Small Vessels Research Articles

Characterization of cognitive decline in long-duration type 1 diabetes by cognitive, neuroimaging and pathological examinations.

We aimed to characterize factors associated with the under-studied complication of cognitive decline in aging people with long-duration type 1 diabetes (T1D). Joslin "Medalists" (n = 222; T1D ≥ 50 years) underwent cognitive testing. Medalists (n = 52) and age-matched non-diabetic controls (n = 20) underwent neuro- and retinal imaging. Brain pathology (n = 26) was examined. Relationships amongst clinical, cognitive and neuroimaging parameters were evaluated. Compared to controls, Medalists had worse psychomotor function and recall, which associated with female gender, lower visual acuity, reduced physical activity, longer diabetes duration and higher inflammatory cytokines. On neuroimaging, compared to controls, Medalists had significantly lower total and regional brain volumes, equivalent to 9 years of accelerated aging, but small vessel disease markers did not differ. Reduced brain volumes associated with female sex, reduced psychomotor function, worse visual acuity, longer diabetes duration and higher inflammation, but not with glycemic control. Worse cognitive function, lower brain volumes, and diabetic retinopathy correlated with thinning of the outer retinal nuclear layer. Worse baseline visual acuity associated with declining psychomotor function in longitudinal analysis. Brain volume mediated the association between visual acuity and psychomotor function by 57%. Brain pathologies showed decreased volumes, but predominantly mild vascular or Alzheimer's-related pathology. This first comprehensive study of cognitive function, neuroimaging and pathology in aging T1D individuals demonstrated that cognitive decline was related to parenchymal rather than neurovascular abnormalities, unlike type 2 diabetes, suggestive of accelerated aging in T1D. Improving visual acuity could perhaps be an important preventive measure against cognitive decline in people with T1D.

Impaired Resting State Functional Connectivity in CADASIL Mutant Mice.

Background: Cerebral autosomal-dominant arteriopathy, subcortical infarcts, and leukoencephalopathy (CADASIL) is the most prevalent monogenic inherited cause of cerebral small-vessel disease. Despite its prevalence, there is currently no proven therapy to prevent or reverse the progression of the disease. Methods: This study aimed to characterize the functional integrity of long white matter tracts in CADASIL transgenic mice, both with and without focal white matter lesions in the corpus callosum added on, utilizing optical resting-state functional connectivity imaging alongside behavioral examinations. Additionally, we examined the efficacy of tocotrienol, a neuroprotective derivative of vitamin E derived from palm oil, which has shown promise in preventing white matter disease progression in clinical trials involving patients with small vessel disease. Results: At baseline, resting-state inter and intrahemispheric functional connectivity was significantly lower in Notch3R169C than in Notch3WT (p=0.004), and the grid walk test revealed a higher number of foot faults in the Notch3R169C group compared to Notch3WT. Sex did not interact with the genotype on the primary outcomes. Introducing a lesion in the corpus callosum compromised functional connectivity and behavior outcomes in both genotypes to a similar extent; lesion volumes did not differ between the genotypes. Tocotrienol treatment did not show any protective effect on any endpoint. Conclusion: These data show impaired resting-state functional connectivity and increased foot faults in the Notch3R169C mutant model of CADASIL. Future work will aim to test therapeutic or preventive interventions in CADASIL mutants using these measures.

2678 Small vessel disease contributions to acute delirium: a pilot feasibility MRI study

Abstract Background and aims Delirium carries an eightfold risk of future dementia. Small vessel disease (SVD), best seen on MRI, increases delirium risk, yet delirium is understudied in MRI research. We aimed to determine MRI feasibility, tolerability, image usability, and prevalence of acute and chronic SVD lesions in acute delirium. Methods This case–control feasibility study performed MRI (3D T1/T2-weighted, FLAIR, Susceptibility-weighted, and Diffusion-weighted imaging (DWI) on 20 medical inpatients >65 years: 10 with delirium ≥3 weeks and 10 without delirium, matched for vascular risk, Clinical Frailty Scale (CFS), and cognitive status. We excluded acute stroke, agitation necessitating sedation, assistance of >2 staff to mobilise, and MRI contraindications. We measured scan duration, tolerability, image usability, acute infarcts on DWI, and chronic SVD features. Six months later, we recorded CFS and cognitive diagnoses. Results Mean age was 83.5 years (delirium 78.7 vs non-delirium 88.4); 13/20 were female; 17/20 had premorbid cognitive decline/impairment or dementia. Acquisition took mean 26.8 minutes. MRI was well-tolerated in 16/20 (7/10 in delirium arm; 9/10 in non-delirium arm). 4/20 had early scan termination but 20/20 had clinically interpretable images. We detected DWI-hyperintense lesions in 3/10 (33.3%) with delirium (2/10 small subcortical and 1/10 cortical) and in 3/10 (33.3%) without delirium (2/10 small subcortical; 1/10 cortical). Mean SVD score was 2.4 in delirium vs 3.3 without. Conclusions MRI is feasible, usable, and tolerable in delirium, and we detected DWI hyperintense lesions in one third of patients overall. This study indicates acute vascular contributions, including SVD, to delirium, supporting the need for larger studies.

Dual-stream disentangled model for microvascular extraction in five datasets from multiple OCTA instruments

IntroductionOptical Coherence Tomography Angiography (OCTA) is a cutting-edge imaging technique that captures retinal capillaries at micrometer resolution using optical instrument. Accurate segmentation of retinal vasculature is essential for eye related diseases measurement and diagnosis. However, noise and artifacts from different imaging instruments can interfere with segmentation, and most existing deep learning models struggle with segmenting small vessels and capturing low-dimensional structural information. These challenges typically results in less precise segmentation performance.MethodsTherefore, we propose a novel and robust Dual-stream Disentangled Network (D2Net) for retinal OCTA microvascular segmentation. Specifically, the D2Net includes a dual-stream encoder that separately learns image artifacts and latent vascular features. By introducing vascular structure as a prior constraint and constructing auxiliary information, the network achieves disentangled representation learning, effectively minimizing the interference of noise and artifacts. The introduced vascular structure prior includes low-dimensional neighborhood energy from the Distance Correlation Energy (DCE) module, which helps to better perceive the structural information of continuous vessels.Results and discussionTo precisely evaluate our method on small vessels, we delicately establish OCTA microvascular labels by performing comprehensive and detailed annotations on the FOCA dataset, which includes data collected from different instruments, and evaluated the proposed D2Net effectively mitigates the challenges of microvasculature region recognition caused by noise and artifacts. The method achieves more refined segmentation performance. In addition, we validated the performance of D2Net on four OCTA datasets (OCTA-500, ROSE-O, ROSE-Z, and ROSE-H) acquired using different instruments, demonstrating its robustness and generalization capabilities in retinal vessel segmentation compared to other state-of-the-art methods.

Optical coherence tomography angiography in patients with focal epilepsy

PurposeThis study aims to compare optical coherence tomography angiography (OCTA) data in individuals with focal epilepsy and healthy individuals and to investigate the effect of antiseizure medications (ASM) on OCTA data.MethodsWe examined 48 consecutive patients with focal epilepsy and 46 healthy controls. Area and skeleton density of superficial and deep capillary plexuses in the macular area and peripapillary radial capillary plexus were measured.ResultsIn general, no differences in OCTA parameters were found between groups of individuals with epilepsy and healthy individuals. A comparison of individuals with epilepsy with and without comorbid major depressive disorder revealed no differences in OCTA data. However, the area and skeleton densities of the perfused capillary retinal vascular bed in the macular region showed a negative association with the use of valproates and modifiers of the presynaptic release machinery, whereas only the skeleton density of the deep capillary plexus showed a positive association with the use of modulators of voltage-gated sodium channels.ConclusionOCTA revealed different effects of various ASM groups on the perfused macular capillary bed. These findings suggest that OCTA parameters could serve as potential biomarkers for assessing ASM effects on small vessels and capillaries in the brain.

P-1836. SARS-CoV-2 induces blood-brain barrier and choroid plexus barrier impairments and vascular inflammation in mice

Abstract Background The coronavirus disease of 2019 (COVID-19) pandemic has led to more than 700 million confirmed cases and nearly 7 million deaths. Although Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) virus mainly infects the respiratory system, neurological complications are widely reported in both acute infection and long-COVID cases. Despite the success of vaccines and antiviral treatments, neuroinvasiveness of SARS-CoV-2 remains an important question, which is also centered on the mystery whether the virus is capable of breaching the barriers into the central nervous system.Figure 1:SARS-CoV-2 infection in the K18-hACE2 model.(A) Experimental diagram: Eight weeks-old K18-hACE2 mice were intranasally infected with SARS-CoV-2, monitored daily for symptoms, or euthanized at 5 days post-infection (DPI) to collect tissue. (B) Daily weight measurements in K18-hACE2 mice intranasally infected with SARS-CoV-2 isolate USA-WA1/2020. (C)The survival curve showing the probability of survival over 7 days after SARS-CoV-2 infection. (D) Representative mouse brain hemisphere image showing the presence of SARS-CoV-2 nucleocapsid protein by immunohistochemical staining. Boxed regions are shown on the right. Bar: 500 µm. Methods Here using the K18-hACE2 model, we investigated the impact of acute SARS-CoV-2 infection on major parts of neurovascular systems, and found increased incidence of microhemorrhage and significant disruption of both BBB and BCSFB in K18-hACE2 mice after SARS-CoV-2 infection. Cerebral microvascular injury was accompanied by substantial pericyte damage, tight junction loss, astrogliosis, and neuroinflammation in the brain parenchyma. In addition, endothelial activation and vascular inflammation occurred at both BBB and BCSFB, as shown by upregulation of VCAM-1 and COX2 markers.Figure 2:Vascular damage and BBB breakdown in SARS-CoV-2 infected K18-hACE2 model.(A) Representative images showing IgG immunohistochemical staining in K18-hACE2 mouse brain tissues with or without SARS-CoV-2 infection. Boxed regions are shown at the bottom. (B) Representative images showing immunofluorescent staining with IgG, showing the microhemorrhage site in the cortex of K18-hACE2 mice with SARS-CoV-2 infection. Bar: 50 µm. (C) Quantification of the number of microhemorrhages per field of view in the cortex, thalamus, and hippocampus (Hipp). n= 3; ***p< 0.001; two-tailed Student’s t-test. (D) Quantification of the diameters of the microhemorrhages in the cortex, thalamus, and hippocampus. (E) Representative images showing immunofluorescent staining for IgG at the capillary level in the cortex. K18-hACE2 mice with SARS-CoV-2 infection exhibited a significant accumulation of IgG surrounding the microvessels. Bar: 50 µm. (F) Quantification of the number of leaky small blood vessels per field of view in cortex, thalamus, and hippocampus. n= 3; ***p< 0.001; two-tailed Student’s t-test. (G) Quantification of the percentage of leakage vascular area to the total area of blood vessels in cortex, thalamus, and hippocampus. n= 3. Results By studying the K18-hACE2 infection model, we observed clear evidence of microvascular damage and breakdown of the blood-brain barrier (BBB). Mechanistically, SARS-CoV-2 infection caused pericyte damage, tight junction loss, endothelial activation and vascular inflammation, which together drive microvascular injury and BBB impairment. BBB tight junction loss in SARS-CoV-2 infected K18-hACE2 model. (A) The K18-hACE2 mice were used to test the BBB function after SARS-CoV-2 infection. (B) Representative images showing immunofluorescent staining for IgG, ZO-1, and Lectin in the cortex of K18-hACE2 mice. Bar: 50 µm. (C-D) Representative images showing immunofluorescent staining for ZO-1 and Lectin in the thalamus(C) and hippocampus(D) areas of K18-hACE2 mice. Bar: 50 µm. (E) Length of ZO-1-positive profiles in the cortex, thalamus, and Hipp. n= 3; ***p< 0.001; two-tailed Student’s t-test. (F-H) Representative images showing immunofluorescent staining for Claudin5 and Lectin in the cortex(F), thalamus (G), and hippocampus (H) areas of K18-hACE2 mice. Bar: 50 µm. (I) Claudin5 length in the cortex, thalamus and, Hipp. n= 3; ***p< 0.001; two-tailed Student’s t-test. Conclusion The impact of such changes, together with astrogliosis and neuroinflammation, may drive or at least contribute to the neurological complications seen in COVID-19 patients. As SARS-CoV-2 will likely remain a major health issue for years to come, our findings provide a needed understanding of its impact on the major CNS barriers and brain homeostasis at both molecular and cellular levels. Vascular inflammation in SARS-CoV-2 infected K18-hACE2 model (A-C) Representative images showing immunofluorescent staining for VCAM1 and Lectin in the cortex, thalamus, and hippocampus of K18-hACE2 mice. Bar: 50 µm. (D) Quantification of VCAM1 and lectin signal overlap in the cortex, thalamus, and hippocampus. n= 3; ***p< 0.001; two-tailed Student’s t-test. (E-G) Representative images showing immunostaining of COX2 and Lectin in the cortex, thalamus, and hippocampus of K18-hACE2 mice. Bar: 50 µm. (H) Quantification of COX2 and Lectin signal overlap in the cortex, thalamus, and hippocampus areas of K18-hACE2 mice. n= 3; ***p< 0.001; ****p< 0.0001; two-tailed Student’s t-test. (I) Quantification of COX2 relative fluorescence intensity in the cortex, thalamus, and hippocampus of K18-hACE2 mice. n= 3; ***p< 0.001; ****p< 0.0001; two-tailed Student’s t-test. Disclosures All Authors: No reported disclosures

Case report: Spontaneous renal hemorrhage in anti-neutrophil cytoplasmic antibody-associated vasculitis

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a systemic necrotizing vasculitis that predominantly affects small vessels. In this report, we present a typical case of granulomatosis with polyangiitis (GPA) complicated by spontaneous renal hemorrhage (SRH), a rare but potentially severe condition. The patient developed SRH during immunosuppressive therapy but recovered following conservative treatment. We then conducted a systematic literature review on SRH in the context of AAV, and analyzed clinical features, management strategies, and patient prognosis. A total of 15 patients were enrolled for statistical analysis, comprising the one case reported in the current study and 14 from the literature. Of these patients, nine presented with GPA and six showed microscopic polyangiitis (MPA), with a sex distribution of 3:2 males to females. The average patient age was 54.5 years, and ranged from 25 to 82 years. Acute flank pain was the most common clinical manifestation, and was occasionally accompanied by anemia and shock. Treatment varied for the different patients. Eight patients received glucocorticoid and immunosuppressive agents that included rituximab, cyclophosphamide, and azathioprine; five patients underwent transcatheter arterial embolization (TAE); and one patient underwent nephrectomy. Our findings indicate that SRH typically occurs early in the course of AAV and correlates with disease activity, with renal aneurysm rupture as the primary cause. More than half of the patients respond well to corticosteroids and immunosuppressants. Timely TAE is essential for patients showing persistent deterioration despite conservative management.

P-444. Cerebral Small Vessel disease risk in people with HIV and substance use disorder

Abstract Background Cerebral small vessel disease (CSVD) is associated with an increased risk of stroke, dementia, and death. The risk of CSVD in people with HIV (PWH) is twice the general population but the CSVD risk in PWH with substance abuse is poorly defined. With national surveys showing approximately two-thirds of PWH admitting to using an illicit drug in their lifetime, the evaluation of CSVD risk in this population is needful.Table 1:Demographic and Clinical information of CSVD in PWH with substance use disorder (N=23) Methods We retrospectively analyzed brain magnetic resonance imaging (MRI) findings of PWH attending our ambulatory HIV needle exchange clinic. Brain MRIs done in the previous 5 years before study analysis were included. CSVD was determined by Cerebral small vessel disease score (0 to 4), assigning 1 point each for the following: (i) presence of lacunar infarct, (ii) microbleeds, (iii) prominent perivascular spaces, and (iv) white matter hyperintensities. The findings suggestive of CSVD such as age-related white matter changes and chronic microvascular ischemia were also included in the CSVD assessment. Substance use disorder (uncontrolled use of a substance despite harmful consequences) was determined to be present if this was included on the patient diagnosis list.Table 2:Cerebral Small Vessel disease Score in PWH with substance use disorder. 5 participants had a CSVD score of 0 but "age related white matter disease" on Brain MRI Results 51 patients (PWH with substance use disorder) were included in the analysis. 23 participants out of this group had brain MRI imaging out of which 12 (52.2%) had CSVD. The mean age was 50 years. The demographic and clinical data of the cohort are shown in Table 1. The CSVD score ranged from 0 to 3 with an average score of 1. Table 2 illustrates the CSVD score of the cohort. 5 participants had a CSVD score of 0 but a brain MRI report of “age-related white matter changes”. The Pearson Correlation between age and CSVD score was 0.057 with a p-value of 0.86. Conclusion 52% of PWH who use substance have CSVD on MRI brain imaging. This could translate to an increased risk of stroke, cognitive impairment, and death if not recognized early and aggressively addressed. CSVD score provides objective quantification of CSVD but age-related white matter changes, which are not captured on this score may be equally important especially as PWH continues to age. A systematic approach for screening for CSVD in PWH with substance use disorder is warranted to minimize the unfavorable outcomes associated with this cohort. Disclosures All Authors: No reported disclosures

Diagnostic utility of the MTA-Score depending on age and cerebral microangiopathy in times of automated volumetry

To investigate the diagnostic value of the MTA score according to age, cerebral small vessel disease and in times of automated volumetry. Retrospective analysis of patients with subjective cognitive decline (SCD), amnestic mild cognitive impairment (aMCI), Alzheimer's disease (AD) and mixed dementia (MD) who presented to our outpatient dementia clinic between February 2018 and October 2020. Patients underwent cranial magnetic resonance imaging (MRI) including specific MRI sequences needed for automated volumetry. MRI data sets were analyzed regarding MTA score, Fazekas score, hippocampal und temporal lobe percentile and total white matter lesion volume. Within the study period, 242 patients (100 male, 142 female, mean age 74.7±9.9 years) with SCD (n=20), aMCI (n=110), AD (n=62) and MD (n=50) were analyzed. MTA score strongly correlated with age (ρ=0.545; p<0.001), especially regarding the aMCI and AD group. MTA score differentiated only between prodromal and dementia stages (aMCI vs. AD: p=0.005), whereas hippocampal percentile also showed a trend in differentiating between SCD and aMCI. There was a correlation between MTA score and hippocampal percentile (ρ=-0.385; p<0.001), which, on a single group level, could only be shown for the aMCI and AD group. There was significant correlation between MTA score with hippocampal and temporal lobe percentile. MTA score also correlated with Fazekas score (ρ=0.451; p<0.001) which again could only be detected within the aMCI and AD group. But there was no correlation between hippocampal percentile and total white matter lesion volume. When interpreting the MTA score, patient's age needs to be taken into consideration. Especially, in early dementia diagnostics, automated volumetric procedures might be advantageous, but due to the strong correlation of MTA score with hippocampal percentile, the MTA score still is a valid diagnostic marker. Whether hippocampal atrophy is modulated by cerebral small vessel disease still needs to be elucidated.

Genetic Evidence for Causal Effects of circulating remnant lipid profile on cerebral hemorrhage and ischemic stroke: A Mendelian Randomization Study.

Mendelian randomization was employed to investigate the impact of circulating lipids, specifically residual lipids, on the risk of susceptibility to cerebral hemorrhage and ischemic stroke. According to previously studies, we chose 19 circulating lipids, comprising 6 regular lipids and 13 residual lipids, to investigate their potential causal relationship with intracranial hemorrhage and ischemic stroke. The effect estimates were computed utilizing the random-effects inverse-variance-weighted methodology. The findings revealed negative correlations between HDL-C and cerebral hemorrhage and large artery stroke. HDL-C, Apo A1, XS.VLDL.TG, and IDL.TG were found to be negatively correlated with any ischemic stroke. Apo B, TG, LDL-C, L.VLDL-TG, M.VLDL-TG, and S.VLDL-TG exhibited positive correlations with large artery stroke. XL.HDL-TG and IDL.TG were positively correlated with cardioembolic stroke. No significant causal relationship was observed between circulating lipids, with the exception of HDL-C, and cerebral hemorrhage. No causal relationship was identified between any circulating lipids and small vessel stroke. Furthermore, the causal relationships were only found between residual lipids and ischemic stroke. This study provides evidence for the beneficial impact of Apo A1 and HDL-C in reducing the risk of ischemic stroke, as well as the protective effect of HDL-C against cerebral hemorrhage. It highlights the detrimental effects of Apo B, TG, and LDL-C in increasing the risk of ischemic stroke, particularly in cases of large artery stroke. Furthermore, the study underscores the heterogeneity and two-sided effects of the causal relationship between triglyceride-rich lipoproteins and ischemic stroke, offering a promising avenue for the treatment of ischemic stroke.

Extracorporeal shockwave therapy rescued mouse critical limb ischemia via upregulating GPR120 against inflammation and promoting angiogenesis for restoring the blood flow in ischemic zone-experimental study.

This study tested the hypothesis that extracorporeal shockwave therapy (ECSWT) effectively rescues critical limb ischemia (CLI) in mice through the upregulation of GPR120, which protects against inflammation and angiogenesis to restore blood flow in the ischemic area. Compared with the control, ECSWT-induced GPR120-mediated anti-inflammatory effects significantly suppressed the expression of inflammatory signaling biomarkers (TAK1/MAPK family/NF-κB/IL-1β/IL-6/TNF-α/MCP-1) in HUVECs, and these effects were abolished by silencing GPR120 or by the GPR120 antagonist AH7614 (all P < 0.001). C57BL/6 mice (n =40) were equally categorized into Groups 1 (sham-operated control), 2 (CLI), 3 (CLI+ECSWT), and 4 (CLI+ECSWT+AH7614). By Days 7, 14, and 28 just prior to harvesting the quadriceps muscle, the laser Doppler results showed that the ratio of ischemia to normal blood flow (INBF) in the CLI area was highest in Group 1, lowest in Group 2, and significantly greater in Group 3 than in Group 4 (all P < 0.0001). Endothelial cell markers (CD31/vWF) and GPR120+cells exhibited identical patterns of INBF among the groups, whereas angiogenesis biomarkers (CXCR4/SDF-1/VEGF/VEGFR2) were significantly and progressively upregulated from Groups 1 to 4 (all P < 0.0001). The protein levels of inflammation (MMP-9, IL-6, and TNF-α) and oxidative stress (NOX-1 and NOX-2) and the cellular levels of inflammation (CD68+)/DNA damage (γ-H2AX+) displayed opposite patterns, whereas the small vessel density in the CLI area displayed an identical pattern of INBF among the groups (all P < 0.0001). ECSWT rescued CLI by increasing GPR120-mediated suppression of inflammation and enhancing angiogenesis via activation of VEGFR2.

Magnetized peristaltic flow of Sisko nanofluid under thermal radiation and double-diffusive convection with viscous dissipation and slip effects in an asymmetric channel

The phenomenon of peristalsis has gathered significant attention from researchers due to its wide-ranging applications in fields such as biological sciences, industries, and biomechanics. Its practical relevance can be observed in various processes, including blending food in the digestive tract, flow in small blood vessels and the movement of cilia. Inspired by such useful applications, this theoretical study applies an analytical model that examines the movement of magnetically induced Sisko nanofluid in an asymmetric channel considering the factors like viscous dissipation, multiple slip, thermal radiation, and double diffusive convection. The fluid flow was administered using partial differential equations (PDE’s), transformed into a set of interconnected ordinary differential equations. These non-linear equations were further numerically solved by the NDSolve function in Mathematica. According to our outcomes, the temperature profile increases as the thermal slip factor rises. Moreover, the concentration and nanoparticle profile decrease with increasing values of the concentration slip and nanoparticle slip parameters. It can also determine that when the impact of thermal radiation increases, the temperature profile drops. Such a model has practical applications in simulating the small vessel transportation of particle in hemodynamics as well as in the field of biomedical and medical engineering for nanofluid peristaltic pumps.

A Rare Case of Calciphylaxis: A case report

Introduction: Calciphylaxis is a rare and severe disorder characterized by obstructive small vessel disease in the subcutaneous adipose tissue and skin, leading to necrotic skin lesions. The condition poses a significant risk of mortality due to infectious and ischemic complications. Case presentation: We present the case of a 60-year-old woman, with a history of renal lithiasis, hypertension, and end-stage renal disease on hemodialysis complicated by hyperparathyroidism and aortic valve replacement. She developed extensive necrotic lesions on both lower limbs and upper extremities, prompting a diagnosis of calciphylaxis. Radiographic and biopsy findings supported the diagnosis, revealing characteristic calcifications. Treatment involved antibiotics, oral thiosulfate, daily hemodialysis, hyperbaric oxygen therapy, and discontinuation of calcium and alfacalcidol, with alendronate initiation. Unfortunately, despite these interventions, the patient experienced a rapid clinical decline, developing septic shock necessitating bilateral leg amputations. Regrettably, she succumbed to the disease ten days later. Conclusion: This case underscores the challenging prognosis of calciphylaxis and the need for effective therapeutic options, including surgical intervention and access to injectable thiosulfate.

A Forgotten Rare Cause of Unilateral Basal Ganglia Calcinosis Due to Venous Angioma and Complicating Acute Stroke Management: A Case Report

Background: Unilateral basal ganglia calcinosis (BGC) is a rare radiological finding that can be diagnosed on computed tomography (CT) and magnetic resonance imaging (MRI) but often presents challenges for clinicians and radiologists in determining its underlying cause. So far, only a few potential causes that could explain unilateral BGC have been described in the literature. Case Report: A 54-year-old Caucasian male was admitted to a tertiary university hospital due to the sudden onset of speech impairment and right-sided weakness. The patient had no significant medical history prior to this event. Non-enhanced computed tomography (NECT) of the brain revealed no evidence of acute ischemia; CT angiography (CTA) showed acute left middle cerebral artery (MCA) M2 segment occlusion. CT perfusion (CTP) maps revealed an extensive penumbra-like lesion, which is potentially reversible upon achieving successful recanalization. However, a primary neoplastic tumor with calcifications in the basal ganglia was initially interpreted as the potential cause; therefore, acute stroke treatment with intravenous thrombolysis was contraindicated. A follow-up CT examination at 24 h revealed an ischemic lesion localized to the left insula, predominantly involving the left parietal lobe and the superior gyrus of the left temporal lobe. Subsequent gadolinium-enhanced brain MRI revealed small blood vessels draining into the subependymal periventricular veins on the left basal ganglia. Digital subtraction angiography was conducted, confirming the diagnosis of venous angioma. Conclusions: Unilateral BGC caused by venous angioma is a rare entity with unclear pathophysiological mechanisms and heterogeneous clinical presentation. It may mimic conditions such as intracerebral hemorrhage or hemorrhagic brain tumors, complicating acute stroke management, as demonstrated in this case. Surrounding tissue calcification may provide a valuable radiological clue in diagnosing venous angiomas DVAs and vascular malformations.

Successful switching treatment of mepolizumab for refractory eosinophilic granulomatosis with polyangiitis and multiple organ dysfunction under benralizumab treatment: A case report.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare necrotising vasculitis affecting small vessels accompanied by eosinophilic inflammation. Biological therapies, particularly anti-interleukin-5 (IL-5) monoclonal antibodies, have been shown to be effective in treating refractory EGPA. Mepolizumab, an anti-IL-5 monoclonal antibody, has been approved in Japan for the treatment of EGPA and has a significant glucocorticoid-sparing effect. Benralizumab, an anti-IL-5 receptor monoclonal antibody, has also been reported to reduce the glucocorticoid dose in patients with EGPA. However, several investigators have reported the development of EGPA during biologic treatment. Herein, we present a case of development of refractory EGPA under benralizumab treatment. Although the initial treatment with high-dose glucocorticoids and the administration of benralizumab were temporally effective, the patient's condition did not improve, and the eosinophil count reelevated. After switching benralizumab to mepolizumab, the patient's condition improved, and remission was achieved. Our report suggested that mepolizumab may be an effective treatment option for refractory EGPA after failure of benralizumab treatment.

Automated 3D Quantitative Analysis of Intrapulmonary Vessel Volume on Noncontrast CT in Healthy Individuals

Objective: This study aimed to compare automated three-dimensional Intrapulmonary Vessel Volume (IPVV) differences between lung and mediastinal windows in healthy individuals using quantitative measurements obtained from chest Computed Tomography (CT) plain scans. Methods: A total of 258 participants (aged 21–83 years) with negative chest CT scans from routine physical examinations conducted between January to November 2023 were retrospectively enrolled. For each healthy participant, an algorithm was used to automatically extract total lung IPVVs as well as IPVVs for vessels of specific diameter. Differences in IPVVs were then compared between those extracted using the lung window and those extracted using the mediastinal window. Results: The IPVVs for the entire lung, intrapulmonary arteries, intrapulmonary veins, and small pulmonary vessels (categorized by different diameters) extracted from the lung window were significantly higher than those extracted from the mediastinal window (p&lt;0.01). No significant sex-based differences in IPVV were observed for pulmonary arteries and veins with diameters between 0.8 and 1.6 mm, as well as pulmonary veins with diameters between 2.4 and 3.2 mm. However, in pulmonary arteries and veins with diameters between 1.6 and 2.4 mm, females had significantly higher IPVVs than males. In all other cases, IPVVs were larger in males than in females. Conclusion: This method of automatic IPVV extraction and quantitative assessment has been proven to be feasible. Automated IPVV expression effectively identified morphological characteristics of intrapulmonary vessels. The study has concluded IPVVs extracted from the lung window to be generally larger than those extracted from the mediastinal window.

Light chain Split Luciferase assay implicates pathological NOTCH3 thiol reactivity in inherited cerebral small vessel disease.

Stereotyped mutations in NOTCH3 drive CADASIL, the leading inherited cause of stroke and vascular dementia. The vast majority of these mutations result in alterations in the number of cysteines in the gene product. However, non-cysteine altering pathogenic mutations have also been identified, making it challenging to discriminate pathogenic from benign NOTCH3 sequence variants. Here, we present a method for quantitative assessment of NOTCH3 mutants, the light chain split luciferase (LSL) assay. In LSL, NOTCH3 mutant fragments, cloned between a split luciferase open reading frame, are transfected into cells, producing secreted luciferase activity that is dependent on the normal structure of NOTCH3. Insertion of point mutants that cause CADASIL results in significantly lower activity. Using a panel of 47 sequences, we determined the sensitivity and specificity of LSL for pathogenic NOTCH3 mutation discrimination to be 100% and 93%. LSL was also modestly successful in differentiated pathogenic proteins responsible for Marfan's disease and Stiff Skin Syndrome. Two additional parameters from the LSL analysis (TCEP rescue of activity and secretion index), were also shown to be useful in characterizing NOTCH3 mutants. We show that the spacing and primary sequence of the light chain module is an important component of the LSL assay, as a single light chain cysteine is critical for pathogenic sequence discrimination. Furthermore, we show that activity of CADASIL mutant reporters is amplified by application of cysteine-reactive iodoacetamide, suggesting that LSL may be deployed to screen for novel compounds that suppress pathogenic conformations of NOTCH3.

Characterizing the underlying microangiopathy of deep cerebellar intracerebral hemorrhage.

While cerebral amyloid angiopathy is likely responsible for intracerebral hemorrhage (ICH) occurring in superficial (grey matter, vermis) cerebellar locations, it is unclear whether hypertensive arteriopathy (HA), the other major cerebral small vessel disease (cSVD), is associated with cerebellar ICH (cICH) in deep (white matter, deep nuclei, cerebellar peduncle) regions. We tested the hypothesis that HA-associated neuroimaging markers are significantly associated with deep cICH compared to superficial cICH. Brain MRI scans from consecutive non-traumatic cICH patients admitted to a referral center were analyzed for cSVD markers. Clinical risk factors, left ventricular hypertrophy (LVH, a marker of hypertensive end-organ damage), and neuroimaging markers were compared between patients with deep and superficial cICH in univariate and multivariable models. Hypertension and LVH were more common among 83 (64%) patients with deep cICH compared to 46 (36%) with superficial cICH. HA-related markers such as peri-basal ganglia white matter hyperintensity pattern, deep lacunes, severe basal ganglia enlarged perivascular spaces, and deep cerebral microbleeds (CMBs) were more common among those with deep vs. superficial cICH. Strictly lobar CMBs were less common among patients with deep cICH, whereas mixed-location CMBs were more common. After multivariable adjustment, LVH (aOR 4.06, 95% CI [1.22-13.50], p = 0.02), deep lacunes (aOR 6.02, 95% CI [1.46-24.89], p = 0.01), and strictly lobar CMBs (aOR 0.09, 95% CI [0.02-0.45], p < 0.01) remained significantly associated with deep cICH. Because HA-associated markers are significantly associated with deep cICH, it is likely HA is the dominant underlying microangiopathy of this ICH subtype.

Perivascular and parenchymal brain fluid diffusivity in patients with a recent small subcortical infarct.

Fluid exchanges between perivascular spaces (PVS) and interstitium may contribute to the pathophysiology of small vessel disease (SVD). We aimed to analyze water diffusivity measures and their relationship with PVS and other SVD imaging markers. We enrolled 50 consecutive patients with a recent small subcortical infarct. We collected clinical variables, including vascular risk factors and sleep quality scales. All patients underwent a 3-Tesla MRI with standard structural sequences and multishell-diffusion images to obtain extracellular free water content (FW) and water diffusivity along the perivascular space (ALPS) index. We obtained volumetric measurements of white matter hyperintensities (WMH) and PVS, and the number of lacunes and microbleeds. To analyze the association between PVS, ALPS index, FW, and SVD imaging features, we utilized linear regression models including age, sex, history of hypertension and diabetes, Pittsburgh Sleep Quality Index, WMH, and brain volume. All patients (mean age 70 years, 36% women) had usable data. FW and PVS were strongly associated in all models (0.008 < Beta < 0.054; P < 0.045). Higher FW was related to the other SVD features in univariable models and remained significant for WMH (1.175 < Beta < 1.262; P < 0.001) and brain volume (Beta < 0.0001; P < 0.002) in multivariable models. ALPS index was not associated with FW, PVS, or any other SVD markers. The increased extracellular water in SVD suggests that impaired brain fluid exchanges, PVS dilation, and other SVD features are linked. Further investigation is needed to determine the specificity of the ALPS index to PVS diffusion.

Rationale and Design of the Prevail Global Trial Program Evaluating the Prevail Drug-Coated Balloon in Patients with In-stent Restenosis and De Novo Small Vessel Disease.

In-stent restenosis (ISR) remains the leading cause of treatment failure following percutaneous coronary intervention (PCI) with contemporary drug-eluting stents. Especially in small caliber coronary arteries, restenosis is common following PCI and represents a treatment challenge. Drug-coated balloons (DCB) are an attractive alternative to stents for treatment of both ISR and small vessel disease. The safety and efficacy of the Prevail DCB will be assessed for (1) the treatment of ISR and (2) de novo lesions in small vessels. Prevail Global is a prospective, international, dual cohort clinical study enrolling (1) patients undergoing PCI for ISR in a randomized controlled trial (1:1) design comparing the Prevail DCB versus an FDA-approved DCB (AgentTM, Boston Scientific Corporation, Natick MA), and (2) patients with de novo small vessel disease undergoing PCI with the Prevail DCB as part of a single-arm study compared with a historical control. The primary endpoint is target lesion failure, defined as a composite of cardiac death, target vessel myocardial infarction, or clinically-driven target lesion revascularization at 12 months post procedure. Patient follow-up is planned for 1 month, 6 months, and yearly through 5 years. Enrollment is expected to start in early 2025. The Prevail Global study will directly assess the safety and efficacy of the Prevail DCB for the treatment of ISR and de novo small vessel lesions. Prevail Global, NCT06535854, is registered at https://clinicaltrials.gov/study/NCT06535854.