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Abstract To investigate the location of white matter lesions (WMLs) in migraineurs with right‒to‒left shunts (RLS); the relationships among the severity of WMLs, changes in brain structural volume and RLS shunts; and the relationships among the severity of WMLs, changes in brain structural volume and degree of headache in RLS migraine patients. A total of 102 migraineurs with RLS admitted to the affiliated Central Hospital of Dalian University of Technology from December 2018 to December 2022 were enrolled in this study. RLS flow and the 6-item Headache Impact Test (HIT-6) scores were recorded to reflect the degree of headache. The brain structural volumes of 102 migraineurs with RLS were calculated from T1-weighted images via artificial intelligence, and the brain structural volumes of healthy controls matched according to age and sex were also calculated. The correlations among WML location, RLS, headache degree, WML severity and brain structural volume changes in migraineurs were analyzed. (1) The WMLs of migraineurs with RLS were concentrated mainly in the white matter of the lateral ventricular margin and deep white matter. Subcortical WMLs were concentrated mainly in the parietal lobe, occipital lobe and frontal lobe. (2) There were no significant differences in the WML variables of cerebral white matter high signal volume, ratio of high-signal white matter volume to whole-brain white matter volume (%) or Fazekas score among migraineurs with different RLS flows, but there were significant differences in WML variables among migraineurs with RLS with different HIT-6 grades and MIDAS grades. RLS flow, HIT-6 score and MIDAS grade were not correlated with the WML variables measured in this study. (3) There was a significant difference in the volume of the precentral gyrus between migraineurs with RLS and normal controls (P

BackgroundMethodsResultsConclusionChildhood chronic non-infectious uveitis (cNIU) is a challenging disease whose differential diagnosis may include demyelinating diseases. We aim to describe the white matter abnormalities (WMA) in brain MRI in childhood cNIU.This is a multicentric retrospective study involving children with cNIU followed at the Pediatric rheumatology units of Florence and the ophthalmology department of the UMC Utrecht who underwent a Brain MRI. Demographic, clinical, laboratory and imaging information was collected. The presence of WMA was considered as the main outcomeData of 123 children was collected (66 from Utrecht and 57 from Florence), of whom 51 were males, with a median uveitis onset at age 9 years (range 3–16) for the UMC Utrecht and 8.75 years (range 1.6–15.1) for Florence. We evaluated 39 children with anterior uveitis, 35 with intermediate uveitis, 1 with posterior uveitis and 48 with panuveitis. Uveitis was idiopathic in 105. On brain MRI, 33 patients (26.8%) showed WMA, and most of them had non-anterior uveitis (72.8%). WMA were more frequent in males (χ2 5.25, p = 0.02). No difference in underlying systemic disease was seen between patients with and without WMA, but 40% of patients with TINU and 27.3% of patients with idiopathic uveitis showed WMA. None of the patients received a diagnosis of demyelinating disease during follow-up.As WMA were found in 26.8% of patients who were screened in our cohort, brain MRI might be useful in cNIU. However, the clinical significance of these WMA could not be determined in this study. An interdisciplinary evaluation is necessary to assess the appropriate management, and a longer follow up is necessary to determine the prognosis of some of these WMA. [ABSTRACT FROM AUTHOR]

Background and purpose: Peak width of skeletonized mean diffusivity (PSMD) is an MRI-based biomarker that may reflect white matter lesions (WML). PSMD is based on skeletonization of MR DTI data and histogram analysis. Both chronic renal failure (CRF) and WML may be affected by multisystemic small-vessel disorder. We aimed to explore the relationship between PSMD and estimated glomerular filtration rate (eGFR). Methods: Fifty followed-up CRF patients matched for age, sex, hypertension and smoking status were enrolled and classified into a progressive group (n = 16) and stable group (n = 34) based on eGFR levels. Longitudinal and horizontal differences of PSMD were compared between the progressive and stable groups at the initial and follow-up time points. Pearson's correlation was used for correlation of eGFR with PSMD and WML (per Fazekas scale score). ROC was used to measure the sensitivity of PSMD and WML score to changes of eGFR. Results: At the follow-up time point, PSMD of the progressive group was significantly higher than at the initial time point (p < 0.001), and PSMD of the progressive group was significantly higher than stable group (p < 0.001). PSMD and eGFR were significantly correlated. AUC curves explored that PSMD (PSMD changes at the follow-up and initial time points) and follow-up PSMD was better for the classification of progressive and stable groups. Conclusion: PSMD has significant correlation with eGFR, PSMD can reveal a close relationship between WML and CRF. [ABSTRACT FROM AUTHOR]

目的 为缺血性脑白质病变（ischemic white matter lesion，IWML）患者认知障碍进展的评估提供影像依据。 方法 回顾性纳入2018年1月—2021年12月就诊于首都医科大学附属北京天坛医院的IWML患者，按照认知功能测评结果分为：非痴呆血管性认知障碍（non-dementia vascular cognitive impairment，VCIND）组、血管性痴呆（vascular dementia，VaD）组。同期入组认知功能和头颅MRI检查正常的就诊患者为正常对照（normal control，NC）组。所有患者均完善了静息态功能MRI检查及注意功能检查，包括Stroop色-词干扰测试B（Stroop color-word interference B test，Stroop B），Stroop色-词干扰测试C（Stroop color-word interference C test，Stroop C），数字连线测验A（trail making test A，TMT-A）和符号数字转换测试（symbol digit modalities test，SDMT）。使用独立成分分析选择左侧和右侧额顶叶网络、初级和次级视觉网络、背侧注意网络5个脑区，选择9个主要区域为感兴趣区，提取每个脑区Z值，作为脑区两两间的功能连接（functional connectivity，FC）值。进行VCIND、VaD和NC组FC差异分析，并进一步分析VCIND、VaD两组脑区间FC变化与注意功能评分的相关性。 结果 共纳入60例患者，其中男性29例（48.3%）。NC组24例，VCIND组19例，VaD组17例。结果提示，与NC组相比，VCIND组完成Stroop B（P＜0.01）、TMT-A（P=0.01）评分更高，SDMT评分更低（P=0.01）；VaD组完成Stroop B、Stroop C及TMT-A评分更高（均P＜0.01），SDMT评分更低（P＜0.01）。与VCIND组相比，VaD组完成Stroop B（P＜0.01）、Stroop C（P＜0.01）及TMT-A（P=0.01）评分更高，SDMT评分（P＜0.01）更低。FC分析显示，与NC组相比，VCIND组右侧背外侧前额叶皮质和左侧顶上小叶（P=0.01）、右侧背外侧前额叶皮质和楔叶（P=0.04）之间的FC值增高；与VCIND组相比，VaD组右侧背外侧前额叶皮质与楔叶（P=0.02）之间的FC值增高。右侧背外侧前额叶皮质和左侧顶上小叶之间的FC值与Stroop C用时呈负相关（r=－0.365，P=0.04），其余脑区之间的FC值与其他注意功能评分项目无显著相关性。 结论 随着认知功能下降，IWML患者执行网络与背侧注意网络、初级视觉网络间的FC值升高，部分脑区间FC的改变伴随着更差的注意功能。 Abstract: Objective To provide an imaging reference for assessing cognitive dysfunction progression in patients with ischemic white matter lesion (IWML). Methods Patients with IWML admitted to Beijing Tiantan Hospital, Capital Medical University from January 2018 to December 2021 were retrospectively included. They were divided into two groups according to the results of the cognitive function assessment: the non-dementia vascular cognitive impairment (VCIND) group and the vascular dementia (VaD) group. Patients with normal cognitive function and brain MRI results were enrolled in the normal control (NC) group at the same time. All patients underwent resting state functional MRI examination and attention function tests, including Stroop color-word interference B test (Stroop B), Stroop color-word interference C test (Stroop C), trail making test A (TMT-A), and symbol digit modalities test (SDMT). The left frontoparietal network, right frontoparietal network, primary visual network, secondary visual network, and dorsal attention network were selected by independent component analysis. Nine major regions were chosen as regions of interest, and the Z value of each brain region was extracted as the functional connectivity (FC) value of the pairwise brain interval. The differences in FC among the three groups were analyzed, and the correlation between altered FC and attention function scores in VCIND and VaD groups was further investigated. Results Among 60 eligible patients, 29 (48.3%) being male. There were 24 cases in the NC group, 19 cases in the VCIND group, and 17 cases in the VaD group. The results suggested that compared with the NC group, the VCIND group had higher scores on the Stroop B (P

White Matter Lesion is a common imaging manifestation in the current clinical MRI (Magnetic Resonance Imaging) examination, especially in elderly patients. The etiology is complex and the clinical manifestations are different. The white matter lesions may increase the risk of stroke, mental and emotional disorders, motor dysfunction and cognitive dysfunction, seriously affecting patients’ quality of life. This article reviews the correlation between WML and MRI from the aspects of histopathology, pathophysiological mechanism and age, hypertension, sleep quality, physical activity and cognitive disorder, analyzes influencing factors of white matter lesions in elderly people, and provides reference for diagnosis, treatment and prognosis of the disease. (脑白质病变(WML)在是一种在老年人群中常见的影像学改变, 是脑小血管病的影像学特征之一, 病因复杂, 临床表现不一, 若未能及时干预, 可进展为脑卒中、精神情感异常、运动功能障碍以及认知功能障碍等, 严重影响患者生活质量。本研究从病理组织学、病理生理机制及年龄、高血压、睡眠质量、体力活动及认知障碍等方面与WML的相关性进行综述, 进一步分析老年患者发生WML的影响因素, 以为相关诊断、治疗及预后提供数据参考。)

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Background: White matter lesion (WML) is common in aging brain and is associated with cognitive impairment and dementia. However, recent studies reported an association between patent foramen ovale (PFO) and WML in migraineurs, especially in young, middle-aged migraineurs. Our retrospective, case-control study aims to describe the clinical characteristics of WML in this population and to explore potential risk factors. Methods: 226 patients with migraine and PFO were consecutively initially screened. Relevant factors were selected by the least absolute shrinkage and selection operator (LASSO) regression and multivariable logistic regression model. A Nomogram was employed to visualize the prediction model conveniently. The discrimination and calibration abilities were evaluated using the Receiver Operating Characteristic (ROC) curve, the Hosmer-Lemeshow test, and calibration curves. Results: One hundred and nineteen participants were ultimately enrolled in our study, with a median age of 36.9 ± 12.7 years and 80.7% of females. Brain magnetic resonance imaging MRI showed 67 (56.3%) patients had WML, whereas 52 (43.7%) patients were categorized into the non-WML group. LASSO regression screened out potential variables and subsequent multivariate analysis finally identified age, mean platelet volume, and fibrinogen (FIB) as independent predictive factors of WML. The area under the ROC curve (AUC) was 0.807. Hosmer-Lemeshow test and calibration curve verified a consistency between the predicted and actual probability. Conclusion: The predictive nomogram established and validated in our study may assist clinicians in screening WML among young middle-aged migraineurs with PFO and developing individualized preventive and treatment strategies. Supplementary Material Supplementary Material File [ABSTRACT FROM AUTHOR]

Cerebral white matter lesions (WML) encompass axonal loss and demyelination and are assumed to be associated with small vessel disease (SVD)-related ischaemia. However, our previous study in the parietal lobe white matter revealed that WML in Alzheimer's disease (AD) are linked with degenerative axonal loss secondary to the deposition of cortical AD pathology. Furthermore, neuroimaging data suggest that pathomechanisms for the development of WML differ between anterior and posterior lobes with AD-associated degenerative mechanism driving posterior white matter disruption, and both AD-associated degenerative and vascular mechanisms contributed to anterior matter disruption. In this pilot study, we used human post-mortem brain tissue to investigate the composition and aetiology of frontal WML from AD and non-demented controls to determine if frontal WML are SVD-associated and to reveal any regional differences in the pathogenesis of WML. Frontal WML tissue sections from 40 human post-mortem brains (AD, n = 19; controls, n = 21) were quantitatively assessed for demyelination, axonal loss, cortical hyperphosphorylated tau (HPτ) and amyloid-beta (Aβ) burden, and arteriolosclerosis as a measure of SVD. Biochemical assessment included Wallerian degeneration-associated protease calpain and the myelin-associated glycoprotein to proteolipid protein ratio as a measure of ante-mortem ischaemia. Arteriolosclerosis severity was found to be associated with and a significant predictor of frontal WML severity in both AD and non-demented controls. Interesting, frontal axonal loss was also associated with HPτ and calpain levels were associated with increasing Aβ burden in the AD group, suggestive of an additional degenerative influence. To conclude, this pilot data suggest that frontal WML in AD may result from both increased arteriolosclerosis and AD-associated degenerative changes. These preliminary findings in combination with previously published data tentatively indicate regional differences in the aetiology of WML in AD, which should be considered in the clinical diagnosis of dementia subtypes: posterior WML maybe associated with degenerative mechanisms secondary to AD pathology, while anterior WML could be associated with both SVD-associated and degenerative mechanisms.

Clinical magnetic resonance images (MRIs) lack a standard intensity scale due to differences in scanner hardware and the pulse sequences used to acquire the images. When MRIs are used for quantification, as in the evaluation of white matter lesions (WMLs) in multiple sclerosis, this lack of intensity standardization becomes a critical problem affecting both the staging and tracking of the disease and its treatment. This paper presents a study of harmonization on WML segmentation consistency, which is evaluated using an object detection classification scheme that incorporates manual delineations from both the original and harmonized MRIs. A cohort of ten people scanned on two different imaging platforms was studied. An expert rater, blinded to the image source, manually delineated WMLs on images from both scanners before and after harmonization. It was found that there is closer agreement in both global and per-lesion WML volume and spatial distribution after harmonization, demonstrating the importance of image harmonization prior to the creation of manual delineations. These results could lead to better truth models in both the development and evaluation of automated lesion segmentation algorithms.

Patients with Parkinson's disease are highly vulnerable for cognitive decline. Thus, early intervention by means of working memory training (WMT) may be effective for the preservation of cognition. However, the influence of structural brain properties, i.e., cortical thickness and volume of white matter lesions on training responsiveness have not been studied. Here, behavioral and neuroimaging data of 46 patients with Parkinson's disease, 21 of whom engaged in home-based, computerized adaptive WMT, was analyzed. While cortical thickness and white matter lesions volume were associated with cognitive performance at baseline, these structural brain properties do not seem to determine WMT responsiveness. [ABSTRACT FROM AUTHOR]

Background: Quantitative susceptibility mapping (QSM) is a quantitative measure based on magnetic resonance imaging sensitive to iron and myelin content. This makes QSM a promising non-invasive tool for multiple sclerosis (MS) in research and clinical practice. Objective: We performed a systematic review and meta-analysis on the use of QSM in MS. Methods: Our review was prospectively registered on PROSPERO (CRD42022309563). We searched five databases for studies published between inception and 30th April 2023. We identified 83 English peer-reviewed studies that applied QSM images on MS cohorts. Fifty-five included studies had at least one of the following outcome measures: deep grey matter QSM values in MS, either compared to healthy controls (HC) (k = 13) or correlated with the score on the Expanded Disability Status Scale (EDSS) (k = 7), QSM lesion characteristics (k = 22) and their clinical correlates (k = 17), longitudinal correlates (k = 11), histological correlates (k = 7), or correlates with other imaging techniques (k = 12). Two meta-analyses on deep grey matter (DGM) susceptibility data were performed, while the remaining findings could only be analyzed descriptively. Results: After outlier removal, meta-analyses demonstrated a significant increase in the basal ganglia susceptibility (QSM values) in MS compared to HC, caudate (k = 9, standardized mean difference (SDM) = 0.54, 95 % CI = 0.39–0.70, I2 = 46 %), putamen (k = 9, SDM = 0.38, 95 % CI = 0.19–0.57, I2 = 59 %), and globus pallidus (k = 9, SDM = 0.48, 95 % CI = 0.28–0.67, I2 = 60 %), whereas thalamic QSM values exhibited a significant reduction (k = 12, SDM = −0.39, 95 % CI = −0.66–−0.12, I2 = 84 %); these susceptibility differences in MS were independent of age. Further, putamen QSM values positively correlated with EDSS (k = 4, r = 0.36, 95 % CI = 0.16–0.53, I2 = 0 %). Regarding rim lesions, four out of seven studies, representing 73 % of all patients, reported rim lesions to be associated with more severe disability. Moreover, lesion development from initial detection to the inactive stage is paralleled by increasing, plateauing (after about two years), and gradually decreasing QSM values, respectively. Only one longitudinal study provided clinical outcome measures and found no association. Histological data suggest iron content to be the primary source of QSM values in DGM and at the edges of rim lesions; further, when also considering data from myelin water imaging, the decrease of myelin is likely to drive the increase of QSM values within WM lesions. Conclusions: We could provide meta-analytic evidence for DGM susceptibility changes in MS compared to HC; basal ganglia susceptibility is increased and, in the putamen, associated with disability, while thalamic susceptibility is decreased. Beyond these findings, further investigations are necessary to establish the role of QSM in MS for research or even clinical routine.

The spatial distribution patterns of cerebral microbleeds are associated with different types of cerebral small vessel disease (CSVD). This study aims to examine the disparities in brain imaging markers of CSVD among patients diagnosed with possible amyloid and non-amyloid small vessel disease. The head MR scans including susceptibility-weighted imaging (SWI) sequences from 351 patients at our institute were collected for analysis. CSVD imaging markers were quantified or graded across various CSVD dimensions in the patient images. Patients were categorized into the cerebral amyloid angiopathy group (CAA), hypertensive arteriopathy group (HA), or mixed small vessel disease group (Mixed), based on the spatial distribution of microbleeds. White matter lesions (WML) were segmented using an artificial neural network and assessed via a voxel-wise approach. Significant differences were observed among the three groups in several indices: microbleed count, lacune count at the centrum semiovale and basal ganglia levels, grade of enlarged perivascular space (EPVS) at the basal ganglia, and white matter lesion volume. These indices were substantially higher in the Mixed group compared to the other groups. Additionally, the incidences of cerebral hemorrhages (χ2 = 7.659, P = 0.006) and recent small subcortical infarcts (χ2 = 4.660, P = 0.031) were significantly more frequent in the HA group than in the CAA group. These results indicate that mixed spatial distribution patterns of microbleeds demonstrated the highest burden of cerebral small vessel disease. Microbleeds located in the deep brain regions were associated with a higher incidence of recent small subcortical infarcts and cerebral hemorrhages compared to those in the cortical areas.

Background: Nearly 1 million Americans are living with multiple sclerosis (MS) and 30–50% will experience memory dysfunction. It remains unclear whether this memory dysfunction is due to overall white matter lesion burden or damage to specific neuroanatomical structures. Here we test if MS memory dysfunction is associated with white matter lesions to a specific brain circuit. Methods: We performed a cross-sectional analysis of standard structural images and verbal memory scores as assessed by immediate recall trials from 431 patients with MS (mean age 49.2 years, 71.9% female) enrolled at a large, academic referral center. White matter lesion locations from each patient were mapped using a validated algorithm. First, we tested for associations between memory dysfunction and total MS lesion volume. Second, we tested for associations between memory dysfunction and lesion intersection with an a priori memory circuit derived from stroke lesions. Third, we performed mediation analyses to determine which variable was most associated with memory dysfunction. Finally, we performed a data-driven analysis to derive de-novo brain circuits for MS memory dysfunction using both functional (n = 1000) and structural (n = 178) connectomes. Results: Both total lesion volume (r = 0.31, p < 0.001) and lesion damage to our a priori memory circuit (r = 0.34, p < 0.001) were associated with memory dysfunction. However, lesion damage to the memory circuit fully mediated the association of lesion volume with memory performance. Our data-driven analysis identified multiple connections associated with memory dysfunction, including peaks in the hippocampus (T = 6.05, family-wise error p = 0.000008), parahippocampus, fornix and cingulate. Finally, the overall topography of our data-driven MS memory circuit matched our a priori stroke-derived memory circuit. Conclusions: Lesion locations associated with memory dysfunction in MS map onto a specific brain circuit centered on the hippocampus. Lesion damage to this circuit fully mediated associations between lesion volume and memory. A circuit-based approach to mapping MS symptoms based on lesions visible on standard structural imaging may prove useful for localization and prognosis of higher order deficits in MS. [ABSTRACT FROM AUTHOR]

To elucidate the incidence and outcomes of childhood-onset epilepsy and associated factors in term-born patients with basal ganglia and thalamic lesion (BGTL)-induced dyskinetic cerebral palsy (DCP) caused by perinatal hypoxic-ischemic encephalopathy (HIE). We studied 104 term-born patients with BGTL-induced DCP (63 males and 41 females, aged 2–22 years) to investigate the incidence of epilepsy and the factors related to its development. We used multivariate analysis to assess perinatal factors, gross motor function, and the extent of brain lesions. We also investigated the seizure onset, clinical course, and electroencephalography (EEG) characteristics. The cumulative epilepsy incidence was 36%. Multiple logistic regression analysis revealed that deep white matter lesions were the only independent risk factor for epilepsy. The confirmed seizure types included epileptic spasms (ES, n = 13), myoclonic seizures (MS, n = 6), and focal-onset seizures (FS, n = 24). Only patients with deep white matter lesions exhibited ES or MS. The symptoms of FS resembled those of self-limited epilepsy with centrotemporal spikes; however, only half of the patients reached remission by the time of investigation, and four patients had more than one seizure per month despite appropriate drug therapy. Focal spikes in the peri-rolandic area were detected not only in patients with FS but also in half of the patients without epilepsy. One-third of term-born patients with BGTL-induced DCP caused by perinatal HIE develop epilepsy, and deep white matter lesions increase the likelihood of epilepsy. Preparation for early-onset ES, MS, and subsequent FS is beneficial. • Investigated the incidence of epilepsy in 104 patients with BGTL-induced DCP. • One-third of patients with BGTL-induced DCP developed epilepsy. • Deep white matter lesions were the only independent risk factor for epilepsy. • Preparation for early-onset ES, MS, and subsequent FS is desirable. [ABSTRACT FROM AUTHOR]

Loneliness has an important impact on memory function in late life. However, the neural mechanism by which loneliness detrimentally influences memory function remains elusive. Furthermore, it remains unclear whether the association between loneliness and memory function varies by gender. The current study aimed to investigate the neural mechanism underlying the association between loneliness and episodic memory function and explore whether it varies with gender among cognitively normal older adults. A total of 173 community-dwelling adults aged 60 years or older from the Korean Social Life, Health, and Aging Project (KSHAP) study (mean age = 71.87) underwent an assessment of loneliness, neuropsychological testing, and structural magnetic resonance imaging. The association between loneliness and episodic memory function was mediated by the volume of white matter hyperintensities (WMHs), but not by hippocampal or gray matter volumes. In addition, the association between loneliness and memory function through WMHs was significantly moderated by gender; specifically, the indirect effect was significant among men but not among women. The study suggests that WMHs may be a potential neurological mechanism that causes late-life memory dysfunction associated with loneliness in older men. The findings underscore the need for gender-specific interventions to mitigate memory impairment associated with late-life loneliness, with significant public health implications. [ABSTRACT FROM AUTHOR]

Introduction: Early identification of patients at high risk of progression could help with a personalised treatment strategy. Magnetic resonance imaging (MRI) measures have been proposed to predict long-term disability in multiple sclerosis (MS), but a reliable predictor that can be easily implemented clinically is still needed. Aim: Assess MRI measures during the first 5 years of the MS disease course for the ability to predict progression at 10+ years. Methods: Eighty-two MS patients (53 females), with ≥10 years of clinical follow-up and having two MRI scans, were included. Clinical data were obtained at baseline, follow-up and at ≥10 years. White matter lesion (WML) counts and volumes, and four linear brain sizes were measured on T2/FLAIR 'Fluid-Attenuated-Inversion-Recovery' and T1-weighted images. Results: Baseline and follow-up inter-caudate diameter (ICD) and third ventricular width (TVW) measures correlated positively with Expanded Disability Status Scale, ≥10 or more of WMLs showed a high sensitivity in predicting progression, at ≥10 years. A steeper rate of lesion volume increase was observed in subjects converting to secondary progressive MS. The sensitivity and specificity of both ICD and TVW, to predict disability at ≥10 years were 60% and 64%, respectively. Conclusion: Despite advances in brain imaging and computerised volumetric analysis, ICD and TVW remain relevant as they are simple, fast and have the potential in predicting long-term disability. However, in this study, despite the statistical significance of these measures, the clinical utility is still not reliable. [ABSTRACT FROM AUTHOR]

Elevated plasma neurofilament light chain (NfL) is associated with dementia though underlying mechanisms remain unknown. We examined cross-sectional relationships of time-dependent plasma NfL with selected brain structural magnetic resonance imaging (sMRI) prognostic markers of dementia. The sample was drawn from the Healthy Aging in Neighborhoods of Diversity Across the Life Span (HANDLS) study, selecting participants with complete v 1 (2004–2009) and v 2 (2009–2013) plasma NfL exposure and ancillary sMRI data at v scan (2011–2015, n = 179, mean v 1 to v scan time: 5.4 years). Multivariable-adjusted linear regression models were conducted, overall, by sex, and race, correcting for multiple testing with q-values. NfL (v1) was associated with larger WMLV (both Log e transformed), after 5–6 years' follow-up, overall (β = +2.131 ± 0.660, b = +0.29, p = 0.001, and q = 0.0029) and among females. NfLv 2 was linked to a 125 mm3 lower left hippocampal volume (p = 0.004 and q = 0.015) in reduced models, mainly among males, as was observed for annualized longitudinal change in NfL (δNfL bayes). Among African American adults, NfL v1 was inversely related to total, gray and white matter volumes. Plasma NfL may reflect future brain pathologies in middle-aged adults. [ABSTRACT FROM AUTHOR]

Background and objective: This study aims to examine the role of neurovascular coupling (NVC) in vascular cognitive impairment (VCI) by investigating the relationship between white matter lesion (WML) burden, NVC, and cognitive deficits. Additionally, we aim to explore the potential of NVC as a tool for understanding the neural mechanisms underlying VCI. Methods: This study included thirty-eight small vessel disease cognitive impairment (SVCI) patients, 34 post-stroke cognitive impairment (PSCI) patients, and 43 healthy controls (HC). Comprehensive assessments, including neuroimaging and neuropsychological testing, were conducted to evaluate cognitive function. WML burden was measured and correlated with NVC coefficients to examine the relationship between white matter pathology and NVC. Mediation analysis was employed to explore the link relationship between NVC, WML burden, and cognitive function. Results: The present study showed that NVC was significantly reduced in the SVCI and PSCI groups compared with HCs at both whole-brain and brain region level. The analysis revealed notable findings regarding NVC in relation to WML burden and cognitive function in VCI patients. Specifically, reduced NVC coefficients were observed within higher order brain systems responsible for cognitive control and emotion regulation. Mediation analysis demonstrated that NVC played a mediating role in the relationship between WML burden and cognitive impairment. Conclusion: This study reveals the mediating role of NVC in the relationship between WML burden and cognitive function in VCI patients. The results demonstrate the potential of the NVC as an accurate measure of cognitive impairment and its ability to identify specific neural circuits affected by WML burden. [ABSTRACT FROM AUTHOR]

Background: Cognitive deficits considerably contribute to the patient's burden in Parkinson's disease (PD). While cognitive decline is linked to neuronal dysfunction, the additional role of white matter lesions (WML) is discussed controversially. Objective: To investigate the influence of WML, in comparison to neuronal dysfunction, on cognitive deficits in PD. Methods: We prospectively recruited patients with PD who underwent neuropsychological assessment using the Mattis Dementia Rating Scale 2 (DRS‐2) or Parkinson Neuropsychometric Dementia Assessment (PANDA) and both MRI and PET with [18F]fluorodeoxyglucose (FDG). WML‐load and PD cognition‐related covariance pattern (PDCP) as a measure of neuronal dysfunction were read out. Relationship between cognitive performance and rank‐transformed WML was analyzed with linear regression, controlling for the patients' age. PDCP subject scores were investigated likewise and in a second step adjusting for age and WML load. Results: Inclusion criteria were met by 76 patients with a mean (± SD) age of 63.5 ± 9.0 years and disease duration of 10.7 ± 5.4 years. Neuropsychological testing revealed front executive and parietal deficits and a median DRS‐2 score of 137 (range 119–144)/144 and PANDA score of 22 (range 3–30)/30. No association between WML and cognition was observed, whereas PDCP subject scores showed a trend‐level negative correlation with the DRS‐2 (P = 0.060) as well as a negative correlation with PANDA (P = 0.049) which persisted also after additional correction for WML (P = 0.039). Conclusion: The present study indicates that microangiopathic WML do not have a relevant impact on neurocognitive performance in PD whereas neuronal dysfunction does. [ABSTRACT FROM AUTHOR]

Aims: White matter lesions (WMLs) are involved in the pathological processes leading to cognitive decline and dementia. We examined the mechanisms underlying the exacerbation of ischemia‐induced cognitive impairment and WMLs by diet‐induced obesity, including lipopolysaccharide (LPS)‐triggered neuroinflammation via toll‐like receptor (TLR) 4. Methods: Wild‐type (WT) and TLR4‐knockout (KO) C57BL/6 mice were fed a high‐fat diet (HFD) or low‐fat diet (LFD), and subjected to bilateral carotid artery stenosis (BCAS). Diet groups were compared for changes in gut microbiota, intestinal permeability, systemic inflammation, neuroinflammation, WML severity, and cognitive dysfunction. Results: In WT mice, HFD induced obesity and increased cognitive impairment and WML severity compared with LFD‐fed mice following BCAS. HFD caused gut dysbiosis and increased intestinal permeability, and plasma LPS and pro‐inflammatory cytokine concentrations. Furthermore, HFD‐fed mice had higher LPS levels and higher neuroinflammatory status, including increased TLR4 expression, in WMLs. In TLR4‐KO mice, HFD also caused obesity and gut dysbiosis but did not increase cognitive impairment or WML severity after BCAS. No difference was found between HFD‐ and LFD‐fed KO mice for LPS levels or inflammatory status in either plasma or WMLs. Conclusion: Inflammation triggered by LPS–TLR4 signaling may mediate obesity‐associated exacerbation of cognitive impairment and WMLs from brain ischemia. [ABSTRACT FROM AUTHOR]

Genetic leukoencephalopathies (gLEs) are a highly heterogeneous group of rare genetic disorders. The spectrum of gLEs varies among patients of different ages. Distinct from the relatively more abundant studies of gLEs in children, only a few studies that explore the spectrum of adult gLEs have been published, and it should be noted that the majority of these excluded certain gLEs. Thus, to date, no large study has been designed and conducted to characterize the genetic and phenotypic spectra of gLEs in adult patients. We recruited a consecutive series of 309 adult patients clinically suspected of gLEs from Beijing Tiantan Hospital between January 2014 and December 2021. Whole exome sequencing, mitochondrial DNA sequencing, and repeat analysis of NOTCH2NLC, FMR1, DMPK and ZNF9 were performed for patients. We describe the genetic and phenotypic spectra of the set of patients with a genetically confirmed diagnosis and summarize their clinical and radiological characteristics. A total of 201 patients (65%) were genetically diagnosed, while 108 patients (35%) remained undiagnosed. The most frequent diseases were NOTCH3 (25%), NOTCH2NLC (19%), ABCD1 (9%), CSF1R (7%), and HTRA1 (5%)-related leukoencephalopathies. Based on a previously proposed pathological classification, the gLEs in our cohort were divided into leukovasculopathies (35%), leuko-axonopathies (31%), myelin disorders (21%), microgliopathies (7%), and astrocytopathies (6%). Patients with NOTCH3 mutations accounted for 70% of the leukovasculopathies, followed by HTRA1 (13%) and COL4A1/2 (9%). The leuko-axonopathies contained the richest variety of associated genes, of which NOTCH2NLC comprised 62%. Among myelin disorders, demyelinating leukoencephalopathies (61%)-mainly adrenoleukodystrophy and Krabbe disease-accounted for the majority, while hypomyelinating leukoencephalopathies (2%) were rare. CSF1R was the only mutated gene detected in microgliopathy patients. Leukoencephalopathy with vanishing white matter disease due to mutations in EIF2B2-5 accounted for half of the astrocytopathies. We characterized the genetic and phenotypic spectra of adult gLEs in a large Chinese cohort. The most frequently mutated genes were NOTCH3, NOTCH2NLC, ABCD1, CSF1R, and HTRA1. [ABSTRACT FROM AUTHOR]

Chronic active and slowly expanding lesions with smouldering inflammation are neuropathological correlates of progressive multiple sclerosis pathology. T1 hypointense volume and signal intensity on T1-weighted MRI reflect brain tissue damage that may develop within newly formed acute focal inflammatory lesions or in chronic pre-existing lesions without signs of acute inflammation. Using a recently developed method to identify slowly expanding/evolving lesions in vivo from longitudinal conventional T2- and T1-weighted brain MRI scans, we measured the relative amount of chronic lesion activity as measured by change in T1 volume and intensity within slowly expanding/evolving lesions and non-slowly expanding/evolving lesion areas of baseline pre-existing T2 lesions, and assessed the effect of ocrelizumab on this outcome in patients with primary progressive multiple sclerosis participating in the phase III, randomized, placebo-controlled, double-blind ORATORIO study (n = 732, NCT01194570). We also assessed the predictive value of T1-weighted measures of chronic lesion activity for clinical multiple sclerosis progression as reflected by a composite disability measure including the Expanded Disability Status Scale, Timed 25-Foot Walk and 9-Hole Peg Test. We observed in this clinical trial population that most of total brain non-enhancing T1 hypointense lesion volume accumulation was derived from chronic lesion activity within pre-existing T2 lesions rather than new T2 lesion formation. There was a larger decrease in mean normalized T1 signal intensity and greater relative accumulation of T1 hypointense volume in slowly expanding/evolving lesions compared with non-slowly expanding/evolving lesions. Chronic white matter lesion activity measured by longitudinal T1 hypointense lesion volume accumulation in slowly expanding/evolving lesions and in non-slowly expanding/evolving lesion areas of pre-existing lesions predicted subsequent composite disability progression with consistent trends on all components of the composite. In contrast, whole brain volume loss and acute lesion activity measured by longitudinal T1 hypointense lesion volume accumulation in new focal T2 lesions did not predict subsequent composite disability progression in this trial at the population level. Ocrelizumab reduced longitudinal measures of chronic lesion activity such as T1 hypointense lesion volume accumulation and mean normalized T1 signal intensity decrease both within regions of pre-existing T2 lesions identified as slowly expanding/evolving and in non-slowly expanding/evolving lesions. Using conventional brain MRI, T1-weighted intensity-based measures of chronic white matter lesion activity predict clinical progression in primary progressive multiple sclerosis and may qualify as a longitudinal in vivo neuroimaging correlate of smouldering demyelination and axonal loss in chronic active lesions due to CNS-resident inflammation and/or secondary neurodegeneration across the multiple sclerosis disease continuum.

The blood-brain barrier (BBB) regulates cerebrovascular permeability and leakage of blood-derived fibrinogen. Dysfunction of the BBB has been associated with cerebral arteriolosclerosis small vessel disease (SVD) and white matter lesions (WML). Furthermore, BBB dysfunction is associated with the pathogenesis of Alzheimer's disease (AD) with the presence of CSF plasma proteins suggested to be a potential biomarker of AD. We aimed to determine if extravascular fibrinogen in the white matter was associated with the development of AD hallmark pathologies, i.e., hyperphosphorylated tau (HPτ) and amyloid-β (Aβ), as well as SVD, cerebral amyloid angiopathy (CAA) and measures of white matter damage. Using human post-mortem brains, parietal tissue from 20 AD and 22 non-demented controls was quantitatively assessed for HPτ, Aβ, white matter damage severity, axonal density, demyelination and the burden of extravascular fibrinogen in both WML and normal appearing white matter (NAWM). SVD severity was determined by calculating sclerotic indices. WML- and NAWM fibrinogen burden was not significantly different between AD and controls nor was it associated with the burden of HPτ or Aβ pathology, or any measures of white matter damage. Increasing severity of SVD was associated with and a predictor of both higher WML- and NAWM fibrinogen burden (all P

Aim: To explore whether immune checkpoint inhibitors (ICIs) increase the incidence of radiation-induced brain injury in lung cancer patients with brain metastases. Methods: According to whether they received ICIs within 6 months before and after cranial radiotherapy (CRT), all patients were divided into two groups: ICIs + CRT group and CRT + non-ICIs group. Results: The incidence of radiation necrosis (RN) in the CRT + ICIs group was 14.3%, while that in the CRT + non-ICIs group was 5.8% (p = 0.090). If ICIs were used within 3 months of CRT, there was statistical significance. A maximum diameter of brain metastasis >3.3 cm and cumulative radiation dose of metastatic lesions >75.7 Gy were risk factors for RN. Conclusion: ICIs could increase the risk of RN, especially when used within 3 months of CRT. [ABSTRACT FROM AUTHOR]

Introduction: Patients with transient ischemic attack (TIA) and minor stroke demonstrate cognitive impairment, and a four-fold risk of late-life dementia. Aim: To study the extent to which the rates of brain volume loss in TIA patients differ from healthy controls and how they are correlated with cognitive impairment. Methods: TIA or minor stroke patients were tested with a neuropsychological battery and underwent T1 weighted volumetric magnetic resonance imaging scans at fixed intervals over a 3 years period. Linear mixed effects regression models were used to compare brain atrophy rates between groups, and to determine the relationship between atrophy rates and cognitive function in TIA and minor stroke patients. Results: Whole brain atrophy rates were calculated for the TIA and minor stroke patients; n = 38 between 24 h and 18 months, and n = 68 participants between 18 and 36 months, and were compared to healthy controls. TIA and minor stroke patients demonstrated a significantly higher whole brain atrophy rate than healthy controls over a 3 years interval (p = 0.043). Diabetes (p = 0.012) independently predicted higher atrophy rate across groups. There was a relationship between higher rates of brain atrophy and processing speed (composite P = 0.047 and digit symbol coding P = 0.02), but there was no relationship with brain atrophy rates and memory or executive composite scores or individual cognitive tests for language (Boston naming, memory recall, verbal fluency or Trails A or B score). Conclusion: TIA and minor stroke patients experience a significantly higher rate of whole brain atrophy. In this cohort of TIA and minor stroke patients changes in brain volume over time precede cognitive decline.

Cerebral white matter lesion (WML) and lacunar infarction (LI) were primary causes of cognitive deficit. Our study aimed to investigate the correlation between LI and cognitive deficit in the elderly with WML. A total of 118 participants (96 WML patients and 22 controls) were consecutively enrolled according to neuroimaging diagnosis of magnetic resonance imaging for this retrospective study. Neuroimaging evaluation and cognitive function assessment were analyzed. Compared with the controls, moderate and severe WML groups had significantly lower scores of Mini-mental State Examination (MMSE) and Montreal Cognitive Assessment (MOCA). Most cognitive domains of MOCA scores decreased, corresponding to the severity of WMLs. While there was no significant difference in score of MMSE between deep WML (DWML) and periventricular WML (PVL) groups, the scores of visuospatial/executive and naming function domains of MOCA appeared to be low in the DWML group. The scores of MMSE and MOCA were higher in only WMLs (WML−) group than WMLs combined with LIs (WML+) group, except for the naming cognitive domain. Moreover, LIs were independently correlated with the cognitive deficit in the elderly with WMLs. In the elderly with WMLs, the presence of LIs is associated with further aggravation of cognitive deficit.

Rationale & Objective: Chronic kidney disease, defined by albuminuria and/or reduced estimated glomerular filtration rate (eGFR), has been reported to be associated with brain atrophy and/or higher white matter lesion volume (WMLV), but there are few large-scale population-based studies assessing this issue. This study aimed to examine the associations between the urinary albumin-creatinine ratio (UACR) and eGFR levels and brain atrophy and WMLV in a large-scale community-dwelling older population of Japanese. Study Design: Population-based cross-sectional study. Setting & Participants: A total of 8,630 dementia-free community-dwelling Japanese aged greater than or equal to 65 years underwent brain magnetic resonance imaging scanning and screening examination of health status in 2016-2018. Exposures: UACR and eGFR levels. Outcomes: The total brain volume (TBV)-to-intracranial volume (ICV) ratio (TBV/ICV), the regional brain volume-to-TBV ratio, and the WMLV-to-ICV ratio (WMLV/ICV). Analytical Approach: The associations of UACR and eGFR levels with the TBV/ICV, the regional brain volume-to-TBV ratio, and the WMLV/ICV were assessed by using an analysis of covariance. Results: Higher UACR levels were significantly associated with lower TBV/ICV and higher geometric mean values of the WMLV/ICV (P for trend = 0.009 and

Postoperative cognitive dysfunction (POCD) is a common complication of the central nervous system after surgery, especially in elderly patients. Many factors can influence POCD, one of which is white matter lesion. Nowadays, stellate ganglion block (SGB) is considered as an effective intervention for postoperative cognitive dysfunction and SIRT1 may play a role in that, but the exact mechanism remains unclear. Therefore, the underlying mechanisms that SGB improves postoperative cognitive dysfunction through SIRT1 in aged rats and its association with white matter lesion are yet to be elucidated. The role of SIRT1 in the process that stellate ganglion block improves the cognitive impairment, and its association with white matter lesion was investigated using splenectomy-induced POCD model. To investigate this result further, we performed transection of the cervical sympathetic trunk on the basis of POCD model, and the role of SIRT1 was then verified again by intraperitoneal injection of EX527 (5 mg/kg) five min before surgery. Data show that SGB treatment has neuroprotective effects in POCD rats. SGB treatment can ameliorate cognitive impairment, neuroinflammation and neuronal apoptosis in white matter. Moreover, SGB treatment enhanced the expression of SIRT1 in the hippocampus and white matter, decreased NF-κB activity in the hippocampus and white matter. It also increased the levels of inflammatory factor in serum and white matter, primarily at the level of anti-inflammatory factor. These findings indicated that SIRT1-mediate white matter repair could be a new therapeutic target for neurodegenerative illnesses. [ABSTRACT FROM AUTHOR]

Background: The diagnostic value of carotid plaque characteristics based on higher-resolution vessel wall MRI (HRVW-MRI) combined with white matter lesion (WML) burden for the risk of ischemic stroke is unclear., Purpose: To combine carotid plaque features and WML burden to construct a hybrid model for evaluating ischemic stroke severity and prognosis in patients with symptomatic carotid artery stenosis., Study Type: Retrospective., Subjects: One hundred and ninty-three patients with least one confirmed carotid atherosclerotic stenosis ≥30% and cerebrovascular symptoms within the last 2 weeks (136 in the training cohort and 57 in the test cohort)., Field Strength/sequence: 3.0T, T2-weighted fluid attenuated inversion recovery (T2-FLAIR) and diffusion-weighted imaging (DWI); HRVW-MRI: 3D T1-weighted variable flip angle fast spin-echo sequences (VISTA), T2-weighted VISTA, simultaneous noncontrast angiography and intraplaque hemorrhage (SNAP), and contrast-enhanced T1-VISTA., Assessment: The following features of the plaques or vessel wall were assessed by three MRI readers independently: calcification (CA), intraplaque hemorrhage (IPH), lipid-rich necrotic core (LRNC), ulceration, plaque enhancement (PE), maximum vessel diameter (Max VD), maximum wall thickness (Max WT), total vessel area (TVA), lumen area (LA), plaque volume, and lumen stenosis. WMLs were graded visually and categorized as absent-to-mild WMLs (Fazekas score 0-2) or moderate-severe WMLs (Fazekas score 3-6). WML volumes were quantified using a semiautomated volumetric analysis program. Modified Rankin scores (mRS) were assessed at 90 days, following an outpatient interview, or by telephone., Statistical Tests: LASSO-logistic regression analysis was performed to construct a model. The performance of the model was evaluated using receiver operating characteristic (ROC) curve analyses, calibration curves, decision curve analyses, and clinical imaging curves. Conditional logistic regression analysis was used to explore the associations between the hybrid model-derived score and the modified Rankin Scale (mRS) score at 90 days., Results: The model was constructed using five selected features, including IPH, plaque enhancement, ulceration, NWI, and total Fazekas score in deep WMLs (DWMLs). The hybrid model yielded an area under the curve of 0.92 (95% confidence interval [CI] 0.87-0.97) in the training cohort and 0.88 (0.80-0.96) in the test cohort. Furthermore, the hybrid model-derived score (odds ratio = 1.28; 95% CI 1.06-1.53) was independently associated with the mRS score 90 days after stroke., Data Conclusions: The hybrid model constructed using MRI plaque characteristics and WML burden has potential to be an effective noninvasive method of assessing ischemic stroke severity. The model-derived score has promising utility in judging neurological function recovery., Technical Efficacy: Stage 2., (© 2024 International Society for Magnetic Resonance in Medicine.)

Background: Lesions in the periventricular, (juxta)cortical, and infratentorial region, as visible on brain MRI, are part of the diagnostic criteria for Multiple sclerosis (MS) whereas lesions in the subcortical region are currently only a marker of disease activity. It is unknown whether MS lesions follow individual spatial patterns or whether they occur in a random manner across diagnostic regions. Aim: First, to describe cross-sectionally the spatial lesion patterns in patients with MS. Second, to investigate the spatial association of new lesions and lesions at baseline across diagnostic regions. Methods: Experienced neuroradiologists analyzed brain MRI (3D, 3T) in a cohort of 330 early MS patients. Lesions at baseline and new solitary lesions after two years were segmented (manually and by consensus) and classified as periventricular, (juxta)cortical, or infratentorial (diagnostic regions) or subcortical—with or without Gadolinium-enhancement. Gadolinium enhancement of lesions in the different regions was compared by Chi square test. New lesions in the four regions served as dependent variable in four zero-inflated Poisson models each with the six independent variables of lesions in the four regions at baseline, age and gender. Results: At baseline, lesions were most often observed in the subcortical region (mean 13.0 lesions/patient), while lesion volume was highest in the periventricular region (mean 2287 µl/patient). Subcortical lesions were less likely to show gadolinium enhancement (3.1 %) than juxtacortical (4.3 %), periventricular (5.3 %) or infratentorial lesions (7.2 %). Age was inversely correlated with new periventricular, juxtacortical and subcortical lesions. New lesions in the periventricular, juxtacortical and infratentorial region showed a significant autocorrelative behavior being positively related to the number of lesions in the respective regions at baseline. New lesions in the subcortical region showed a different behavior with a positive association with baseline periventricular lesions and a negative association with baseline infratentorial lesions. Conclusion: Across regions, new lesions do not occur randomly; instead, new lesions in the periventricular, juxtacortical and infratentorial diagnostic region are associated with that at baseline. Lesions in the subcortical regions are more closely related to periventricular lesions. Moreover, subcortical lesions substantially contribute to lesion burden in MS but are less likely to show gadolinium enhancement (than lesions in the diagnostic regions).

Background: Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is a new autoimmune disease of CNS, that can be associated with other autoimmune diseases, also about 20% of them are related to neoplasms. This disease is usually single-episode and is resolved with a course of corticosteroids. But in recurrent cases, maintenance treatment is required, in which case the choice of treatment is challenging, especially if there is another autoimmune disease at the same time.Case presentation: Here, a 37-year-old man is introduced who suffered from hallucinations and visual and auditory hallucinations along with a convulsion, followed by ataxia and headache. On examination, the patient had vitiligo lesions that had not been treated before. In the patient's MRI, typical GFAP astrocytopathy lesions were seen, and due to a period of recurrence of symptoms after initial treatment with corticosteroid pulse, the patient was treated with plasmapheresis and then rituximab.Discussion: Considering that the patient's symptoms were initially purely psychiatric and he had a history of substance abuse, the diagnosis is at risk of misdiagnosis and the lack of diagnostic criteria for this disease makes the diagnosis more difficult. This patient had another treatment challenge due to the simultaneous presence of another autoimmune disease and the recurrence of symptoms after a course of treatment. Anyway, according to the experience of using anti-CD20 in similar autoimmune diseases, it seems reasonable to use rituximab in this patient.Conclusion: Due to the rarity and novelty of this disease and the smaller number of patients who relapse, fewer studies have been published in this field, and choosing the appropriate treatment for these patients requires more and more detailed studies.

Background and purpose: As a part of the natural course of ischemic stroke, hemorrhagic transformation (HT) is a serious complication after reperfusion treatment, which may affect the prognosis of patients with ischemic stroke. White matter lesions (WMLs) refer to focal lesions on neuroimaging and have been suggested to indicate a high risk of HT. This systematic review and meta-analysis aimed to summarize current evidence on the relation between WML and HT. Methods: This systematic review was prepared with reference to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We searched PubMed, Embase, Web of Science, and Cochrane Library databases for publications on WML and HT in patients with ischemic stroke. Odds ratios (ORs) and 95% confidence intervals (CIs) from eligible studies were combined to quantify the association between the severity of WML and the risk of HT. In addition, the descriptive analysis was adopted to evaluate the influence of different WML distributions on predicting HT. Results: A total of 2,303 articles were identified after removing duplicates through database searching, and 41 studies were included in our final analysis. The meta-analysis showed that the presence of WML was associated with HT (OR = 1.62, 95%CI 1.08–2.43, p = 0.019) and symptomatic intracerebral hemorrhage (sICH) (OR = 1.64, 95%CI 1.17–2.30, p = 0.004), and moderate-to-severe WML indicated a high risk of HT (OR = 2.03, 95%CI 1.33–3.12, p = 0.001) and sICH (OR = 1.92, 95%CI 1.31–2.81, p < 0.001). The dose–response meta-analysis revealed risk effects of increasing the severity of WML on both HT and ICH. In addition, both periventricular WML (PWML) (five of seven articles) and deep WML (DWML) (five of six articles) were shown to be associated with HT. Conclusions: White matter lesions are associated with overall HT and sICH in patients with ischemic stroke, and more severe WMLs indicate a high risk of HT and sICH. In addition, both PWML and DWMLs could be risk factors for HT. [ABSTRACT FROM AUTHOR]

We investigated whether myelin is associated with gait parameters in older adults with cerebral small vessel disease (cSVD). Cross-sectional data from sixty-four participants with cSVD and mild cognitive impairment were analyzed. Myelin was assessed via MRI multi-echo gradient and spin echo T 2 relaxation sequence, indexed as myelin water fraction (MWF). Gait was assessed using an electronic walkway. Hierarchical regression models adjusting for total intracranial volume, age, sex, Mini-Mental State Examination, and body mass index were conducted to determine associations between MWF and gait parameters. Significant models were further adjusted for white matter hyperintensities. Sixty-four participants were included (mean [SD], age = 75.2y [5.4], 62.5% female). In adjusted models, lower MWF in the cingulum (p = 0.015), superior longitudinal fasciculus (p = 0.034), posterior corona radiata (p = 0.039), and body of the corpus callosum (p = 0.040) was associated with higher cycle time variability. White matter hyperintensities weakened these associations. Lower myelin in specific white matter tracts may contribute to higher gait variability, increasing the overall risk of mobility impairment. [ABSTRACT FROM AUTHOR]

Heavy alcohol consumption is associated with deleterious changes in the brain but associations of moderate alcohol intake are not well understood. We examined the association of alcohol consumption with brain white matter health in 377 middle-aged men (56-66 years old; mean 61.8 ± 2.6 years) who were participants in the Vietnam Era Twin Study of Aging (VETSA). T1-, T2-, proton density-, and diffusion-weighted magnetic resonance images were obtained. Diffusion measures were quantified from 12 major white matter tracts. Global white matter lesion (WML) burden was also quantified. Mixed effects linear models examined differences in diffusivity and WMLs by amount of alcohol intake. Analyses adjusted for numerous demographic, health, and lifestyle variables. An inverted-U association was found between alcohol intake and fractional anisotropy (FA) in several tracts, including the inferior-frontal-occipital fasciculus, uncinate fasciculus, superior longitudinal fasciculus, the forceps minor and the anterior thalamic radiations. In these tracts, FA increased with increasing alcohol intake, peaking with moderate alcohol intake (9-28 drinks in 14 days), and declining with heavier intake. Associations remained significant after exclusion of individuals with diabetes or hypertension. There was a U-shaped association in WML burden with highest burden among never drinkers and heavy drinkers (>28 drinks in 14 days). This association was no longer significant after exclusion of individuals with hypertension, since WML burden among heavy drinkers no longer differed from that of other drinkers. This suggests that hypertension related to heavy alcohol intake may contribute to WML burden observed among heavy drinkers. Together, these correlational results suggest that among middle-aged men, moderate drinking may be associated with metrics of better white matter health, particularly microstructural measures, whereas drinking beyond recommended guidelines may be associated with both microstructural and macrostructural white matter damage.

• With differences between SVD and LVD, the prevalences of SVDs were associated with severe CA stenoses. • SVD includes white matter lesions, LI and CMBs, however CMBs were not associated with severe CA stenoses. • Hyperlipidemia related to atherosclerosis might reduce the prevalence of deep CMBs and mixed CMBs. Small vessel diseases (SVDs) are often asymptomatic. However, SVDs significantly influence the prognosis in patients with large vessel diseases (LVDs). We investigated asymptomatic cerebral findings on 3-Tesla MRI in patients with severe carotid artery (CA) stenoses, compared to peoples without a past history of neurological disorders, including strokes. We retrospectively analyzed the prevalences of various asymptomatic cerebral findings which were intracerebral hemorrhages (ICHs), cortical superficial siderosis, ventricular dilatation (Evans' index) and SVDs including cerebral microbleeds (CMBs), lacunar infarctions (LIs), deep white matter hyperintensities (WMHs), periventricular hyperintensities (PVHs). The prevalence of each finding was compared using multivariate logistic regression models with adjustment for stroke risk factors. We evaluated the findings in 54 patients with severe CA stenosis treated by stenting (CA stenosis group) and 200 adults with health screening tests of the brain and no past history of neurological disorders (control group). Multivariate analyses adjusted for age ≥ 65 years old, female gender, hypertension, hyperlipidemia, diabetes mellitus, alcohol consumption, and smoking index revealed that the prevalences of severe PVHs, severe deep WMHs, asymptomatic deep ICHs, and asymptomatic LIs were significantly higher in the CA stenosis group than the control group. However, there were no significant differences in the prevalences of CMBs, or the remaining asymptomatic findings described above. With pathological differences between SVD and LVD, asymptomatic SVDs except CMBs and deep ICHs often co-exists severe CA stenosis as a presentative LVD. [ABSTRACT FROM AUTHOR]

Background Schizophrenia is a psychiatric disorder including multiple clinical symptoms such as severe psychosis and cognitive dysfunction. DHF-7 is a novel dihydroflavanone derivative that was designed and synthesized to treat schizophrenia. This study aimed to investigate the effects and mechanisms of DHF-7 in a mouse model of schizophrenia induced by a combination of cuprizone and MK-801. Methods After intragastric administration of DHF-7 for 7 weeks, open field, Y-maze, and novel object recognition tests were performed to detect behavioral changes in the mouse model. White matter lesions and myelin loss were determined using transmission electron microscopy and oil red O staining. Western blotting and immunohistochemistry were used to detect the expression of the related proteins. Results The results showed that DHF-7 treatment significantly improved cognitive impairment and positive symptoms in the model mice. Moreover, DHF-7 alleviated white matter lesions and demyelination and promoted the differentiation and maturation of oligodendrocytes for remyelination in the corpus callosum of model mice. The mechanistic study showed that DHF-7 increased the expression of brain-derived neurotrophic factor and phosphorylated Fyn, thus activating the tyrosine kinase receptor B (Trk B)/Fyn/N-methyl-D-aspartate receptor subunit 2 B (NMDAR2B) and Raf/mitogen-activated protein kinase (MEK)/ extracellular signal-related kinase (ERK) signaling pathways. Conclusions Our results provide an experimental basis for the development of DHF-7 as a novel therapeutic agent for schizophrenia. [ABSTRACT FROM AUTHOR]

Abstract Background Subcortical ischemic vascular dementia, one of the major subtypes of vascular dementia, is characterized by lacunar infarcts and white matter lesions caused by chronic cerebral hypoperfusion. In this study, we used a mouse model of bilateral common carotid artery stenosis (BCAS) to investigate the role of B-cell translocation gene 2 (BTG2), an antiproliferation gene, in the white matter glial response to chronic cerebral hypoperfusion. Methods Btg2 −/− mice and littermate wild-type control mice underwent BCAS or sham operation. Behavior phenotypes were assessed by open-field test and Morris water maze test. Brain tissues were analyzed for the degree of white matter lesions and glial changes. To further confirm the effects of Btg2 deletion on proliferation of glial cells in vitro, BrdU incorporation was investigated in mixed glial cells derived from wild-type and Btg2 −/− mice. Results Relative to wild-type mice with or without BCAS, BCAS-treated Btg2 −/− mice exhibited elevated spontaneous locomotor activity and poorer spatial learning ability. Although the severities of white matter lesions did not significantly differ between wild-type and Btg2 −/− mice after BCAS, the immunoreactivities of GFAP, a marker of astrocytes, and Mac2, a marker of activated microglia and macrophages, in the white matter of the optic tract were higher in BCAS-treated Btg2 −/− mice than in BCAS-treated wild-type mice. The expression level of Gfap was also significantly elevated in BCAS-treated Btg2 −/− mice. In vitro analysis showed that BrdU incorporation in mixed glial cells in response to inflammatory stimulation associated with cerebral hypoperfusion was higher in Btg2 −/− mice than in wild-type mice. Conclusion BTG2 negatively regulates glial cell proliferation in response to cerebral hypoperfusion, resulting in behavioral changes.

Abstract Background White matter hyperintensities (WMH) are frequently found in Alzheimer’s disease (AD). Commonly considered as a marker of cerebrovascular disease, regional WMH may be related to pathological hallmarks of AD, including beta-amyloid (Aβ) plaques and neurodegeneration. The aim of this study was to examine the regional distribution of WMH associated with Aβ burden, glucose hypometabolism, and gray matter volume reduction. Methods In a total of 155 participants (IMAP+ cohort) across the cognitive continuum from normal cognition to AD dementia, FLAIR MRI, AV45-PET, FDG-PET, and T1 MRI were acquired. WMH were automatically segmented from FLAIR images. Mean levels of neocortical Aβ deposition (AV45-PET), temporo-parietal glucose metabolism (FDG-PET), and medial-temporal gray matter volume (GMV) were extracted from processed images using established AD meta-signature templates. Associations between AD brain biomarkers and WMH, as assessed in region-of-interest and voxel-wise, were examined, adjusting for age, sex, education, and systolic blood pressure. Results There were no significant associations between global Aβ burden and region-specific WMH. Voxel-wise WMH in the splenium of the corpus callosum correlated with greater Aβ deposition at a more liberal threshold. Region- and voxel-based WMH in the posterior corpus callosum, along with parietal, occipital, and frontal areas, were associated with lower temporo-parietal glucose metabolism. Similarly, lower medial-temporal GMV correlated with WMH in the posterior corpus callosum in addition to parietal, occipital, and fontal areas. Conclusions This study demonstrates that local white matter damage is correlated with multimodal brain biomarkers of AD. Our results highlight modality-specific topographic patterns of WMH, which converged in the posterior white matter. Overall, these cross-sectional findings corroborate associations of regional WMH with AD-typical Aß deposition and neurodegeneration.

Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system, where ongoing demyelination and remyelination failure are the major factors for progressive neurological disability. In this report, we employed a comprehensive proteomic approach and immunohistochemical validation to gain insight into the pathobiological mechanisms that may be associated with the progressive phase of MS. Isolated proteins from myelinated regions, demyelinated white-matter lesions (WMLs), and gray-matter lesions (GMLs) from well-characterized progressive MS brain tissues were subjected to label-free quantitative mass spectrometry. Using a system-biology approach, we detected increased expression of proteins belonging to mitochondrial electron transport complexes and oxidative phosphorylation pathway in WMLs. Intriguingly, many of these proteins and pathways had opposite expression patterns and were downregulated in GMLs of progressive MS brains. A comparison to the human MitoCarta database mapped the mitochondrial proteins to mitochondrial subunits in both WMLs and GMLs. Taken together, we provide evidence of opposite expression of mitochondrial proteins in response to demyelination of white- and gray-matter regions in progressive MS brain. Graphical summary of the main findings of the study. [ABSTRACT FROM AUTHOR]

Oligodendrocytes are vulnerable to genetic and environmental insults and its injury leads to demyelinating diseases. The roles of ErbB receptors in maintaining the CNS myelin integrity are largely unknown. Here, we overactivate ErbB receptors that mediate signaling of either neuregulin (NRG) or epidermal growth factor (EGF) family growth factors and found their synergistic activation caused deleterious outcomes in white matter. Sustained ErbB activation induced by the tetracycline-dependent mouse tool Plp-tTA resulted in demyelination, axonal degeneration, oligodendrocyte precursor cell (OPC) proliferation, astrogliosis, and microgliosis in white matter. Moreover, there was hypermyelination before these inflammatory pathologic events. In contrast, sustained ErbB activation induced by another tetracycline-dependent mouse tool Sox10+/rtTA caused hypomyelination in the corpus callosum and optic nerve, which appeared to be a developmental deficit and did not associate with OPC regeneration, astrogliosis, or microgliosis. By tracing the differentiation states of cells expressing tetracycline-controlled transcriptional activator (tTA)/reverse tTA (rtTA)-dependent transgene or pulse-labeled reporter proteins in vitro and in vivo, we found that Plp-tTA targeted mainly mature oligodendrocytes (MOs), whereas Sox10+/rtTA targeted OPCs and newly-formed oligodendrocytes (NFOs). The distinct phenotypes of mice with ErbB overactivation induced by Plp-tTA and Sox10+/rtTA consolidated their nonoverlapping targeting preferences in the oligodendrocyte lineage, and enabled us to demonstrate that ErbB overactivation in MOs induced necroptosis that caused inflammatory demyelination, whereas in OPCs induced apoptosis that caused noninflammatory hypomyelination. Early interference with aberrant ErbB activation ceased oligodendrocyte deaths and restored myelin development in both mice. This study suggests that aberrant ErbB activation is an upstream pathogenetic mechanism of demyelinating diseases, providing a potential therapeutic target. [ABSTRACT FROM AUTHOR]

In this article, we introduce less-known features of white matter lesions in patients with multiple sclerosis, which can be identified on MR sequences sensitive to changes in local susceptibility. The central vein sign indicates a finding of a vein passing through a white matter lesion and can be found in more than half of the white matter lesions in patients with multiple sclerosis. The iron rim sign is a thin annular rim of a white matter lesion caused by accumulation of iron laden macrophages and microglia, typically in chronic-active lesions. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system, where ongoing demyelination and remyelination failure are the major factors for progressive neurological disability. In this report, we employed a comprehensive proteomic approach and immunohistochemical validation to gain insight into the pathobiological mechanisms that may be associated with the progressive phase of MS. Isolated proteins from myelinated regions, demyelinated white-matter lesions (WMLs), and gray-matter lesions (GMLs) from well-characterized progressive MS brain tissues were subjected to label-free quantitative mass spectrometry. Using a system-biology approach, we detected increased expression of proteins belonging to mitochondrial electron transport complexes and oxidative phosphorylation pathway in WMLs. Intriguingly, many of these proteins and pathways had opposite expression patterns and were downregulated in GMLs of progressive MS brains. A comparison to the human MitoCarta database mapped the mitochondrial proteins to mitochondrial subunits in both WMLs and GMLs. Taken together, we provide evidence of opposite expression of mitochondrial proteins in response to demyelination of white- and gray-matter regions in progressive MS brain.

Fingolimod and natalizumab are approved disease-modifying drugs in relapsing–remitting multiple sclerosis (RRMS). The two drugs have different modes of action and may therefore influence different aspects of MS-related tissue damage. In this retrospective cohort study, we longitudinally compared patients treated with fingolimod and patients treated with natalizumab by measures based on structural magnetic resonance imaging (MRI). We included patients with RRMS given that two standardized MRI scans under the same drug were available with an interval of at least 6 months both from therapy start to baseline scan and from baseline scan to follow-up scan. After matching for age, baseline and follow-up scans from 93 patients (fingolimod, 48; natalizumab, 45) were investigated. Mean follow-up time was 1.9 years. We determined the number of new white matter lesions as well as thalamic, cortical, and whole-brain atrophy. After scaling for time of the interscan interval, measures were analyzed by group comparisons and, to account for demographic and clinical characteristics, by multiple regression models and a binary logistic regression model. Compared to natalizumab, fingolimod treatment went along with more new white matter lesions (median [interquartile range, IQR] 0.0 [0.0; 0.7] vs. 0.0 [0.0; 0.0] /year; p < 0.01) whereas whole-brain atrophy was lower (median [IQR] 0.2 [0.0; 0.5] vs. 0.5 [0.2; 1.0] %/year; p = 0.01). These significant differences were confirmed by multiple regression models and the binary logistic regression model. In conclusion, our observation is compatible with stronger neuroprotective properties of fingolimod compared to natalizumab. [ABSTRACT FROM AUTHOR]

• A novel mouse model of schizophrenia was established by MK-801 plus Cuprizone. • The novel model showed severe memory deficits, hyperactivity and anxiety disorder. • The novel model showed obvious demyelination and white matter damage. • The novel model displayed dysregulations in Fyn and NMDARs. Schizophrenia is a mental illness characterized by episodes of psychosis, apathy, social withdrawal, and cognitive impairment. White matter lesions and glutamatergic hypofunction are reported to be the key pathogeneses underlying the multiple clinical symptoms of schizophrenia. Cuprizone (CPZ) is a copper chelator that selectively injures oligodendrocytes, and MK-801 is an antagonist of the N -methyl d -aspartate (NMDA) receptor. To better mimic the psychosis and complicated pathogenesis of schizophrenia, a novel possible mouse model was established by the combination of CPZ and MK-801. After exposure to CPZ for 5 weeks, the mice received a daily intraperitoneal injection of MK-801 for 2-weeks. Behavioral changes in the mouse model were evaluated using Y-maze, object recognition, and open field tests. Pathological changes were observed by transmission electron microscopy, oil red O staining, immunohistochemistry, and western blotting. The results showed that the novel mouse model induced by CPZ plus MK-801 exhibited severe spatial and recognition memory deficits, hyperactivity, and anxiety disorder. Moreover, the mice showed obvious demyelination and white matter damage and decreased expression levels of myelin basic protein (MBP) and 2′,3′-cyclic nucleotide-3′-phosphodiesterase (CNPase) in the corpus callosum. Furthermore, the phosphorylation levels of Fyn and NMDA receptor 2B in the corpus callosum and NMDA receptor 1 in the cerebral cortex were noticeably decreased. Taken together, the novel mouse model induced by the combination of cuprizone and MK-801 showed comprehensive behavioral and neurobiological changes, which might make it a suitable animal model for schizophrenia. [ABSTRACT FROM AUTHOR]