Cerebral Disease Research Articles

Hypertensive pregnancy disorder, an under-recognized women specific risk factor for heart failure?

During pregnancy, the maternal cardiovascular (CV) system undergoes major haemodynamic alterations ensuring adequate placental perfusion and a healthy pregnancy course. Hypertensive disorders of pregnancy (HDP) occur in almost 10% of gestations and preeclampsia, a more severe form, in 3-4%. Women with HDP demonstrated impaired myocardial function, biventricular chamber dysfunction and adverse biventricular remodelling. Shortly after delivery, women who experienced HDP express increased risk of classic CV risk factors such as hypertension, renal disease, abnormal lipid profile, and diabetes. Within the first two decades following a HDP, women experience increased rates of heart failure, chronic hypertension, ischaemic heart and cerebral disease. The mechanism underlying the relationship between HDP in younger women and CV disease later in life could be explained by sharing pre-pregnancy CV risk factors or due to a direct impact of HDP on the maternal CV system conferring a state of increased susceptibility to future metabolic or haemodynamic insults. Racial disparities in CV risk and social determinants of health also play an important role in their remote CV risk. Although there is general agreement that women who suffered from HDP should undertake early CV screening to allow appropriate prevention and timely treatment, a screening and intervention protocol has not been standardized due to limited available evidence. In this review, we discuss why women with hypertensive pregnancy may be disproportionately affected by heart failure with preserved ejection fraction and how cardiac remodelling during or after pregnancy may influence its development.

Quantitative and Computational Spinal Imaging in Neurodegenerative Conditions and Acquired Spinal Disorders: Academic Advances and Clinical Prospects.

Introduction: Quantitative spinal cord imaging has facilitated the objective appraisal of spinal cord pathology in a range of neurological conditions both in the academic and clinical setting. Diverse methodological approaches have been implemented, encompassing a range of morphometric, diffusivity, susceptibility, magnetization transfer, and spectroscopy techniques. Advances have been fueled both by new MRI platforms and acquisition protocols as well as novel analysis pipelines. The quantitative evaluation of specific spinal tracts and grey matter indices has the potential to be used in diagnostic and monitoring applications. The comprehensive characterization of spinal disease burden in pre-symptomatic cohorts, in carriers of specific genetic mutations, and in conditions primarily associated with cerebral disease, has contributed important academic insights. Methods: A narrative review was conducted to examine the clinical and academic role of quantitative spinal cord imaging in a range of neurodegenerative and acquired spinal cord disorders, including hereditary spastic paraparesis, hereditary ataxias, motor neuron diseases, Huntington's disease, and post-infectious or vascular disorders. Results: The clinical utility of specific methods, sample size considerations, academic role of spinal imaging, key radiological findings, and relevant clinical correlates are presented in each disease group. Conclusions: Quantitative spinal cord imaging studies have demonstrated the feasibility to reliably appraise structural, microstructural, diffusivity, and metabolic spinal cord alterations. Despite the notable academic advances, novel acquisition protocols and analysis pipelines are yet to be implemented in the clinical setting.

Progress on the Mechanisms and Neuroprotective Benefits of Dexmedetomidine in Brain Diseases.

Dexmedetomidine, a highly specific α2 agonist, has been extensively utilized in clinical sedation and surgical anesthesia since its introduction in 2000 due to its excellent sympatholytic, sedative, and analgesic effects. This review aimed to identify new approaches for the treatment of patients with brain disorders by thoroughly describing the mechanism of action of dexmedetomidine and examining its neuroprotective effects from the standpoints of basic and clinical research. The PubMed and Web of Science databases were searched using the keywords dexmedetomidine and related brain diseases, although relevant articles from the last decade were included for detailed summarization and analysis. Dexmedetomidine has shown strong neuroprotective effects, such as protection of the blood-brain barrier, decreased neuronal death, maintained hemodynamic stability, and reduced postoperative agitation and cognitive dysfunction. Furthermore, dexmedetomidine has been shown to exert various neuroprotective effects, including anti-inflammatory and antioxidative stress effects, modulation of autophagy, and reduction of apoptosis in cerebral diseases. Dexmedetomidine acts as a neuroprotective agent against brain diseases during all phases of treatment. However, clinical trials with larger sample sizes are required to optimize dosage and dosing strategies.

Avicularin Treatment Ameliorates Ischemic Stroke Damage by Regulating Microglia Polarization and its Exosomes via the NLRP3 Pathway.

Avicularin (AL), an ingredient of Banxia, has anti-inflammatory properties in cerebral disease and regulates polarization of macrophages, but its effects on ischemic stroke (IS) damage have not been studied. In vivo, AL was administered by oral gavage to middle cerebral artery occlusion/reperfusion (MCAO/R) C57BL/6J mice in doses of 1.25, 2.5, and 5 mg/kg/day for seven days, and, in vitro, AL was added to treat oxygen-glucose deprivation (OGD)-BV2 cells. Modified neurological severity score, Triphenyltetrazolium chloride (TTC) staining, brain-water-content detection, TdT-mediated dUTP nick-end labeling (TUNEL) assay, flow cytometry, immunofluorescence assay, Enzyme linked immunosorbent assay (ELISA), and Western-blot analysis were used to investigate the functions and mechanism of the effect of AL treatment on IS. The exosomes of AL-treated microglia were studied by transmission electron microscope (TEM), nanoparticle tracking analyzer (NTA), and Western-blot analysis. AL treatment reduced the neurological severity score, infarct volume, brain-water content, neuronal apoptosis, and the release of inflammatory factors, that were induced by MCAO/R. Notably, M2 microglia polarization was promoted but M1 microglia polarization was inhibited by AL in the ischemic penumbra of MCAO/R mice. Subsequently, anti-inflammatory and polarization-regulating effects of AL were verified in vitro. Suppressed NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome activation was found in the ischemic penumbra of animal and Oxygen-Glucose Deprivation/Reoxygenation (OGD/R) cells treated with AL, as evidenced by decreasing NLRP3-inflammasome-related protein and downstream factors. After AL treatment, the anti-apoptosis effect of microglial exosomes on OGD/R primary cortical neurons was increased. AL reduce inflammatory responses and neuron death of IS-associated models by regulating microglia polarization by the NLRP3 pathway and by affecting microglial exosomes.

Silent cerebral microvascular disease and longitudinal risk of cognitive decline in atrial fibrillation

Abstract Background A relationship between silent stroke and cognitive disorder has recently been suggested in patients with nonvalvular atrial fibrillation (NVAF). This research is an exploratory research study to investigate the occurrence of asymptomatic cerebrovascular disorders with NVAF. Methods The SKAF (Silent cerebral microvascular disease and longitudinal risK of cognitive decline in Atrial Fibrillation) study is a prospective, investigator-initiated, multicenter, observational study of Japanese patients with NVAF aged 60 years or older. We had planned to enroll two hundred NVAF patients with no history of symptomatic stroke or dementia, and an anticoagulant therapy with edoxaban is being performed or an anticoagulant therapy is not being performed, and one hundred patients with sinus rhythm, for comparison. We collected patient characteristics, clinical course, the data of head MRI test and cognitive function test (Montreal Cognitive Assessment (MoCA)) at the baseline and the 24 months follow-up. The primary endpoint was the composite of silent ischemic stroke and micro-bleeding over a 24-month follow-up period. The secondary endpoint was cognitive decline over a 24-month follow-up period. Results The study was started in October 2016, with a planned 2-year recruitment period. As of January 31, 2018, a total of 326 patients were enrolled. Of those, 99 patients with sinus rhythm (SR group) and 214 patients with NVAF (NVAF group) were analyzed (male, 193 (62%) patients; age, 72.2±6.5 years). 156 of 195 (80%) patients with NVAF received the anticoagulant therapy with edoxaban. There was no significant difference of the primary composite for the endpoints between two groups (17.4% versus 17.4%; p=1.00). The incidences of silent ischemic stroke and micro-bleeding in SR and NVAF groups over a 24-month follow-up period were 9.3% and 10.8% (p= 0.833), and 8.1% and 9.2% (p=1.00), respectively. The NVAF group exhibited a significantly larger decline in cognition changes in MoCA score than SR group (-0.830 versus 0,000; p=0.0131). Notably, NVAF was found to be associated with cognitive decline. Conclusion The SKAF registry provided an equivalent risk of silent cerebral microvascular disease in patients with SR and NVAF. Clinically, NVAF had an impact on cognitive decline.

Independent association between radial secondary access and stroke in patients undergoing transcatheter aortic valve implantation

Abstract Background Radial access has become the primary approach for invasive coronary angiography due to its lower complication rate than femoral access. Transcatheter aortic valve implantation (TAVI) frequently requires a secondary access, which has traditionally been femoral access. However, radial access for TAVI is feasible and gaining popularity, but data on its safety and complication rates is still limited. Purpose To evaluate the occurrence of stroke rate in patients undergoing a TAVI procedure with femoral or radial secondary access. Methods A prospective single-center TAVI registry of 2327 patients who received a TAVI procedure between 2019 and 2022 was conducted. All procedures had the primary access over the femoral route. 337 (14.5%) patients had a secondary access over the radial route, whereas 1990 (85.5%) received a femoral secondary access. The primary endpoint was the occurrence of stroke within the hospital stay. Both groups were compared using the t-test or the Mann-Whitney U test according to the distribution of the data. In a second step, a multivariable model was created in which parameters were included that were associated with the endpoint in the previous analysis, as well as parameters that are known to be associated with stroke. Results: Patients were 81.1 ± 6.3 years old, with a Euroscore II of 5.3 ± 6. A total of 610 (26.2%) patients received a balloon-expandable valve. The primary endpoint (stroke within 30 days of the TAVI procedure) was met by 94 (4%) of all patients. Stroke occurred more often in the group with radial secondary access (6.6% (22) vs. 3.6%(72), p = 0.012). Other significant differences between the two groups included (radial vs. femoral access): burden of atrial fibrillation (36.8% vs. 44.6%, p = 0.007), arterial hypertension (87.4% vs. 92%, p = 0.007), Euroscore II (4.6 vs. 5.5, p = 0.006), and frailty (25.2% vs. 40%, p < 0.001). There were no significant differences between the two groups in terms of secondary diagnosis of diabetes or coronary artery disease, age, occurrence of NYHA class III/IV, gender, or cerebral artery disease. In the multivariate analysis including Age, Euroscore II, NYHA class, gender, secondary diagnosis of arterial Hypertension, diabetes or cerebral artery disease, arterial fibrillation, Frailty and radial secondary access, only radial secondary access was independently associated with in-hospital stroke (p = 0.01). Conclusion Radial secondary access was significantly associated with an increased risk of in-hospital stroke following transcatheter aortic valve implantation (TAVI) in our study population. Intense manipulation of the guidewire and catheter to reach the ascending aorta at the beginning of the procedure and to reach the descending aorta for the final angiogram of the primary access vessel may be causative and should be minimized.

Lifestyle in patients with hypertension from the Shoulder to Shoulder Foundation

Introduction: Arterial hypertension (AHT) is defined as a disorder in which the blood vessels frequently have high tension, increasing the risk of cardiovascular, cerebral, and renal diseases, etc. Objective: To determine the lifestyles of patients with hypertension of the Hombro a Hombro Foundation, Santo Domingo, 2022. Methodology: The research is quantitative, data on the lifestyles of patients with arterial hypertension were collected, with a descriptive, cross-sectional level in which the collected data was stored and analyzed. The population consisted of 50 patients with arterial hypertension from the Shoulder to Shoulder Foundation. Results: Determining that within the healthy parameters are the physical condition, physical activity and sport; self-care and medical care; eating habits; the consumption of substances and some parameters on rest, although the last one could show that there is a small problem due to unhealthy practices. Conclusions: there are still patients who do not adhere to a new lifestyle, and work must continue to improve and treat as much as possible for the patient to adapt to this new stage, allowing him to be healthier

AI-based 3D analysis of retinal vasculature associated with retinal diseases using OCT angiography.

Retinal vasculature is the only vascular system in the human body that can be observed in a non-invasive manner, with a phenotype associated with a wide range of ocular, cerebral, and cardiovascular diseases. OCT and OCT angiography (OCTA) provide powerful imaging methods to visualize the three-dimensional morphological and functional information of the retina. In this study, based on OCT and OCTA multimodal inputs, a multitask convolutional neural network model was built to realize 3D segmentation of retinal blood vessels and disease classification for different retinal diseases, overcoming the limitations of existing methods that can only perform 2D analysis of OCTA. Two hundred thirty sets of OCT and OCTA data from 109 patients, including 138,000 cross-sectional images in normal and diseased eyes (age-related macular degeneration, retinal vein occlusion, and central serous chorioretinopathy), were collected from four commercial OCT systems for model training, validation, and testing. Experimental results verified that the proposed method was able to achieve a DICE coefficient of 0.956 for 3D segmentation of blood vessels and an accuracy of 91.49% for disease classification, and further enabled us to evaluate the 3D reconstruction of retinal vessels, explore the interlayer connections of superficial and deep vasculatures, and reveal the 3D quantitative vessel characteristics in different retinal diseases.

Simultaneous Infantile Spasms and Focal Seizures: A Rarely Reported Combined Seizure Phenomenon on Video Electroencephalogram (VEEG).

Focal seizures (FS) have previously been described before or after infantile spasm (IS) clusters, but FS occurring simultaneously with an IS cluster has been rarely reported in the EEG literature. We present three cases where focal seizures (FS) occurred concurrently during an infantile spasm (IS) cluster on VEEG. On VEEG, onset of IS cluster preceded FS in all three patients; however, patient three was diagnosed with FS prior to the onset of IS. FS duration ranged from 10-90 s and was electrographic-only in two out of the three patients. Unfortunately, the first two patients are now deceased, and for patient two no etiology was ever identified. Currently, patient three is free of spasms as well as seizures but has global developmental delay; no definite etiology has been identified for their presentation. Concurrent FS with IS suggests that the seizure types may be generated in different brain areas with one seizure type potentially triggering the other and is generally reflective of multifocal or diffuse cerebral disease with a poor prognosis as was seen in at least two of our patients. Our three cases of IS where FS occurred concurrently contribute to the limited existing data describing this phenomenon on VEEG.

Quantitative EEG Spectral Features Differentiate Genetic Epilepsies and Predict Neurologic Outcomes.

EEG plays an integral part in the diagnosis and management of children with genetic epilepsies. Nevertheless, how quantitative EEG features differ between genetic epilepsies and neurological outcomes remains largely unknown. Here, we aimed to identify quantitative EEG biomarkers in children with epilepsy and a genetic diagnosis in STXBP1 , SCN1A , or SYNGAP1 , and to assess how quantitative EEG features associate with neurological outcomes in genetic epilepsies more broadly. We analyzed individuals with pathogenic variants in STXBP1 (95 EEGs, n =20), SCN1A (154 EEGs, n =68), and SYNGAP1 (46 EEGs, n =21) and a control cohort of individuals without epilepsy or known cerebral disease (847 EEGs, n =806). After removing artifacts and epochs with excess noise or altered state from EEGs, we extracted spectral features. We validated our preprocessing pipeline by comparing automatically-detected posterior dominant rhythm (PDR) to annotations from clinical EEG reports. Next, as a coarse measure of pathological slowing, we compared the alpha-delta bandpower ratio between controls and the different genetic epilepsies. We then trained random forest models to predict a diagnosis of STXBP1 , SCN1A , and SYNGAP1 . Finally, to understand how EEG features vary with neurological outcomes, we trained random forest models to predict seizure frequency and motor function. There was strong agreement between the automatically-calculated PDR and clinical EEG reports ( R 2 =0.75). Individuals with STXBP1 -related epilepsy have a significantly lower alpha-delta ratio than controls ( P< 0.001) across all age groups. Additionally, individuals with a missense variant in STXBP1 have a significantly lower alpha-delta ratio than those with a protein-truncating variant in toddlers ( P< 0.001), children ( P =0.02), and adults ( P< 0.001). Models accurately predicted a diagnosis of STXBP1 (AUC=0.91), SYNGAP1 (AUC=0.82), and SCN1A (AUC=0.86) against controls and from each other in a three-class model (accuracy=0.74). From these models, we isolated highly correlated biomarkers for these respective genetic disorders, including alpha-theta ratio in frontal, occipital, and parietal electrodes with STXBP1 , SYNGAP1 , and SCN1A , respectively. Models were unable to predict seizure frequency (AUC=0.53). Random forest models predicted motor scores significantly better than age-based null models ( P< 0.001), suggesting spectral features contain information pertinent to gross motor function. In summary, we demonstrate that STXBP1 -, SYNGAP1- , and SCN1A -related epilepsies have distinct quantitative EEG signatures. Furthermore, EEG spectral features are predictive of some functional outcome measures in patients with genetic epilepsies. Large-scale retrospective quantitative analysis of clinical EEG has the potential to discover novel biomarkers and to quantify and track individuals' disease progression across development.

Complex regulation of tau phosphorylation by the endothelin system in brain microvascular endothelial cells (BMVECs): link to barrier function.

Endothelin-1 (ET-1), the most potent vasoconstrictor identified to date, contributes to cerebrovascular dysfunction. ET-1 levels in postmortem brain specimens from individuals diagnosed with Alzheimer's disease (AD) and related dementias (ADRD) were shown to be related to cerebral hypoxia and disease severity. ET-1-mediated vascular dysfunction and ensuing cognitive deficits have also been reported in experimental models of AD and ADRD. Moreover, studies also showed that ET-1 secreted from brain microvascular endothelial cells (BMVECs) can affect neurovascular unit integrity in an autocrine and paracrine manner. Vascular contributions to cognitive impairment and dementia (VCID) is a leading ADRD cause known to be free of neuronal tau pathology, a hallmark of AD. However, a recent study reported cytotoxic hyperphosphorylated tau (p-tau) accumulation, which fails to bind or stabilize microtubules in BMVECs in VCID. Thus, the study aimed to determine the impact of ET-1 on tau pathology, microtubule organization, and barrier function in BMVECs. Cells were stimulated with 1 μM ET-1 for 24 h in the presence/absence of ETA (BQ123; 20 μM) or ETB (BQ788; 20 μM) receptor antagonists. Cell lysates were assayed for an array of phosphorylation site-specific antibodies and microtubule organization/stabilization markers. ET-1 stimulation increased p-tau Thr231 but decreased p-tau Ser199, Ser262, Ser396, and Ser214 levels only in the presence of ETA or ETB antagonism. ET-1 also impaired barrier function in the presence of ETA antagonism. These novel findings suggest that (1) dysregulation of endothelial tau phosphorylation may contribute to cerebral microvascular dysfunction and (2) the ET system may be an early intervention target to prevent hyperphosphorylated tau-mediated disruption of BMVEC barrier function.

Association between uric acid and cognitive function in maintenance hemodialysis patient

Background: Chronic kidney disease (CKD) is an independent risk factor for cognitive dysfunction. Hyperuricemia is prevalent in CKD patients and has been associated with cognitive dysfunction. Hyperuricemia has been associated with an increased risk for cerebral microvascular disease. Aims and Objectives: The study aimed to evaluate the association between uric acid level and cognitive function in maintenance hemodialysis patients. Materials and Methods: The study was conducted on 90 maintenance hemodialysis patients. Serum uric acid (sUA) level was measured in patients on maintenance hemodialysis and cognitive performance was assessed by the Standardized Mini-Mental State Examination score. Results: There was a significant association between sUA level and cognitive function in hemodialysis patients. Patient with higher sUA levels was found to have poor cognitive function (P&lt;0.05). There was a significant negative correlation between sUA and cognitive function which revealed an increase in sUA will decrease the cognitive function (P&lt;0.05). In our study, there was a significant association between sUA and cognitive function in hemodialysis patients. Patients with hyperuricemia had poor cognitive function. Conclusion: In our study, there was a significant association between sUA and cognitive function in hemodialysis patients. Patients with hyperuricemia had poor cognitive function.

The nitration of SIRT6 aggravates neuronal damage during cerebral ischemia-reperfusion in rat

Ischemic stroke is a major cause of death and disability. The activation of neuronal nitric oxide synthase (nNOS) and the resulting production of nitric oxide (NO) via NMDA receptor-mediated calcium influx play an exacerbating role in cerebral ischemia reperfusion injury. The NO rapidly reacts with superoxide (O2-) to form peroxynitrite (ONOO-), a toxic molecule may modify proteins through tyrosine residue nitration, ultimately worsening neuronal damage. SIRT6 has been proven to be crucial in regulating cell proliferation, death, and aging in various pathological settings. We have previous reported that human SIRT6 tyrosine nitration decreased its intrinsic catalytic activity in vitro. However, the exact role of SIRT6 function in the process of cerebral ischemia reperfusion injury is not yet fully elucidated. Herein, we demonstrated that an increase in the nitration of SIRT6 led to reduce its enzymatic activity and aggravated hippocampal neuronal damage in a rat model of four-artery cerebral ischemia reperfusion. In addition, reducing SIRT6 nitration resulted in increase the activity of SIRT6, alleviating hippocampal neuronal damage. Moreover, SIRT6 nitration affected its downstream molecule activity such as PARP1 and GCN5, promoting the process of neuronal ischemic injury in rat hippocampus. Additionally, treatment with NMDA receptor antagonist MK801, or nNOS inhibitor 7-NI, and resveratrol (an antioxidant) diminished SIRT6 nitration and the catalytic activity of downstream molecules like PARP1 and GCN5, thereby reducing neuronal damage. Finally, in the biochemical regulation of SIRT6 activity, tyrosine 257 was essential for its activity and susceptibility to nitration. Replacing tyrosine 257 with phenylalanine in rat SIRT6 attenuated the death of SH-SY5Y neurocytes under oxygen-glucose deprivation (OGD) conditions. These results may offer further understanding of SIRT6 function in the pathogenesis of cerebral ischemic diseases.

Differences in the Adverse Event Profiles of Sodium-Glucose Cotransporter 2 Inhibitors used in Patients with DiabetesMellitus and Heart Failure: An Analysis Using the Japanese Adverse Drug Event Report Database.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have recently become a standard treatment for heart failure and renal failure. The number of patients using these drugs is expected to increase further. However, no adverse drug event profiles have been published for the use of SGLT2i in patients without diabetes. To analyze and clarify the differences in adverse event profiles associated with the use of SGLT2i in patients with diabetes or heart failure using the Japanese Adverse Drug Event Report (JADER) database, a Japanese reporting system for adverse events. The JADER database, containing reports submitted between April 2004 and January 2024, was used. Our study focused on patients with diabetes or heart failure, analyzing adverse events associated with empagliflozin and dapagliflozin. The reporting odds ratio (ROR) and 95% confidence interval (CI) were calculated for signal detection. We identified risks of adverse drug events such as ketoacidosis, urinary tract infection, dehydration, and acidosis in both patient groups. However, the risks of cerebral infarction and ischemic heart disease were identified only in patients with diabetes, while risks of renal dysfunction, hypoglycemia, and sepsis were identified only in those with heart failure. Adverse events should be managed appropriately for patients using SGLT2i, as the adverse event profiles differ between those with diabetes and those with heart failure. Understanding these differences is crucial for improving patient safety and optimizing treatment outcomes.

Exercise preconditioning mitigates brain injury after cerebral ischemia-reperfusion injury in rats by restraining TIMP1.

Cerebral ischemic disease is a common cerebrovascular disease, especially ischemic stroke. Exercise has protective functions on brain tissues following cerebral ischemia-reperfusion injury (CIRI), but its preventive effects and mechanisms in CIRI remain unclear. We aimed to investigate the effects and mechanisms of exercise preconditioning on CIRI. The middle cerebral artery occlusion (MCAO) operation was prepared to establish CIRI rats. All rats were randomized into the MCAO, exercise (exercise preconditioning plus MCAO operation), vector (exercise preconditioning, MCAO operation plus intraventricular injection of empty vector), and tissue inhibitor of metalloprotease 1 overexpression (OE-TIMP1, exercise preconditioning, MCAO operation plus intraventricular injection of OE-TIMP1) groups. The results indicated that exercise preconditioning suppressed approximately 66.67% of neurological deficit scores and 73.79% of TIMP1 mRNA expression in MCAO rats, which were partially offset by OE-TIMP1. The protective effects of exercise against neuron death status and cerebral infarction size in MCAO rats were reversed by OE-TIMP1. It also confirmed that exercise weakened apoptosis and oxidative stress damage, with notable increases of B-cell lymphoma-2, superoxide dismutase, and glutathione peroxidase production, and evident decreases of BCL2-associated X, caspase 3, and malondialdehyde in MCAO rats, while these effects were partially reversed by OE-TIMP1. Additionally, the inhibitory effects of exercise on the protein levels of TIMP1, hypoxia-inducible factor-alpha, vascular endothelial growth factor receptor 2, vascular endothelial growth factor, and neurogenic locus notch homolog protein 1 in MCAO rats were partially reversed by OE-TIMP1. Altogether, exercise preconditioning had protective effects on CIRI by restraining TIMP1, which provided new therapeutic strategies for preventing CIRI.

Cognitive Functions of long-COVID Patients Depend Strongly on Whether or Not They had Cerebral Disease during the SARS-CoV-2 Infection

Cognitive Functions of long-COVID Patients Depend Strongly on Whether or Not They had Cerebral Disease during the SARS-CoV-2 Infection

Identification of potential biomarkers of cuproptosis in cerebral ischemia.

Cerebral ischemia can cause mild damage to local brain nerves due to hypoxia and even lead to irreversible damage due to neuronal cell death. However, the underlying pathogenesis of this phenomenon remains unclear. This study utilized bioinformatics to explore the role of cuproptosis in cerebral ischemic disease and its associated biomarkers. R software identified the overlap of cerebral ischemia and cuproptosis genes, analyzed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG), and explored hub genes. Expressions and localizations of hub genes in brain tissue, cells, and immune cells were analyzed, along with predictions of protein structures, miRNAs, and transcription factors. A network was constructed depicting hub gene co-expression with miRNAs and interactions with transcription factors. Ferredoxin 1 (FDX1) expression was determined using qRT-PCR. Ten cuproptosis-related genes in cerebral ischemia were identified, with GO analysis revealing involvement in acetyl-CoA synthesis, metabolism, mitochondrial function, and iron-sulfur cluster binding. KEGG highlighted processes like the tricarboxylic acid cycle, pyruvate metabolism, and glycolysis/gluconeogenesis. Using the Human Protein Atlas, eight hub genes associated with cuproptosis were verified in brain tissues, hippocampus, and AF22 cells. Lipoyl(octanoyl) transferase 1 (LIPT1), was undetected, while others were found in mitochondria or both nucleus and mitochondria. These genes were differentially expressed in immune cells. FDX1, lipoic acid synthetase (LIAS), dihydrolipoamide S-acetyltransferase (DLAT), pyruvate dehydrogenase E1 component subunit alpha 1 (PDHA1), PDHB, and glutaminase (GLS) were predicted to target 111 miRNAs. PDHA1, FDX1, LIPT1, PDHB, LIAS, DLAT, GLS, and dihydrolipoamide dehydrogenase (DLD) were predicted to interact with 11, 10, 10, 9, 8, 7, 5, and 4 transcription factors, respectively. Finally, FDX1 expression was significantly upregulated in the hippocampus of ovariectomized rats with ischemia. This study revealed an association between cerebral ischemic disease and cuproptosis, identifying eight potential target genes. These findings offer new insights into potential biomarkers for the diagnosis, treatment, and prognosis of cerebral ischemia, and provide avenues for the exploration of new medical intervention targets.

Diffusion Tensor Imaging in Boys With Adrenoleukodystrophy: Identification of Cerebral Disease and Association With Neurocognitive Outcomes.

Childhood cerebral adrenoleukodystrophy (C-ALD) is a severe inflammatory demyelinating disease that must be treated at an early stage to prevent permanent brain injury and neurocognitive decline. In standard clinical practice, C-ALD lesions are detected and characterized by a neuroradiologist reviewing anatomical MRI scans. We aimed to assess whether diffusion tensor imaging (DTI) is sensitive to the presence and severity of C-ALD lesions and to investigate associations with neurocognitive outcomes after hematopoietic cell therapy (HCT). In this retrospective cohort study, we analyzed high-resolution anatomical MRI, DTI, and neurocognitive assessments from boys with C-ALD undergoing HCT at the University of Minnesota between 2011 and 2021. Longitudinal DTI data were compared with an age-matched group of boys with ALD and no lesion (NL-ALD). DTI metrics were obtained for atlas-based regions of interest (ROIs) within 3 subdivisions of the corpus callosum (CC), corticospinal tract (CST), and total white matter (WM). Between-group baseline and slope differences in fractional anisotropy (FA) and axial (AD), radial (RD), and mean (MD) diffusivities were compared using analysis of covariance accounting for age, MRI severity (Loes score), and lesion location. Among patients with NL-ALD (n = 14), stable or increasing FA, stable AD, and stable or decreasing RD and MD were generally observed during the 1-year study period across all ROIs. In comparison, patients with mild posterior lesions (Loes 1-2; n = 13) demonstrated lower baseline FA in the CC splenium (C-ALD 0.50 ± 0.08 vs NL-ALD 0.58 ± 0.04; pBH = 0.022 adjusted Benjamini-Hochberg p-value), lower baseline AD across ROIs (e.g., C-ALD 1.34 ± 0.03 ×10-9 m2/s in total WM vs NL-ALD 1.38 ± 0.04 ×10-9 m2/s; pBH = 0.005), lower baseline RD in CC body and CST, and lower baseline MD across ROIs except CC splenium. Longitudinal slopes in CC splenium showed high sensitivity and specificity in differentiating early C-ALD from NL-ALD. Among all patients with C-ALD (n = 38), baseline Loes scores and DTI metrics were associated with post-HCT neurocognitive functions, including processing speed (e.g., FA WM Spearman correlation coefficient R = 0.64) and visual-motor integration (e.g., FA WM R = 0.71). DTI was sensitive to lesion presence and severity as well as clinical neurocognitive effects of C-ALD. DTI metrics quantify C-ALD even at an early stage.

The relationship between intraoperative surrogates of vascular stiffness, cerebral aneurysms, and surgical outcomes

ObjectiveIncreased arterial stiffness has been linked to aneurysm formation in the systemic and cerebral circulations, though the role played by arterial stiffness in the cerebral vasculature continues to be refined. This study assesses whether intraoperative surrogates of arterial stiffness differ between patients with cerebral aneurysms and controls, and the extend that these indices relate to outcomes following open surgical treatment. MethodsWe evaluated patients in a prospectively maintained database who underwent cerebral aneurysm surgery, and compared them to controls without cerebral aneurysms. Arterial stiffness was estimated using the intraoperative ambulatory arterial stiffness index (AASI) and average pulse pressure (PP). ResultsWe analyzed 214 cerebral aneurysm patients and 234 controls. Patients in the aneurysm group were predominantly female and had a higher incidence of hypertension, diabetes mellitus, and vascular disease. They also demonstrate elevated AASI and average PP. When stratified by the occurrence of subarachnoid hemorrhage (SAH) or unfavorable neurological outcome, the AASI and average PP were not highly associated with the occurrence of SAH but were highly associated with unfavorable neurological outcomes. After multivariable analysis, both the AASI and average PP were no longer associated with unfavorable neurological outcomes, however elevated age, strongly linked with arterial stiffness, became a key predictive variable. ConclusionReadily obtained intraoperative surrogates of arterial stiffening demonstrates its presence in those with cerebral aneurysm disease and the extent that it does it may meaningfully direct their clinical course. However, multivariable analysis demonstrates limitations of using arterial stiffness measures to predict clinical outcomes.

Blood-Brain-Barrier (BBB) Targeting Nanoparticulate Drug Delivery Modules to Treat Cerebrovascular Disorders: Current State of the Art

Blood Brain Barrier (BBB) provides a protective shield for the human nervous system, facilitating essential biochemical processes while also acting as a strong defense mechanism against pathogens and harmful substances, including drugs. While this barrier protects the brain, it makes it difficult to deliver therapeutics to treat cerebral diseases such as ischemia and acute arterial thrombosis, both of which cause significant global mortality and morbidity. The urgent need for thrombolytic agents to treat cerebral ischemia emphasizes the importance of drugs that can efficiently penetrate the BBB. However, conventional thrombolytics have limitations due to low BBB permeability. To overcome this barrier, various nanoparticle-based targeting strategies have been developed. These nano-technological solutions provide advantages such as enhanced permeability, decreased toxicity risks, and increased bioavailability when compared to other drug delivery methods.