Genome-Wide Mendelian Randomization Study Reveals Druggable Genes for Cerebral Small Vessel Disease.

BACKGROUND: Cerebral small vessel disease (CSVD) is a group of neurological disorders that affect the small blood vessels within the brain, for which no effective treatments are currently available. We conducted a Mendelian randomization (MR) study to identify candidate therapeutic genes for CSVD. METHODS: We retrieved genome-wide association study data from 6 recently conducted, extensive investigations focusing on CSVD magnetic resonance imaging markers and performed a 2-sample MR analysis to assess the potential causal effects of gene expression and protein level within druggable genes on CSVD in blood and brain tissues. Colocalization analyses and repeat studies were undertaken to verify the relationship. Additionally, mediation analysis was conducted to explore the potential mechanisms involving druggable genes and known risk factors for CSVD. Finally, phenome-wide MR analyses were applied to evaluate the potential adverse effects related to the identified druggable genes for CSVD treatment. RESULTS: Overall, 5 druggable genes consistently showed associations with CSVD in MR analyses across both the discovery and validation cohorts. Notably, the ALDH2 and KLHL24 genes were identified as associated with CSVD in both blood and brain tissues, whereas the genes ADRB1, BTN3A2, and EFEMP1 were exclusively detected in brain tissue. Moreover, mediation analysis elucidated the proportion of the total effects mediated by CSVD risk factors through candidate druggable genes, which ranged from 5.5% to 18.5%, and offered potential explanations for the observed results. A comprehensive phenome-wide MR analysis further emphasized both the therapeutic benefits and potential side effects of targeting these candidate druggable genes. CONCLUSIONS: This study provides genetic evidence supporting the potential therapeutic benefits of targeting druggable genes for treating CSVD, which will be useful for prioritizing CSVD drug development.

Automated diffusion-weighted image analysis along the perivascular space index reveals glymphatic dysfunction in association with brain parenchymal lesions.

Brain glymphatic dysfunction is critical in neurodegenerative processes. While animal studies have provided substantial insights, understandings in humans remains limited. Recent attention has focused on the non-invasive evaluation of brain glymphatic function. However, its association with brain parenchymal lesions in large-scale population remains under-investigated. In this cross-sectional analysis of 1030 participants (57.14 ± 9.34 years, 37.18% males) from the Shunyi cohort, we developed an automated pipeline to calculate diffusion-weighted image analysis along the perivascular space (ALPS), with a lower ALPS value indicating worse glymphatic function. The automated ALPS showed high consistency with the manual calculation of this index (ICC = 0.81, 95% CI: 0.662-0.898). We found that those with older age and male sex had lower automated ALPS values (ß = -0.051, SE = 0.004, p < .001, per 10 years, and ß = -0.036, SE = 0.008, p < .001, respectively). White matter hyperintensity (ß = -2.458, SE = 0.175, p < .001) and presence of lacunes (OR = 0.004, 95% CI < 0.002-0.016, p < .001) were significantly correlated with decreased ALPS. The brain parenchymal and hippocampal fractions were significantly associated with decreased ALPS (ß = 0.067, SE = 0.007, p < .001 and ß = 0.040, SE = 0.014, p = .006, respectively) independent of white matter hyperintensity. Our research implies that the automated ALPS index is potentially a valuable imaging marker for the glymphatic system, deepening our understanding of glymphatic dysfunction.

Value of conventional ultrasound and shear­wave elastography in the assessment of mesenteric lymphadenitis in a paediatric population.

The present retrospective study was designed to explore the value of conventional ultrasound (US) and Virtual Touch Tissue Imaging and Quantification (VTIQ) in the assessment of mesenteric lymphadenitis (ML) in a paediatric population. A total of 103 patients with ML and 60 healthy paediatric patients were examined. VTIQ was performed to assess mesenteric lymph node (MLN) stiffness via shear-wave velocity (SWV). Univariate and multivariate logistic regression analyses were conducted to reveal independent variables for the identification of ML. The diagnostic performance of US, and US combined with VTIQ, were compared. All the quantitative VTIQ parameters (including the SWVMean, SWVMax and SWVMin) were significantly greater for MLNs in the control group than for MLNs in the ML group (all P<0.001). The SWV values in the control group were nearly 2-fold greater than that in the ML group. According to the multivariate logistic regression analysis, the longest diameter [odds ratio (OR)=6.042; P=0.046] was revealed to be the strongest independent predictor for ML, followed by the CRP level (OR=2.310; P<0.001) and the SWVMean (OR=0.106; P<0.001). According to the receiver operating characteristic analysis, the area under the curve (AUC) for US combined with VTIQ was 0.890 (95% CI: 0.831-0.949) with a greater sensitivity of 91.26% and a greater specificity of 86.67% than that for US alone (AUC: 0.798; 95% CI: 0.724-0.872; sensitivity: 79.61%; specificity: 80.00%). A significant negative correlation between increased VTIQ parameters and ML was observed. Utilizing VTIQ to assess MLN stiffness offers a non-invasive, convenient, reliable and reproducible approach for identifying mesenteric lymphadenopathy.

Machine learning on longitudinal multi-modal data enables the understanding and prognosis of Alzheimer's disease progression.

Alzheimer's disease (AD) is a complex pathophysiological disease. Allowing for heterogeneity, not only in disease manifestations but also in different progression patterns, is critical for developing effective disease models that can be used in clinical and research settings. We introduce a machine learning model for identifying underlying patterns in Alzheimer's disease (AD) trajectory using longitudinal multi-modal data from the ADNI cohort and the AIBL cohort. Ten biologically and clinically meaningful disease-related states were identified from data, which constitute three non-overlapping stages (i.e., neocortical atrophy [NCA], medial temporal atrophy [MTA], and whole brain atrophy [WBA]) and two distinct disease progression patterns (i.e., NCA → WBA and MTA → WBA). The index of disease-related states provided a remarkable performance in predicting the time to conversion to AD dementia (C-Index: 0.923 ± 0.007). Our model shows potential for promoting the understanding of heterogeneous disease progression and early predicting the conversion time to AD dementia.

Clinical applications of superb microvascular imaging and virtual touch imaging quantification in pediatric mesenteric lymphadenitis diagnosis: A promising pathway to enhanced precision.

BACKGROUND: Mesenteric lymphadenitis (ML) demonstrates a distinctive inclination for the pediatric and adolescent demographic and the diagnosis of ML in young children poses a substantial challenge. OBJECTIVE: This prospective study aimed to assess the diagnostic efficacy of Superb Microvascular Imaging (SMI) and Virtual Touch Tissue Imaging quantification (VTIQ) in distinguishing pediatric mesenteric lymphadentitis. METHODS: We examined 82 mesentric lymph node (MLN) in pediatric patients with mesenteric lymphadentitis and 50 MLN in a healthy group. SMI was utilized to evaluate vascularity within the MLN, while MLN stiffness, quantified as shear wave velocity (SWV) in meters per second (m/s), was assessed using VTIQ. We compared the diagnostic performance of greyscale Ultrasound, US combined with SMI, US combined with VTIQ, and US combined with both SMI and VTIQ. RESULTS: SMI revealed a significant distinction between mesenteric lymphadentitis and normal MLN (p <  0.001). MLN affected by mesenteric lymphadentis exhibited increased vascularity (marked vascularity: 13/82, 15.85%) compared to normal MLN (marked vascularity: 1/50, 2.00%). Statistically significant differences were observed in SWV values beween mesenteric lymphadentitis and normal MLN (all p-values <0.001). The mean and minimum SWV values for MLN with mesenteric lymphadentitis were 1.66±0.77 m/s and 1.51±0.53 m/s, respectively. Control group SWV values were approximately three times higher than those in the mesenteric lymphadenitis group. The highest area under the curve values were achieved with the combination of all three modalities (0.837, 95% confidence interval: 0.763- 0.896), followed by US + VTIQ (0.795, 0.716- 0.860), US + SMI (0.753, 0.670- 0.824) and US alone (0.642, 0.554- 0.724). CONCLUSION: SMI and VTIQ offer a promising noninvasive adjunct to grayscale ultrasound for identifying mesenteric lymphadentitis in pediatric patients.

Association of Rare NOTCH3 Variants With Prevalent and Incident Stroke and Dementia in the General Population.

BACKGROUND: It is uncertain whether rare NOTCH3 variants are associated with stroke and dementia in the general population and whether they lead to alterations in cognitive function. This study aims to determine the associations of rare NOTCH3 variants with prevalent and incident stroke and dementia, as well as cognitive function changes. METHODS AND RESULTS: In the prospective community-based Shunyi Study, a total of 1007 participants were included in the baseline analysis. For the follow-up analysis, 1007 participants were included in the stroke analysis, and 870 participants in the dementia analysis. All participants underwent baseline brain magnetic resonance imaging, carotid ultrasound, and whole exome sequencing. Rare NOTCH3 variants were defined as variants with minor allele frequency <1%. A total of 137 rare NOTCH3 carriers were enrolled in the baseline study. At baseline, rare NOTCH3 variant carriers had higher rates of stroke (8.8% versus 5.6%) and dementia (2.9% versus 0.8%) compared with noncarriers. After adjustment for associated risk factors, the epidermal growth factor-like repeats (EGFr)-involving rare NOTCH3 variants were associated with a higher risk of prevalent stroke (odds ratio [OR], 2.697 [95% CI, 1.266-5.745]; P=0.040) and dementia (OR, 8.498 [95% CI, 1.727-41.812]; P=0.032). After 5 years of follow-up, we did not find that the rare NOTCH3 variants increased the risk of incident stroke and dementia. There was no statistical difference in the change in longitudinal cognitive scale scores. CONCLUSIONS: Rare NOTCH3 EGFr-involving variants are genetic risk factors for stroke and dementia in the general Chinese population.

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.

LncRNA RP11-10E18.7 cooperates with lncRNA RP11-481C4.2 to affect the overall survival of breast cancer patients: a TCGA-based retrospective study.

Background: As either oncogenes or tumor suppressor genes, long non-coding RNAs (lncRNAs) have a major role in both tumorigenesis and progression of human cancers, including breast cancer (BC). However, the statistical correlation between the lncRNA-lncRNA interaction and prognosis of BC remains unclear. Methods: We analyzed the fragments per kilobase per million (FPKM) lncRNA expression data in tumor tissue samples from 890 female patients with BC in The Cancer Genome Atlas (TCGA) between May 2021 and October 2022. The Cox proportional hazards model adjusted for age, race, clinical stage, neoadjuvant therapy, estrogen receptor (ER), and progesterone receptor (PR) was adopted to evaluate the lncRNA-lncRNA interaction regarding overall survival (OS) of BC. The multiple comparison was corrected by Bonferroni method. Results: RP11-10E18.7×RP11-481C4.2 was significantly associated with OS of BC patients [hazard ratio (HR)interaction =1.04, 95% confidence interval (CI): 1.03-1.06, P=3.35×10-9]. Then, gene-gene interaction analysis was performed for genes co-expressed with lncRNAs. FOXA1×U2SURP (HRinteraction =1.49, 95% CI: 1.28-1.73, P=2.16×10-7) was found to have a similar interactive pattern to RP11-10E18.7×RP11-481C4.2. after classifying the patients by intersection (3.47), we observed that the effect of FOXA1 opposite in patients with different U2SURP expression level (HRhigh vs. low =0.58, 95% CI: 0.34-0.99, P=0.046 in low expression of U2SURP; HRhigh vs. low =1.56, 95% CI: 1.18-2.87, P=0.029 in high expression of U2SURP). Conclusions: Our comprehensive study identified RP11-10E18.7×RP11-481C4.2 as a potential biomarker of BC prognosis. The results play an essential role in the impact of lncRNA-lncRNA interaction on BC survival. Our findings elucidated potential molecular mechanisms of BC progression under complex association patterns and provided potential dynamic and reversible therapeutic targets for BC patients.