Corpus Callosum Regions Research Articles

Evaluation of microstructural brain changes in post-coronavirus disease 2019 (COVID-19) patients with neurological symptoms: a cross-sectional study.

Changes in both the vascular system and brain tissues can occur after a prior episode of coronavirus disease 2019 (COVID-19), detectable through modifications in diffusion parameters using magnetic resonance imaging (MRI) techniques. These changes in diffusion parameters may be particularly prominent in highly organized structures such as the corpus callosum (CC), including its major components, which have not been adequately studied following COVID-19 infection. Therefore, the study aimed to evaluate microstructural changes in whole-brain (WB) diffusion, with a specific focus on the CC. A total of 101 probands (age range from 18 to 69 years) participated in this retrospective study, consisting of 55 volunteers and 46 post-COVID-19 patients experiencing neurological symptoms. The participants were recruited from April 2022 to September 2023 at the Institute for Clinical and Experimental Medicine in Prague, Czech Republic. All participants underwent MRI examinations on a 3T MR scanner with a diffusion protocol, complemented by additional MRI techniques. Two volunteers and five patients were excluded from the study due to motion artefacts, severe hypoperfusion or the presence of lesions. Participants were selected by a neurologist based on clinical examination and a serological test for COVID-19 antibodies. They were then divided into three groups: a control group of healthy volunteers (n=28), an asymptomatic group (n=25) with a history of infection but no symptoms, and a symptomatic group (n=41) with a history of COVID-19 and neurological symptoms. Symptomatic patients did not exhibit neurological symptoms before contracting COVID-19. Diffusion data underwent eddy current and susceptibility distortion corrections, and fiber tracking was performed using default parameters in DSI studio. Subsequently, various diffusion metrics, were computed within the reconstructed tracts of the WB and CC. To assess the impact of COVID-19 and its associated symptoms on diffusion indices within the white matter of the WB and CC regions, while considering age, we employed a statistical analysis using a linear mixed-effects model within the R framework. Statistical analysis revealed a significant difference in mean diffusivity (MD) between the symptomatic and control groups in the forceps minor (P=0.001) and CC body (P=0.003). In addition to changes in diffusion, alterations in brain perfusion were observed in two post-COVID-19 patients who experienced a severe course. Furthermore, hyperintense lesions were identified in subcortical and deep white matter areas in the vast majority of symptomatic patients. The main finding of our study was that post-COVID-19 patients exhibit increased MD in the forceps minor and body of the CC. This finding suggests a potential association between microstructural brain changes in post-COVID-19 patients and reported neurological symptoms, with significant implications for research and clinical applications.

Mass Spectrometry Imaging Reveals Region-Specific Lipid Alterations in the Mouse Brain in Response to Efavirenz Treatment.

Efavirenz (EFV) is a commonly used drug to treat human immunodeficiency virus infection and is known to exert adverse effects on the brain. Although it is known that EFV is associated with abnormal plasma lipid levels, the changes in the spatial localization of individual lipid molecules in brain tissue following EFV treatment are yet to be explored. In this study, we employed a matrix-assisted laser desorption/ionization mass spectrometry imaging approach to determine region-specific lipid alterations in mouse brains following EFV treatment. We detected unique spatial localization patterns of phosphatidylcholine (PC), sphingomyelin (SM), ceramide phosphoinositol (PI-Cer), and hexosylceramide (HexCer) molecules in the mouse brain. Interestingly, PC(32:0), PC(38:5), and SM(36:1;O2) showed high abundance in the hippocampus region, whereas PI-Cer(38:8) exhibited low abundance in the hippocampus region of the EFV-treated mouse brains. Additionally, we observed low abundance of PC(38:6), PC(40:6), and PI-Cer(40:3) in the thalamus region of the EFV-treated mouse brains. Furthermore, SM(40:1;O2), SM(42:2;O2), SM(42:1;O2), SM(43:2;O2), and SM(43:1;O2) exhibited their accumulation in the corpus callosum region of the EFV-treated mouse brains as compared to controls. However, HexCer(42:1;O3) exhibited depletion in the corpus callosum region in response to EFV treatment. To characterize the expression patterns of proteins, including lipid metabolizing enzymes, in response to EFV treatment, mass spectrometry-based proteomics was utilized. From these, the expression levels of 12 brain proteins were found to be significantly decreased following EFV treatment. Taken together, these multiomics data provide important insights into the effects of EFV on brain lipid metabolism.

The Corpus Callosum in Schizoaffective Disorder: A Shape Analysis Study

Objective: The corpus callosum is the largest white matter structure in the human brain that connects the cortical regions of both hemispheres. Diseases could lead to degenerative alterations in brain structures such as the corpus callosum (CC). Studies have associated CC abnormalities with Schizoaffective Disorder (SAD) symptoms. We predicted that there may be differences in the CC, an important structure connecting the two halves of the brain, in patients with SAD. The present study aims to analyze the CC of patients with statistical shape analysis (SSA) and compare the findings with healthy controls. Methods: Thirty-nine SAD patients and 39 healthy individuals (11 females and 28 males) of similar age that included subjects participated in the study. CC landmarks were marked on the mid-sagittal images of each participant. The mean ‘Procrustes’ point was determined, and shape deformations were analyzed with thin plate spline analysis. Results: Significant differences were observed between the shapes of CC in the two groups, and maximum CC deformation was observed in the posterior regions of SAD patients. There was no significant difference between the CC area of the SAD patients and the controls. Conclusion: In the present study, the maximum deformation was observed in the posterior region (isthmus and splenium) and the rostrum of the CC. The first CC region, the rostrum (+genu), connects prefrontal and premotor regions, which are associated with cognitive information (landmarks = 1, 7, 8, 9, 13, 15, and 12). The second area, the splenium, connects temporal and occipital cortical areas. These predominantly have auditory, peripheral, and central visual stimulation functions (landmarks = 5, 3, and 4). The current study could assist future studies on the etiology, diagnosis, and treatment of SAD.

CCADD: An online webserver for Alzheimer's disease detection from brain MRI

Alzheimer's disease (AD) imposes a growing burden on public health due to its impact on memory, cognition, behavior, and social skills. Early detection using non-invasive brain magnetic resonance images (MRI) is vital for disease management. We introduce CCADD (Corpus Callosum-based Alzheimer's Disease Detection), a user-friendly webserver that automatically identifies and segments the corpus callosum (CC) region from brain MRI slices. Extracted shape and size-based features of CC are fed into Support Vector Machines (SVM), Random Forest (RF), eXtreme Gradient Boosting (XGBoost), K-Nearest Neighbor (KNN), and Artificial Neural Network (ANN) classifiers to predict AD or Mild Cognitive Impairment (MCI). Exhaustive benchmarking on ADNI data reveals high prediction accuracies for different AD severity levels. CCADD empowers clinicians and researchers for AD detection. This server is available at: http://www.hpppi.iicb.res.in/add.

Differential Effects of Aging on Regional Corpus Callosum Microstructure and the Modifying Influence of Pulse Pressure.

The corpus callosum is composed of several subregions, distinct in cellular and functional organization. This organization scheme may render these subregions differentially vulnerable to the aging process. Callosal integrity may be further compromised by cardiovascular risk factors, which negatively influence white matter health. Here, we test for heterochronicity of aging, hypothesizing an anteroposterior gradient of vulnerability to aging that may be altered by the effects of cardiovascular health. In 174 healthy adults across the adult lifespan (mean age = 53.56 ± 18.90; range, 20-94 years old, 58.62% women), pulse pressure (calculated as participant's systolic minus diastolic blood pressure) was assessed to determine cardiovascular risk. A deterministic tractography approach via diffusion-weighted imaging was utilized to extract fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD) from each of five callosal subregions, serving as estimates of microstructural health. General linear models tested the effects of age, hypertension, and pulse pressure on these cross-sectional metrics. We observed no significant effect of hypertensive diagnosis on callosal microstructure. We found a significant main effect of age and an age-pulse pressure interaction whereby older age and elevated pulse pressure were associated with poorer FA, AD, and RD. Age effects revealed nonlinear components and occurred along an anteroposterior gradient of severity in the callosum. This gradient disappeared when pulse pressure was considered. These results indicate that age-related deterioration across the callosum is regionally variable and that pulse pressure, a proxy of arterial stiffness, exacerbates this aging pattern in a large lifespan cohort.

Exosome-specific loading Sox10 for the treatment of Cuprizone-induced demyelinating model

Demyelination is a pathological feature commonly observed in various central nervous system diseases. It is characterized by the aggregation of oligodendrocyte progenitor cells (OPCs) in the lesion area, which face difficulties in differentiating into mature oligodendrocytes (OLGs). The differentiation of OPCs requires the presence of Sox10, but its expression decreases under pathological conditions. Therefore, we propose a therapeutic strategy to regulate OPCs differentiation and achieve myelin repair by endogenously loading Sox10 into exosomes. To accomplish this, we generated a lentivirus-armed Sox10 that could anchor to the inner surface of the exosome membrane. We then infected HEK293 cells to obtain exosomes with high expression of Sox10 (exosomes-Sox10, ExoSs). In vitro, experiments confirmed that both Exos and ExoSs can be uptaken by OPCs, but only ExoSs exhibit a pro-differentiation effect on OPCs. In vivo, we administered PBS, Exos, and ExoSs to cuprizone-induced demyelinating mice. The results demonstrated that ExoSs can regulate the differentiation of PDGFRα+ OPCs into APC+ OLGs and reduce myelin damage in the corpus callosum region of the mouse brain compared to other groups. Further testing suggests that Sox10 may have a reparative effect on the myelin sheath by enhancing the expression of MBP, possibly facilitated by the exosome delivery of the protein into the lesion. This endogenously loaded technology holds promise as a strategy for protein-based drugs in the treatment of demyelinating diseases.

Whole-brain traumatic controlled cortical impact to the left frontal lobe: Magnetic resonance image-based texture analysis.

This research assesses the capability of texture analysis (TA) derived from high-resolution (HR) T2-weighted magnetic resonance imaging to identify primary sequelae following 1-5 hours of controlled cortical impact mild or severe traumatic brain injury (TBI) to the left frontal cortex (focal impact) and secondary (diffuse) sequelae in the right frontal cortex, bilateral corpus callosum, and hippocampus in rats. The TA technique comprised first-order (histogram-based) and second-order statistics (including gray-level co-occurrence matrix, gray-level run length matrix, and neighborhood gray-level difference matrix). Edema in the left frontal impact region developed within 1 hour and continued throughout the 5-hour assessments. The TA features from HR images confirmed the focal injury. There was no significant difference among radiomics features between the left and right corpus callosum or hippocampus from 1 to 5 hours following a mild or severe impact. The adjacent corpus callosum region and the distal hippocampus region (s), showed no diffuse injury 1-5 hours after mild or severe TBI. These results suggest that combining HR images with TA may enhance detection of early primary and secondary sequelae following TBI.

Diffusion tensor-based analysis of white matter in dogs with idiopathic epilepsy.

The understanding of epileptic seizure pathogenesis has evolved over time, and it is now generally accepted that not only are cortical and subcortical areas involved but also the connection of these regions in the white matter (WM). Recent human neuroimaging studies confirmed the involvement of the WM in several epilepsy syndromes. Neuroimaging studies investigating WM integrity with diffusion tensor imaging (DTI) in canine idiopathic epilepsy are lacking. This study aimed to test the hypothesis that WM diffusion changes can be found in dogs affected by idiopathic epilepsy. Twenty-six dogs with idiopathic epilepsy (15 Border Collies and 11 Greater Swiss Mountain dogs) and 24 healthy controls (11 Beagle dogs, 5 Border Collies, and 8 Greater Swiss Mountain dogs) were prospectively enrolled. Most dogs with idiopathic epilepsy (17/26) were enrolled within 3 months after seizure onset. Diffusion tensor imaging of the brain with 32 diffusion directions (low b value = 0 s/mm2; maximal b value = 800 s/mm2) was performed in a 3 Tesla scanner. Tract-based spatial statistics (TBSS), a voxel-based approach, was used to investigate changes in fractional anisotropy (FA) and mean diffusivity (MD) in the idiopathic epilepsy group compared to the healthy control group. Additionally, FA and MD were investigated in the region of corpus callosum and cingulate white matter in both groups. We observed subtle changes in WM DTI between the idiopathic epilepsy group and the healthy control group limited to cingulate WM, with a significantly lower FA in the idiopathic epilepsy group compared to the healthy control group in the region of interest (ROI) approach (p = 0.027). No significant changes were found between the idiopathic epilepsy group and the healthy control group in the TBSS analysis and in the corpus callosum in the ROI approach. This study supports the cingulate area as a target structure in canine epilepsy. The subtle changes only might be explained by the short duration of epilepsy, small sample sizes, and the higher variability in canine brain anatomy. Furthermore, all included dogs showed generalized tonic-clonic seizures, possibly affected by generalized epilepsy syndrome, which are also associated with less pronounced DTI changes in humans than focal epilepsy syndromes.

Severe central nervous system demyelination in Sanfilippo disease.

Chronic progressive neuroinflammation is a hallmark of neurological lysosomal storage diseases, including mucopolysaccharidosis III (MPS III or Sanfilippo disease). Since neuroinflammation is linked to white matter tract pathology, we analyzed axonal myelination and white matter density in the mouse model of MPS IIIC HgsnatP304L and post-mortem brain samples of MPS III patients. Brain and spinal cord tissues of human MPS III patients, 6-month-old HgsnatP304L mice and age- and sex-matching wild type mice were analyzed by immunofluorescence to assess levels of myelin-associated proteins, primary and secondary storage materials, and levels of microgliosis. Corpus callosum (CC) region was studied by transmission electron microscopy to analyze axon myelination and morphology of oligodendrocytes and microglia. Mouse brains were analyzed ex vivo by high-filed MRI using Diffusion Basis Spectrum Imaging in Python-Diffusion tensor imaging algorithms. Analyses of CC and spinal cord tissues by immunohistochemistry revealed substantially reduced levels of myelin-associated proteins including Myelin Basic Protein, Myelin Associated Glycoprotein, and Myelin Oligodendrocyte Glycoprotein. Furthermore, ultrastructural analyses revealed disruption of myelin sheath organization and reduced myelin thickness in the brains of MPS IIIC mice and human MPS IIIC patients compared to healthy controls. Oligodendrocytes (OLs) in the CC of MPS IIIC mice were scarce, while examination of the remaining cells revealed numerous enlarged lysosomes containing heparan sulfate, GM3 ganglioside or "zebra bodies" consistent with accumulation of lipids and myelin fragments. In addition, OLs contained swollen mitochondria with largely dissolved cristae, resembling those previously identified in the dysfunctional neurons of MPS IIIC mice. Ex vivo Diffusion Basis Spectrum Imaging revealed compelling signs of demyelination (26% increase in radial diffusivity) and tissue loss (76% increase in hindered diffusivity) in CC of MPS IIIC mice. Our findings demonstrate an important role for white matter injury in the pathophysiology of MPS III. This study also defines specific parameters and brain regions for MRI analysis and suggests that it may become a crucial non-invasive method to evaluate disease progression and therapeutic response.

10079-MPC-6 RADIOLOGICAL AND MOLECULAR ANALYSIS OF WHO GRADE 4 BUTTERFLY GLIOMAS WITH A TAILORED SURGICAL APPROACH

Abstract OBJECT Surgical resection for butterfly gliomas (bG) are still under debate, but recent findings have shown that surgery prolongs survival. However, clinical and molecular background of bG still remains unknown and surgical strategies based on such findings are scarce. OBJECTS AND METHODS We treated 39 bG patients between 2005 and 2023, including 32 cases of glioblastoma and 5 cases of astrocytoma, WHO grade 4, IDH-mutant. For the validation, we reviewed 968 MRI obtained from the public datasets (UPENN-GBM, n=611; TCGA-GBM, n=255; CPTAC-GBM, n=61; IvyGAP, n=41). RESULTS Molecular analyses revealed that 51.3% of TERT promoter mutations, 59.0% of EGFR amplification/gain, 38.5% of PTEN hemi/homozygous, and 51.3% of CDKN2A hemi/homozygous deletion. Sequential radiological imaging before typical bG diagnosis demonstrated that bG harbors two subtypes which are corpus callosum (CC)-type and hemispheric (H)-type. The multisampling of H-type showed that accumulating alterations in the CC lesions than hemisphere, indicating an invasive trajectory from the hemisphere to the CC region. Survival analysis presented that CC-type was significantly poorer overall survival (OS) than H-type (263 days and 691 days, respectively, P = 0.018). The validation cohort also supported the poor survival of CC-type. CONCLUSION Our detail analyses demonstrated the possibility of two subtypes in bG. Unilateral trans-cortical approach from the larger tumor size with CC removal is favored in the H-type. On the other hand, bilateral trans-sulcal and interhemispheric approaches preserving the intact cortex and cingulate gyrus is an alternative for CC-type.

Assessment of Cerebral White Matter Involvement in Amyotrophic Lateral Sclerosis Patients With Disease Progression and Cognitive Impairment by Fixel-Based Analysis and Neurite Orientation Dispersion and Density Imaging.

Previous studies using emerging diffusion MRI techniques have revealed damage to the white matter (WM) microstructure in amyotrophic lateral sclerosis (ALS), particularly the influence of crossed fibers, but there is a lack of subgroup analyses. To detect WM microstructural changes in ALS patients using fixel-based analysis (FBA) and neurite orientation dispersion and density imaging (NODDI) MRI. Prospective. Thirty-six ALS patients (aged 60.50 ± 9.5 years) and 25 healthy controls (HCs) (aged 58.90 ± 8.1 years). 3 T; NODDI and FBA (b-values = 0, 1000, and 2500 seconds/mm2). Subgroups were performed according to progression rate and cognition, including fast and slow progression (FP/SP), ALS with and without cognitive impairment (ALS-ci/ALS-nci). Fiber density (FD), fiber-bundle cross-section (FC), combined fiber density and cross-section (FDC), neurite density index (NDI), orientation dispersion index (ODI), isotropic volume fraction (ISO), and fractional anisotropy (FA) were calculated and their correlation with clinical variables examined. Chi-square test, Mann-Whitney U test, two-sample t test, partial correlation analysis, and false discovery rate (FDR) corrected. A P-value <0.05 was considered significant. ALS patients had lower FD and FDC values predominantly in the corticospinal tract (CST) and corpus callosum (CC) regions, as well as lower NDI value in the CC, radial crown, and internal capsule compared to HCs. Subgroup analysis based on progression rate and cognitive function showed significant differences in FBA results. The FC in the right CST region was significantly lower in the FP than SP, and the FD in the CC region was significantly lower in the ALS-ci than ALS-nci. Furthermore, a negative correlation was found between the mean FC value and the rate of progression in ALS patients (r = -0.408). FBA is a powerful tool for detecting complex cerebral WM microstructural damage for evaluating ALS cognition and disease progression.

Acupuncture Alleviates Chronic Ischemic White Matter Injury in SHR Rats via JNK-NMDAR Circuit.

To study the protective mechanism of acupuncture at "Jiangya Recipe" on chronic ischemic white matter injury in spontaneously hypertensive rats (SHR) and the regulation of Jun N-terminal kinase-N-methyl-D-aspartate receptor (JNK-NMDAR) loop. A hypertensive white matter injury model was established in 46 male SHR rats aged 11 weeks by bilateral common carotid artery tapering (SHR-2VGO). In the SHR sham operation group, only bilateral common carotid arteries were isolated and in the SHR-2VGO modeling group, 36 rats were used for microcoil spring clip implantation to narrow the common carotid arteries and then, after 2 weeks of modeling, rats with impaired motor function were removed, and SHR-2VGO rats with successful final models were randomly divided into the model group, JNK blocking group, and acupuncture group. The sham operation group, model group, and JNK blocking group underwent the same grasping fixation, and the acupuncture group received acupuncture at acupoints "Jiangya Fang" once daily. In the JNK blocker group, an injection cannula was implanted into the lateral ventricle and sp600125 was injected into the lateral ventricle at 4.5 ul/day for 4 weeks. One week after the end of the intervention, white matter lesions were detected by MRI DWI and T2 imaging, and the learning and memory ability of rats was tested by Y-Maze and Passive Avoidance. Myelin density was detected by luxol fast blue (LFB) staining, also axon arrangement, myelin integrity, and thickness of neurons were detected by electron microscopy; neuronal morphology and the number of Nissl bodies in the hippocampus were detected by Nissl staining, dendritic spine density changes were detected by Golgi staining, and JNK, NMDAR1, and N-methyl-D-receptor 2B (NMDAR2B) in DG, CA3 region of hippocampus were detected by immunohistochemistry, protein expression of p-JNK/JNK, p-NMDAR1/NMDAR1, NMDAR2B, GSK3β protein expression in the fimbria of hippocampus was detected by Western blot. The Y maze test of SHR-2VGO+Acu and SHR-2VGO+ sp600125 group showed that the spontaneous alternating reaction rate increased significantly. At the same time, the incubation period increased significantly and the number of errors decreased significantly in Passive Avoidance. MRI T2WI showed that the white matter high signal of the corpus callosum, internal capsule and hippocampal fimbria in the SHR-2VGO+ sp600125 and SHR-2VGO+Acu groups was significantly lower than that in the SHR-2VGO model group, and the striatum and anterior commissure were not obvious. DWI showed that the SHR-2VGO model group had scattered high signal and limited diffusion movement in both the internal capsule and striatum, but the difference between groups was not obvious. Compared with SHR-2VGO rats, LFB staining of SHR-2VGO + sp600125 and SHR-2VGO +Acu groups showed significant relaxation of myelin porosity in corpus callosum, striatum, inner capsule, anterior commissure and hippocampal fimbria, and electron microscopy showed improved axonal myelin integrity and thickness in corpus callosum region. Also, the number of blue patchy Nissl bodies increased, and the number and complexity of dendritic spines increased significantly in Golgi staining. Immunohistochemical detection showed that JNK levels in DG and CA3 region were increased and NMDAR1 and NMDAR2B levels were decreased in SHR-2VGO+Acu and SHR-2VGO+ sp600125 groups. Meanwhile, protein expressions of GSK3β, NMDAR1/p-NMDAR1 and NMDAR2B in fimbria of hippocampus were increased, and JNK/P-JNK protein expression decreased. Acupuncture can increase the density and thickness of myelin sheath in white matter areas of corpus callosum, anterior commissure and hippocampal fimbria, increase the number and length of hippocampal neuronal dendrites, and improve hypertensive white matter injury and cognitive decline through JNK-NMDAR pathway.

NIMG-61. RADIOLOGICAL, CLINICAL, AND MOLECULAR ANALYSES UNRAVEL DISTINCT SUBTYPES OF ADULT GRADE 4 BUTTERFLY GLIOMAS AFFECTING THE PROGNOSIS

Abstract Gliomas located at the corpus callosum (CC) and invading the bilateral hemispheres is known as butterfly gliomas (bG). Images of bG are frequently used as the hallmark of glioblastoma (GB); however, the molecular background and origins of bG remain unknown. We collected 37 bG patients, including 32 cases of GB and 5 cases of astrocytoma, WHO grade 4, IDH-mutant. Our dataset included extremely rare sequential radiological imaging before receiving a definitive diagnosis of bG. One case emerged from CC and subsequently became bG, whereas five cases emerged from the cerebral hemisphere and became bG, suggesting distinct radiological origins exist in bG. Reflecting this observation to further analysis, we subdivided the cohort into CC-type (n = 15) and hemispheric-type (n = 22) based on the ratio calculated by the tumor volume at CC and hemisphere. Survival analysis presented that CC-type was significantly poorer overall survival (OS) than hemispheric-type (P = 0.010), indicating that bG has clinically distinct two subtypes. Molecular analyses revealed that TERT promoter mutations and IDH1 mutations were observed in 73.3% and 0% in the CC-type, whereas 36.4% and 22.7% in the hemispheric-type, respectively. Other alterations such as MGMT promoter methylation, EGFR amplification/gain, CDKN2A hemi/homozygous deletion, and PTEN hemi/homozygous deletion remained the same between two groups. None of the patients had H3F3A, HIST1H3B, or BRAF mutations. In the hemispheric-type, the multisampling of hemispheric and CC specimens revealed accumulating alterations in the CC lesions, indicating an invasive trajectory from the hemisphere to the CC region. For the validation, we reviewed 993 MRI obtained from the public datasets (TCGA-GBM, CPTAC-GBM, IvyGap, and UPenn-GBM) and found the same trend: CC-type presented poor OS. bG is not a sole subtype with just extensive invasion from the hemisphere. Our results highlight the pathophysiology of bG and may influence its management.

Metabolite Variations in the Hippocampus and Corpus Callosum of Patients with Mild Cognitive Impairment Using Magnetic Resonance Spectroscopy with Three-Dimensional Chemical Shift Images.

This study compared the metabolites in the brain regions of hippocampus and corpus callosum between patients with mild cognitive impairment (MCI) and healthy controls using no-radiation and high-sensitivity magnetic resonance spectroscopy (MRS) with three-dimensional chemical shift images (3D-CSI). Twenty volunteers (seven patients with MCI and 13 healthy controls) aged 50-71 years were recruited for this prospective study. MRS with 3D-CSI images of a variety of metabolites was collected from the hippocampus and corpus callosum. Sex and weight showed no significant differences between the two groups. The metabolite levels in the hippocampus and corpus callosum of the MCI group were generally lower than in those of the healthy group, especially for creatine (p < 0.001 in the hippocampus and p = 0.020 in the corpus callosum) and N-acetyl aspartate/creatine (p < 0.001 in the hippocampus and p = 0.020 in the corpus callosum); however, choline/creatine showed a significant difference (p < 0.001) only in the hippocampus, and myo-inositol/creatine showed a significant difference (p < 0.001) only in the corpus callosum. Our study demonstrated that MRS with 3D-CSI can be used to measure these metabolite levels to determine the differences between patients with MCI and healthy individuals. This would aid early diagnosis of MCI in clinical practice, and patients could receive prompt intervention to improve their quality of life.

Estimating axon radius using diffusion-relaxation MRI: calibrating a surface-based relaxation model with histology.

Axon radius is a potential biomarker for brain diseases and a crucial tissue microstructure parameter that determines the speed of action potentials. Diffusion MRI (dMRI) allows non-invasive estimation of axon radius, but accurately estimating the radius of axons in the human brain is challenging. Most axons in the brain have a radius below one micrometer, which falls below the sensitivity limit of dMRI signals even when using the most advanced human MRI scanners. Therefore, new MRI methods that are sensitive to small axon radii are needed. In this proof-of-concept investigation, we examine whether a surface-based axonal relaxation process could mediate a relationship between intra-axonal T2 and T1 times and inner axon radius, as measured using postmortem histology. A unique in vivo human diffusion-T1-T2 relaxation dataset was acquired on a 3T MRI scanner with ultra-strong diffusion gradients, using a strong diffusion-weighting (i.e., b = 6,000 s/mm2) and multiple inversion and echo times. A second reduced diffusion-T2 dataset was collected at various echo times to evaluate the model further. The intra-axonal relaxation times were estimated by fitting a diffusion-relaxation model to the orientation-averaged spherical mean signals. Our analysis revealed that the proposed surface-based relaxation model effectively explains the relationship between the estimated relaxation times and the histological axon radius measured in various corpus callosum regions. Using these histological values, we developed a novel calibration approach to predict axon radius in other areas of the corpus callosum. Notably, the predicted radii and those determined from histological measurements were in close agreement.

Empirical relationship between TEM-derived myelin volume fraction and MRI-R2 values in aging ex vivo rat corpus callosum

Ex vivo ratiometric measurements of short- and long-T2 components using the multiple spin echo sequence of MRI are often employed to evaluate alterations in myelin content in the white matter (WM) of the brain. However, the relationship between absolute MRI-T2 values (long-T2 component) and myelin volumetric information in aged ex vivo rodent WM appears to be influenced by factors such as animal species, field strength, and fixation durations/washing. Here, multiple spin echo sequence-based MRI-R2 (the reciprocal of T2) values were measured in the corpus callosum (CC) region in the post-mortem rat brains (n = 9) of different age groups with common fixation techniques without washing at 7 T. Transmission electron microscopy (TEM)-based quantification of myelin volume fraction (MVF) and corresponding Monte-Carlo simulation to estimate relaxation rates (R2,IE) due to diffusion in the presence of inhomogeneous magnetic field perturbation in intra- and extra-cellular (IE) spaces were respectively performed. To determine whether the short-T2 components originating from myelin water were mixed with long-T2 components from IE water or were undetectable, the MVF values obtained from TEM results were respectively compared with MRI-R2 and R2,IE values. A significant correlation (Pearson's correlation coefficient r = 0.8763; p < 0.01) of average MRI-R2 and MVF values was observed. Estimated R2,IE values from Monte-Carlo simulations in IE water signals were also positively correlated (r = 0.8281; p < 0.01) with MVF values. However, the magnitudes of R2,IE values were much smaller than those observed for MRI-R2 values, indicating that changes in R2 related MVF are likely dominated by myelin water components. Such comparisons between independent parameters from MRI, TEM, and simulations support the suggestion that myelin water signals were indistinguishably mixed to exhibit mono-exponential T2 relaxation, and multiple spin echo sequence-based MRI-R2 values in aging ex vivo rat CC without prolonged washing still reflect the volumetric information of myelin, likely due to enhanced water exchange across the myelin.

Exploring interhemispheric connectivity using the directional tract density patterns of the corpus callosum

The corpus callosum (CC) is one of the most important interhemispheric white matter tracts that connects interrelated regions of the cerebral cortex. Its disruption has been investigated in previous studies and has been found to play an important role in several neurodegenerative disorders. Currently available methods to assess the interhemispheric connectivity of the CC have several limitations: i) they require the a priori identification of specific cortical regions as targets or seeds, ii) they are limited by the characterization of only small components of the structure, primarily voxels that constitute the mid-sagittal slice, and iii) they use global measures of microstructural integrity, which provide only limited characterization. In order to address some of these limitations, we developed a novel method that enables the characterization of white matter tracts covering the structure of CC, from the mid-sagittal plane to corresponding regions of cortex, using directional tract density patterns (dTDPs). We demonstrate that different regions of CC have distinctive dTDPs that reflect a unique regional topology. We conducted a pilot study using this approach to evaluate two different datasets collected from healthy subjects, and we demonstrate that this method is reliable, reproducible, and independent of diffusion acquisition parameters, suggesting its potential applicability to clinical applications.

Fine‐grained ordering of white matter degeneration in the Alzheimer’s disease pathophysiological cascade

AbstractBackgroundThe role of white matter (WM) neurodegeneration in Alzheimer’s disease (AD) is poorly understood. Fine‐grained sequencing of WM neurodegeneration could provide new avenues for early diagnosis and novel disease‐modifying therapies to slow or halt AD progression. Previous approaches are limited by their coarse granularity and incomplete disease coverage. In this study, we apply event‐based disease progression modelling (DPM) (Fonteijn et al, Neuroimage, 2012), which can provide fine‐grained ordering, to estimate progression of regional WM abnormality in AD.MethodDiffusion tensor imaging (DTI) markers of WM abnormality and Freesurfer volumetric markers of grey matter (GM) atrophy were obtained from ADNI. DTI markers were hemisphere‐averaged and GM volumes were normalised by head size. Eleven WM ROIs with reported AD abnormality and 4 reference GM ROIs were selected for sequencing (abbreviations in Table 1), yielding complete data for 83 cognitively normal subjects, 40 AD patients and 102 MCI subjects. Event‐based DPM (github.com/ucl‐pond/kde_ebm) was used to estimate a data‐driven sequence of neurodegeneration and its uncertainty (positional variance), and individuals were assigned to their most likely stage (Young et al., Brain, 2014). Resampling analysis assessed the robustness of the estimated sequence.ResultFig. 1 shows the first data‐driven sequence of WM abnormalities in AD, including positional variance, with GM abnormality events for reference. The earliest WM events are increases in mean diffusivity (MD) in CGH and axial diffusivity (AxD) in FX and BCC. Subsequently, a cascade of AxD events in corpus callosum regions precedes abnormality in other medial temporal lobe WM structures.Fig. 2 shows the sequence is relatively robust under resampling, with low positional variance and similar median positions for most ROIs. Subject staging (Fig. 3, 4) shows that the fine‐grained approach splits MCI subjects with hippocampal atrophy into those with hippocampal atrophy and those with additional increased MD in CGH.ConclusionThis study finds WM microstructural abnormality among the earliest events in AD. Early hippocampal WM abnormality and corpus callosum ordering are consistent with early memory deficits in AD and inferences from cruder group‐based comparisons. The order suggests Wallerian degeneration rather than retrogenesis is the primary driver of WM neurodegeneration in AD.

Axon fiber orientation as the source of T1 relaxation anisotropy in white matter: A study on corpus callosum in vivo and ex vivo.

Recent studies indicate that T1 in white matter (WM) is influenced by fiber orientation in B0 . The purpose of the study was to investigate the interrelationships between axon fiber orientation in corpus callosum (CC) and T1 relaxation time in humans in vivo as well as in rat brain ex vivo. Volunteers were scanned for relaxometric and diffusion MRI at 3 T and 7 T. Angular T1 plots from WM were computed using fractional anisotropy and fiber-to-field-angle maps. T1 and fiber-to-field angle were measured in five sections of CC to estimate the effects of inherently varying fiber orientations on T1 within the same tracts in vivo. Ex vivo rat-brain preparation encompassing posterior CC was rotated in B0 and T1 , and diffusion MRI images acquired at 9.4 T. T1 angular plots were determined at several rotation angles in B0 . Angular T1 plots from global WM provided reference for estimated fiber orientation-linked T1 changes within CC. In anterior midbody of CC in vivo, where small axons are dominantly present, a shift in axon orientation is accompanied by a change in T1 , matching that estimated from WM T1 data. In CC, where large and giant axons are numerous, the measured T1 change is about 2-fold greater than the estimated one. Ex vivo rotation of the same midsagittal CC region of interest produced angular T1 plots at 9.4 T, matching those observed at 7 T in vivo. These data causally link axon fiber orientation in B0 to the T1 relaxation anisotropy in WM.

Progranulin deficiency results in sex-dependent alterations in microglia in response to demyelination.

Heterozygous mutations in the granulin (GRN) gene, resulting in the haploinsufficiency of the progranulin (PGRN) protein, is a leading cause of frontotemporal lobar degeneration (FTLD). Complete loss of the PGRN protein causes neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disorder. Polymorphisms in the GRN gene have also been associated with several other neurodegenerative diseases, including Alzheimer's disease (AD), and Parkinson's disease (PD). PGRN deficiency has been shown to cause myelination defects previously, but how PGRN regulates myelination is unknown. Here, we report that PGRN deficiency leads to a sex-dependent myelination defect with male mice showing more severe demyelination in response to cuprizone treatment. This is accompanied by exacerbated microglial proliferation and activation in the male PGRN-deficient mice. Interestingly, both male and female PGRN-deficient mice show sustained microglial activation after cuprizone removal and a defect in remyelination. Specific ablation of PGRN in microglia results in similar sex-dependent phenotypes, confirming a microglial function of PGRN. Lipid droplets accumulate in microglia specifically in male PGRN-deficient mice. RNA-seq analysis and mitochondrial function assays reveal key differences in oxidative phosphorylation in male versus female microglia under PGRN deficiency. A significant decrease in myelination and accumulation of myelin debris and lipid droplets in microglia were found in the corpus callosum regions of FTLD patients with GRN mutations. Taken together, our data support that PGRN deficiency leads to sex-dependent alterations in microglia with subsequent myelination defects.