Increased Mean Diffusivity Research Articles

Causal relationships between cortical brain structural alterations and migraine subtypes: a bidirectional Mendelian randomization study of 2,347 neuroimaging phenotypes

BackgroundPrevious studies have shown that migraines are associated with brain structural changes. However, the causal relationships between these changes and migraine, as well as its subtypes, migraine with aura (MA) and migraine without aura (MO), remain largely unclear.MethodsWe utilized genome-wide association study (GWAS) summary statistics from European cohorts for 2,347 cortical structural magnetic resonance imaging (MRI) phenotypes, derived from both T1-weighted and diffusion tensor imaging scans (n = 36,663), with migraine and its subtypes (n = 147,970–375,752). Cortical phenotypes included both macrostructural (e.g., cortical thickness, surface area) and microstructural (e.g., fractional anisotropy, mean diffusivity) features. Genetic correlations were first assessed to identify significant associations, followed by bidirectional Mendelian randomization (MR) analyses to determine causal relationships between these brain phenotypes and migraine, as well as its subtypes (MA and MO). Sensitivity analyses were applied to ensure the robustness of the results.ResultsGenetic correlation analysis identified 510 significant associations between cortical structural phenotypes and migraine across 401 distinct traits. Forward MR analysis revealed nine significant causal effects of cortical structural changes on migraine risk. Specifically, increased cortical thickness and local gyrification index in specific cortical regions were associated with a decreased risk of overall migraine, MA, and MO, while intracellular volume fraction and orientation diffusion index in specific regions increased the risk of MA and MO. Reverse MR analysis demonstrated that MA causally increased mean diffusivity in the insular and frontal opercular cortex. Sensitivity analyses confirmed the robustness of these findings, with no evidence of horizontal pleiotropy or heterogeneity.ConclusionThis study identifies causal relationships between cortical neuroimaging phenotypes and migraine, highlighting potential biomarkers for migraine diagnosis, treatment, and prevention.

Prediction of epileptogenicity in patients with tuberous sclerosis complex using multimodal cerebral MRI

ObjectiveEpilepsy is the most common complication and cause of morbidity and mortality in tuberous sclerosis complex (TSC). Surgery is associated with an increased probability of achieving seizure-freedom. However, the preoperative noninvasive localisation of epileptogenic tubers remains challenging. This study aimed to identify multimodal magnetic resonance imaging (MRI) biomarkers of epilepsy in patients with TSC and develop a prediction model of epileptogenicity in these patients. MethodsPatients with TSC, with or without epilepsy, were recruited. All patients underwent MRI scanning, including T1WI, T2WI, T2W-FLAIR, DTI, and multi-parametric MR with a flexible design (MULTIPLEX). We compared the multimodal cerebral MRI characteristics of the cortical tubers, subependymal nodules, and perilesional tissue between patients with TSC with or without epilepsy and developed a prediction model for epileptogenicity. ResultsAmong the patients with TSC, 32 with and 16 without epilepsy underwent MRI. Higher proton-density mapping (PD) of cortical tubers and decreased fractional anisotropy (FA), increased mean diffusivity (MD), and increased radial diffusivity (RD) of subependymal nodules were associated with epileptogenicity in both the centre and perilesional tissue, independent of TSC gene variation. Based on the above findings, we developed a prediction model for epileptogenicity with an area under the curve of 0.973, specificity of 0.909, and sensitivity of 0.963 (P < 0.001). ConclusionIn patients with TSC, high PD of the cortical tubers, decreased FA, and elevated MD/RD of the subependymal nodules were significantly associated with epileptogenicity. A prediction model based on multimodal cerebral MRI characteristics has the potential to evaluate the likelihood of epilepsy in patients with TSC.

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.

Effect of worry, depressed affect, and sensitivity to environmental stress owing to neurotic personality on MRI markers of cerebral small vessel disease: A univariable and multivariable Mendelian randomization study

ObjectiveNeuroticism was found to be associated with cerebral small vessel disease (CSVD) in observational studies. We aimed to explore the causal relationship between distinct components of neuroticism and CSVD. MethodsTwo-sample mendelian randomization (MR) study was conducted to explore the bidirectional causal relationships between three genetically distinct subclusters of neuroticism (depressed affect, worry, and sensitivity to environmental stress and adversity [SESA]) and MRI markers of CSVD using publicly available genome-wide association studies (GWAS) data. Inverse variance weighted (IVW) method was used for the primary causal estimates. Alternative MR approaches and extensive sensitivity analyses were conducted to ensure the robustness of the findings. Multivariable MR (MVMR) analysis was used to estimate the direct causal effects with adjustment of other known risk factors for CSVD. ResultsGenetically determined SESA was significantly associated with reduced fractional anisotropy (FA) (beta: -1.94, 95%CI: -3.04 to -0.84, p=5.29e-4), and associated with increased mean diffusivity (MD) (beta=1.55, 95%CI: 0.29 to 2.81, p=0.016) and white matter hyperintensities (WMH) (beta=0.25, 95% CI: 0.03 to 0.47, p=0.029) at the nominally significant level. MVMR analysis suggested the significant associations remained significant after accounting for body mass index (BMI), smoking, alcohol drinking, type 2 diabetes (T2D), hypertension, and depression. The other two neuroticism subclusters (depressed affect and worry) didn't have significant causal effects on the MRI markers. In the reverse MR analysis with the MRI markers as exposures, no significant associations were found. ConclusionThis study supported the casual role of SESA in the development of CSVD. Further research to explore the underlying mechanism are warranted.

Increased mean diffusivity of the caudal motor SNc identifies patients with REM sleep behaviour disorder and Parkinson’s disease

Idiopathic rapid eye movement sleep behaviour disorder (iRBD)—a Parkinson’s disease (PD) prodrome—might exhibit neural changes similar to those in PD. Substantia nigra pars compacta (SNc) degeneration underlies motor symptoms of PD. In iRBD and early PD (ePD), we measured diffusion MRI (dMRI) in the caudal motor SNc, which overlaps the nigrosome-1—the earliest-degenerating dopaminergic neurons in PD—and in the striatum. Nineteen iRBD, 26 ePD (1.7 ± 0.03 years), and 46 age-matched healthy controls (HCs) were scanned at Western University, and 47 iRBD, 115 ePD (0.9 ± 0.01 years), and 56 HCs were scanned through the Parkinson’s Progression Markers Initiative, using 3T MRI. We segmented the SNc and striatum into subregions using automated probabilistic tractography to the cortex. We measured mean diffusivity (MD) and fractional anisotropy (FA) along white-matter bundles and subregional surfaces. We performed group-level and classification analyses. Increased caudal motor SNc surface MD was the only iRBD-HCs and ePD-HCs difference replicating across datasets (padj < 0.05). No iRBD-ePD differences emerged. Caudal motor SNc surface MD classified patient groups from HCs at the single-subject level with good-to-excellent balanced accuracy in an independent sample (0.91 iRBD and 0.86 iRBD and ePD combined), compared to fair performance for total SNc surface MD (0.72 iRBD and ePD). Caudal motor SNc surface MD correlated significantly with MDS-UPDRS-III scores in ePD patients. Using dMRI and automated segmentation, we detected changes suggesting altered microstructural integrity in iRBD and ePD in the nigrostriatal subregion known to degenerate first in PD. Surface MD of the caudal motor SNc presents a potential measure for inclusion in neuroimaging biomarkers of iRBD and PD.

Insulin resistance and white matter microstructural abnormalities in nondiabetic adult: A population-based study.

Insulin resistance (IR) is of growing concern yet its association with white matter integrity remains controversial. We aimed to investigate the association between IR and white matter integrity in nondiabetic adults. This cross-sectional analysis was conducted based on the PolyvasculaR Evaluation for Cognitive Impairment and vaScular Events (PRECISE) study. A total of 1709 nondiabetic community-dwelling adults with available diffusion-weighted imaging based on brain magnetic resonance imaging and completed oral glucose tolerance test were included. IR was measured noninvasively by insulin sensitivity indices (ISI), including ISIcomposite and ISI0,120, as well as homeostasis model assessment of insulin resistance (HOMA-IR). White matter microstructure abnormalities were identified by diffusion-weighted imaging along with tract-based spatial statistical analysis to compare diffusion metrics between groups. The multivariable linear regression models were applied to measure the association between white matter microstructure abnormalities and IR. A total of 1709 nondiabetic individuals with a mean age of 60.8 ± 6.4 years and 54.1% female were included. We found that IR was associated with a significant increase in mean diffusivity, axial diffusivity, and radial diffusivity extensively in cerebral white matter in regions such as the anterior corona radiata, superior corona radiata, anterior limb of internal capsule, external capsule, and body of corpus callosum. The pattern of associations was more marked for ISIcomposite and ISI0,120. However, the effect of IR on white matter integrity was attenuated after, in addition, adjustment for history of hypertension and cardiovascular disease and antihypertensive medication use. Our findings indicate a significant association between IR and white matter microstructural abnormalities in nondiabetic middle-aged community residents, while these associations were greatly influenced by the history of hypertension and cardiovascular disease, and antihypertensive medication use. Further investigation is needed to clarify the role of IR in white matter integrity, whereas prophylactic strategies of maintaining a low IR status may ameliorate disturbances in white matter integrity. The data that support the findings of this study are available from the corresponding authors upon reasonable request.

Presence of Auditory Pathway Abnormalities in Children With Neurofibromatosis Type 1 With Brainstem Focal Areas of Abnormal Signal Intensity: Diffusion Tensor Imaging Features.

Background: To investigate whether there is a difference in mean diffusivity (MD) and fractional anisotropy (FA) values in the auditory pathways of neurofibromatosis type 1 patients with and without focal areas of abnormal signal intensity (FASI) compared to healthy controls by using diffusion tensor imaging (DTI). Methods: Patients were classified as group 1 with focal areas of abnormal signal intensity in the brainstem, group 2 without focal areas of abnormal signal intensity, and healthy control group 3 according to the MRI findings. Mean diffusivity and fractional anisotropy values of lateral lemniscus, inferior colliculus, corpus geniculatum mediale, Heschl gyrus, and brainstem were compared between groups. The correlation between mean diffusivity and fractional anisotropy values of auditory pathways and age was investigated. Results: There was a significant difference between group 1 and group 2 in terms of mean diffusivity and fractional anisotropy values at lateral lemniscus, inferior colliculus, corpus geniculatum mediale, and Heschl gyrus. Increased mean diffusivity and decreased fractional anisotropy values at brainstem were found in group 1. There was a significant difference between group 1 and group 3 in terms of mean diffusivity values at all auditory pathways. Fractional anisotropy values obtained from lateral lemniscus, inferior colliculus, and Heschl gyrus decreased in group 1 compared with group 3. There was a negative correlation between mean diffusivity values and positive correlation between fractional anisotropy values at lateral lemniscus, inferior colliculus, Heschl gyrus, and age. Conclusions: Our diffusion tensor imaging findings show that the neuronal integrity of the auditory pathways is affected in neurofibromatosis type 1 patients with brainstem focal areas of abnormal signal intensity. We think that the disappearance of brainstem focal areas of abnormal signal intensity associated with myelin repair and the regression of diffusion tensor imaging changes in the auditory pathways occur simultaneously with advancing age in patients with neurofibromatosis type 1.

Bidirectional two-sample Mendelian randomization analyses support causal relationships between structural and diffusion imaging-derived phenotypes and the risk of major neurodegenerative diseases

Previous observational investigations suggest that structural and diffusion imaging-derived phenotypes (IDPs) are associated with major neurodegenerative diseases; however, whether these associations are causal remains largely uncertain. Herein we conducted bidirectional two-sample Mendelian randomization analyses to infer the causal relationships between structural and diffusion IDPs and major neurodegenerative diseases using common genetic variants-single nucleotide polymorphism (SNPs) as instrumental variables. Summary statistics of genome-wide association study (GWAS) for structural and diffusion IDPs were obtained from 33,224 individuals in the UK Biobank cohort. Summary statistics of GWAS for seven major neurodegenerative diseases were obtained from the largest GWAS for each disease to date. The forward MR analyses identified significant or suggestively statistical causal effects of genetically predicted three structural IDPs on Alzheimer’s disease (AD), frontotemporal dementia (FTD), and multiple sclerosis. For example, the reduction in the surface area of the left superior temporal gyrus was associated with a higher risk of AD. The reverse MR analyses identified significantly or suggestively statistical causal effects of genetically predicted AD, Lewy body dementia (LBD), and FTD on nine structural and diffusion IDPs. For example, LBD was associated with increased mean diffusivity in the right superior longitudinal fasciculus and AD was associated with decreased gray matter volume in the right ventral striatum. Our findings might contribute to shedding light on the prediction and therapeutic intervention for the major neurodegenerative diseases at the neuroimaging level.

Dynamic Mechanism of Cerebral Venous Disruption: Longitudinal Evidence From a Community-Based Cohort.

This study aims to investigate the temporal and spatial patterns of structural brain injury related to deep medullary veins (DMVs) damage. This is a longitudinal analysis of the population-based Shunyi cohort study. Baseline DMVs numbers were identified on susceptibility-weighted imaging. We assessed vertex-wise cortex maps and diffusion maps at both baseline and follow-up using FSL software and the longitudinal FreeSurfer analysis suite. We performed statistical analysis of global measurements and voxel/vertex-wise analysis to explore the relationship between DMVs number and brain structural measurements. A total of 977 participants were included in the baseline, of whom 544 completed the follow-up magnetic resonance imaging (age 54.97±7.83 years, 32% men, mean interval 5.56±0.47 years). A lower number of DMVs was associated with a faster disruption of white matter microstructural integrity, presented by increased mean diffusivity and radial diffusion (β=0.0001 and SE=0.0001 for both, P=0.04 and 0.03, respectively), in extensive deep white matter (threshold-free cluster enhancement P<0.05, adjusted for age and sex). Of particular interest, we found a bidirectional trend association between DMVs number and change in brain volumes. Specifically, participants with mild DMVs disruption showed greater cortical enlargement, whereas those with severe disruption exhibited more significant brain atrophy, primarily involving clusters in the frontal and parietal lobes (multiple comparison corrected P<0.05, adjusted for age, sex, and total intracranial volume). Our findings posed the dynamic pattern of brain parenchymal lesions related to DMVs injury, shedding light on the interactions and chronological roles of various pathological mechanisms.

Structural Changes in Brain White Matter Tracts Associated With Overactive Bladder Revealed by Diffusion Tensor Magnetic Resonance Imaging: Findings From a Symptoms of Lower Urinary Tract Dysfunction Research Network Cross-Sectional Case-Control Study.

Our objective was to investigate structural changes in brain white matter tracts using diffusion tensor imaging (DTI) in patients with overactive bladder (OAB). Treatment-seeking OAB patients and matched controls enrolled in the cross-sectional case-control LURN (Symptoms of Lower Urinary Tract Dysfunction Research Network) Neuroimaging Study received a brain DTI scan. Microstructural integrity of brain white matter was assessed using fractional anisotropy (FA) and mean diffusivity. OAB and urgency urinary incontinence (UUI) symptoms were assessed using the OAB Questionnaire Short-Form and International Consultation on Incontinence Questionnaire-Urinary Incontinence. The Lower Urinary Tract Symptoms Tool UUI questions and responses were correlated with FA values. Among 221 participants with evaluable DTI data, 146 had OAB (66 urinary urgency-only without UUI, 80 with UUI); 75 were controls. Compared with controls, participants with OAB showed decreased FA and increased mean diffusivity, representing greater microstructural abnormalities of brain white matter tracts among OAB participants. These abnormalities occurred in the corpus callosum, bilateral anterior thalamic radiation and superior longitudinal fasciculus tracts, and bilateral insula and parahippocampal region. Among participants with OAB, higher OAB Questionnaire Short-Form scores were associated with decreased FA in the left inferior fronto-occipital fasciculus, P < .0001. DTI differences between OAB and controls were driven by the urinary urgency-only (OAB-dry) but not the UUI (OAB-wet) subgroup. Abnormalities in microstructural integrity in specific brain white matter tracts were more frequent in OAB patients. More severe OAB symptoms were correlated with greater degree of microstructural abnormalities in brain white matter tracts in patients with OAB. ClinicalTrials.gov: NCT02485808.

Greater methylation of the IL-6 promoter region is associated with decreased integrity of the corpus callosum in schizophrenia

BackgroundSchizophrenia is associated with chronic subclinical inflammation and decreased integrity of the corpus callosum (CC). Our previous study showed associations between peripheral IL-6 levels and the integrity of the CC. Epigenetic studies show associations between methylation of the genes related to immunological processes and integrity of the CC. AimTo investigate correlations between methylation status of IL-6 promotor and peripheral IL-6 levels and the integrity of the CC in schizophrenia. Material and methodsThe participants were 29 chronic schizophrenia patients (SCH) and 29 controls. Decreased integrity of the CC was understood as increased mean diffusivity (MD) and/or decreased fractional anisotropy (FA) in diffusion tensor imaging. Peripheral IL-6 concentrations were measured in serum samples and IL-6 promoter methylation status of 6 CpG sites was analyzed in peripheral leukocytes by pyrosequencing. ResultsModerate positive correlations were found between CpG1 methylation and the MD of proximal regions of the CC (CCR1–CCR3) and between CpGmean and MD of CCR1 in SCH. Weaker positive correlations were found for CpGmean with CCR2 and CCR3 and negative correlations were found for CpG1 and FA of CCR3 in SCH. Multivariate regression showed that methylation of CpG1, type of antipsychotic treatment, and their interaction were significant independent predictors of MD of CCR1 in SCH. Methylation of CpG2 was negatively correlated with serum IL-6 in SCH. ConclusionsThe methylation level of the IL-6 promotor region in peripheral leukocytes is associated with the integrity of the CC in schizophrenia and this association may depend on the type of antipsychotic treatment. Further studies are necessary to explain the mechanisms of the observed associations.

Influences of amyloid-β and tau on white matter neurite alterations in dementia with Lewy bodies

Dementia with Lewy bodies (DLB) is a neurodegenerative condition often co-occurring with Alzheimer’s disease (AD) pathology. Characterizing white matter tissue microstructure using Neurite Orientation Dispersion and Density Imaging (NODDI) may help elucidate the biological underpinnings of white matter injury in individuals with DLB. In this study, diffusion tensor imaging (DTI) and NODDI metrics were compared in 45 patients within the dementia with Lewy bodies spectrum (mild cognitive impairment with Lewy bodies (n = 13) and probable dementia with Lewy bodies (n = 32)) against 45 matched controls using conditional logistic models. We evaluated the associations of tau and amyloid-β with DTI and NODDI parameters and examined the correlations of AD-related white matter injury with Clinical Dementia Rating (CDR). Structural equation models (SEM) explored relationships among age, APOE ε4, amyloid-β, tau, and white matter injury. The DLB spectrum group exhibited widespread white matter abnormalities, including reduced fractional anisotropy, increased mean diffusivity, and decreased neurite density index. Tau was significantly associated with limbic and temporal white matter injury, which was, in turn, associated with worse CDR. SEM revealed that amyloid-β exerted indirect effects on white matter injury through tau. We observed widespread disruptions in white matter tracts in DLB that were not attributed to AD pathologies, likely due to α-synuclein-related injury. However, a fraction of the white matter injury could be attributed to AD pathology. Our findings underscore the impact of AD pathology on white matter integrity in DLB and highlight the utility of NODDI in elucidating the biological basis of white matter injury in DLB.

Subclinical Metabolic and Cardiovascular Factors and Brain White Matter Microstructural Integrity in Young Women.

Women who have experienced pregnancy complications, specifically preeclampsia and gestational diabetes, have well documented increased risks of cardiovascular, metabolic, and neurological disease later in life. This study examined how specific cardiovascular and metabolic risk factors for preeclampsia assessed in a non-pregnant state were associated with brain white matter microstructural integrity. This study examined sixty-two healthy women (mean age 31 ± 5years) who received metabolic and cardiovascular assessments as well as multiple modality MRI imaging. Participants were either nulliparous (n = 31) or had a history of preterm preeclampsia (n = 31). Imaging included acquisition Diffusion Tensor Imaging (DTI) to assess white matter integrity within the brain. We hypothesized that healthy, young, non-pregnant women with cardiovascular and metabolic profiles suggesting elevated risk would have decreased white matter integrity, represented by lower Fractional Anisotropy (FA) and increased Mean Diffusivity (MD) estimates in the posterior cortical areas of the brain. We observed increased white matter degradation (lower FA and increased MD) in posterior and occipital tracts, commissural fibers, and subcortical structures in women with increased adiposity, worse measures of cardiovascular and metabolic function, including greater insulin resistance (HOMA-IR), hyperlipidemia, elevated blood pressure, and increased arterial stiffness. The relationships detected between subclinical cardiovascular and metabolic phenotypes and increased white matter disruption at a young age, outside of pregnancy, are indicative that adverse changes are detectable long before cognitive clinical presentation. This may suggest that many of the long-term cardiovascular and metabolic risks of aging are influenced by physiologic aging trajectories rather than damage caused by pregnancy complications.

Effect of cerebral small vessel disease on the integrity of cholinergic system in mild cognitive impairment patients: a longitudinal study

We aimed to investigate the effect of cerebral small vessel disease (SVD) on cholinergic system integrity in mild cognitive impairment (MCI) patients. Nucleus basalis of Meynert (NBM) volume and cholinergic pathways integrity was evaluated at baseline, 1-, 2-, and 4-year follow-ups in 40 cognitively unimpaired (CU) participants, 29 MCI patients without SVD, and 23 MCI patients with SVD. We compared cholinergic markers among three groups and examined their associations with SVD burden in MCI patients. We used linear mixed models to assess longitudinal changes in cholinergic markers over time among groups. Mediation analysis was employed to investigate the mediating role of cholinergic system degeneration between SVD and cognitive impairment. Increased mean diffusivity (MD) in medial and lateral pathways was observed in MCI patients with SVD compared to those without SVD and CU participants. Both MCI groups showed decreased NBM volume compared to CU participants, while there was no significant difference between the two MCI groups. Longitudinally, compared to CU participants, MCI patients with SVD displayed a more rapid change in MD in both pathways, but not in NBM volume. Furthermore, SVD burden was associated with cholinergic pathway disruption and its faster rate of change in MCI patients. However, mediation analyses showed that cholinergic pathways did not mediate significant indirect effects of SVD burden on cognitive impairment. Our findings suggest that SVD could accelerate the degeneration of cholinergic pathways in MCI patients. However, they do not provide evidence to support that SVD could contribute to cognitive impairment through cholinergic system injury.

White matter microstructural alterations in patients with anti-N-methyl-D-aspartate receptor encephalitis: A tract-based spatial statistics study

BackgroundCognitive impairment is common in patients with anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis; however, neural mechanisms underlying this impairment remain unclear. Diffusion tensor imaging (DTI) is a potential method for studying the condition of white matter fibers in patients with anti-NMDAR encephalitis, allowing for an analysis of the neuroimaging mechanisms of cognitive impairment in conjunction with cognitive scales. This study aimed to explore white matter microstructural alterations and their correlation with cognitive function in patients with anti-NMDAR encephalitis. MethodsDTI data were collected from 22 patients with anti-NMDAR encephalitis (aged 29.00(19.75, 39.50) years; 12 males, 10 females) and 20 healthy controls (HCs) (aged 24.50(21.25, 32.00); 12 males, 8 females) matched for age, sex, and educational level. Changes in the white matter microstructure were analyzed using tract-based spatial statistics. Pearson correlation analysis was used to explore the correlation between white matter integrity and neuropsychological scores. ResultsCompared with HCs, patients with anti-NMDAR encephalitis showed decreased fractional anisotropy and increased mean diffusivity values in extensive white matter regions, which were associated with disease severity, memory, and executive and visuospatial functions. ConclusionWidespread impairment of the structural integrity of the white matter in the brain is significantly associated with cognitive dysfunction in patients with anti-NMDAR encephalitis, providing neuroimaging evidence for studying the underlying mechanisms.

Bilateral brain microstructural alterations in patients with left-sided classic trigeminal neuralgia: a diffusion kurtosis imaging study.

White matter microstructural abnormalities in patients with classic trigeminal neuralgia (TN) have been observed. However, the impact of classic TN in both hemispheres, the difference and extent of alterations in bilateral hemispheres, and the relationship between the impaired area and pain conduction are not fully understood. The purpose of this study was to investigate brain microstructural alterations and compare the bilateral hemispheres in patients with unilateral classic TN, as well as to explore their clinical implications. The authors performed a cross-sectional study of 36 patients with left classic TN (TN group; age 40-66 years) and 36 healthy controls (HC group; age 40-66 years). Diffusion kurtosis imaging (DKI; b-values = 0, 1250, and 2500 sec/mm2) was performed in all patients using a 3T MRI scanner. The FMRIB Software Library with tract-based spatial statistics was used to analyze intergroup differences in both hemispheres. Atlas-based region of interest analysis was conducted in fiber tracts and gray matter structures. Decreased fractional anisotropy (FA) and increased mean diffusivity in 2.70% and 5.34% of white matter regions, such as the corona radiata, corpus callosum, internal capsule, superior longitudinal fasciculus, and cingulum, were detected in the TN group compared with the HC group (p < 0.05, family-wise error correction). Reduced mean kurtosis (MK), axial kurtosis, and radial kurtosis were detected in the bilateral thalamus in TN patients. The FA and MK values decreased asymmetrically in both cerebral hemispheres. Atlas-based region of interest analysis revealed more pronounced FA and MK reductions in the left thalamus and posterior corona radiata. There were negative associations of disease duration and pain intensity with the MK values in the thalamus, internal capsule, and superior corona radiata. The authors concluded that unilateral TN could have asymmetrical microstructural alterations in bilateral hemispheres, which might be due to the compromised fiber tract integrity and abnormal neurons and synapses. The thalamus could be an important relay station in the pain conduction and modulation pathway and could have microstructural abnormalities in both the left and right sides. DKI could provide important information on the CNS pathophysiology of TN and assist in prognostic evaluation.

Abstract TMP7: Disruption of Blood Brain Barrier is Associated With Silent Cerebral Infarcts in Patients With Sickle Cell Disease

Background: Microvascular thromboinflammation is a major pathomechanism underlying vaso-occlusive crisis in patients with sickle cell disease (SCD), yet its role underlying the elevated stroke risk in SCD is unclear. Tissue-based blood brain barrier (BBB) imaging, as a metric of cerebral thromboinflammation, has not been well studied in SCD. We hypothesized that BBB permeability would be increased in patients with SCD and associated with ischemic burden. Methods: Ten young adults with SCD and 17 controls underwent dynamic contrast-enhanced and multimodal MRI to quantify BBB gadolinium leakage rates (Ktrans), white matter microstructural disruption (increased mean diffusivity, MD), and volume of silent cerebral infarcts (SCI). Infarct voxels were removed to avoid the confounding effects of measuring Ktrans in previously infarcted tissue. Whole brain mean Ktrans measures were compared between SCD vs. controls. Bivariate Spearman’s rank correlations measured relationships between Ktrans and SCI volume / MD. Results: BBB permeability, measured by whole brain Ktrans, was elevated in SCD vs. controls (Fig A). Compared to controls, Ktrans was elevated in SCD with infarcts (B), while SCD without infarcts did not differ from controls. In participants with infarcts, Ktrans, measured within non-infarcted tissue, positively correlated with SCI volume (Rho=0.6, p =0.015, C). Furthermore, whole brain Ktrans, positively correlated with MD in normal appearing white matter (Rho=0.5, p =0.01). Conclusion: Our preliminary data suggest BBB permeability is elevated and associated with stroke and microstructural injury in young adults with SCD. We are enrolling more participants. Children with SCD may also have BBB injury but will require a novel non-contrasted MR approach to assess. BBB permeability may provide new insight into the increased stroke risk in SCD. Targeting thromboinflammation and preserving BBB integrity may lead to novel neuroprotective pathways.

Plasma Apo-E mediated corticospinal tract abnormalities and suicidality in patients with major depressive disorder.

This study aims to explore the link between Apo-E, brain white matter, and suicide in patients with major depressive disorder (MDD) to investigate the potential neuroimmune mechanisms of Apo-E that may lead to suicide. Thirty-nine patients with MDD (22 patients with suicidality) and 57 age, gender, and education-matched healthy controls participated in this study, provided plasma Apo-E samples, and underwent diffusion tensor imaging scans. Plasma Apo-E levels and white matter microstructure were analyzed among the MDD with suicidality, MDD without suicidality, and HC groups using analysis of variance with post hoc Bonferroni correction and tract-based spatial statistics (TBSS) with threshold-free cluster enhancement correction. Mediation analysis investigated the relationship between Apo-E, brain white matter, and suicidality in MDD. The MDD with suicidality subgroup had higher depressive and suicide scores, longer disease course, and lower plasma Apo-E levels than MDD without suicidality. TBSS revealed that the MDD non-suicide subgroup showed significantly increased mean diffusivity in the left corticospinal tract and body of the left corpus callosum, as well as increased axial diffusivity in the left anterior corona radiata and the right posterior thalamic radiation compared to the suicidal MDD group. The main finding was that the increased MD of the left corticospinal tract contributed to the elevated suicide score, with Apo-E mediating the effect. Preliminary result that Apo-E's mediating role between the left corticospinal tract and the suicide factor suggests the neuroimmune mechanism of suicide in MDD. The study was registered on ClinicalTrials.gov (NCT03790085).

Sex differences in functional and structural alterations of hippocampus region in chronic pain: a DTI and resting-state fMRI study.

It is well known that there are significant differences in the prevalence of chronic pain between males and females. Human and animal imaging studies have shown that chronic pain profoundly alters the structure and function of brain regions. However, there is limited research on the sex-specific mechanisms underlying the brain plasticity and adaptive changes associated with chronic pain. In this article, we conducted a multimodal study to evaluate how nerve injury-induced chronic pain affects the brain. Male and female Sprague-Dawley (SD) rats with spared nerve injury (SNI) model underwent resting-state functional magnetic resonance imaging (rs-fMRI) (male sham group: n = 18; male SNI group: n = 18; female sham group: n = 20; female SNI group: n = 18) and magnetic resonance diffusion tensor imaging (DTI) (male sham group: n = 23; male SNI group: n = 21; female sham group: n = 20; female SNI group: n = 21) scanning. ICA method, Fractional amplitude of low-frequency fluctuations (fALFF), immunofluorescence staining, and graph theory analysis was utilized to extract the rs-fMRI changes of brain regions of each group. Using SNI model, which promotes long-lasting mechanical allodynia, we found that neuropathic pain deeply modified the intrinsic organization of the brain functional network in male and female rats (main effect of operation: F = 298.449, P < 0.001). 64 independent components (ICs) in the brain were divided and assigned to 16 systems. In male rats, we observed significant alterations in the microstructure of the hippocampal cornu ammonis 1 and cornu ammonis 2 (CA1/CA2) region, as indicated by increased mean diffusivity (MD) (CA1_L: P = 0.02; CA1_R: P = 0.031; CA2_L: P = 0.035; CA2_R: P = 0.015) and radial diffusivity (RD) (CA1_L: P = 0.028; CA1_R: P = 0.033; CA2_L: P = 0.037; CA2_R: P = 0.038) values, along with enhanced activating transcription factor 3 (ATF3) expression. Conversely, in female rats, we found significant increases in the fractional amplitude of low frequency fluctuations (fALFF) value within the hippocampal dentate gyrus (DG) (F = 5.419, P = 0.023), accompanied by elevated c-Fos signal (F = 6.269, P = 0.031). Furthermore, graph theory analysis revealed notable differences in the small-world network of the hippocampal system in female rats, characterized by reduced small-world attributes and increased inter-nodal transmission efficiency. Our study indicates sex differences in structural and functional alterations in the hippocampal system in rats under chronic pain conditions. The results suggest that the hippocampus system plays an important role in the different mechanisms of chronic pain in different sexes. These findings provide reliable insights to explore the complex mechanisms underlying sex differences in chronic pain.

Diffusion MRI tracks cortical microstructural changes during the early stages of Alzheimer's disease.

There is increased interest in developing markers reflecting microstructural changes that could serve as outcome measures in clinical trials. This is especially important after unexpected results in trials evaluating disease-modifying therapies targeting amyloid-β (Aβ), where morphological metrics from MRI showed increased volume loss despite promising clinical treatment effects. In this study, changes over time in cortical mean diffusivity, derived using diffusion tensor imaging, were investigated in a large cohort (n = 424) of non-demented participants from the Swedish BioFINDER study. Participants were stratified following the Aβ/tau (AT) framework. The results revealed a widespread increase in mean diffusivity over time, including both temporal and parietal cortical regions, in Aβ-positive but still tau-negative individuals. These increases were steeper in Aβ-positive and tau-positive individuals and robust to the inclusion of cortical thickness in the model. A steeper increase in mean diffusivity was also associated with both changes over time in fluid markers reflecting astrocytic activity (i.e. plasma level of glial fibrillary acidic protein and CSF levels of YKL-40) and worsening of cognitive performance (all P < 0.01). By tracking cortical microstructural changes over time and possibly reflecting variations related to the astrocytic response, cortical mean diffusivity emerges as a promising marker for tracking treatments-induced microstructural changes in clinical trials.