiple Sclerosis

Nitric oxide (NO) has been implicated in the pathophysiology of both experimental autoimmune encephalomyelitis and multiple sclerosis (MS). NO-mediated protein damage in MS appears to be confined to large plaques where 3-nitrotyrosine has been detected. To determine whether nitrosative damage takes place beyond visible MS plaques, the occurrence of various NO-triggered protein modifications in normal-appearing white matter (NAWM) of eight MS brains was assessed and compared to that in white matter (WM) of four control brains. As determined by amino acid analysis and western blotting, no evidence of tyrosine nitration was found in the MS samples studied, suggesting that they did not contain appreciable amounts of plaque-derived material. The amino acid composition of total myelin proteins and proteolipid protein (PLP) was also unaltered in the diseased tissue, as was the fatty acid composition of PLP. In addition, we detected no changes in the number of protein free thiols suggesting that oxidation do not occur to any appreciable extent. However, the levels of nitrite in MS-NAWM were higher than those in control WM, while in the MS-gray matter (GM) the concentration of this ion was unaltered. Furthermore, five of the MS samples analyzed, and the same as those with high levels of glial fibrilary acidic protein, showed increased amounts of protein nitrosothiols as determined by the "biotin switch" method. S-nitrosation of GM proteins was again normal. There was no indication of N-nitrosation of tryptophan and N-terminal amino groups in both control and MS tissue. Overall, the data suggests that WM, but not GM, from MS brains is subjected to considerable nitrosative stress. This is the first report to present direct evidence of increased protein S-nitrosation and nitrite content in the brain parenchyma of MS patients.

White matter damage in Alzheimer's disease assessed in vivo using diffusion tensor magnetic resonance imaging

Objective: To investigate the extent and the nature of white matter tissue damage of patients with Alzheimer's disease using diffusion tensor magnetic resonance imaging (DT-MRI). Background: Although Alzheimer's disease pathology...