Small Vessels Research Articles

Cortical surface-based morphometry in cognitive impairment in sporadic cerebral small vessel disease

Background: Analysis of structural MR images plays a key role in assessing the underlying substrate of cognitive impairment (CI) in sporadic age-related cerebral small vessel disease (SVD), leading to up to 45% of all cases of dementia. The variety of MR-morphometry results in SVD requires extensive research and comparisons with clinical data. Aims: to assess the characteristics of brain atrophy in cognitive impairment in patients with SVD using surface-based morphometry (SBM). Materials and methods: A prospective study was conducted assessing patients with SVD and CI of varying severity (subjective - subCI, moderate - MCI and dementia) and a group of volunteers matched by gender and age. MRI was performed with subsequent analysis of MRI signs of SVD and calculation of the general SVD index and processing of T1mpr images using the SBM method with general and regional quantitative assessment of the brain, including the thickness of the cerebral cortex. Results: the main group with SVD consisted of 173 patients, the control group included 47 healthy volunteers. As the severity of structural changes in the brain and the severity of CI increased, there was a significant (p0.05) decrease in the thickness of the cortex of certain regions according to a similar pattern: the cingulate gyri, mainly their posterior sections; medial and middle sections of the frontal lobes, various parts of the insular cortex, temporo-parietal areas (especially the supramarginal gyri). The volume of the brain itself (total volume, gray and white matter) in SVD had significant differences only with controls, but not between groups of patients with different severity of CI. The volume of white matter hyperintensities was significantly different between the groups with dementia and MCI, dementia and sub-CI (p 0.0001). Conclusions: The data obtained during the study confirm the secondary/mixed nature of atrophy in SVD. The wide variety of regions with significant thinning of the cortex limits the specification of the progression of CI in SVD based on their atrophy. This allows the quantitative measurement of the cortex to be used only as an auxiliary method in assessing the prediction of SVD progression.

Intimal Macrovascular Pericytes: Their Role in Vascular Biology and Atherogenesis.

Atherosclerosis remains a major challenge to global healthcare despite decades of research and constant trials of novel therapeutic approaches. One feature that makes atherosclerosis treatment so elusive is an insufficient understanding of its origins and the early stages of the pathological process, which limits our means of effective prevention of the disease. Macrovascular pericytes are cells with distinct shapes that are located in the arterial wall of larger vessels and are in many aspects similar to microvascular pericytes that maintain the functionality of small vessels and capillaries. This cell type combines the residual contractile function of smooth muscle cells with a distinct stellar shape that allows these cells to make numerous contacts between themselves and the adjacent endothelial layer. Moreover, pericytes can take part in the immune defense and are able to take up lipids in the course of atherosclerotic lesion development. In growing atherosclerotic plaques, the morphology and function of pericytes change dramatically due to phagocytic and synthetic phenotypes that are actively involved in lipid accumulation and extracellular matrix synthesis. In this review, we summarize our knowledge of this less-studied cell type and its role in atherosclerosis.

The contribution of white matter changes to clinical phenotype in progressive supranuclear palsy

White matter hyperintensities (WMH) are considered magnetic brain imaging (MRI) biomarkers of cerebral small vessel disease but their clinical role in neurodegenerative-related disorders is poorly understood. This study describes the distribution of WMH on brain MRI in Progressive Supranuclear Palsy (PSP) in comparison with Parkinson’s disease (PD) and explores their possible impact on disease’s features. Sixty PSP and 33 PD patients were included. Motor symptoms, cardiovascular risk factors and the age-related white matter changes (ARWMC) score was computed to rate WMH for both groups. Pearson’s correlation and linear or logistic regression analysis were used to check for relationships between ARWMC and PSP clinical scores. The mean (standard deviation) ARWMC total score in the PSP cohort was 4.66 (3.25). Any degree of WMH was present in 68% of PSP (ARWMC +). Compared to ARWMC-, ARWMC + did not have greater disease severity or more cardiovascular risk factors. WMH were frequently localized in fronto-parietal lobes and were mild in severity. Linear regression analysis showed that ARWMC total score was related to the PSP-rating scale, irrespective of age, disease duration and the Charlson modified comorbidity index. Logistic regression analysis confirmed that ARWMC total score was related to the use of wheelchair, irrespective of above-mentioned covariates. Vascular risk factors as well as severity and distribution of WMH did not have an impact on the PSP phenotype. No differences were found with PD patients. Our results suggest that WMH in PSP might be markers of neurodegenerative-related pathology rather than being simple expression of atherosclerotic cerebrovascular changes.

Length matters: Effects of fishing gear and fishing behavior on the catch efficiency of demersal seines

Raiding seals pose a big problem to gillnet fishers in areas with high seal abundances. As moving to active gears could be a potential solution for that problem, one gear of particular interest in areas with relatively flat sea bed structure is the so-called “MiniSeine” – a demersal seine that is reduced in size so it can be operated from small vessels. Besides its ability to catch most of the species targeted by gillnet fishers, it offers various advantages compared to other active gears. To reduce the gear in size to fit on a small vessel, the present study assessed how seine rope length (4 coils vs 8 coils), seine rope diameter (18 mm vs. 22 mm) and seine net configurations of different sizes and shapes (three different designs) affect the catch efficiency and the ratio of fish below minimum conservation reference size (MCRS). In general, shorter seine ropes (4 coils) resulted in significantly lower catches than longer ones (8 coils), except for the smallest seine configuration. Larger seine net configurations and longer seine ropes caught generally less fish below MCRS, both up to around 10 %. The seine rope diameter did not affect catches significantly. As potential “adjusting screw” to counteract lower catches due to shorter seine ropes, the effect of different layout patterns of the seine ropes on the catch efficiency was assessed. Laying out the second seine rope perpendicular to the first one can increase the fishing area to more than three times while CPUE showed a tendency to be increased compared to the standard layout pattern. Besides its importance for a successful development of the MiniSeine, these findings are of equal interest for the large-scale demersal seine fishery.

An application and discussion of wide-band signal processing technology in the primary calibration for hydrophones

Abstract Wide-band signals are potentially available in the measurement of transducers, which can obtain wide-band responses of electroacoustic parameters of them directly. The hydrophone of B&K 8103 is calibrated in a Φ 1.2 m×1.8 m small water vessel by wide-band signal processing technology in the frequency range of 3.15 kHz to 100 kHz. A thin pellicle co-vibrates with acoustic particle in the free-field, and its oscillation can be detected by a laser Doppler vibrometer, which can estimate the acoustic pressure distribution. The transfer function model is established in a small water vessel, and the wide-band frequency responses of the transfer impedance of transducer and hydrophone as well as the transfer impedance of transducer and pellicle in the small water vessel are calculated respectively. The wide-band signal processing technology of frequency domain filter process are used, which can isolate the reflecting acoustic wave from the boundaries and the surface of the water vessel. To verify the accuracy of the wide-band calibration measurements, the calibration results are compared with that using tone-burst signals in the water vessel and using free-field reciprocity method in the large water tank. The comparisons show that their calibration results are in a good agreement with each other, and the maximum deviation is 0.7 dB. All these demonstrate that the wide-band signal processing technology described is accurate and stable.

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL): A rare cause of ischemic stroke in young

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is the second known genetic form of cerebral small vessel disease after cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). It is a very rare single gene disorder affecting cerebral small blood vessels. Diagnosis of CARASIL should strongly be suspected in a young non-hypertensive patient with lacunar stroke in the basal ganglia and brainstem and alopecia limited to scalp.

Numerical and experimental studies on propulsion performance of a novel tandem paddles propulsor

Normally, small unmanned vessels used to clean floating litter on water adopt a paddle wheel as a propulsor to satisfy its shallow-draft requirements; however, this type of propulsor has bulky structures and inefficient propulsion. In this study, a novel tandem paddles propulsor (TPP) was developed, and its propulsion performance was analyzed and compared with that of a paddle wheel propulsor (PWP). Using the RNG k-ε turbulence model and sliding grid technique, the hydrodynamic performance of the PWP was simulated in computational fluid dynamics (CFD) software to verify the reliability of the numerical method. Subsequently, the propulsion performances of the two types of propulsors were simulated with different immersion depths and advanced coefficients, and the differences in their mechanical characteristics and flow field evolution were discussed and compared. The results indicate that the proposed TPP generates 2.75 times more thrust and 1.99 times greater efficiency than the PWP, exhibiting superior propulsion capability in shallow-draft vessels.

The CT and pathological features of intestinal inflammatory myofibroblastic tumor

AbstractTo explore computed tomography (CT) findings and pathological features of intestinal inflammatory myofibroblastic tumors (IMT). A retrospective review was conducted on the CT features of five patients with pathologically confirmed IMT, which were then compared with the corresponding pathological findings. The study included four female and one male patients. The tumors were located in the rectum (n = 1), small intestine (n = 2), or cecum (n = 2). One patient exhibited a cystic solid mass with exophytic growth and the solid components showed moderate enhancement. Additionally, flaky low‐density, marginal line‐like calcified shadows were observed around the lesions. Two cases presented as solid masses within the lumen of the intestinal tract, showing obvious non‐uniform enhancement along with visible enhancement shadows of small blood vessels. One patient had a metastasis. In two other cases, solid masses grew outside the lumen of the intestinal tract, demonstrating progressive and delayed enhancement on enhanced scans, as well as local nodular enhancement and ring enhancement. These two cases also exhibited focal sarcomatoid lesions, along with their respective IMTs. Histologically, these tumors mainly consist of proliferating spindle myofibroblast cells accompanied by variable infiltration by interstitial inflammatory cells, such as fibroblasts. Immunohistochemical analysis revealed positive staining for smooth muscle actin (SMA) in ~80% of the cells tested, while vimentin staining was positive in ~60% of the cells. Intestinal IMT is an extremely rare tumor with imaging features that can reflect the underlying pathological characteristics to some extent, thus aiding diagnosis.

P197 PULSE WAVE ANALYSIS IN POST COVID PATIENTS WITH AND WITHOUT DE NOVO ARTERIAL HYPERTENSION. HOSPITAL UNIVERSITARIO DE LOS ANDES (HULA) VENEZUELA. 2021-2023

Background and Objective: COVID 19 infection is characterized by an acute respiratory process that can range from mild to severe and has been related to short- and long-term complications. Post COVID 19 syndrome has been described among these long-term complications, where alterations in pulse wave velocity define vascular alteration, increasing risk of systemic arterial hypertension. The objective is analyze pulse wave velocity and arterial stiffness in post-COVID 19 patients with and without de novo arterial hypertension at the HULA, Venezuela between 2021-2023. Methods: Observational case-control study on pulse wave velocity in post-COVID-19 patients with and without de novo arterial hypertension in the HULA post-COVID-19 consultation, 2021-2023. Results: The sample consisted of 90 patients: 30 cases and 60 controls, there was no statistically significant difference in variables such as sex, body mass index (BMI) and abdominal circumference between both cohorts, with a predominance of the age group between 35 to 49 years with 33.3%, and less frequency at the extremes of life, where the group of 18-34 years and over 65 corresponded to 20%, there was a statistically significant association between syndrome post COVID 19 and arterial stiffness, the risk of de novo arterial hypertension was found to be 4.9 times and 7.9 times higher in the small and large vessel arterial stiffness group compared to the group without arterial stiffness, respectively. Conclusions: It is impressive that the age group between 35 and 49 years has a higher risk of developing arterial hypertension associated with COVID 19, the alteration of pulse wave analysis in the patients in the consultation post COVID 19 was associated with a higher risk of developing de novo arterial hypertension compared to those who did not present alterations.

Aberrant brain structural-functional connectivity coupling associated with cognitive dysfunction in different cerebral small vessel disease burdens.

Emerging evidence suggests that cerebral small vessel disease (CSVD) pathology changes brain structural connectivity (SC) and functional connectivity (FC) networks. Although network-level SC and FC are closely coupled in the healthy population, how SC-FC coupling correlates with neurocognitive outcomes in patients with different CSVD burdens remains largely unknown. Using multimodal MRI, we reconstructed whole-brain SC and FC networks for 54 patients with severe CSVD burden (CSVD-s), 106 patients with mild CSVD burden (CSVD-m), and 79 healthy controls. We then investigated the aberrant SC-FC coupling and functional network topology in CSVD and their correlations with cognitive dysfunction. Compared with controls, the CSVD-m patients showed no significant change in any SC-FC coupling, but the CSVD-s patients exhibited significantly decreased whole-brain (p = 0.014), auditory/motor (p = 0.033), and limbic modular (p = 0.011) SC-FC coupling. For functional network topology, despite no change in global efficiency, CSVD-s patients exhibited significantly reduced nodal efficiency of the bilateral amygdala (p = 0.024 and 0.035) and heschl gyrus (p = 0.001 and 0.005). Notably, for the CSVD-s patients, whole-brain SC-FC coupling showed a significantly positive correlation with MoCA (r = 0.327, p = 0.020) and SDMT (r = 0.373, p = 0.008) scores, limbic/subcortical modular SC-FC coupling showed a negative correlation (r = -0.316, p = 0.025) with SCWT score, and global/local efficiency (r = 0.367, p = 0.009 and r = 0.353, p = 0.012) showed a positive correlation with AVLT score. For the CSVD-m group, whole-brain and auditory/motor modular SC-FC couplings showed significantly positive correlations with SCWT (r = 0.217, p = 0.028 and r = 0.219, p = 0.027) and TMT (r = 0.324, p = 0.001 and r = 0.245, p = 0.013) scores, and global/local efficiency showed positive correlations with AVLT (r = 0.230, p = 0.020 and r = 0.248, p = 0.012) and SDMT (r = 0.263, p = 0.008 and r = 0.263, p = 0.007) scores. Our findings demonstrated that decreased whole-brain and module-dependent SC-FC coupling associated with reduced functional efficiency might underlie more severe burden and worse cognitive decline in CSVD. SC-FC coupling might serve as a more sensitive neuroimaging biomarker of CSVD burden and provided new insights into the pathophysiologic mechanisms of clinical development of CSVD.

Biocompatible Liquid Embolic for the Treatment of Microvascular Hemorrhage.

Persistent or recurrent bleeding from microvessels inaccessible for direct endovascular intervention is a major problem in medicine today. Here, an innovative catheter-directed liquid embolic (P-LE) is bioengineered for rapid microvessel embolization to treat small vessel hemorrhage. Tested in rodent, porcine, and canine animal models under normal and coagulopathic conditions, P-LE outperformed clinically used embolic materials in both survival and non-survival experiments, effectively occluding vessels as small as 40 microns with no signs of recanalization. P-LE occlusion is independent of the coagulation cascade, and its resistance to displacement is ≈ 8 times greater than systolic blood pressure. P-LE is also found to be biocompatible and x-ray visible and does not require polymerization or a chemical reaction to embolize. To simulate the clinical scenario, acute microvascular hemorrhage is created in the pig kidney, liver, or stomach; these are successfully treated with P-LE achieving immediate hemostasis. Furthermore, P-LE is found to be bactericidal to highly resistant patient-derived bacteria, suggesting that P-LE may also protect against infectious complications that may occur following embolization procedures. P-LE is safe, easy to use, and effective in treating -microvessel hemorrhage.

Advancing cerebral small vessel disease diagnosis: Integrating quantitative susceptibility mapping with MRI-based radiomics.

Cerebral small vessel disease (CSVD) is a neurodegenerative disease with hidden symptoms and difficult to diagnose. The diagnosis mainly depends on clinical symptoms and neuroimaging. Therefore, we explored the potential of combining clinical detection with MRI-based radiomics features for the diagnosis of CSVD in a large cohort. A total of 118 CSVD patients and 127 healthy controls underwent quantitative susceptibility mapping and 3D-T1 scans, and all completed multiple cognitive tests. Lasso regression was used to select features, and the radiomics model was constructed based on the regression coefficients of these features. Clinical cognitive and motor tests were added to the model to construct a hybrid model. All models were cross-validated to analyze the generalization ability of the models. The AUCs of the radiomics and hybrid models in the internal test set were 0.80 and 0.87, respectively. In the validation set, the AUCs were 0.77 and 0.79, respectively. The hybrid model demonstrated higher decision efficiency. The Trail Making Test, which enhances the diagnostic performance of the model, is associated with multiple brain regions, particularly the right cortical nuclei and the right fimbria. The hybrid model based on radiomics features and cognitive tests can achieve quantitative diagnosis of CSVD and improve the diagnostic efficiency. Furthermore, the reduced processing capacity due to atrophy of the right cortical nucleus and right fimbria suggests the importance of these regions in improving the diagnostic accuracy of the model.

Improved Dementia Prediction in Cerebral Small Vessel Disease Using Deep Learning-Derived Diffusion Scalar Maps From T1.

Cerebral small vessel disease is the most common pathology underlying vascular dementia. In small vessel disease, diffusion tensor imaging is more sensitive to white matter damage and better predicts dementia risk than conventional magnetic resonance imaging sequences, such as T1 and fluid attenuation inversion recovery, but diffusion tensor imaging takes longer to acquire and is not routinely available in clinical practice. As diffusion tensor imaging-derived scalar maps-fractional anisotropy (FA) and mean diffusivity (MD)-are frequently used in clinical settings, one solution is to synthesize FA/MD from T1 images. We developed a deep learning model to synthesize FA/MD from T1. The training data set consisted of 4998 participants with the highest white matter hyperintensity volumes in the UK Biobank. Four external validations data sets with small vessel disease were included: SCANS (St George's Cognition and Neuroimaging in Stroke; n=120), RUN DMC (Radboud University Nijmegen Diffusion Tensor and Magnetic Resonance Imaging Cohort; n=502), PRESERVE (Blood Pressure in Established Cerebral Small Vessel Disease; n=105), and NETWORKS (n=26), along with 1000 normal controls from the UK Biobank. The synthetic maps resembled ground-truth maps (structural similarity index >0.89 for MD maps and >0.80 for FA maps across all external validation data sets except for SCANS). The prediction accuracy of dementia using whole-brain median MD from the synthetic maps is comparable to the ground truth (SCANS ground-truth c-index, 0.822 and synthetic, 0.821; RUN DMC ground truth, 0.816 and synthetic, 0.812) and better than white matter hyperintensity volume (SCANS, 0.534; RUN DMC, 0.710). We have developed a fast and generalizable method to synthesize FA/MD maps from T1 to improve the prediction accuracy of dementia in small vessel disease when diffusion tensor imaging data have not been acquired.

Exploration of a comprehensive index for predicting cognitive impairment in patients with cerebral small vessel disease and white matter lesions

Background & Objective: The objective of this study was to explore the risk factors for cognitive impairment in patients with cerebral small vessel disease (CSVD), and to construct a predictive model for cognitive impairment in CSVD patients, providing personalized diagnostic and treatment strategies for patients. Methods: Clinical data and blood indicators of CSVD patients admitted to the Department of Neurology at the Second Affiliated Hospital of Shandong First Medical University from February 2022 to February 2023 were collected. Additionally, these patients underwent cranial MRI examinations and completed neurological and psychological assessments, including the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE). Based on the MoCA and MMSE results, the patients were divided into the cognitive impairment group and the normal cognitive group. Clinical data, blood indicators, and white matter lesion (WML) grades were compared between the two groups. Univariate logistic regression analysis was performed to identify the risk factors for cognitive impairment in CSVD patients. Using MoCA assessment results as the gold standard and several clinical indicators as independent variables, a logistic regression model was constructed. Predicted values were calculated based on this model, and a receiver operating characteristic (ROC) curve for the comprehensive diagnosis of multiple variables was plotted to evaluate the model’s accuracy. Results: A total of 134 CSVD patients were included, and cognitive impairment occurred in 98 cases, with an incidence rate of 73.13%, while 36 patients did not have cognitive impairment. Univariate logistic regression analysis of the collected variables identified eight factors: age, education level, hypertension, diabetes, cerebral hemorrhage, low-density lipoprotein cholesterol (LDL-C), hyperhomocysteine (HHCY), and WML grading. Multivariate logistic regression analysis identified age, LDL-C, and WML grading as the final predictive factors, establishing a combined diagnostic model to predict the probability of cognitive impairment in patients. The constructed ROC curve for the comprehensive diagnosis of multiple variables yielded an area under the curve of 0.870, indicating good accuracy. To facilitate clinical diagnosis, the combined diagnostic model was simplified into an L score calculation formula, with the optimal cutoff value of 5.223. When the L score is <5.223, the patient can be considered not having cognitive impairment, while an L score >5.223 indicates cognitive impairment, allowing for the prediction of the risk of cognitive impairment in patients. Conclusion: Age, education level, hypertension, diabetes, cerebral hemorrhage, LDL-C, HHCY, and WML grading are related risk factors for cognitive impairment in CSVD patients. Age, LDL-C, and WML grading are independent risk factors for cognitive impairment in CSVD patients. The clinical predictive model for cognitive impairment in cerebral small vessel disease, constructed using the final predictive factors, showed good performance and clinical utility. It facilitates individualized risk assessment for cognitive impairment in CSVD patients and allows for targeted follow-up observation for high-risk individuals.

Computational imaging for rapid detection of grade-I cerebral small vessel disease (cSVD)

An early identification and subsequent management of cerebral small vessel disease (cSVD) grade 1 can delay progression into grades II and III. Machine learning algorithms have shown considerable promise in medical image interpretation automation. An experimental cross-sectional study aimed to develop an automated computer-aided diagnostic system based on AI (artificial intelligence) tools to detect grade 1-cSVD with improved accuracy. Patients with Fazekas grade 1 cSVD on Non-Contrast Magnetic Resonance Imaging (MRI) Brain of age >40 years of both genders were included. The dataset was pre-processed to be fed into a 3D convolutional neural network (CNN) model. A 3D stack with the shape (120, 128, 128, 1) containing axial slices from the brain magnetic resonance image was created. The model was created from scratch and contained four convolutional and three fully connected (FC) layers. The dataset was preprocessed by making a 3D stack, and normalizing, resizing, and completing the stack was performed. A 3D-CNN model architecture was designed to train and test preprocessed images. We achieved an accuracy of 93.12 % when 2D axial slices were used. When the 2D slices of a patient were stacked to form a 3D image, an accuracy of 85.71 % was achieved on the test set. Overall, the 3D-CNN model performed very well on the test set. The earliest and the most accurate diagnosis from computational imaging methods can help reduce the huge burden of cSVD and its associated morbidity in the form of vascular dementia.

Cold case: COVID-19-triggered type 1 cryoglobulinemia

A 42-year-old male was referred to the internal medicine department because of renal failure and persistent malaise after a recent SARS-CoV-2 infection. Blood results showed anemia and severe renal insufficiency (hemoglobin of 10.3 g/dL and a creatinine of 2.19 mg/dL). Additional tests revealed a type I cryoglobulinemia with a cryoprecipitate composed of dual IgM (kappa and lambda). Further investigations on the cryoprecipitate revealed that the immunoglobulins were directed against SARS-CoV-2 antigens. In the meanwhile, our patient noticed improvement of his symptoms accompanied by resolution of laboratory abnormalities. Three months later, the cryoglobulin could no longer be detected.Type 1 cryoglobulinemia is usually associated with lymphoproliferative disorders and is characterized by various symptoms caused by cryoprecipitates occluding small blood vessels. This is, to our knowledge, the first case of type I cryoglobulinemia with proven precipitation of SARS-CoV-19 antibodies. COVID-19 induced cryoglobulinemia appears to have a mild disease course and to be self-limiting upon viral clearance.

Association between optic disc pallor and lacunar stroke

ObjectiveTo test for associations between optic disc pallor and two clinical variables: ischaemic stroke subtype (cortical and lacunar) and cerebral small vessel disease (SVD) scores in a cohort of hospital...

Collagen IV deficiency causes hypertrophic remodeling and endothelium-dependent hyperpolarization in small vessel disease with intracerebral hemorrhage

Genetic variants in COL4A1 and COL4A2 (encoding collagen IV alpha chain 1/2) occur in genetic and sporadic forms of cerebral small vessel disease (CSVD), a leading cause of stroke, dementia and intracerebral haemorrhage (ICH). However, the molecular mechanisms of CSVD with ICH and COL4A1/COL4A2 variants remain obscure. Vascular function and molecular investigations in mice with a Col4a1 missense mutation and heterozygous Col4a2 knock-out mice were combined with analysis of human brain endothelial cells harboring COL4A1/COL4A2 mutations, and brain tissue of patients with sporadic CSVD with ICH. Col4a1 missense mutations cause early-onset CSVD independent of hypertension, with enhanced vasodilation of small arteries due to endothelial dysfunction, vascular wall thickening and reduced stiffness. Mechanistically, the early-onset dysregulated endothelium-dependent hyperpolarization (EDH) is due to reduced collagen IV levels with elevated activity and levels of endothelial Ca2+-sensitive K+ channels. This results in vasodilation via the Na/K pump in vascular smooth muscle cells. Our data support this endothelial dysfunction preceding development of CSVD-associated ICH is due to increased cytoplasmic Ca2+ levels in endothelial cells. Moreover, cerebral blood vessels of patients with sporadic CSVD show genotype-dependent mechanisms with wall thickening and lower collagen IV levels in those harboring common non-coding COL4A1/COL4A2 risk alleles. COL4A1/COL4A2 variants act in genetic and sporadic CSVD with ICH via dysregulated EDH, and altered vascular wall thickness and biomechanics due to lower collagen IV levels and/or mutant collagen IV secretion. These data highlight EDH and collagen IV levels as potential treatment targets. MRC, Wellcome Trust, BHF.

Cerebral blood flow and cognition after 3 months tadalafil treatment in small vessel disease (ETLAS-2): study protocol for a randomized controlled trial

BackgroundTargeted treatment is highly warranted for cerebral small vessel disease, a causal factor of one in four strokes and a major contributor to vascular dementia. Patients with cerebral small vessel disease have impaired cerebral blood flow and vessel reactivity. Tadalafil is a specific phosphodiesterase 5 inhibitor shown to improve vascular reactivity in the brain.MethodsThe ETLAS-2 trial is a phase 2 double-blind, randomized placebo-controlled, parallel trial with the feasibility of tadalafil as the primary outcome. The trial aims to include 100 patients with small vessel occlusion stroke or transitory ischemic attacks and signs of cerebral small vessel disease more than 6 months before administration of study medication. Patients are treated for 3 months with tadalafil 20 mg or placebo daily and undergo magnetic resonance imaging (MRI) to evaluate changes in small vessel disease according to the STandards for ReportIng Vascular changes on nEuroimaging (STRIVE) criteria as well as cerebral blood flow, cerebrovascular reactivity, and neurovascular coupling in a functional MRI sub-study. The investigation includes comprehensive cognitive testing using paper–pencil tests and Cambridge Neuropsychological Test Automated Battery (CANTAB) tests in a cognitive sub-study.DiscussionThe ETLAS-2 trial tests the feasibility of long-term treatment with tadalafil and explores vascular and cognitive effects in cerebral small vessel disease in trial sub-studies. The study aims to propose a new treatment target and improve the understanding of small vessel disease. Currently, 64 patients have been included and the trial is estimated to be completed in the year 2024.Trial registrationClinicaltrials.gov, NCT05173896. Registered on 30 December 2021.

Mediastinal fibrosis as a puzzling presentation: A clinical conundrum in rheumatology: A case report

Granulomatosis with polyangiitis (GPA) is a type of small vessel vasculitis, most commonly involving the respiratory tract and kidneys. It can occasionally present with mass-like lesions at various sites, including the brain, orbit, skin, genitals, retroperitoneum, and mediastinum. Presentation with mediastinal fibrosis is rare and less commonly recognized. The current study presents the case of a mediastinal mass causing pulmonary artery compression and subsequent pulmonary hypertension (PH) that required stenting. Despite inconclusive mediastinal biopsy results, the integration of clinical, radiological, and laboratory findings led to the diagnosis of ANCA-associated vasculitis, highlighting the challenges and necessity of a multi-modal diagnostic approach in real-world clinical scenarios. This case underscores the importance of considering ANCA-associated vasculitis as a potential etiology in patients presenting with mediastinal fibrosis. Early recognition and appropriate management are crucial in optimizing outcomes for patients with this rare and challenging manifestation.