Cerebral White Matter Lesions Research Articles

White matter biomarker for predicting de novo Parkinson's disease using tract-based spatial statistics: a machine learning-based model.

Parkinson's disease (PD) is an irreversible, chronic degenerative disease of the central nervous system, potentially associated with cerebral white matter (WM) lesions. Investigating the microstructural alterations within the WM in the early stages of PD can help to identify the disease early and enable intervention to reduce the associated serious threats to health. This study selected 227 cases from the Parkinson's Progression Markers Initiative (PPMI) database, including 152 de novo PD patients and 75 normal controls (NC). Whole-brain voxel analysis of the WM was performed using the tract-based spatial statistics (TBSS) method. The WM regions with statistically significant differences (P<0.05) between the PD and NC groups were identified and used as masks. The mask was applied to each case's fractional anisotropy (FA) image to extract voxel values as feature vectors. Geometric dimensionality reduction was then applied to eliminate redundant values in the feature vectors. Subsequently, the cases were randomly divided into a training group (158 cases, including 103 PD patients and 55 NC) and a test group (69 cases, including 49 PD patients and 20 NC). The least absolute shrinkage and selection operator (LASSO) regression algorithm was employed to extract the minimal set of relevant features, then the random forest (RF) algorithm was utilized for classification using 5-fold cross validation. The resulting model was further integrated with clinical factors to create a comprehensive prediction model. In comparison to the NC group, the FA values in PD patients exhibited a statistically significant decrease (P<0.05), indicating the presence of widespread WM lesions across multiple brain regions. Moreover, the PD prediction model, constructed based on these WM lesion regions, yielded prediction accuracy (ACC) and area under the receiver operating characteristic (ROC) curve (AUC) values of 0.778 and 0.865 in the validation set, and 0.783 and 0.831 in the test set, respectively. Furthermore, the performance of the integrated model showed some improvement, with ACC and AUC values in the test set reaching 0.804 and 0.844, respectively. The quantitative calculation of WM lesion area on FA images using the TBSS method can serve as a neuroimaging biomarker for diagnosing and predicting early PD at the individual level. When integrated with clinical variables, the predictive performance improves.

Transcript Profiles of Microglia/Macrophage Cells at the Borders of Chronic Active and Subpial Gray Matter Lesions in Multiple Sclerosis.

Microglia/macrophages line the border of demyelinated lesions in both cerebral white matter and the cortex in the brains of multiple sclerosis patients. Microglia/macrophages associated with chronic white matter lesions are thought to be responsible for slow lesion expansion and disability progression in progressive multiple sclerosis, whereas those lining gray matter lesions are less studied. Profiling these microglia/macrophages could help to focus therapies on genes or pathways specific to lesion expansion and disease progression. We compared the morphology and transcript profiles of microglia/macrophages associated with borders of white matter (WM line) and subpial gray matter lesions (GM line) using laser capture microscopy. We performed RNA sequencing on isolated cells followed by immunocytochemistry to determine the distribution of translational products of transcripts increased in WM line microglia. Cells in the WM line appear activated, with shorter processes and larger cell bodies, whereas those in the GM line appear more homeostatic, with smaller cell bodies and multiple thin processes. Transcript profiling revealed 176 genes in WM lines and 111 genes in GM lines as differentially expressed. Transcripts associated with immune activation and iron homeostasis were increased in WM line microglia, whereas genes belonging to the canonical Wnt signaling pathway were increased in GM line microglia. We propose that the mechanisms of demyelination and dynamics of lesion expansion are responsible for differential transcript expression in WM lines and GM lines, and posit that increased expression of the Fc epsilon receptor, spleen tyrosine kinase, and Bruton's tyrosine kinase, play a key role in regulating microglia/macrophage function at the border of chronic active white matter lesions. ANN NEUROL 2024;95:907-916.

Efficacy and Safety of the Natural Killer T Cell-Stimulatory Glycolipid OCH-NCNP1 for Patients With Relapsing Multiple Sclerosis: Protocol for a Randomized Placebo-Controlled Clinical Trial.

Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system that causes myelin sheath damage and axonal degeneration. The glycolipid (2S, 3S, 4R)-1-O-(α-d-galactosyl)-2-tetracosanoylamino-1,3,4-nonaetriol (OCH-NCNP1 or OCH) exerts an immunoregulatory action that suppresses T helper (Th)1 cell-mediated immune responses through natural killer T cell activation, selective interleukin-4 production, and Th2 bias induction in human CD4-positive natural killer T cells. This trial aims to investigate the efficacy and safety of the immunomodulator OCH in patients with relapsing MS through 24-week repeated administration. This protocol describes a double-blind, multicenter, placebo-controlled, randomized phase II clinical trial that was initiated in September 2019. The participants were randomly assigned to either a placebo control group or an OCH-NCNP1 group and the investigational drug (3.0 mg) was orally administered once weekly for the 24-week duration. Major inclusion criteria are as follows: patients had been diagnosed with relapsing MS (relapsing-remitting and/or secondary progressive MS) based on the revised McDonald criteria or were diagnosed with MS by an attending physician as noted in their medical records; patients with at least two medically confirmed clinical exacerbations within 24 months prior to consent or one exacerbation within 12 months prior to consent; patients with at least one lesion suspected to be MS on screening magnetic resonance imaging (MRI); and patients with 7 points or less in the Expanded Disability Status Scale during screening. Major exclusion criteria are as follows: diagnosis of neuromyelitis optica and one of optic neuritis, acute myelitis, and satisfying at least two of the following three items: (1) spinal cord MRI lesion extending across at least three vertebral bodies, (2) no brain MRI lesions during onset (at least four cerebral white matter lesions or three lesions, one of which is around the lateral ventricle), and (3) neuromyelitis optica-immunoglobulin G or antiaquaporin-4 antibody-positive. Outcome measures include the primary outcome of MRI changes (the percentage of subjects with new or newly expanded lesions at 24 weeks on T2-weighted MRI) and the secondary outcomes annual relapse rate (number of recurrences per year), relapse-free period (time to recurrence), sustained reduction in disability (SRD) occurrence rate, period until SRD (time to SRD occurrence), no evidence of disease activity, and exploratory biomarkers from phase I trials (such as gene expression, cell frequency, and intestinal and oral microbiome). We plan to enroll 30 patients in the full analysis set. Enrollment was closed in June 2021 and the study analysis was completed in March 2023. This randomized controlled trial will determine whether OCH-NCNP1 is effective and safe in patients with MS as well as provide evidence for the potential of OCH-NCNP1 as a therapeutic agent for MS. ClinicalTrials.gov NCT04211740; https://clinicaltrials.gov/study/NCT04211740. DERR1-10.2196/46709.

Anti-leucine-rich Glioma-inactivated 1 Protein-antibody Positive Encephalitis with Extensive Unilateral Cerebral Cortex and White Matter Lesions.

Encephalitis caused by antibodies targeting the leucine-rich glioma-inactivated 1 protein receptor, which belongs to the anti-voltage-gated potassium channel receptor complex, is characterized by hyponatremia, progressive cognitive impairment, seizures, and psychiatric disorders. The patient initially presented with faciobrachial dystonic seizures and subsequently developed encephalopathy. Brain magnetic resonance imaging revealed atypical unilateral hyperintense signals in the cerebral cortex and white matter. Intravenous corticosteroid pulse therapy effectively improved faciobrachial dystonic seizures and brain lesions.

Age-related decline in cerebral oxygen consumption in multiple sclerosis

Cerebral oxygen metabolism is altered in relapsing-remitting multiple sclerosis (RRMS), possibly a result of disease related cerebral atrophy with subsequent decreased oxygen demand. However, MS inflammation can also inhibit brain metabolism. Therefore, we measured cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2) using MRI phase contrast mapping and susceptibility-based oximetry in 44 patients with early RRMS and 36 healthy controls. Cerebral atrophy and white matter lesion load were assessed from high-resolution structural MRI. Expanded Disability Status Scale (EDSS) scores were collected from medical records. The CMRO2 was significantly lower in patients (−15%, p = 0.002) and decreased significantly with age in patients relative to the controls (−1.35 µmol/100 g/min/year, p = 0.036). The lower CMRO2 in RRMS was primarily driven by a higher venous oxygen saturation in the sagittal sinus (p = 0.007) and not a reduction in CBF (p = 0.69). There was no difference in cerebral atrophy between the groups, and no correlation between CMRO2 and MS lesion volume or EDSS score. Therefore, the progressive CMRO2 decline observed before the occurrence of significant cerebral atrophy and despite adequate CBF supports emerging evidence of dysfunctional cellular respiration as a potential pathogenic mechanism and therapeutic target in RRMS.

U-fiber analysis: a toolbox for automated quantification of U-fibers and white matter hyperintensities.

Whether white matter hyperintensities (WMHs) involve U-fibers is of great value in understanding the different etiologies of cerebral white matter (WM) lesions. However, clinical practice currently relies only on the naked eye to determine whether WMHs are in the vicinity of U-fibers, and there is a lack of good neuroimaging tools to quantify WMHs and U-fibers. Here, we developed a multimodal neuroimaging toolbox named U-fiber analysis (UFA) that can automatically extract WMHs and quantitatively characterize the volume and number of WMHs in different brain regions. In addition, we proposed an anatomically constrained U-fiber tracking scheme and quantitatively characterized the microstructure diffusion properties, fiber length, and number of U-fibers in different brain regions to help clinicians to quantitatively determine whether WMHs in the proximal cortex disrupt the microstructure of U-fibers. To validate the utility of the UFA toolbox, we analyzed the neuroimaging data from 246 patients with cerebral small vessel disease (cSVD) enrolled at Zhongshan Hospital between March 2018 and November 2019 in a cross-sectional study. According to the manual judgment of the clinician, the patients with cSVD were divided into a WMHs involved U-fiber group (U-fiber-involved group, 51 cases) and WMHs not involved U-fiber group (U-fiber-spared group, 163 cases). There were no significant differences between the U-fiber-spared group and the U-fiber-involved group in terms of age (P=0.143), gender (P=0.462), education (P=0.151), Mini-Mental State Examination (MMSE) scores (P=0.151), and Montreal Cognitive Assessment (MoCA) scores (P=0.411). However, patients in the U-fiber-involved group had higher Fazekas scores (P<0.001) and significantly higher whole brain WMHs (P=0.046) and deep WMH volumes (P<0.001) compared to patients in the U-fiber-spared group. Moreover, the U-fiber-involved group had higher WMH volumes in the bilateral frontal [P(left) <0.001, P(right) <0.001] and parietal lobes [P(left) <0.001, P(right) <0.001]. On the other hand, patients in the U-fiber-involved group had higher mean diffusivity (MD) and axial diffusivity (AD) in the bilateral parietal [P(left, MD) =0.048, P(right, MD) =0.045, P(left, AD) =0.015, P(right, AD) =0.015] and right frontal-parietal regions [P(MD) =0.048, P(AD) =0.027], and had significantly reduced mean fiber length and number in the right parietal [P(length) =0.013, P(number) =0.028] and right frontal-parietal regions [P(length) =0.048] compared to patients in the U-fiber-spared group. Our results suggest that WMHs in the proximal cortex may disrupt the microstructure of U-fibers. Our tool may provide new insights into the understanding of WM lesions of different etiologies in the brain.

Association between brain imaging biomarkers and continuous glucose monitoring-derived glycemic control indices in Japanese patients with type 2 diabetes mellitus

IntroductionAlthough type 2 diabetes mellitus (T2DM) is associated with alterations in brain structure, the relationship between glycemic control indices and brain imaging markers remains unclear. This study aimed to investigate...

A nomogram for predicting cerebral white matter lesions in elderly men.

This study aimed to develop a nomogram tool to predict cerebral white matter lesions (WMLs) in elderly men. Based on a retrospective cohort from January 2017 to December 2019, a multivariate logistic analysis was performed to construct a nomogram for predicting WMLs. The nomogram was further validated using a follow-up cohort between January 2020 and December 2022. The calibration curve, receiver operating characteristics (ROC) curves, and the decision curves analysis (DCA) were used to evaluate discrimination and calibration of this nomogram. A total of 436 male patients were enrolled in this study, and all 436 patients were used as the training cohort and 163 follow-up patients as the validation cohort. A multivariate logistic analysis showed that age, cystatin C, uric acid, total cholesterol, platelet, and the use of antiplatelet drugs were independently associated with WMLs. Based on these variables, a nomogram was developed. The nomogram displayed excellent predictive power with the area under the ROC curve of 0.951 [95% confidence interval (CI), 0.929-0.972] in the training cohort and 0.915 (95% CI, 0.864-0.966) in the validation cohort. The calibration of the nomogram was also good, as indicated by the Hosmer-Lemeshow test with p-value of 0.594 in the training cohort and 0.178 in the validation cohort. The DCA showed that the nomogram holds good clinical application value. We have developed and validated a novel nomogram tool for identifying elderly men at high risk of WMLs, which exhibits excellent predictive power, discrimination, and calibration.

Construction and validation of a nomogram model to predict symptomatic intracranial hemorrhage after intravenous thrombolysis in elderly population with severe white matter lesions

Background and Objective: Elderly people are at high prevalence of atherosclerotic cerebral infarction. Cerebral white matter lesions (WMLs) increase the risk of bleeding after intravenous thrombolysis (IVT) although they may also require the IVT. The aim of this study is to develop a clinical nomogram model for post-IVT symptomatic intracranial hemorrhage (sICH), with the aim to prevent sICH in elderly patients with severe WMLs when IVT is being considered. Methods: This is a large single-center retrospective analysis study of elderly patients with severe WMLs receiving IVT from January 2018 to December 2022. Univariate and multi-factor logistic regression analysis were used to construct nomogram model, and a series of validations were performed on the model. Results: More than 2,000 patients with IVT were screened for inclusion in this study after cranial magnetic resonance imaging evaluation. Out of these, 163 elderly patients had cerebral WMLs, and 25 had sICH. In univariate analysis, history of hypertension (p=0.037), hyperlipidemia (p&lt;0.001), NIHSS score before IVT (p&lt;0.001), low-density lipoprotein levels (p=0.016), cholesterol levels (p=0.020), platelet count (p=0.006), systolic blood pressure (p&lt;0.001), diastolic blood pressure (p&lt;0.001) were significantly associated with sICH. In a multifactorial analysis, the NIHSS score before IVT (OR 42.056 CI 7.308-242.012, p&lt;0.001), and diastolic blood pressure (OR 1.050 CI 1.002-1.100, p=0.040) were found to be significantly associated with sICH after IVT. The four most significant risk factors from logistic regression are subsequently fitted to create a predictive model. The accuracy was verified using calibration curves, decision curves, and clinical impact curves, and the model was considered to have strong stability. Conclusions: The NHISS score before IVT and diastolic blood pressure are independent risk factors for sICH after IVT in elderly patients with severe WMLs. The models are highly accurate and can be applied clinically to provide a reliable predictive basis for IVT in elderly patients with severe WMLs.

Sex Differences in the Association between Hemoglobin A1c and Cerebral White Matter Lesions in the General Japanese Population

The influence of diabetes and associated sex differences on cerebral white matter lesions (WML) is unclear. We used data from a cross-sectional study uploaded to the DATADRYAD website by Shinkawa et al. to investigate differences in the association between hemoglobin A1c (HbA1c) levels and cerebral WML between men and women. The average age of all participants was 56.4 ± 11.5 years old, and approximately 51.89% of them were men. A linear relationship between HbA1c and cerebral WML was detected in men. Fully adjusted binary logistic regression showed no association of HbA1c with cerebral WML in men. A nonlinear relationship between HbA1c and cerebral WML was detected in women, whose cutoff point was 5.6%. The effect sizes and confidence intervals of the left and right sides of the inflection point were OR = 0.21 (95% CI 0.06, 0.69, P = 0.0098 ) and OR = 3.5 (95% CI 1.50, 8.15, P = 0.0037 ), respectively. In the higher HbA1c group, further subgroup analysis showed a stronger association between HbA1c and cerebral WML in women ( OR = 3.83 , 95% CI 1.68, 8.72 P = 0.0014 ) than in men ( OR = 1.02 , 95% CI 0.76, 1.36 P = 0.8986 ) ( P for interaction with sex was 0.0004). A stronger effect of HbA1c on the risk of cerebral WML in women than in men was found in the higher HbA1c group.

Neddylation in the chronically hypoperfused corpus callosum: MLN4924 reduces blood-brain barrier injury via ERK5/KLF2 signaling

Blood-brain barrier (BBB) breakdown and cerebrovascular dysfunction may contribute to the pathology in white matter lesions and consequent cognitive decline caused by cerebral hypoperfusion. Neddylation is the process of attaching a ubiquitin-like molecule NEDD8 (neuronal precursor cell-expressed developmentally downregulated protein 8) to specific targets. By modifying protein substrates, neddylation plays critical roles in various important biological processes. However, whether neddylation influences the pathogenesis of hypoperfused brain remains unclear. In the present study, cerebral hypoperfusion-induced white matter lesions were produced by bilateral common carotid artery stenosis in mice. The function of the neddylation pathway, BBB integrity, cerebrovascular dysfunction, myelin density in the corpus callosum and cognitive function were determined. We show that NEDD8 conjugation aberrantly amplified in microvascular endothelium in the corpus callosum following cerebral hypoperfusion. MLN4924, a small-molecule inhibitor of NEDD8-activating enzyme currently in clinical trials, preserved BBB integrity, attenuated glial activation and enhanced oligodendrocyte differentiation, and reduced hypoperfusion-induced white matter lesions in the corpus callosum and thus improved cognitive performance via inactivating cullin-RING E3 ligase (CRL). Administration of MLN4924 caused the accumulation of ERK5 and KLF2. The ERK5 inhibitor BIX 02189, down-regulated MLN4924-induced activation of KLF2 and reversed MLN4924-mediated increase in pericyte coverage and junctional proteins. Furthermore, BIX 02189 blocked MLN4924-afforded protection against BBB disruption and white matter lesions in the corpus callosum. Collectively, our results revealed that neddylation impairs vascular function and thus exacerbated the pathology of hypoperfused brain and that inhibition of neddylation with MLN4924 may offer novel therapeutic opportunities for cerebral hypoperfusion-associated cognitive impairment.

CSF, Blood, and MRI Biomarkers in Skogholt's Disease-A Rare Neurodegenerative Disease in a Norwegian Kindred.

Skogholt's disease is a rare neurological disorder that is only observed in a small Norwegian kindred. It typically manifests in adulthood with uncharacteristic neurological symptoms from both the peripheral and central nervous systems. The etiology of the observed cerebral white matter lesions and peripheral myelin pathology is unclear. Increased cerebrospinal fluid (CSF) concentrations of protein have been confirmed, and recently, very high concentrations of CSF total and phosphorylated tau have been detected in Skogholt patients. The symptoms and observed biomarker changes in Skogholt's disease are largely nonspecific, and further studies are necessary to elucidate the disease mechanisms. Here, we report the results of neurochemical analyses of plasma and CSF, as well as results from the morphometric segmentation of cerebral magnetic resonance imaging. We analyzed the biomarkers Aβ1--42, Aβ1-40, Aβx-38, Aβx-40, Aβx-42, total and phosphorylated tau, glial fibrillary acidic protein, neurofilament light chain, platelet-derived growth factor receptor beta, and beta-trace protein. All analyzed CSF biomarkers, except neurofilament light chain and Aβ1/x-42, were increased several-fold. In blood, none of these biomarkers were significantly different between the Skogholt and control groups. MRI volumetric segmentation revealed decreases in the ventricular, white matter, and choroid plexus volumes in the Skogholt group, with an accompanying increase in white matter lesions. The cortical thickness and subcortical gray matter volumes were increased in the Skogholt group. Pathophysiological changes resulting from choroidal dysfunction and/or abnormal CSF turnover, which may cause the increases in CSF protein and brain biomarker levels, are discussed.

Circulating microRNAs correlate with structural and functional MRI parameters in patients with multiple sclerosis.

Circulating microRNAs are promising biomarkers for multiple sclerosis (MS). Our aim was to correlate serum microRNA levels with various magnetic resonance imaging (MRI) parameters. We recruited 50 MS patients and measured cervical spine and cerebral white matter lesions together with regional brain volumes. Microstructural changes in the white matter were investigated with diffusion tensor imaging. Magnetic resonance spectroscopy was performed to measure cerebral metabolites. Functional connectivity within the default mode network was examined with resting-state functional MRI. On the day of the MRI measurements, we collected serum samples and carried out quantitative analysis of ten pre-selected microRNAs using droplet digital PCR. Serum level of miR-143.3p could differentiate between MS subtypes and had lower levels in progressive MS types. We found significant associations between microRNA levels and MRI measures: (1) higher miR-92a.3p and miR-486.5p levels were associated with greater total white matter lesion volumes within the cervical spine, (2) decreased miR-142.5p levels was associated with reduced total creatinine concentration and (3) miR-92a.3p, miR-142.5p and miR-486.5p levels were associated with functional connectivity strengths between specific nodes of the default mode network. Specifically, we found a negative association between miR-92a.3p and miR-486.5p levels and connectivity strength between the lateral temporal cortex and posterior inferior parietal lobule, and a positive association between miR-142.5p level and connectivity strength between the retrosplenial cortex and temporal pole. However, miRNA levels were not associated with regional brain volumes. We provide here further evidence that circulating microRNAs may show correlation with both structural and functional neuroimaging outcomes in patients with MS.

Abstract P230: Central Artery Pulsatile Hemodynamics Are Associated With Cerebral Total, Periventricular, And Deep White Matter Lesions: Role Of Reservoir-excess Pressure Components.

Introduction: Accumulating evidence suggests that increased central, rather than peripheral, blood pressure (BP) may be a better predictor of cardiovascular risk. The shape of the central BP waveform is determined by ventricular-arterial interactions that can be quantified via novel hemodynamic analyses, from which some parameters have been implicated in the development of cardiac, vascular, and renal dysfunction. Comparatively, the potential effect of central pulsatile hemodynamics on brain structure has been understudied. Thus, we sought to determine the association of novel central hemodynamic parameters with cerebral white matter lesions. Methods: Central BP waveforms were measured in 130 healthy adults (age 63±6y; 58% female) via non-invasive carotid tonometry and modeled using reservoir-excess pressure analysis to separate the central BP waveform into a reservoir (Rp TI ) and excess (Ep TI ) pressure component. Systolic (Sk) and diastolic (Dk) rate constants were estimated from the rate of increase and decrease of the Rp TI component, respectively. Total, periventricular, and deep cerebral white matter lesion volumes (WMLV) were estimated from T2 weighted and FLAIR MRI and adjusted for total intracranial volume. Results: Both Sk and Ep TI were correlated with total (Sk: r = -0.19, p = 0.033; Ep TI : r = 0.21, p = 0.016), periventricular (Sk: r = -0.18, p = 0.037; Ep TI : r = 0.23, p = 0.009), and deep (Sk: r = -0.28, p = 0.002; Ep TI : r = 0.20, p = 0.027) WMLV. The association of Sk with total ( B = -0.032; 95% confidence interval [CI] = -0.054, -0.010; p = 0.0056), periventricular ( B = -0.030; 95%CI = -0.051, -0.009; p = 0.0063), and deep ( B = -0.064; 95%CI = -0.101, -0.028; p &lt;0.001) WMLV remained significant in multivariable analyses adjusting for age, sex, BMI, peripheral pulse pressure, carotid-femoral pulse wave velocity, heart rate, and non-HDL cholesterol. Additionally, the association between Ep TI and deep WMLV persisted in multivariable analysis ( B = 0.158; 95%CI = 0.045, 0.271; p = 0.007). Conclusion: Pulsatile components of central artery hemodynamics are associated with cerebral WMLV independent of traditional cardiovascular risk factors. In particular, Sk may represent a novel biomarker of early central BP-related cerebral white matter damage.

1715-P: Osteopenic Obesity Is Associated with Small Vessel Disease in Old Adults—The Bunkyo Health Study

Obesity is one of the most important causes of metabolic disorders and cardiovascular events. Indeed, while the presence of cerebral small vessel disease (SVD) that includes silent brain infarcts, cerebral white matter lesions, and microhemorrhage increased the risk of stroke &amp;gt; 3-fold, and dementia &amp;gt; 2-fold, respectively, obesity has been identified as a risk factor for SVD. On the other hand, low bone mineral density (BMD), is also recognized as a risk factor for SVD. Whereas obesity is generally associated with high BMD, it has recently been reported that there is a special subtype of osteopenic obesity in which obesity and low BMD coexist. Thus, we hypothesized that this osteopenic obesity is at high risk for SVD. To test this hypothesis, we studied 1531 (641 male and 890 female) old adults aged 65 to 85 years without a history of stroke (Bunkyo Health Study). All subjects underwent dual-energy X-ray absorptiometry, brain MRI, and blood sampling, and they were classified into four groups according to the presence or absence of obesity and osteopenia (men) or osteoporosis (women) diagnosed by the BMD at the hip joint. The mean age of the subjects was 73.0 years. The prevalence of osteopenic obesity was 7.8% and 8.0% for men and women, respectively. While overall prevalence of SVD was 25% in men and 22% in women, the prevalence of SVD in osteopenic obesity was 46% and 42%, respectively. Logistic regression analysis revealed that odds ratio [95% CI] for SVD in control, obesity, osteopenia/osteoporosis and osteopenic obesity were 1.00, 1.203 [0.730-1.982], 0.970 [0.670-1.549] and 3.024 [1.560-5.861] in men and 1.00, 1.452 [0.818-2.575], 1.548 [1.012-2.368], 2.747 [1.489-5.069] in women, respectively. In conclusion, osteopenic obesity was independently associated with the presence of SVD in old adults without a history of stroke. Disclosure N.Ito: None. Y.Yoshizawa: None. H.Watada: Research Support; Boehringer Ingelheim Japan, Inc., Mitsubishi Tanabe Pharma Corporation, LifeScan Diabetes Institute, Eli Lilly Japan K.K., Sun Pharmaceutical Industries Ltd., Teijin Pharma Limited, Taisho Pharmaceutical Holdings Co., Ltd., Ono Pharmaceutical Co., Ltd., Kowa Company, Ltd., Merck Sharp &amp; Dohme Corp., Sanwa Kagaku Kenkyusho, Speaker's Bureau; Mitsubishi Tanabe Pharma Corporation, Taiho Pharmaceutical Co. Ltd., Novo Nordisk, Abbott Japan Co., Ltd., Astellas Pharma Inc., Merck Sharp &amp; Dohme Corp., Kissei Pharmaceutical Co., Ltd., AstraZeneca, Ono Pharmaceutical Co., Ltd., Boehringer Ingelheim Japan, Inc., Sanofi, Sun Pharmaceutical Industries Ltd., Eli Lilly Japan K.K. Y.Tamura: None. H.Kaga: None. Y.Someya: None. H.Tabata: None. S.Kakehi: None. M.Kiya: None. T.Tajima: None. H.Naito: None. Funding Strategic Research Foundation at Private Universities (S1411006); Ministry of Education, Culture, Sports, Science and Technology of Japan (18H03184); Mizuno Sports Promotion Foundation; Mitsui Life Social Welfare Foundation

Mechanisms of Cognitive Improvement After Carotid Endarterectomy: Results of an Autopsy

To develop a clinically meaningful definition of cognitive change before and after carotid endarterectomy (CEA), we categorized patients with “improved postoperative function” and “non-improved postoperative function” based on subjective assessment and neuropsychological tests. The results showed that 11% of the patients showed an improvement in postoperative function. Through single-photon emission computerized tomography (SPECT), positron emission tomography (PET), magnetic resonance imaging (MRI), etc., it was found that improvement of cerebral blood flow by carcinoembryonic antigen (CEA) → improvement of cerebral metabolism → improvement of cerebral cortical neuroreceptor function and cerebral white matter microstructure → improvement of cognitive function. The degree of preoperative cerebral hemispheric white matter lesions was the rate-limiting factor for improvement in cognitive function.

Construction and validation of a nomogram model to predict symptomatic intracranial hemorrhage after intravenous thrombolysis in severe white matter lesions.

Cerebral white matter lesions (WMLs) increase the risk of bleeding after intravenous thrombolysis (IVT) but are also considered to require IVT. Its risk factors and predictive models are still poorly studied. The aim of this study is to develop a clinically applicable model for post-IVT haemorrhage. It offers the possibility to prevent symptomatic intracranial hemorrhage (sICH) in patients with IVT in severe WMLs. A large single-center observational study conducted a retrospective analysis of IVT in patients with severe WMLs from January 2018 to December 2022. Univariate and multi-factor logistic regression results were used to construct nomogram model, and a series of validations were performed on the model. More than 2,000 patients with IVT were screened for inclusion in this study after cranial magnetic resonance imaging evaluation of 180 patients with severe WMLs, 28 of whom developed sICH. In univariate analysis, history of hypertension (OR 3.505 CI 2.257-4.752, p = 0.049), hyperlipidemia (OR 4.622 CI 3.761- 5.483, p < 0.001), the NIHSS score before IVT (OR 41.250 CI 39.212-43.288, p < 0.001), low-density lipoprotein levels (OR 1.995 CI 1.448-2.543, p = 0.013), cholesterol levels (OR 1.668 CI 1.246-2.090, p = 0.017), platelet count (OR 0.992 CI 0.985-0.999, p = 0.028), systolic blood pressure (OR 1.044 CI 1.022-1.066, p < 0.001), diastolic blood pressure (OR 1.047 CI 1.024-1.070, p < 0.001) were significantly associated with sICH. In a multifactorial analysis, the NIHSS score before IVT (OR 94.743 CI 92.311-97.175, p < 0.001), and diastolic blood pressure (OR 1.051 CI 1.005-1.097, p = 0.033) were considered to be significantly associated with sICH after IVT as risk factors for the occurrence of sICH. The four most significant factors from logistic regression are subsequently fitted to create a predictive model. The accuracy was verified using ROC curves, calibration curves, decision curves, and clinical impact curves, and the model was considered to have high accuracy (AUC 0.932, 95% 0.888-0.976). The NHISS score before IVT and diastolic blood pressure are independent risk factors for sICH after IVT in patients with severe WMLs. The models based on hyperlipidemia, the NIHSS score before IVT, low-density lipoprotein and diastolic blood pressure are highly accurate and can be applied clinically to provide a reliable predictive basis for IVT in patients with severe WMLs.

Ebselen alleviates white matter lesions and improves cognitive deficits by attenuating oxidative stress via Keap1/Nrf2 pathway in chronic cerebral hypoperfusion mice

Oxidative stress is crucial in cerebral white matter lesions (WMLs) induced by chronic cerebral hypoperfusion. Therefore, ameliorating oxidative damage is considered to be a beneficial strategy for the treatment of WMLs. Ebselen (EbSe), a small lipid organoselenium compound, its lipid peroxidation activity is mediated through the glutathione peroxidase-mimetic properties. This study aimed to investigate the role of EbSe in WMLs after bilateral common carotid artery stenosis (BCAS). The BCAS model can moderately reduce cerebral blood flow, and mimics white matter damage caused by chronic cerebral hypoperfusion or small vessel disease. Laser Speckle Contrast Imaging (LSCI) was used to monitor the cerebral blood flow of mice. The spatial learning and memory were tested by using the eight-arm maze. LFB staining was used to detect demyelination. The expression of MBP, GFAP and Iba1 was assayed by immunofluorescence. The demyelination was assessed by Transmission Electron Microscope (TEM). The activities of MDA, SOD and GSH-Px were detected by assay kits. The mRNA levels of SOD, GSH-Px and HO-1 was detected by realtime PCR. The activation of the Nrf2/ARE pathway and the expression of SOD, GSH-Px and HO-1was assessed by Western blot. EbSe ameliorated cognitive deficits and white matter lesions induced by bilateral common carotid artery stenosis (BCAS). The expression of GFAP and Iba1 was decreased in the corpus callosum of BCAS mice after EbSe treatment. Moreover, EbSe alleviated the level of MDA by elevating the expression and mRNA of SOD, GSH-Px and HO-1 in BCAS mice. Furthermore, EbSe promoted the dissociation of the Keap1/Nrf2 complex, resulting in the accumulation of Nrf2 in the nucleus. This study demonstrates a favorable effect of EbSe on cognitive impairment in a chronic cerebral hypoperfusion model, and the improvement of EbSe's antioxidant property is mediated by Keap1/Nrf2 pathway.

White-Matter Lesions and Cortical Cerebral Blood Flow Evaluation by 3D Arterial Spin-Labeled Perfusion MRI in Asymptomatic Divers: Correlation with Patent Foramen Ovale Ocurrence.

Cerebral white-matter lesions (cWML) can be caused by dilation of Virchow-Robin spaces or may correspond to true lacunar ischemic lesions. The aim of our study was to evaluate in asymptomatic divers the relationship between the presence of patent foramen ovale (PFO) and cWML, as well as their possible effects on cortical cerebral blood flow (CBF) by magnetic resonance (MRI) through the arterial spin labeling (ASL) sequence. Transthoracic echocardiography was performed for the identification of PFO, and cerebral magnetic resonance including the 3D-ASL sequence for CBF quantification. Thirty-eight divers, with a mean age 45.8 ± 8.6 years, were included. Nineteen healthy volunteers, mean age 41 ± 15.2 years, served as the control group. A total of 28.9% of divers had completed more than 1000 dives. It was found that 26.3% of divers presented with PFO in the echocardiographic study. cWML was evidenced in 10.5% of diver MRI studies. There was no statistically significant relationship between the presence of PFO and cWML (p = 0.95). We observed a lower blood flow in all brain areas assessed by the 3D-ASL sequence in the group of divers, compared with the control group. We did not find statistical differences in CBF as a function of the presence or absence of PFO, number of dives, or cWML evidence.

Clinical significance of fractional anisotropy in cerebral white matter regional vulnerability caused by carbon monoxide poisoning: A systematic review and meta-analysis

Carbon monoxide poisoning (COP) can lead to various cerebral white matter (WM) lesions across different disease phases and clinical manifestations, and fractional anisotropy (FA) of diffusion tensor imaging has been widely applied to investigate WM injury in these patients. Here we conducted a systematic review and meta-analysis to investigate the utility of FA in evaluating the regional vulnerability of WM injury caused by COP and explore differences between different disease phases and patient subtypes. We systematically searched PubMed, Medline, Scopus and reference lists of appropriate publications to identify relevant studies. Eight studies with 217 patients with COP and 207 healthy controls (HCs) were included. Eight regions of interest were available to investigate regional vulnerability. The results showed the most significant decrease in FA in orbitofrontal subcortical regions. Comparisons of different disease phases revealed lower FA in the centrum semiovale and corpus callosum in the acute phase, while in the chronic phase, only FA in the centrum semiovale remained significantly decreased. Analysis of different patient subtypes showed that the FA values in the splenium of the corpus callosum were significantly decreased in the patients with delayed neurologic sequelae (DNS) but not in the mixed population (with and without DNS). In conclusion, this meta-analysis highlights the frontal-subcortical regional vulnerability in COP. FA changes in the corpus callosum across different disease phases reflect alterations in underlying microstructures. Extended corpus callosum injury involving the splenium could be an imaging biomarker of the occurrence of DNS.