Intelligent cholinergic white matter pathways algorithm based on U-net reflects cognitive impairment in patients with silent cerebrovascular disease.

BACKGROUND AND OBJECTIVE: The injury of the cholinergic white matter pathway underlies cognition decline in patients with silent cerebrovascular disease (SCD) with white matter hyperintensities (WMH) of vascular origin. However, the evaluation of the cholinergic white matter pathway is complex with poor consistency. We established an intelligent algorithm to evaluate WMH in the cholinergic pathway. METHODS: Patients with SCD with WMH of vascular origin were enrolled. The Cholinergic Pathways Hyperintensities Scale (CHIPS) was used to measure cholinergic white matter pathway impairment. The intelligent algorithm used a deep learning model based on convolutional neural networks to achieve WMH segmentation and CHIPS scoring. The diagnostic value of the intelligent algorithm for moderate-to-severe cholinergic pathway injury was calculated. The correlation between the WMH in the cholinergic pathway and cognitive function was analysed. RESULTS: A number of 464 patients with SCD were enrolled in internal training and test set. The algorithm was validated using data from an external cohort comprising 100 patients with SCD. The sensitivity, specificity and area under the curve of the intelligent algorithm to assess moderate and severe cholinergic white matter pathway injury were 91.7%, 87.3%, 0.903 (95% CI 0.861 to 0.952) and 86.5%, 81.3%, 0.868 (95% CI 0.819 to 0.921) for the internal test set and external validation set. for the. The general cognitive function, execution function and attention showed significant differences among the three groups of different CHIPS score (all p<0.05). DISCUSSION: We have established the first intelligent algorithm to evaluate the cholinergic white matter pathway with good accuracy compared with the gold standard. It helps more easily assess the cognitive function in patients with SCD.

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

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

White matter integrity mediates the associations between white matter hyperintensities and cognitive function in patients with silent cerebrovascular diseases.

OBJECTIVE: To evaluate the relationships between cognitive function and white matter hyperintensity volume (WMHV) in patients with silent cerebrovascular disease and to investigate whether white matter integrity or brain atrophy play a role in this association. METHODS: Automated Fiber Quantification and Voxel- based morphometry were used to track and identify the integrity of 20 well-defined white matter tracts and to measure the gray matter volume (GMV). A linear regression model was applied for examining the associations between cognitive function and WMHV and mediation analysis was used to identify the roles of white matter integrity or GMV in the influence of WMHV on cognitive function. RESULTS: Two hundred and thirty-six individuals were included for analysis. Executive function was linearly associated with fractional anisotropy (FA) of the right interior frontal occipital fasciculus (IFOF) (ß = 0.193; 95% CI, 0.126 to 1.218) and with WMHV (ß = -0.188; 95% CI, -0.372 to -0.037). Information processing speed was linearly associated with WMHV (ß = -0.357; 95% CI, -0.643 to -0.245), FA of the right anterior thalamic radiation (ATR) (ß = 0.207; 95% CI, 0.116 to 0.920), and FA of the left superior longitudinal fasciculus (SLF) (ß = 0.177; 95% CI, 0.103 to 1.315). The relationship between WMHV and executive function was mediated by FA of the right IFOF (effect size = -0.045, 95% CI, -0.015 to -0.092). Parallel mediation analysis showed that the association between WMHV and information processing speed was mediated by FA of the right ATR (effect size = -0.099, 95% CI, -0.198 to -0.038) and FA of the left SLF (effect size = -0.038, 95% CI, -0.080 to -0.003). CONCLUSION: These findings suggest a mechanism by which WMH affects executive function and information processing speed by impairing white matter integrity. This may be helpful in providing a theoretical basis for rehabilitation strategies of cognitive function in patients with silent cerebrovascular diseases.

Vascular Remodeling, Oxidative Stress, and Disrupted PPARγ Expression in Rats of Long-Term Hyperhomocysteinemia with Metabolic Disturbance.

Hyperhomocysteinemia, a risk factor for vascular disease, is associated with metabolic syndrome. Our study was aimed at exploring the effect of long-term hyperhomocysteinemia with metabolic disturbances on vascular remodeling. We also studied oxidative stress and expression of PPARγ in the coronary arteriole as a possible mechanism underlying vascular remodeling. Rats were treated with standard rodent chow (Control) or diet enriched in methionine (Met) for 48 weeks. Plasma homocysteine, blood glucose, serum lipids, malondialdehyde (MDA), superoxide dismutase (SOD), and nitric oxide (NO) levels were measured. Coronary arteriolar and carotid arterial remodeling was assessed by histomorphometric techniques and the expression of PPARγ in vessel wall was investigated. In Met group, an increase in the level of fasting blood glucose, serum triglyceride, total cholesterol, MDA, and NO, a decline in the serum SOD level, and increased collagen deposition in coronary and carotid arteries were found. Moreover, we detected decreased expression of PPARγ in the coronary arterioles in Met group. In summary, our study revealed metabolic disturbances in this model of long-term hyperhomocysteinemia together with vascular remodeling and suggested that impaired oxidative stress, endothelium dysfunction, and decreased PPARγ expression in the vessel wall could be underlying mechanisms.

Mild hypothermia protects rat neuronal injury after intracerebral hemorrhage via attenuating endoplasmic reticulum response induced neuron apoptosis.

BACKGROUND AND PURPOSE: Mild hypothermia has been proved to reduce global and focal cerebral ischemic injury in rodents by preventing cellular apoptosis through several pathways. However, whether hypothermia will be beneficial for intracerebral hemorrhage (ICH) and its underlying mechanisms haven't reached a consensus. It has been implicated that endoplasmic reticulum (ER) stress plays a role in the secondary injury after ICH in rats. In this study, we aimed to investigate whether mild hypothermia would attenuate ICH induced neuronal injury via regulating ER stress. METHODS: The model of ICH was induced by injecting autologous blood (120µl) into the rat striatum. Rats were divided into sham, normothermic (NT) and hypothermic (HT) groups. HT group were subjected to mild hypothermia (33°C-35°C) for 2days starting from 6h after ICH. Neurological deficits were evaluated. The ER stress related proteins (GRP78, CHOP and p-eIF2α) and the apoptosis associated indicators (cleaved caspase3, Bcl-2 and Bim) around hematoma were assessed by western blot, qRT-PCR (quantificational real-time polymerase chain reaction), immunofluorescence and TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling) assay. RESULTS: Neurological deficits following ICH were reduced in HT group compared to NT group. Protein levels of GRP78, CHOP and p-eIF2α significantly increased after ICH in both NT and HT group compared to sham group, which was consistent with the trend of cleaved-caspase3 at protein level, and Bim, Bcl-2 at gene level. In comparison to NT group, GRP78, CHOP, p-eIF2α, cleaved caspase-3 and Bim all decreased, while Bcl-2 increased in HT group. Additionally, apoptotic cells detected by TUNEL staining significantly decreased in the HT group. CONCLUSION: Mild hypothermia could attenuate ICH caused neuron injury by decreasing ER response-induced neuron apoptosis.

Acute phase homocysteine related to severity and outcome of atherothrombotic stroke.

BACKGROUND: Homocysteine (HCY) is associated with risk of stroke, but whether HCY affects stroke severity and prognosis remains controversial. We hypothesized HCY has an impact on atherothrombosis and this prospective study was aimed to explore the association between acute phase HCY with stroke severity and outcome in patients with atherothrombosis. METHODS: Patients <72 h after symptom onset were categorized by the modified Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification and those typed as atherothrombosis were included. Neurologic function was assessed with National Institute of Health Stroke Score (NIHSS) <72 h after symptom onset and Modified Rankin Scale (mRS) and Barthel Index (BI) 6-month, 12-month and 18-month poststroke respectively. HCY was recorded <72 h after symptom onset. Participants were divided into hHCY (HCY>15 µmol/l) and nhHCY (HCY≤15 µmol/l). The correlation between HCY and mRS was analyzed. RESULTS: 125 of 130 participants without HCY interventional therapy completed the 18-month follow-up. There was no difference in demographics, histories of hypertension, diabetes mellitus, coronary heart disease, previous cerebral vascular event, and plasma low-density lipoprotein between hHCY and nhHCY. NIHSS, mRS were significantly higher and BI was significantly lower in hHCY than in nhHCY. The 18-month recurrence rate in hHCY (21.0%) was significantly higher than that in nhHCY (6.8%). Spearman correlation analysis revealed correlation between HCY and mRS (p=0.000). By ordinal logistic regression, HCY was an independent predictor of 18-month mRS (odds ratio 1.08, 95% confidence interval 1.04-1.13, p=0.000). CONCLUSIONS: Acute phase elevated HCY correlated with severity and prognosis in patients with atherothrombotic stroke.