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.

Risk factor differences in five-year progression of Intracranial artery stenosis and cerebral small vessel disease in general population.

BACKGROUND: Intracranial artery stenosis (ICAS) and cerebral small vessel disease (CSVD) are associated with a heavy socioeconomic burden; however, their longitudinal changes remain controversial. METHODS: We conducted a longitudinal analysis on 756 participants of Shunyi Cohort who underwent both baseline and follow-up brain magnetic resonance imaging (MRI) and MR angiography in order to investigate the risk factors for ICAS and CSVD progression in community population. Incident ICAS was defined as new stenosis occurring in at least one artery or increased severity of the original artery stenosis. CSVD markers included lacunes, cerebral microbleeds (CMB), and white matter hyperintensities (WMH). RESULTS: After 5.58 ± 0.49 years of follow-up, 8.5% of the 756 participants (53.7 ± 8.0 years old, 65.1% women) had incident ICAS. Body mass index (BMI) (OR = 1.09, 95% CI = 1.01-1.17, p = 0.035) and diabetes mellitus (OR = 2.67, 95% CI = 1.44-4.93, p = 0.002) were independent risk factors for incident ICAS. Hypertension was an independent risk factor for incident lacunes (OR = 2.12, 95% CI = 1.20-3.77, p = 0.010) and CMB (OR = 2.32, 95% CI = 1.22-4.41, p = 0.011), while WMH progression was primarily affected by BMI (ß = 0.108, SE = 0.006, p = 0.002). A higher LDL cholesterol level was found to independently protect against WMH progression (ß = -0.076, SE = 0.027, p = 0.019). CONCLUSIONS: Modifiable risk factor profiles exhibit different in patients with ICAS and CSVD progression. Controlling BMI and diabetes mellitus may help to prevent incident ICAS, and antihypertensive therapy may conduce to mitigate lacunes and CMB progression. LDL cholesterol may play an inverse role in large arteries and small vessels.

Phenotypes Associated with NOTCH3 Cysteine-Sparing Mutations in Patients with Clinical Suspicion of CADASIL: A Systematic Review.

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is caused by NOTCH3 mutations affecting the number of cysteines. The pathogenic role of cysteine-sparing NOTCH3 mutations with typical clinical CADASIL syndrome is still debated. This review aimed to characterize NOTCH3 cysteine-sparing mutations in patients with clinical suspicion of CADASIL. Articles on NOTCH3 cysteine-sparing mutations with clinical suspicion of CADASIL were reviewed. Clinical and radiological cerebral phenotypes data were extracted and characterized across regions and compared with phenotypes of typical CADASIL patients. We screened 298 NOTCH3 cysteine-sparing mutation individuals from 20 publications, and mutations in exon 3 were the most frequently reported (21.46%). Gait impairment (76.47%), cognitive impairment (67.47%), and stroke (62.37%) were the three most common clinical phenotypes; the most frequent radiological cerebral phenotypes were lacunes (74.29%) and cerebral microbleeds (72.73%). Compared with CADASIL patients, cognitive impairment and cerebral microbleed frequencies were significantly higher in patients with NOTCH3 cysteine-sparing mutations, while the white matter hyperintensities in anterior temporal polar and external capsule were rarely observed. Compared with Western patients, radiological phenotypes were more common than clinical phenotypes in cysteine-sparing Asian patients. More than half of cysteine-sparing patients had positive granular osmiophilic material deposits. NOTCH3 cysteine-sparing mutations in patients with clinical suspicion of CADASIL mainly manifested with gait and cognitive impairment but rare white matter hyperintensities in anterior temporal pole and external capsule. Further studies are warranted to pay attention to atypical NOTCH3 variants, which could guide specific diagnosis and help unravel underlying mechanisms.

Correlation between Circle of Willis configuration and intracranial arterial dolichoectasia, and genetic contributions.

OBJECTIVES: Intracranial arterial dolichoectasia (IADE) is characterized by the dilation, elongation, and tortuosity of intracranial arteries. We aimed to investigate the association between variations of the Circle of Willis (COW) and IADE in the general population, as well as estimate the genetic correlation between COW variations and IADE. METHODS: A total of 981 individuals from a population-based cohort were included. Brain magnetic resonance angiography was performed to assess COW variants and measure the diameters of intracranial arteries. IADE was defined as a total intracranial volume-adjusted diameter ≥ 2 standard deviations. Logistic regression models were used to analyze the association between COW variations and IADE. The heritability and genetic correlation were estimated using genome-wide complex trait analysis (GCTA) based on single nucleotide polymorphism (SNP) array data. RESULTS: The prevalence of IADE was 6.2 %. Hypoplastic/absent A1 segments were associated with an increase in contralateral ICA diameter (ß ± SE, 0.279 ± 0.049; p = 0.001) and a decrease in ipsilateral ICA diameter (ß ± SE, -0.300 ± 0.050; p = 0.001). Fetal-type posterior cerebral artery (FTP) was associated with a larger ICA diameter (ß ± SE, 0.326 ± 0.048; p = 0.001) and a smaller BA diameter (ß ± SE, -0.662 ± 0.043; p = 0.001). FTP revealed a positive genetic correlation with ICA dilation (rG = 0.259 ± 0.175; p = 0.0009) and a negative genetic correlation with BA dilation (rG = -0.192 ± 0.153, p = 0.015). CONCLUSIONS: There was an association between COW variations and larger intracranial arterial diameters in the general population. Genetic factors may play a role in the development of intracranial arterial dilation and the formation of COW variants.

Association between Anatomical Variations of the Circle of Willis and Covert Vascular Brain Injury in the General Population.

BACKGROUND AND PURPOSE: The circle of Willis (COW) is a circulatory anastomosis located at the base of the brain. Little is known about the association between covert vascular brain injury and COW configurations in the general population. We explored this relationship in a community-based Chinese sample. METHODS: A total of 1,055 patients (mean age, 54.8 ± 8.9 years; 36.0% men) without intracranial arterial stenosis were included in the analysis. Magnetic resonance imaging was performed to evaluate the presence of imaging markers of covert vascular brain injury, including white matter hyperintensities (WMHs), lacunes, cerebral microbleeds (CMBs), enlarged perivascular spaces, and brain atrophy. Magnetic resonance angiography was used to classify the COW configurations according to the completeness, symmetry, and presence of the fetal posterior cerebral artery (FTP). The association between vascular lesions and variations in COW was analyzed. RESULTS: Among the 1,055 patients, 104 (9.9%) had a complete COW. Completeness correlated with age (p = 0.001). Incomplete COW was positively associated with WMH severity (OR = 2.071; 95% CI, 1.004-4.270) and CMB presence (OR = 1.542; 95% CI, 1.012-2.348), independent of age and sex. The presence of FTP was associated with lacunes (OR = 1.878; 95% CI, 1.069-3.298), more severe WMHs (OR = 1.739; 95% CI, 1.064-2.842), and less severe enlarged perivascular spaces (OR = 0.562; 95% CI, 0.346-0.915). CONCLUSIONS: COW configuration was significantly related to various covert vascular brain injuries.

Different Types of Circulatory Inflammatory Biomarkers Associated with Cerebral Arterial Atherosclerosis and Dolichoectasia.

BACKGROUND: Although inflammation is found to be related to arteriopathy pathogenesis, it is yet to be determined the distinct correlations of specific inflammatory biomarker types contributing to different cerebral large vessel diseases. We aimed to investigate the association between multiple inflammatory biomarkers and cerebral atherosclerosis and dolichoectasia in a community-based sample. METHODS: A total of 960 participants of the Shunyi study were included. A panel of 14 circulatory inflammatory biomarkers was assessed and then grouped in three sets as systemic, endothelial-related, and media-related inflammation, based on underlying different inflammatory cascades. Intracranial atherosclerotic stenosis (ICAS), dolichoectasia estimated by magnetic resonance angiography, and carotid plaques estimated by ultrasound were also performed. RESULTS: Endothelial-related inflammatory group was related to the presence of ICAS (R2 = 0.215, p = 0.024) and carotid plaques (R2 = 0.342, p = 0.013). Backward stepwise elimination showed that E-selectin was prominent (ß = 0.67, 95% CI: 0.54-0.85, p = 0.001; ß = 0.79, 95% CI: 0.68-0.93, p = 0.005). Systemic inflammatory group was associated with an increased basilar artery diameter (R2 = 0.051, p < 0.001), and backward stepwise elimination showed that IL-6 was prominent (ß = 0.07, 95% CI: 0.03-0.11, p < 0.001). CONCLUSION: Different types of inflammatory biomarkers were associated with atherosclerosis and dolichoectasia, respectively, implying dissimilar inflammatory processes. Further confirming of their distinct anti-inflammatory roles as potential therapeutic targets is warrant.

Recurrent headache and visual symptoms in a young man: a rare neuronal intranuclear inclusion disease case report.

BACKGROUND: Neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disease. Patients with NIID may present with heterogeneous clinical symptoms, including episodic encephalopathy, dementia, limb weakness, cerebellar ataxia, and autonomic dysfunction. Among the NIID cases reported in China, patients often have complicated and severe manifestations. Therefore, many clinicians do not consider the disease when the patient presents with relatively minor complaints. CASE PRESENTATION: We present the case of a 39-year-old man showing migraine-aura-like symptoms for the past 3 years. Brain magnetic resonance imaging (MRI) revealed hyperintense signals in the splenium of the corpus callosum and corticomedullary junction on diffusion-weighted imaging (DWI) over time. In addition, brain atrophy that was not concomitant with the patient's age was detected while retrospectively reviewing the patient's imaging results. Genetic analysis and skin biopsy confirmed a diagnosis of NIID. The patient was treated with sibelium, and the symptoms did not recur. DISCUSSION AND CONCLUSIONS: Migraine-aura-like symptoms may be the predominant clinical presentation in young patients with NIID. Persistent high-intensity signals on DWI in the brain and early-onset brain atrophy might be clues for the diagnosis of NIID.

Machine Learning Assisted Doppler Features for Enhancing Thyroid Cancer Diagnosis: A Multi-Cohort Study.

BACKGROUND: This pilot study aims at exploiting machine learning techniques to extract color Doppler ultrasound (CDUS) features and to build an artificial neural network (ANN) model based on these CDUS features for improving the diagnostic performance of thyroid cancer classification. METHODS: A total of 674 patients with 712 thyroid nodules (TNs) (512 from internal dataset and 200 from external dataset) were randomly selected in this retrospective study. We used ANN to build a model (TDUS-Net) for classifying malignant and benign TNs using both the automatically extracted quantitative CDUS features (whole ratio, intranodular ratio, peripheral ratio, and number of vessels) and gray-scale ultrasound (US) features defined by the American College of Radiology (ACR) Thyroid Imaging Reporting and Data System (TI-RADS). Then, we compared the diagnostic performance of the model, the performance of another ANN model based on the gray-scale US features alone (TUS-Net), and that of radiologists. RESULTS: The TDUS-Net (0.898, 95% CI: 0.868-0.922) achieved a higher area under the curve (AUC) than that of TUS-Net (0.881, 95% CI: 0.850-0.908) in the internal tests. Compared with radiologists, TDUS-Net (AUC: 0.925, 95% CI: 0.880-0.958) performed better than radiologists (AUC: 0.810, 95% CI: 0.749-0.862) in the external tests. CONCLUSIONS: Applying a machine learning model by combining both gray-scale US features and CDUS features can achieve comparable or even higher performance than radiologists in classifying TNs.

Rare NOTCH3 Variants in a Chinese Population-Based Cohort and Its Relationship With Cerebral Small Vessel Disease.

BACKGROUND AND PURPOSE: Researches on rare variants of NOTCH3 in the general Chinese population are lacking. This study aims to describe the spectrum of rare NOTCH3 variants by whole-exome sequencing in a Chinese community-based cohort and to investigate the association between rare NOTCH3 variants and age-related cerebral small vessel disease. METHODS: The cross-sectional study comprised 1065 participants who underwent whole-exome sequencing and brain magnetic resonance imaging. NOTCH3 variants with minor allele frequency<1% in all 4 public population databases (1000 Genomes, ESP6500siv2_ALL, GnomAD_ALL, and GnomAD_EAS) were defined as rare variants. Multivariable linear and logistic regressions were used to investigate the associations between rare NOTCH3 variants and volume of white matter hyperintensities and cerebral small vessel disease burden. Clinical and imaging characteristics of rare NOTCH3 variant carriers were summarized. RESULTS: Sixty-five rare NOTCH3 variants were identified in 147 of 1065 (13.8%) participants, including 57 missense single nucleotide polymorphisms (SNPs), 5 SNPs in splice branching sites, and 3 frameshift deletions. A significantly higher volume of white matter hyperintensities and heavier burden of cerebral small vessel disease was found in carriers of rare NOTCH3 EGFr (epidermal growth factor-like repeats)-involving variants, but not in carriers of EGFr-sparing variants. The carrying rate of rare EGFr-involving NOTCH3 variants in participants with dementia or stroke was significantly higher than those without dementia or stroke (12.4% versus 6.6%, P=0.041). Magnetic resonance imaging signs suggestive of CADASIL were found in 3.4% (5/145) rare EGFr cysteine-sparing NOTCH3 variant carriers but not in 2 cysteine-altering NOTCH3 variant carriers. CONCLUSIONS: Carriers of rare NOTCH3 variants involving the EGFr domain may be genetically predisposed to age-related cerebral small vessel disease in the general Chinese population.

MXene-assisted organic electrochemical transistor biosensor with multiple spiral interdigitated electrodes for sensitive quantification of fPSA/tPSA.

BACKGROUND: The ratio of fPSA/tPSA in the "grey zone" of tPSA with the concentration range between 4 ng/ml and 10 ng/ml is significant for diagnosis of prostate cancer, and highly efficiency quantification of the ratio of fPSA/tPSA remain elusive mainly because of their extremely low concentration in patients' peripheral blood with high biosample complexity. METHODS: We presented an interdigitated spiral-based MXene-assisted organic electrochemical transistors (isMOECTs) biosensor for highly sensitive determination of fPSA/tPSA. The combination of MXene and the interdigitated multiple spiral architecture synergistically assisted the amplification of amperometric signal of biosensor with dual functionalizations of anti-tPSA and anti-fPSA. RESULTS: The ultrasensitivity of the biosensor was enhanced by tunable multiple spiral architecture and MXene nanomaterials; and the sensor exhibited improved detection limit of tPSA and fPSA down to 0.01 pg/ml and acceptable performance of selectivity, repeatability and stability. Moreover, the isMOECTs displayed area under the curve (AUC) value of 0.8138, confirming the potential applications of isMOECTs in clinics. CONCLUSIONS: The merits of isMOECTs biosensor demonstrated the reliability of MXene-assisted organic electrochemical transistor biosensor with multiple interdigitated spiral for ultrasensitive quantification of fPSA/tPSA, suggesting potential current and future point-of-care testing applications.

Lacune and Large Perivascular Space: Two Kinds of Cavities Are of Different Risk Factors and Stroke Risk.

BACKGROUND AND PURPOSE: To compare the risk factors and risk of stroke between lacune and large perivascular spaces (PVSs) in a community-based sample. METHODS: Large PVSs were assessed using 3.0T MRI in a population-based cohort consisting of 1,204 participants. The relationship between cardiovascular risk factors, neuroimaging changes, and incidental stroke risk and the presence of lacune or large PVSs was assessed with univariate and multivariable ordinal logistic regression analysis. RESULTS: Of the 1,204 study participants (55.7 ± 9.3 years, 37.0% men), a total of 347 large PVSs were detected in 235 (19.5%) subjects, while a total of 219 lacunes were detected in 183 subjects (15.2%). The presence of lacunes was found to be significantly associated with age, male gender, hypertension, and diabetes, whereas only age (p < 0.01) and ApoEε4 carrier status (p < 0.01) were related to the presence of large PVSs. Those who had lacunes detected on MRI at baseline had a significant increased risk of stroke (hazard ratio [HR] 4.68; 95% confidence interval [CI], 1.15-19.07) during the 3-year follow-up independent of age, gender, and other vascular risk factors. However, there was no significant relationship between the presence of large PVSs and incident stroke (HR 3.84; 95% CI, 0.82-18.04). CONCLUSIONS: The lack of association between large PVSs and cardiovascular risk factors or risk of stroke indicated a nonvascular pathogenic mechanism underlying large PVSs, suggesting the importance of distinguishing large PVSs from lacunes in clinical practice.

Pathologic T-cell response in ischaemic failing hearts elucidated by T-cell receptor sequencing and phenotypic characterization.

AIMS: A persistent cardiac T-cell response initiated by myocardial infarction is linked to subsequent adverse ventricular remodelling and progression of heart failure. No data exist on T-cell receptor (TCR) repertoire changes in combination with phenotypic characterization of T cells in ischaemic failing human hearts. METHODS AND RESULTS: Analysis of TCR repertoire with high-throughput sequencing revealed that compared with T cells in control hearts, those in ischaemic failing hearts showed a clonally expanded TCR repertoire but similar usage patterns of TRBV-J rearrangements and V gene segments; compared with T cells in peripheral blood, those in ischaemic failing hearts exhibited a restricted and clonally expanded TCR repertoire and different usage patterns of TRBV-J rearrangements and V gene segments, suggesting the occurrence of tissue-specific T-cell expansion in ischaemic failing hearts. Consistently, TCR clonotype sharing was prominent in ischaemic failing hearts, especially in hearts of patients who shared human leucocyte antigen (HLA) alleles. Furthermore, ischaemia heart failure (IHF) heart-associated clonotypes were more frequent in peripheral blood of IHF patients than in that of controls. Heart-infiltrating T cells displayed memory- and effector-like characteristics. Th1 cells were the predominant phenotype among CD4+ T cells; CD8+ T cells were equally as abundant as CD4+ T cells and produced high levels of interferon-γ, granzyme B, and perforin. CONCLUSION: We provide novel evidence for a tissue-specific T-cell response predominated by Th1 cells and cytotoxic CD8+ T cells in ischaemic failing human hearts that may contribute to the progression of heart failure.

Clinical Features of CVT in Women and Effect on Subsequent Pregnancy: A Follow-Up Study in a Chinese National Comprehensive Hospital.

BACKGROUND AND OBJECTIVE: Cerebral venous thrombosis (CVT) is not rare in women of childbearing age. Chinese couples have been encouraged to have two children by the new family-planning policy. Concerns have been raised about the effect of CVT on subsequent pregnancies, but few studies have focused on the Chinese population. We aimed to analyze the clinical features of Chinese female CVT patients of childbearing age and study the outcome of their subsequent pregnancies after CVT. METHODS: We retrospectively analyzed the clinical data of female patients at fertile age (15-45 years) diagnosed with CVT in our hospital between January 2009 and January 2019. Information on recurrence of venous thrombotic events as well as obstetrical outcomes of subsequent pregnancies was obtained and evaluated during follow-up. RESULTS: A total of 72 patients were enrolled, mean age at CVT onset was 29.4 ± 7.9 years. The main risk factors included autoimmune system disease (27.8%), pregnancy or puerperium (12.5%), and inherited thrombophilia (11.1%). Furthermore, 58 patients were followed up for a mean time of 63.1 ± 31.4 months and 17 new pregnancies occurred in 13 women. Among the 17 pregnancies, one CVT (5.9%) recurred in a patient with antiphospholipid syndrome. Overall, 10 (58.8%) pregnancies resulted in the birth of healthy children, including 8 full-term and 2 preterm births; 7 were terminated, including 3 (17.6%) spontaneous abortions. All patients with spontaneous abortions had antiphospholipid syndrome or Behcet's disease. CONCLUSIONS: Autoimmune system disease was the most common risk factor in Chinese female CVT patients. Recurrent pregnancy-associated CVT was infrequent in women with prior CVT, but attention should be paid during subsequent pregnancies.

Evaluation of Mesenteric Lymph Nodes in a Pediatric Population with Mesenteric Lymphadenitis Using Superb Microvascular Imaging.

BACKGROUND This study aimed to evaluate superb microvascular imaging (SMI) as an adjunctive imaging method to evaluate mesenteric lymph nodes in children with mesenteric lymphadenitis compared with healthy children. MATERIAL AND METHODS A retrospective study compared children with mesenteric lymphadenitis (n=27) and healthy children (n=30). Lymph node size was determined using grayscale ultrasonography and parameters of lymph node vascularity were compared using color Doppler flow imaging (CDFI) and SMI. The diagnostic performance of ultrasound (US), US combined with SMI, and US combined with CDFI were compared. RESULTS Lymph nodes from children with mesenteric lymphadenitis (n=77) and normal lymph nodes (n=84) were evaluated by SMI, which showed that the least diameter of lymph nodes in cases of mesenteric lymphadenitis was 0.58±0.15 mm and of normal mesenteric lymph nodes was 0.47±0.08 mm (p<0.001). SMI identified 92.6% of abnormal mesenteric lymph nodes while CDFI detected 85.2%. US combined with SMI had the highest sensitivity (81.5%), and specificity (78.9%) compared with US alone (sensitivity, 63.0%; specificity, 64.9%), and compared with US combined with CDFI (sensitivity, 74.1%; specificity, 75.4%). US combined with SMI and US combined with CDFI achieved the same specificity (76.7%), which was higher than that of US alone (66.7%). CONCLUSIONS SMI was superior to color Doppler flow imaging in evaluating the microvasculature in lymphadenopathy in mesenteric lymphadenitis. SMI may be used as an adjunct to grayscale ultrasonography to assist in identifying mesenteric lymphadenopathy in pediatric patients.

Prostate Cancer Vascularity: Superb Microvascular Imaging Ultrasonography with Histopathology Correlation.

BACKGROUND The aim of this study was to evaluate the association between prostate cancer (PCa) vascularity detected by superb microvascular imaging (SMI) and Gleason score in biopsy specimens. MATERIAL AND METHODS A total of 119 patients with suspected PCa before biopsy underwent gray-scale ultrasound (US), color Doppler ultrasound (CDUS), and SMI imaging between June 2018 and March 2019. Vascularity quantity was assessed by SMI and compared with that of CDUS. The vessel parameter was also compared with the Gleason score. The sensitivity of PCa was compared between transrectal ultrasound guided systematic biopsy (SB) and SMI-guided targeted biopsy (SMI-guided TB). RESULTS Pathology confirmed 74 of 119 patients had PCa. The microvascular quantity of PCa patients was significantly higher than that of non-malignant patients. SMI detected blood vessels in 97.3% (72/74) in the malignant group, while CDUS identified blood flow signals in 90.5% (67/74) of the PCa group. SMI visualized enriched microvascular in PCa of Gleason 8 (54.5%) and Gleason 9 (92.3%). There was a positive correlation between microvascular quantity detected by SMI and Gleason score, with a correlation coefficient of 0.373 (P<0.001). SMI-guided TB cores were significantly more likely than SB cores to detect PCa (OR=12.83, P<0.001). CONCLUSIONS SMI could be promising as a useful imaging technique in the detection and characterization of PCa. There was a positive correlation between microvascular quantity detected by SMI and Gleason score.

Strain Elastography-Targeted Biopsy: Does Prostate Volume Affect Prostate Cancer Detection?

BACKGROUND The present study aimed to assess the correlation between prostate volume and prostate cancer (PCa) detection by strain elastography (SE)-guided targeted biopsy (TB) compared with conventional transrectal ultrasound (TRUS)-guided systematic biopsy (SB). MATERIAL AND METHODS This retrospective study enrolled 357 patients suspected to have PCa. All patients received TRUS-guided 10-core SB and SE-guided TB. The sensitivity for PCa detected by SE-guided TB was compared with that by TRUS-guided SB, in combination with prostate biopsy pathology. The correlation between the prostate volume and the detection rate of SE-guided TB was investigated. RESULTS PCa was pathologically confirmed in 151 out of 357 patients. The by-patient detection rate of TRUS-guided SB was 72.8% (110/151). Subsequently, a further increase of 6.6% (10/151) in PCa determination was obtained by the SE-guided TB. The sensitivity of SE-guided TB for patients with prostate volume <30 ml, 30-50 ml, 51-80 ml, and >80 ml was 91.7% (44/48), 80.3% (53/66), 70.4% (19/27), and 40.0% (4/10), respectively (p=0.002). For patients with a prostate volume less than 30 ml, SE-guided TB (91.7%) had a higher sensitivity than SB (62.5%) (p<0.007). CONCLUSIONS SE-guided TB has a higher detection rate of PCa in comparison with TRUS-guided SB. There was also a negative correlation between prostate volume and SE-guided TB. Therefore, use of SE-guided TB may complement use of conventional SB, especially for patients with smaller prostate volume.

Evaluating the Efficacy of Atorvastatin on Patients with Carotid Plaque by an Innovative Ultrasonography.

BACKGROUND: The present study aimed to explore the efficacy of atorvastatin on patients with carotid plaque, applying superb microvascular imaging (SMI), and contrast-enhanced ultrasound (CEUS) for evaluating carotid intraplaque neovascularization. METHODS: A total of 82 patients (82 carotid plaques) who were randomized into treatment group and control group underwent conventional ultrasound, CEUS, and SMI examinations. Patients in treatment group received a dose of 20 mg atorvastatin per day for 6 months while those in control group received placebo instead. Lipid parameters were assessed and intraplaque neovascularization were evaluated by CEUS and SMI before and 6 months after atorvastatin treatment. RESULTS: No significant differences were found between the 2 groups at the study entry. Patients with atorvastatin treatment received marked improvement in total cholesterol, triglyceride, and LDL-cholesterol compared with those in control group (P < .001). In treatment group, SMI-detected intraplaque neovascularization reduced from 69.23% to 48.72% while CEUS-detected ones reduced from 76.92% to 69.23%. By contrast, the percentage of intraplaque neovascularization in control group did not change too much either by SMI (65.12%, 67.44%) or CEUS (74.41%, 74.41%). The consistency between CEUS and SMI was above .75 at all assessments (P < .001). CONCLUSIONS: Atorvastatin treatment works for patients with carotid plaque by reducing LDL-cholesterol and improving plaque regression. Second, the consistency between SMI and CEUS in visualizing intraplaque neovascularization is good. That indicates a high possibility to identify carotid plaque instability by a safer and cheaper ultrasonography without contrast agent.

[Clinical Characteristics of Autoimmune Disease with Dual Seropositive Antibodies of Leucine-rich Glioma Inactivated 1 and Contactin-associated Protein 2].

Objective To explore the clinical characteristics of autoimmune disease with dual seropositive antibodies of leucine-rich glioma inactivated 1(LGI1)and contactin-associated protein 2(Caspr2).Methods The clinical data of seven patients with dual seropositive LGI1 and Caspr2 antibodies who were admitted to the Neurology Department of Peking Union Medical College Hospital from July 2014 to December 2017 were retrospectively analyzed.Results Central,peripheral and autonomic nervous systems were all involved in the seven cases;100%(7/7)presented with insomnia,myokymia,neuropahic pain and hyperhydrosis;71%(5/7)showed memory decline or psychiatric and behavioral symptoms;57%(4/7)had urinary hesitation or constipation;and 43%(3/7)had seizure.Electromyography showed 100%(6/6) of the patients had prolonged afterdischarges following normal M waves and/or abnormal spontaneous firing.Electroencephalography revealed slow waves or basic rhythm slowing in 71%(5/7)of patients.Electrocardiography showed sinus tachycardia,axis deviation,and prolonged QT intervals in 71%(5/7)of patients.One patient died from arrhythmia before immunotherapy.One died from pulmonary infection after immunotherapy.Improvement with immunotherapy was documented in the other five cases.No relapse was noted during the 1-2-year follow-up.Conclusions Autoimmune disease with dual seropositive antibodies of LGI1 and Caspr2 can diffusely affect the central,peripheral,and autonomic nervous systems.The possibility of this disease should be considered in patients with acute and subacute onset of neuropsychiatric symptoms,especially in patients with accompanying insomnia,myokymia,and hyperhydrosis.

Burden of Dilated Perivascular Spaces, an Emerging Marker of Cerebral Small Vessel Disease, Is Highly Heritable.

BACKGROUND AND PURPOSE: The genetic contribution to dilated perivascular space (dPVS) burden-an emerging MRI marker of cerebral small vessel disease-is unknown. We measured the heritability of dPVS burden and its shared heritability with other MRI markers of cerebral small vessel disease. METHODS: The study sample comprised 1597 participants from the population-based Three City (3C) Dijon Study, with brain MRI and genome-wide genotyping (mean age, 72.8±4.1 years; 61% women). dPVS burden and lacunar brain infarcts were rated on a semiquantitative scale, whereas an automated algorithm generated white matter hyperintensity volume (WMHV). We estimated dPVS burden heritability and shared heritability with WMHV and lacunar brain infarcts using the genome-wide complex trait analysis tool, on unrelated participants, adjusting for age, sex, intracranial volume, and principal components of population stratification. RESULTS: dPVS burden was significantly correlated with WMHV and lacunar brain infarcts, the strongest correlation being found between WMHV and dPVS in basal ganglia. Heritability estimates were h2=0.59±0.24 (P=0.007) for dPVS burden, h2=0.54±0.24 (P=0.010) for WMHV, and h2=0.48±0.81 (P=0.278) for lacunar brain infarcts. We found a nonsignificant trend toward shared heritability between dPVS and WMHV (rg=0.41±0.28; P=0.096), which seemed driven by dPVS in basal ganglia (rg=0.72±0.61; P=0.126) and not dPVS in white matter (rg=-0.10±0.36; P=0.393). A genetic risk score for WMHV based on published loci was associated with increased dPVS burden in basal ganglia (P=0.031). CONCLUSIONS: We provide evidence for important genetic contribution to dPVS burden in older community-dwelling people, some of which may be shared with WMHV. Differential heritability patterns for dPVS in white matter and basal ganglia suggest at least partly distinct underlying biological processes.