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

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

Extracellular Vesicles Play a Central Role in Cerebral Venous Disease-Associated Brain Atrophy.

Cerebral venous abnormalities, distinct from traditional arterial diseases, have been linked to brain atrophy in a previous community-based cohort study, specifically in relation to the reduction of deep medullary veins (r-DMVs). To better understand the properties and biological functions of serum extracellular vesicles (EVs) in cerebral venous disease-associated brain atrophy, EVs are extracted from the serum of both participants with r-DMV and normal controls and analyzed their proteomic profiles using Tandem Mass Tag label quantitation analysis. Phenotypic experiments showed that EVs from individuals with r-DMVs are able to disrupt the normal functions of neurons, endothelial cells, and smooth muscle cells, and induce A1 reactive astrocytes. Additionally, this study provided a comprehensive characterization of the proteomic profile of DMV EVs and found that the collagen hydroxyproline is upregulated, while complement C3 is downregulated in the r-DMV group, suggesting that r-DMV may not be a simple pathological phenomenon and highlighting the potential involvement of EVs in the progression of brain atrophy in r-DMVs which has implications for the development of future therapeutic strategies.

Deep medullary veins are associated with widespread brain structural abnormalities.

Our aim is to investigate the association of cerebral deep medullary veins (DMVs) with white matter microstructural integrity and regional brain atrophy in MRI. In a community-based cohort of 979 participants (mean age 55.4 years), DMVs were identified on susceptibility-weighted imaging. Brain structural measurements including gray matter and hippocampus volumes, as well as diffusion tensor metrics, were evaluated. The mean (SD)number of DMVs was 19.0 (1.7). A fewer number of DMVs was related to lower fractional anisotropy and higher mean diffusivity in multiple voxels on the white matter skeleton (threshold-free cluster enhancement corrected p < 0.05, adjusted for age and sex). Also, fewer DMVs were significantly related to a lower gray matter fraction and a hippocampal fraction (0.10 and 0.11 per DMV, respectively; SE, 0.03 for both; p < 0.001 for both). A significant correlation between DMVs' reduction and cortical atrophy was observed in the bilateral occipital lobes, temporal lobes, hippocampus, and frontal lobes (p < 0.001, adjusted for age, sex, and total intracranial volume). Our results provided evidence that cerebral small venules disease play a role in brain parenchymal lesions and neurodegenerative processes.

Immunoreactivity and a new staining method of monocarboxylate transporter 1 located in endothelial cells of cerebral vessels of human brain in distinguishing cerebral venules from arterioles.

Distinguishing brain venules from arterioles with arteriolosclerosis is less reliable using traditional staining methods. We aimed to immunohistochemically assess the monocarboxylate transporter 1 (MCT1), a specific marker of venous endothelium found in rodent studies, in different caliber vessels in human brains. Both largeand small-caliber cerebral vessels were dissected from four autopsy donors. Immunoreactivity for MCT1 was examined in all autopsied human brain tissues, and then each vessel was identified by neuropathologists using hematoxylin and eosin stain, the Verhoeff's Van Gieson stain, immunohistochemical stain with antibodies for α-smooth muscle actin and MCT1 in sequence. A total of 61 cerebral vessels, including 29 arteries and 32 veins were assessed. Immunoreactivity for MCT1 was observed in the endothelial cells of various caliber veins as well as the capillaries, whereas that was immunenegative in the endothelium of arteries. The different labeling patterns for MCT1 could aid in distinguishing various caliber veins from arteries, whereas assessment using the vessel shape, the internal elastic lamina, and the pattern of smooth muscle fibers failed to make the distinction between small-caliber veins and sclerotic arterioles. In conclusion, MCT1 immunohistochemical staining is a sensitive and reliable method to distinguish cerebral veins from arteries.

Brain deep medullary veins on 3-T MRI in a population-based cohort.

Our aim is to investigate whether vascular risk factors are associated with cerebral deep medullary veins (DMVs) and whether DMVs are associated with MRI markers of cerebral small vessel disease (CSVD) or risk of stroke. In a community-based cohort of 1056 participants (mean age 55.7 years), DMVs were identified on susceptibility-weighted imaging (SWI) and counted in periventricular regions. Neuroimaging markers including lacunes, whiter matter hyperintensity (WMH), microbleeds, enlarged perivascular space, and brain atrophy were evaluated. The number of DMVs decreased with age (p = 0.007). After adjusting for age and sex, the number of DMVs was not associated with traditional vascular risk factors. Fewer DMVs was associated with increase of WMH and lacunes, but the association vanished after adjustment for vascular risk factors. However, fewer DMVs were independently associated with brain atrophy (p < 0.001). DMVs were not associated with three-year risk of stroke. Our results suggest that DMV is significantly different from other MRI markers of CSVD regarding risk factors, association with other CSVD markers, and risk of stroke. Nonetheless, the significant association between DMV and brain atrophy suggested the potential role of venules in age-related neurodegenerative process, which deserves further investigation.

Long Term Perinatal Deltamethrin Exposure Alters Electrophysiological Properties of Embryonic Ventricular Cardiomyocyte.

Increased use of pyrethroids and the exposure to pyrethroids for pregnant women and children have raised the concerns over the potential effect of pyrethroids on developmental cardiotoxicity and other abnormalities. The purpose of this study was to investigate whether long term perinatal deltamethrin exposure altered embryonic cardiac electrophysiology in mice. Pregnant mice were administered with 0 or 3 mg/kg of deltamethrin by gavage daily from gestational day (gd) 10.5 to gd 17. 5. Whole cell patch-clamp technique was used in electrophysiological study, and real time RT-PCR was applied to analyze the molecular changes for the electrophysiological properties. Deltamethrin exposure resulted in increased mortality of pregnant mice and decreased viability of embryos. Moreover, deltamethrin slowed the maximum depolarization velocity (Vmax), prolonged the action potential duration (APD) and depolarized the maximum diastolic potential (MDP) of embryonic cardiomyocytes. Additionally, perinatal deltamethrin exposure decreased the mRNA expression of Na+ channel regulatory subunit Navß1, inward rectifier K+ channel subunit Kir2.1, and delayed rectifier K+ channel subunit MERG while the L-type Ca2+ channel subunit, Cav1.2 expression was increased. On the contrary, deltamethrin administration did not significantly alter the regulation of ß-adrenergic or muscarinic receptor on embryonic cardiomyocytes. In conclusion, deltamethrin exposure at perinatal stage significantly alters mRNA expression of embryonic cardiac ion channels and therefore influences embryonic cardiac electrophysiological properties. This highlights the need to understand the persistent effects of pyrethroid exposure on cardiac function during embryonic development due to potential for cardiac arrhythmogenicity.

Large Vessel Disease Modifies the Relationship Between Kidney Injury and Cerebral Small Vessel Disease.

Background: Recent studies have shown that renal disease is associated with magnetic resonance imaging (MRI) markers of cerebral small vessel disease (CSVD), independent of traditional vascular risk factors. Although large artery lesions might be involved in the cerebrorenal association, evidence has been lacking. Methods: A total of 928 participants from a population-based cohort study were included. Kidney injury measurements included urinary albumin-to-creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR). CSVD was assessed on MRI by white matter hyperintensity volume (WMHV), lacunes, brain parenchymal fraction (BPF), cerebral microbleeds (CMBs), and perivascular space. Carotid plaques and brachial-ankle pulse wave velocity (baPWV) were used to assess large artery atherosclerosis and stiffness. Multivariable linear and logistic regression and additional interaction models were used for statistical analysis. Results: Individuals with elevated ACR had higher prevalence of lacunes and more WMHV (p = 0.001 and 0.000, respectively), those with decreased eGFR had smaller brain volume, higher prevalence of lacunes and deep CMBs (p = 0.009, p = 0.017) and p = 0.010 respectively). Interaction analysis revealed that carotid plaque and baPWV significantly enhanced the association between eGFR and BPF (p = 0.001 and p = 0.002, respectively), that is, the association of eGFR with BPF was only significant among participants with carotid plaque and higher baPWV. In addition, carotid plaque enhanced the association between ACR and WMHV (p = 0.034) and baPWV enhanced the association between ACR and the presence of lacunes (p = 0.027). Modifying effect of large vessel disease markers on the association between kidney injury measurements and CMBs was not significant. Conclusion: Evaluation of subclinical CVSD in individuals with kidney injury is warranted, especially in those with combined large artery disease.

Increased Soluble CD137 Levels and CD4+ T-Cell-Associated Expression of CD137 in Acute Atherothrombotic Stroke.

As a proinflammatory cytokine, CD137 (4-1BB, TNFRSF9) is present in membrane-bound and soluble forms. Increased expression of CD137 was recently found in T cells in human atherosclerotic plaques. However, the exact role of CD137 in ischemic stroke is not clear. In this study we analyzed the protein levels of soluble CD137 (sCD137) and the expression of CD137 on CD4+ T cells in the peripheral blood of patients with acute atherothrombotic stroke by using the cytometry beads array (CBA) and flow cytometry. Within 24 hours of onset, the stroke patients showed elevated levels of sCD137 (2.7 pg/ml) and CD137 expression on CD4+ T cells (4.9 ± 3.2%) compared with normal controls (1.1 pg/ml, P < 0.01; 1.3 ± 1.0%, P < 0.01). Alterations in CD137 expression may enhance ischemia-induced inflammatory responses via bidirectional signaling and, consequently, aggravate brain injury in early stages of this disorder.

No association of AQP4 polymorphisms with neuromyelitis optica and multiple sclerosis.

Multiple sclerosis (MS) and neuromyelitis optica (NMO) are inflammatory demyelinating disorders of the central nervous system (CNS). Various genetic and environmental factors have been identified to contribute to etiology of MS and NMO. Aquaporin 4 (AQP4), is the most abundant water channel in CNS. AQP4 is expressed in astrocytes of the brain, spinal cord, optic nerve and supportive cells in sensory organs. In contrast to MS, immunoreactivity of AQP4 is abolished in NMO lesions. However, conflicting results have been reported regarding the association between AQP4 polymorphisms and demyelinating disorders. Considering the ethnic differences of genetic variations, replications in other cohorts are required. In this study, single nucleotide polymorphisms (SNPs) of AQP4 gene in patients with NMO/neuromyelitis optica spectrum disorders (NMOSD), and MS in the Northern Han Chinese population were examined. Six selected AQP4 SNPs were genotyped by high-resolution melting (HRM) method. Compared with healthy control (HC), there was no significant difference of AQP4 allele and genotype frequency in MS or NMO/NMOSD group. This study showed no significant association of common AQP4 SNPs with MS or NMO/NMOSD, strongly suggesting that polymorphisms of AQP4 gene are unlikely to confer MS or NMO/NMOSD susceptibility, at least in Northern Han Chinese population.