White Matter Regions Research Articles

White matter engagement in brain networks assessed by integration of functional and structural connectivity

Current models of brain networks may potentially be improved by integrating our knowledge of structural connections, within and between circuits, with metrics of functional interactions between network nodes. The former may be obtained from diffusion MRI of white matter (WM), while the latter may be derived by measuring correlations between resting state BOLD signals from pairs of gray matter (GM) regions. From inspection of diffusion MRI data, it is clear that each WM voxel within a 3D image array may be traversed by multiple WM structural tracts, each of which connects a pair of GM nodes. We hypothesized that by appropriately weighting and then integrating the functional connectivity of each such connected pair, the overall engagement of any WM voxel in brain functions could be evaluated. This model introduces a structural constraint to earlier studies of WM engagement and addresses some limitations of previous efforts to relate structure and function. Using concepts derived from graph theory, we obtained spatial maps of WM engagement which highlight WM regions critical for efficient communications across the brain. The distributions of WM engagement are highly reproducible across subjects and depict a notable interdependence between the distribution of GM activities and the detailed organization of WM. Additionally, we provide evidence that the engagement varies over time and shows significant differences between genders. These findings suggest the potential of WM engagement as a measure of the integrity of normal brain functions and as a biomarker for neurological and cognitive disorders.

Enhancing cognitive performance prediction by white matter hyperintensity connectivity assessment.

White matter hyperintensities of presumed vascular origin (WMH) are associated with cognitive impairment and are a key imaging marker in evaluating brain health. However, WMH volume alone does not fully account for the extent of cognitive deficits and the mechanisms linking WMH to these deficits remain unclear. Lesion network mapping (LNM) enables to infer if brain networks are connected to lesions and could be a promising technique for enhancing our understanding of the role of WMH in cognitive disorders. Our study employed LNM to test the following hypotheses: (1) LNM-informed markers surpass WMH volumes in predicting cognitive performance, and (2) WMH contributing to cognitive impairment map to specific brain networks. We analyzed cross-sectional data of 3,485 patients from 10 memory clinic cohorts within the Meta VCI Map Consortium, using harmonized test results in 4 cognitive domains and WMH segmentations. WMH segmentations were registered to a standard space and mapped onto existing normative structural and functional brain connectome data. We employed LNM to quantify WMH connectivity to 480 atlas-based gray and white matter regions of interest (ROI), resulting in ROI-level structural and functional LNM scores. We compared the capacity of total and regional WMH volumes and LNM scores in predicting cognitive function using ridge regression models in a nested cross-validation. LNM scores predicted performance in three cognitive domains (attention/executive function, information processing speed, and verbal memory) significantly better than WMH volumes. LNM scores did not improve prediction for language functions. ROI-level analysis revealed that higher LNM scores, representing greater connectivity to WMH, in gray and white matter regions of the dorsal and ventral attention networks were associated with lower cognitive performance. Measures of WMH-related brain network connectivity significantly improve the prediction of current cognitive performance in memory clinic patients compared to WMH volume as a traditional imaging marker of cerebrovascular disease. This highlights the crucial role of network integrity, particularly in attention-related brain regions, improving our understanding of vascular contributions to cognitive impairment. Moving forward, refining WMH information with connectivity data could contribute to patient-tailored therapeutic interventions and facilitate the identification of subgroups at risk of cognitive disorders.

Diffusion and functional MRI reveal microstructural and network connectivity impairment in adult-onset neuronal intranuclear inclusion disease.

Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disorder lacking reliable neuroimaging biomarkers. This study aimed to evaluate microstructural and functional connectivity alterations using diffusion kurtosis imaging (DKI) and resting-state fMRI (rs-fMRI), and to investigate their diagnostic potential as biomarkers. Twenty-three patients with NIID and 40 matched healthy controls (HCs) were recruited. Firstly, gray matter (GM) and white matter (WM) changes were assessed by voxel-based analysis (VBA) and tract-based spatial statistics (TBSS). Then we explored modifications in brain functional networks connectivity by independent component analysis. And the relationship between the altered DKI parameters and neuropsychological evaluation was analyzed. Finally, a receiver operating characteristic (ROC) curve was used to evaluate the diagnostic performance of different gray matter and white matter parameters. Compared with the HCs, NIID patients showed reduced mean kurtosis (MK), radial kurtosis (RK), axial kurtosis (AK), and kurtosis fractional anisotropy (KFA) values in deep gray matter regions. Significantly decreased MK, RK, AK, KFA and fractional anisotropy (FA), and increased mean diffusivity (MD) values were observed in extensive white matter fiber tracts. Notable alterations in functional connectivity were also detected. Among all DKI parameters, the diagnostic efficiency of AK in GM and FA in WM regions was the highest. Adult-onset NIID patients exhibited altered microstructure and functional network connectivity. Our findings suggest that DKI parameters may serve as potential imaging biomarkers for diagnosing adult-onset NIID.

Measurement of apparent diffusion coefficient (ADC) in fetal organs and placenta using 3 Tesla magnetic resonance imaging (MRI) across gestational ages

Diffusion-weighted imaging (DWI) is a technique used to probe the random microscopic motion of water protons in living tissue, represented by a parameter measurement of apparent diffusion coefficient (ADC) values. This study aimed to measure the ADC values of various fetal organs and placenta using 3T at various gestational ages. This was a prospective observational study. A total of 103 singleton pregnancies from 20 to 38 weeks of gestational age were included. Diffusion-weighted imaging was performed in the axial plane from the fetal head to the trunk with the following parameters: TR: 2000–2500 ms; TE: 88 ms; FOV: 250 mm; 256 matrix; slice thickness: 4 mm with a 0 mm gap; acquisition time: 1 min, 18 s. Diffusion gradient values were b = 0 and b = 700 s/mm2. ADC was measured in fetal brain regions (frontal white matter, occipital white matter, centrum semiovale, pons, thalamus, cerebellum, and fetal organs (lungs, kidney, and placenta). ANOVA was used to calculate the mean ADC values. Karl Pearson’s coefficient of correlation was used to evaluate the correlation between ADC values and increasing gestational age. The mean ADC values of brain regions were: frontal white matter (1.64 ± 0.08 × 10− 3 mm2 /s, F-39.10,p-<0.001), occipital white matter (1.64 ± 0.06 × 10− 3 mm2/s, F-26.14, p-<0.001), centrum semiovale (1.62 ± 0.03 × 10− 3 mm2/s, F-49.88,p-<0.001, pons (1.23 ± 0.09 × 10− 3 mm2/s F-9.14,p-<0.001) ), Thalamus (1.21 ± 0.07 × 10− 3 mm2/s, F-13.54,p-<0.001) and cerebellum (1.36 ± 0.10 × 10− 3 mm2 /s, F-4.19,p-<0.001). The mean ADC values of fetal organs were lung (1.92 ± 0.15 × 10− 3 mm2 /s, F-28.24, p-<0.001), kidney (1.34 ± 0.11 × 10− 3 mm2 /s, F-1.05, p- 0.37) and placenta (1.94 ± 0.11 × 10− 3 mm2 /s, F-160.33, p-<0.001). White-matter regions showed a significant positive correlation with increasing gestational age. Statistically, a negative correlation was observed between increasing gestational age and ADC measurements obtained in the thalamus, cerebellum, pons, and kidney. This will be one of the first few studies to provide the ADC values of the fetal brain and fetal organs using 3T MRI. The current study shows that diffusion-weighted MRI can offer a promising technique to evaluate the structural development of fetal organs and can potentially lead to a biomarker for predicting the functionality of the fetal organs in abnormalities.

Microangiopathy in temporal lobe epilepsy with diffusion MRI alterations and cognitive decline

White matter microvascular alterations in temporal lobe epilepsy (TLE) may be relevant to acquired neurodegenerative processes and cognitive impairments associated with this condition. We quantified microvascular changes, myelin, axonal, glial and extracellular-matrix labelling in the gyral core and deep temporal lobe white matter regions in surgical resections from 44 TLE patients with or without hippocampal sclerosis. We compared this pathology data with in vivo pre-operative MRI diffusion measurements in co-registered regions and neuropsychological measures of cognitive impairment and decline. In resections, increased arteriolosclerosis was observed in TLE compared to non-epilepsy controls (greater sclerotic index, p < 0.001), independent of age. Microvascular changes included increased vascular densities in some regions but uniformly reduced mean vascular size (quantified with collagen-4, p < 0.05–0.0001), and increased pericyte coverage of small vessels and capillaries particularly in deep white matter (quantified with platelet-derived growth factor receptorβ and smooth muscle actin, p < 0.01) which was more marked the longer the duration of epilepsy (p < 0.05). We noted increased glial numbers (Olig2, Iba1) but reduced myelin (MAG, PLP) in TLE compared to controls, particularly prominent in deep white matter. Gene expression analysis showed a greater reduction of myelination genes in HS than non-HS cases and with age and correlation with diffusion MRI alterations. Glial densities and vascular size were increased with increased MRI diffusivity and vascular density with white matter abnormality quantified using fixel-based analysis. Increased perivascular space was associated with reduced fractional anisotropy as well as age-accelerated cognitive decline prior to surgery (p < 0.05). In summary, likely acquired microangiopathic changes in TLE, including vascular sclerosis, increased pericyte coverage and reduced small vessel size, may indicate a functional alteration in contractility of small vessels and haemodynamics that could impact on tissue perfusion. These morphological features correlate with white matter diffusion MRI alterations and might explain cognitive decline in TLE.

Myelination potential and injury susceptibility of grey versus white matter human oligodendrocytes.

Increasing evidence indicates heterogeneity in functional and molecular properties of oligodendrocyte lineage cells both during development and under pathologic conditions. In multiple sclerosis, remyelination of grey matter lesions exceeds that in white matter. Here we used cells derived from grey matter versus white matter regions of surgically resected human brain tissue samples, to compare the capacities of human A2B5-positive progenitor cells and mature oligodendrocytes to ensheath synthetic nanofibers, and relate differences to the molecular profiles of these cells. For both cell types, the percentage of ensheathing cells was greater for grey matter versus white matter cells. For both grey matter and white matter samples, the percentage of cells ensheathing nanofibers was greater for A2B5-positive cells versus mature oligodendrocytes. Grey matter A2B5-positive cells were more susceptible than white matter A2B5-positive cells to injury induced by metabolic insults. Bulk RNA sequencing indicated that separation by cell type (A2B5-positive vs mature oligodendrocytes) is more significant than by region but segregation for each cell type by region is apparent. Molecular features of grey matter versus white matter derived A2B5-positive and mature oligodendrocytes were lower expression of mature oligodendrocyte genes and increased expression of early oligodendrocyte lineage genes. Genes and pathways with increased expression in grey matter derived cells with relevance for myelination included those related to responses to external environment, cell-cell communication, cell migration, and cell adhesion. Immune and cell death related genes were up-regulated in grey matter derived cells. We observed a significant number of up-regulated genes shared between the stress/injury and myelination processes, providing a basis for these features. In contrast to oligodendrocyte lineage cells, no functional or molecular heterogeneity was detected in microglia maintained in vitro, likely reflecting the plasticity of these cells ex vivo. The combined functional and molecular data indicate that grey matter human oligodendrocytes have increased intrinsic capacity to myelinate but also increased injury susceptibility, in part reflecting their being at a stage earlier in the oligodendrocyte lineage.

Myelin water imaging of in vivo and ex vivo human brains using multi-echo gradient echo at 3 T and 7 T.

To compare the myelin water fraction (MWF) measurements between 3 T and 7 T and between in vivo and ex vivo human brains, and to investigate the relationship between multi-echo gradient-echo (mGRE)-based 3D MWF and myelin content using histological staining, which has not been validated in the human brain. In this study, we performed 3D mGRE-based MWF measurements on five ex vivo human brain hemispheres and five healthy volunteers at 3 T and 7 T with 1 mm isotropic resolution. The data were fitted with the based on a three compartment complex-valued model to estimate MWF. We obtained myelin basic protein (MBP) staining from two tissue blocks and co-registered the MWF map and histology image for voxel-wise correlation between the two. The MWF values measured from 7 T were overall higher than 7 T, but data between the two field strength demonstrated high correlations both in vivo (r = 0.88) and ex vivo (r = 0.83) across 19 white matter regions. Moreover, the MWF measurements showed a good agreement between in vivo and ex vivo assessments at 3 T (r = 0.61) and 7 T (r = 0.54). Based on MBP staining, the MWF values exhibited strong positive correlations with myelin content on both 3 T (r = 0.68 and r = 0.78 for the two tissue blocks) and 7 T (r = 0.64 and r = 0.82 for the two tissue blocks). The findings demonstrated that the mGRE-based MWF mapping can be used to quantify myelin content in the human brain, despite the field-strength dependency of the measurements.

Structure-function coupling in white matter uncovers the hypoconnectivity in autism spectrum disorder

BackgroundAutism Spectrum Disorder (ASD) is a neurodevelopmental disorder associated with alterations in structural and functional coupling in gray matter. However, despite the detectability and modulation of brain signals in white matter, the structure-function coupling in white matter in autism remains less explored.MethodsIn this study, we investigated structural-functional coupling in white matter (WM) regions, by integrating diffusion tensor data that contain fiber orientation information from WM tracts, with functional connectivity tensor data that reflect local functional anisotropy information. Using functional and diffusion magnetic resonance images, we analyzed a cohort of 89 ASD and 63 typically developing (TD) individuals from the Autism Brain Imaging Data Exchange II (ABIDE-II). Subsequently, the associations between structural-functional coupling in WM regions and ASD severity symptoms assessed by Autism Diagnostic Observation Schedule-2 were examined via supervised machine learning in an independent test cohort of 29 ASD individuals. Furthermore, we also compared the performance of multi-model features (i.e. structural-functional coupling) with single-model features (i.e. functional or structural models alone).ResultsIn the discovery cohort (ABIDE-II), individuals with ASD exhibited widespread reductions in structural-functional coupling in WM regions compared to TD individuals, particularly in commissural tracts (e.g. corpus callosum), association tracts (sagittal stratum), and projection tracts (e.g. internal capsule). Notably, supervised machine learning analysis in the independent test cohort revealed a significant correlation between these alterations in structural-functional coupling and ASD severity scores. Furthermore, compared to single-model features, the integration of multi-model features (i.e., structural-functional coupling) performed best in predicting ASD severity scores.ConclusionThis work provides novel evidence for atypical structural-functional coupling in ASD in white matter regions, further refining our understanding of the critical role of WM networks in the pathophysiology of ASD.

Tract-specific magnetization transfer ratio provides insights into the severity of degenerative cervical myelopathy.

Cross-sectional study. This study's goal is to report whether Magnetization Transfer Ratio (MTR) can evaluate the severity of white matter (WM) injury in degenerative cervical myelopathy (DCM). Laureate Institute of Brain Research, USA; Department of Neurosurgery, University of Oklahoma Health Sciences Center, USA. 27 DCM patients were aged-matched with 20 healthy controls (HC) and categorized into treatment groups based on modified Japanese Orthopedic Association (mJOA) severity (11 mild and 16 moderate/severe). Regional and tract MTRs were extracted from the two vertebral levels containing maximum compression within magnetization transfer images. MTR differences between groups were assessed using a one-way ANOVA or Kruskal-Wallis test. The association between MTR and mJOA measures was evaluated using Spearman's correlation. Significant decreases in MTR were found between HC and moderate/severe groups in the overall (p = 0.0065) and ventral (p = 0.0009) WM regions; and ventral corticospinal (p = 0.0101), ventral reticulospinal (p = 0.0084), spinal lemniscus (p = 0.0079), and fasciculus cuneatus (p = 0.0219) tracts. The spinal lemniscus MTR also significantly decreased between HC and mild groups (p = 0.038). Ventral reticulospinal tract MTR correlated with upper (r = 0.439; p = 0.022) and lower (r = 0.386; p = 0.047) limb motor mJOA scores. Significant tract-based MTR changes and correlations align with known DCM symptoms, are demonstrated to be lost at the regional level, and display the inhomogeneous compressive damage occurring within DCM spinal cords.

Subtle motor signs in children with ADHD and their white matter correlates.

Subtle motor signs are a common feature in children with attention-deficit/hyperactivity disorder (ADHD). It has long been suggested that white matter abnormalities may be involved in their presentation, though no study has directly probed this question. The aim of this study was to investigate the relationship between white matter organization and the severity of subtle motor signs in children with and without ADHD. Participants were 92 children with ADHD aged between 8 and 12 years, and 185 typically developing controls. Subtle motor signs were examined using the Physical and Neurological Examination for Soft Signs (PANESS). Children completed diffusion MRI, and fixel-based analysis was performed after preprocessing. Tracts of interest were delineated using TractSeg including the corpus callosum (CC), the bilateral corticospinal tracts (CST), superior longitudinal fasciculus, and fronto-pontine tracts (FPT). Fiber cross-section (FC) was calculated for each tract. Across all participants, lower FC in the CST was associated with higher PANESS Total score (greater motor deficits). Within the PANESS, similar effects were observed for Timed Left and Right maneuvers of the hands and feet, with lower FC of the CST, CC, and FPT associated with poorer performance. No significant group differences were observed in FC in white matter regions associated with PANESS performance. Our data are consistent with theoretical accounts implicating white matter organization in the expression of motor signs in childhood. However, rather than contributing uniquely to the increased severity of soft motor signs in those with ADHD, white matter appears to contribute to these symptoms in childhood in general.

White Matter Magnetic Resonance Diffusion Measures in Multiple Sclerosis with Overactive Bladder.

Lower urinary tract (LUT) symptoms are reported in more than 80% of patients with multiple sclerosis (MS), most commonly an overactive bladder (OAB). The relationship between brain white matter (WM) changes in MS and OAB symptoms is poorly understood. We aim to evaluate (i) microstructural WM differences across MS patients (pwMS) with OAB symptoms, patients without LUT symptoms, and healthy subjects using diffusion tensor imaging (DTI), and (ii) associations between clinical OAB symptom scores and DTI indices. Twenty-nine female pwMS [mean age (SD) 43.3 years (9.4)], including seventeen with OAB [mean age (SD) 46.1 years (8.6)] and nine without LUT symptoms [mean age (SD) 37.5 years (8.9)], and fourteen healthy controls (HCs) [mean age (SD) 48.5 years (20)] were scanned in a 3T MRI with a DTI protocol. Additionally, clinical scans were performed for WM lesion segmentation. Group differences in fractional anisotropy (FA) were evaluated using tract-based spatial statistics. The Urinary Symptom Profile questionnaire assessed OAB severity. A statistically significant reduction in FA (p = 0.004) was identified in microstructural WM in pwMS, compared with HCs. An inverse correlation was found between FA in frontal and parietal WM lobes and OAB scores (p = 0.021) in pwMS. Areas of lower FA, although this did not reach statistical significance, were found in both frontal lobes and the rest of the non-dominant hemisphere in pwMS with OAB compared with pwMS without LUT symptoms (p = 0.072). This study identified that lesions affecting different WM tracts in MS can result in OAB symptoms and demonstrated the role of the WM in the neural control of LUT functions. By using DTI, the association between OAB symptom severity and WM changes were identified, adding knowledge to the current LUT working model. As MS is predominantly a WM disease, these findings suggest that regional WM involvement, including of the anterior corona radiata, anterior thalamic radiation, superior longitudinal fasciculus, and superior frontal-occipital fasciculus and a non-dominant prevalence in WM, can result in OAB symptoms. OAB symptoms in MS correlate with anisotropy changes in different white matter tracts as demonstrated by DTI. Structural impairment in WM tracts plays an important role in LUT symptoms in MS.

Differences in brain structure and cognitive performance between patients with long-COVID and those with normal recovery

BackgroundThe pathophysiology of protracted symptoms after COVID-19 is unclear. This study aimed to determine if long-COVID is associated with differences in baseline characteristics, markers of white matter diffusivity in the brain, and lower scores on objective cognitive testing. MethodsIndividuals who experienced COVID-19 symptoms for more than 60 days post-infection (long-COVID) (n = 56) were compared to individuals who recovered from COVID-19 within 60 days of infection (normal recovery) (n = 35). Information regarding physical and mental health, and COVID-19 illness was collected. The National Institute of Health Toolbox Cognition Battery was administered. Participants underwent magnetic resonance imaging (MRI) with diffusion tensor imaging (DTI). Tract-based spatial statistics were used to perform a whole-brain voxel-wise analysis on standard DTI metrics (fractional anisotropy, axial diffusivity, mean diffusivity, radial diffusivity), controlling for age and sex. NIH Toolbox Age-Adjusted Fluid Cognition Scores were used to compare long-COVID and normal recovery groups, covarying for Age-Adjusted Crystallized Cognition Scores and years of education. False discovery rate correction was applied for multiple comparisons. ResultsThere were no significant differences in age, sex, or history of neurovascular risk factors between the groups. The long-COVID group had significantly (p < 0.05) lower mean diffusivity than the normal recovery group across multiple white matter regions, including the internal capsule, anterior and superior corona radiata, corpus callosum, superior fronto-occiptal fasciculus, and posterior thalamic radiation. However, the effect sizes of these differences were small (all β<|0.3|) and no significant differences were found for the other DTI metrics. Fluid cognition composite scores did not differ significantly between the long-COVID and normal recovery groups (p > 0.05). ConclusionsDifferences in diffusivity between long-COVID and normal recovery groups were found on only one DTI metric. This could represent subtle areas of pathology such as gliosis or edema, but the small effect sizes and non-specific nature of the diffusion indices make pathological inference difficult. Although long-COVID patients reported many neuropsychiatric symptoms, significant differences in objective cognitive performance were not found.

Neurite Orientation Dispersion and Density Imaging (NODDI) reveals white matter microstructural changes in Obstructive Sleep Apnea Hypopnea Syndrome (OSAHS) patients with cognitive impairment

PurposeThis study aimed to assess changes in white matter microstructure among patients undergoing obstructive sleep apnea hypopnea syndrome (OSAHS) complicated by cognitive impairment through neurite orientation dispersion and density imaging (NODDI), and evaluate the relationship to cognitive impairment as well as the diagnostic performance in early intervention. MethodsTotally 23 OSAHS patients, 43 OSAHS patients complicated by cognitive impairment, and 15 healthy controls were enrolled in OSA, OSACI and HC groups of this work. NODDI toolbox and FMRIB's Software Library (FSL) were used to calculate neurite density index (NDI), Fractional anisotropy (FA), volume fraction of isotropic water molecules (Viso), and orientation dispersion index (ODI). Tract-based spatial statistics (TBSS) were carried out to examine the above metrics with one-way ANOVA. This study explored the correlations of the above metrics with mini-mental state examination (MMSE), and montreal cognitive assessment (MoCA) scores. Furthermore, receiver operating characteristic (ROC) curves were plotted. Meanwhile, area under curve (AUC) values were calculated to evaluate the diagnostic performance of the above metrics. ResultsNDI, ODI, Viso, and FA were significantly different among different brain white matter regions, among which, difference in NDI showed the greatest statistical significance. In comparison with HC group, OSA group had reduced NDI and ODI, whereas elevated Viso levels. Conversely, compared to the OSA group, the OSACI group displayed a slight increase in NDI and ODI values, which remained lower than HC group, viso values continued to rise. Post-hoc analysis highlighted significant differences in these metrics, except for FA, which showed no notable changes or correlations with neuropsychological tests. ROC analysis confirmed the diagnostic efficacy of NDI, ODI, and Viso with AUCs of 0.6908, 0.6626, and 0.6363, respectively, whereas FA's AUC of 0.5042, indicating insufficient diagnostic efficacy. ConclusionsThis study confirmed that NODDI effectively reveals microstructural changes in white matter of OSAHS patients with cognitive impairment, providing neuroimaging evidence for early clinical diagnosis and intervention.

Long-term brain structural and cognitive outcomes in a low-risk preterm-born sample

Prematurity has been related to altered brain structure and cognition, and so our aim was to describe them in the absence of major structural brain injury following low-risk preterm birth during adolescence and young adulthood. The sample consisted of 250 participants, 132 of whom were low-risk preterm (30–36 weeks’ gestational age) and 118 were full-term individuals (37–42 weeks’ gestational age), aged between 16 and 38 years old. All participants underwent an extensive neuropsychological assessment. T1- and diffusion-weighted MRI images of 33 low-risk preterm and 31 full-term young adults (20–32 years old) were analyzed. No differences were found in terms of general cognitive functioning score or current socioeconomic status; however, the low-risk preterm group obtained lower scores in phonetic and semantic fluencies, and theory of mind. Significant reductions were identified in the thalamus volume as well as thicker cortex in the inferior temporal gyrus in the low-risk preterm group. Low-risk preterm young adults evidenced greater regional AD and MD compared to the full-term sample; while low-risk preterm group showed lower mean NDI and ODI (FWE-corrected, p < 0.05). Being born preterm is associated with poorer performance in various cognitive domains (i.e., phonetic and semantic fluencies, and theory of mind) later in life, along with differences in normative structural brain development in inferior temporal gyrus and regional white matter microstructure.

Hypertension and cerebral blood flow in the development of Alzheimer's disease.

We investigated the interactive associations between amyloid and hypertension on the entorhinal cortex (EC) tau and atrophy and the role of cerebral blood flow (CBF) as a shared mechanism by which amyloid and hypertension contribute to EC tau and regional white matter hyperintensities (WMHs). We analyzed data from older adults without dementia participating in the Add-Tau study (NCT02958670, n=138) or Alzheimer's Disease Neuroimaging Initiative (ADNI) (n=523) who had available amyloid-positron emission tomography (PET), tau-PET, fluid-attenuated inversion recovery (FLAIR), and T1-weighted magnetic resonance imaging (MRI). A subsample in both cohorts had available arterial spin labeling (ASL) MRI (Add-Tau: n=78; ADNI: n=89). The detrimental effects of hypertension on AD pathology and EC thickness were more pronounced in the Add-Tau cohort. Increased amyloid burden was associated with decreased occipital gray matter CBF in the ADNI cohort. In both cohorts, lower regional gray matter CBF was associated with higher EC tau and posterior WMH burden. Reduced cerebral perfusion may be one common mechanism through which hypertension and amyloid are related to increased EC tau and WMH volume. Hypertension is associated with increased entorhinal cortex (EC) tau, particularly in the presence of amyloid. Decreased cortical cerebral blood flow (CBF) is associated with higher regional white matter hyperintensity volume. Increasing amyloid burden is associated with decreasing CBF in the occipital lobe. MTL CBF and amyloid are synergistically associated with EC tau.

Ferritin loss in astrocytes reduces spinal cord oxidative stress and demyelination in the experimental autoimmune encephalomyelitis (EAE) model.

Demyelinating diseases such as multiple sclerosis (MS) cause myelin degradation and oligodendrocyte death, resulting in the release of toxic iron and iron-induced oxidative stress. Astrocytes have a large capacity for iron transport and storage, however the role of astrocytic iron homeostasis in demyelinating disorders is not completely understood. Here we investigate whether astrocytic iron metabolism modulates neuroinflammation, oligodendrocyte survival, and oxidative stress following demyelination. To this aim, we conditionally knock out ferritin in astrocytes and induce experimental autoimmune encephalomyelitis (EAE), an autoimmune-mediated model of demyelination. Ferritin ablation in astrocytes reduced the severity of disease in both the acute and chronic phases. The day of onset, peak disease severity, and cumulative clinical score were all significantly reduced in ferritin KO animals. This corresponded to better performance on the rotarod and increased mobility in ferritin KO mice. Furthermore, the spinal cord of ferritin KO mice display decreased numbers of reactive astrocytes, activated microglia, and infiltrating lymphocytes. Correspondingly, the size of demyelinated lesions, iron accumulation, and oxidative stress were attenuated in the CNS of ferritin KO subjects, particularly in white matter regions of the spinal cord. Thus, deleting ferritin in astrocytes reduced neuroinflammation, oxidative stress, and myelin deterioration in EAE animals. Collectively, these findings suggest that iron storage in astrocytes is a potential therapeutic target to lessen CNS inflammation and myelin loss in autoimmune demyelinating diseases.

Predicting white-matter hyperintensity progression and cognitive decline in patients with cerebral small-vessel disease: a magnetic resonance-based habitat analysis.

White-matter hyperintensity (WMH) is the key magnetic resonance imaging (MRI) marker of cerebral small-vessel disease (CSVD). This study aimed to investigate whether habitat analysis based on physiologic MRI parameters can predict the progression of WMH and cognitive decline in CSVD. Diffusion- and perfusion-weighted imaging data were obtained from 69 patients with CSVD at baseline and at 1-year of follow-up. The white-matter region was classified into constant WMH, growing WMH, shrinking WMH, and normal-appearing white matter (NAWM) according to the T2-fluid-attenuated inversion recovery (FLAIR) sequences images at the baseline and follow-up. We employed k-means clustering on a voxel-wise basis to delineate WMH habitats, integrating multiple diffusion metrics and cerebral blood flow (CBF) values derived from perfusion data. The WMH at the baseline and the predicted WMH from the habitat analysis were used as regions of avoidance (ROAs). The decreased rate of global efficiency for the whole brain structural connectivity was calculated after removal of the ROA. The association between the decreased rate of global efficiency and Montreal Cognitive Assessment (MoCA) and mini-mental state examination (MMSE) scores was evaluated using Pearson correlation coefficients. We found that the physiologic MRI habitats with lower fractional anisotropy and CBF values and higher mean diffusivity, axial diffusivity, and radial diffusivity values overlapped considerably with the new WMH (growing WMH of baseline) after a 1-year follow-up; the accuracy of distinguishing growing WMH from NAWM was 88.9%±12.7% at baseline. Similar results were also found for the prediction of shrinking WMH. Moreover, after the removal of the predicted WMH, a decreased rate of global efficiency had a significantly negative correlation with the MoCA and MMSE scores at follow-up. This study revealed that a habitat analysis combining perfusion with diffusion parameters could predict the progression of WMH and related cognitive decline in patients with CSVD.

Elevated plasma matrix metalloproteinase 9 in schizophrenia patients associated with poor antipsychotic treatment response and white matter density deficits

Oxidative stress and neuroinflammation contribute to schizophrenia (SCZ) pathology and may influence treatment efficacy. Matrix metalloproteinase 9 (MMP9) is a critical molecular node mediating the interaction between oxidative stress and inflammation, and so may influence treatment efficacy. Here we examined the associations of plasma MMP9 concentration with antipsychotic drug responses, clinical symptoms, and brain structure. A total of 129 healthy controls and 124 patients with SCZ were included in this study. Patients were monitored clinically during 8 weeks of antipsychotic treatment and classified as poor responders (n = 49) or good responders (n = 75). We then compared plasma MMP9 concentrations in healthy controls at baseline and both SCZ responder groups at baseline and after the 8-week antipsychotic treatment regimen. Cognitive function was also examined using the MATRICS Consensus Cognitive Battery. In addition, we extracted regional white matter density from magnetic resonance images of patients. Compared to healthy controls, plasma MMP9 levels were significantly elevated in poor responders at baseline and negatively correlated with both white matter density in the right superior temporal gyrus and the change in cognitive symptoms after treatment. Conversely, there was no significant difference in plasma MMP9 between good responders and healthy controls, and no associations of plasma MMP9 with cognitive symptoms or regional white matter density among good responders. Elevated plasma MMP9 is associated with poor antipsychotic drug efficacy and white matter deficits in SCZ patients, and so may be a useful biomarker to guide personalized treatment.

Development and validation of a perivascular space segmentation method in multi-center datasets

BackgroundPerivascular spaces (PVS) visible on magnetic resonance imaging (MRI) are significant markers associated with various neurological diseases. Although quantitative analysis of PVS may enhance sensitivity and improve consistency across studies, the field lacks a universally validated method for analyzing images from multi-center studies. MethodsWe annotated PVS on multi-center 3D T1-weighted (T1w) images acquired using scanners from three major vendors (Siemens, General Electric, and Philips). A neural network, mcPVS-Net (multi-center PVS segmentation network), was trained using data from 40 subjects and then tested in a separate cohort of 15 subjects. We assessed segmentation accuracy against ground truth masks tailored for each scanner vendor. Additionally, we evaluated the agreement between segmented PVS volumes and visual scores for each scanner. We also explored correlations between PVS volumes and various clinical factors such as age, hypertension, and white matter hyperintensities (WMH) in a larger sample of 1020 subjects. Furthermore, mcPVS-Net was applied to a new dataset comprising both T1w and T2-weighted (T2w) images from a United Imaging scanner to investigate if PVS volumes could discriminate between subjects with differing visual scores. We also compared the mcPVS-Net with a previously published method that segments PVS from T1 images. ResultsIn the test dataset, mcPVS-Net achieved a mean DICE coefficient of 0.80, with an average Precision of 0.81 and Recall of 0.79, indicating good specificity and sensitivity. The segmented PVS volumes were significantly associated with visual scores in both the basal ganglia (r = 0.541, p < 0.001) and white matter regions (r = 0.706, p < 0.001), and PVS volumes were significantly different among subjects with varying visual scores. Segmentation performance was consistent across different scanner vendors. PVS volumes exhibited significant associations with age, hypertension, and WMH. In the United Imaging scanner dataset, PVS volumes showed good associations with PVS visual scores evaluated on either T1w or T2w images. Compared to a previously published method, mcPVS-Net showed a higher accuracy and improved PVS segmentation in the basal ganglia region. ConclusionThe mcPVS-Net demonstrated good accuracy for segmenting PVS from 3D T1w images. It may serve as a useful tool for future PVS research.

Impact of excessive abdominal obesity on brain microstructural abnormality in schizophrenia

Significant evidence links obesity and schizophrenia (SZ), but the brain associations are still largely unclear. 48 people with SZ were divided into two subgroups: patients with lower waist circumference (SZ-LWC: n = 24) and patients with higher waist circumference (SZ-HWC: n = 24). Healthy controls (HC) were included for comparison (HC: n = 27). Using tract-based spatial statistics, we compared fractional anisotropy (FA) of the whole-brain white matter skeleton between these three groups (SZ-LWC, SZ-HWC, HC). Using Free Surfer, we compared whole-brain cortical thickness and the selected subcortical volumes between the three groups. FA of widespread white matter and the mean cortical thickness in the right temporal lobe and insular cortex were significantly lower in the SZ-HWC group than in the HC group. The FA of regional white matter was significantly lower in the SZ-LWC group than in the HC group. There were no significant differences in mean subcortical volumes between the groups. Additionally, the cognitive performances were worse in the SZ-HWC group, who had more severe triglycerides elevation. This study provides evidence for microstructural abnormalities of white matter, cortical thickness and neurocognitive deficits in SZ patients with excessive abdominal obesity.