The pathophysiological mechanism of white matter hyperintensities of cerebral small vessel disease (CSVD) includes an impaired blood-brain barrier (BBB) with increased permeability. Neuroinflammation likely contributes to the disruption of the BBB in CSVD. Therefore, understanding the molecular mechanism of how neuroinflammation causes BBB damage is essential to preventing BBB disruption in CSVD. Matrix metalloproteinase 9 (MMP-9) contributes to BBB damage in neuroinflammatory diseases. In this study, we observed that interleukin-1β (IL-1β)-induced MMP-9 secretion in pericytes increased BBB permeability to sodium fluorescein (Na-F) by damaging the disruption of VE-cadherin, occludin, claudin-5, and zonula occludin-1 (ZO-1). Melatonin reduced BBB permeability to Na-F and inhibited the disruption of the adherens and tight junction proteins. Melatonin also downregulated MMP-9 and upregulated tissue inhibitor of metalloproteinases 1 (TIMP-1) gene expression, which decreased the MMP-9/TIMP-1 ratio. In addition, nuclear translocation of NF-κB/p65 induced by IL-1β in pericytes upregulated MMP-9 expression, which was inhibited by the NF-κB inhibitor PDTC. However, the NOTCH3 inhibitor DAPT significantly inhibited NF-κB/p65 translocation to the nucleus, while melatonin in combination with DAPT significantly prevented NF-κB/p65 translocation than DAPT alone. Our results suggest that melatonin reduced MMP-9-induced permeability of the BBB. Melatonin reduced MMP-9 expression and activity, which was induced by IL-1β through the regulation of the NOTCH3/NF-κB signaling pathway in pericytes, suggesting that pericytes regulate BBB integrity and function.

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ObjectiveAlzheimer's disease (AD) is the most common form of dementia characterized by memory loss at disease onset. The gene mutations in the amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) are the frequent causes of AD. However, the clinical and genetic features of AD overlap with other neurodegenerative diseases. The present study aimed to identify the clinical and genetic characteristics in a Han Chinese AD cohort.MethodsDetailed clinical assessment was applied to all the patients. We screened amyloid precursor protein (APP), PSEN1, PSEN2, and microtubule‐associated protein tau (MAPT) genes were assessed in 83 sporadic AD patients by Sanger sequencing. A total of 25 probands from families with AD were subjected to next‐generation sequencing on 53 dementia‐associated genes to capture the target region, and Sanger sequencing was used to detect the variants in the DNA sequence.Results PSEN1 p.L226R was found in an early‐onset AD (EOAD) family characterized by language impairment at disease onset, a novel probably pathogenetic variant (p.D534H) was identified in a frontal‐temporal dementia gene, TANK‐binding kinase 1 (TBK1) with a typical AD phenotype in a late‐onset AD (LOAD) family, and a PSEN2p.H169N mutation and two benign MAPT (p.Q230R and p.V48L) mutations were detected in three EOAD patients.ConclusionsThus, five variants were identified in a Han Chinese cohort. In the present study, a novel, probably damaging FTLD gene TBK1variant with a typical AD phenotype was detected. Also, the phenotypic characteristics of PSEN1 p.L226R, a PSEN2pathogenic mutation, and two likely benign MAPT variants were described. Hence, screening for mutations in other dementia genes could be further explored in clinically diagnosed AD patients.

Objective The purpose of this study was to identify the prevalence of severe headache or migraine and the association between dietary thiamine and riboflavin intake with headache history using a large, nationally representative population sample. Background Severe headache and migraine are common and disabling neurological disorders worldwide. Previous studies revealed that the B vitamin group, as an important nutrient of diet, can reduce migraine disability. Methods We performed a cross‐sectional study of American adults surveyed in the National Health and Nutrition Examination Survey (NHANES) 1999–2004. Information on headache history was collected in the Miscellaneous Pain section of the Questionnaire Data. Dietary intake data of thiamine and riboflavin were obtained by 24‐h dietary recall interview. Results The present study included 13,439 participants and indicated that 2745/13,439 (21.6%) adults (aged ≥20 years) experienced severe headache or migraine in the past 3 months. Dietary thiamine intake was significantly inversely associated with severe headache or migraine (odds ratio [OR] = 0.93, 95% confidence interval [CI] = 0.88–1.00, p = 0.046). In the stratified analysis, the relationship was maintained in the female group (OR = 0.90, 95% CI = 0.82–0.98, p = 0.022), and the sex interaction term was significant (p = 0.020). However, no significant interaction was found between the age groups (p = 0.352). For dietary riboflavin, no significant negative association was observed between dietary riboflavin intake and headache history (OR = 0.98, 95% CI = 0.94–1.02, p = 0.367). After stratifying by sex or age, there remained no significant relationship between dietary riboflavin and migraine. Conclusions We found that high intake of thiamine was significantly associated with lower odds of migraine, especially in females. In the future, more clinical studies are needed to confirm our conclusions, and additional experiments are needed to explore the possible mechanisms of prevention and treatment for migraine.