Reduction In Blood Flow Research Articles

In Vivo Detection of Age-Related Tortuous Cerebral Small Vessels using Ferumoxytol-enhanced 7T MRI.

Histopathological studies suggest that cerebral small vessel tortuosity is crucial in age-related blood flow reduction and cellular degeneration. However, in vivo evidence is lacking. Here, we used Ferumoxytol-enhanced 7T MRI to directly visualize cerebral small vessels (<300 µm), enabling the identification of vascular tortuosity and exploration of its links to age, tissue atrophy, and vascular risk factors. High-resolution 2D/3D gradient echo MRI at 7T enhanced with Ferumoxytol, an ultrasmall superparamagnetic iron oxide (USPIO), was obtained and analyzed for cerebral small medullary artery tortuosity from 37 healthy participants (21-70 years; mean/SD: 38±14 years; 19 females). Tortuous artery count and tortuosity indices were compared between young and old groups. Age effects on vascular tortuosity were examined through partial correlations and multiple linear regression, adjusting for sex, body mass index (BMI), blood pressure (BP), and other vascular risk factors. Associations between tortuous medullary arteries and tissue atrophy, perivascular spaces (PVS), and white matter (WM) hyperintensities were explored. Age and BMI, rather than BP, showed positive correlations with both tortuous artery count and tortuosity indices. A significant correlation existed between the number of tortuous arteries and WM atrophy. WM lesions were found in proximity to or at the distal ends of tortuous medullary arteries, especially within the deep WM. Moreover, the elderly population displayed a higher prevalence of PVS, including those containing enclosed tortuous arteries. Leveraging the blooming effect of Ferumoxytol, 7T MRI excels in directly detecting cerebral small arterial tortuosity in vivo, unveiling its associations with age, BMI, tissue atrophy, WMH and PVS.

Amyloid Beta-Mediated Neurovascular Toxicity in Alzheimer's Disease.

The brain vascular system receives one-fifth of the total oxygen from the cardiac output, and this transport system is highly dependent on blood-brain barrier (BBB) integrity. The cerebral blood flow is controlled by neurovascular coupling through neurovascular units (NVUs). The NVU includes different types of cells, such as mural cells, astrocytes, pericytes, endothelial cells (ECs), and vascular smooth muscle cells (VSMCs). The cellular composition of NVU varies throughout the vascular tree. Amyloid β (Aβ) is abundantly present in the central nervous system, but the pathological accumulation of misfolded Aβ protein causes vascular damage, resulting in neurovascular dysfunction. Aβ aggregation can activate the astrocytes and endothelial cells. It is followed by pericyte degeneration which results in dysregulation of cerebral blood flow (CBF), neurovascular uncoupling, and BBB breakdown. Thus, understanding the cellular and molecular mechanisms of Aβ-induced neurovascular toxicity is crucial for determining normal and diseased brain function. This chapter discusses the components of NVU, neurovascular uncoupling, Aβ-induced cerebrovascular reactivity, and cerebral blood flow reduction in neurodegenerative disorders, with special emphasis on Alzheimer's disease.

Ruptured abdominal aortic aneurysms early recognition, hemodynamic stabilization, and emergency vascular surgery

Ruptured abdominal aortic aneurysms (rAAAs) are extremely dangerous. Require attention. This thorough review explores the management of rAAA, focusing on the detection stabilizing blood flow and emergency vascular surgery. Recognizing symptoms such as intense abdominal pain, low blood pressure, a pulsating mass in the abdomen, signs of reduced blood flow to the lower limbs, and back pain is crucial for quick identification. Diagnostic imaging techniques like ultrasound and computed tomography angiography (CTA) play a role in confirming the diagnosis and assessing the risk involved. Properly managing hemodynamics by balancing resuscitation efforts with approaches is essential to control ongoing bleeding. Emergency vascular surgery options include aneurysm repair (EVAR) and open repair; the choice depends on factors like anatomy, stability of blood flow, and surgical expertise. Prioritizing optimization to address any health conditions and closely monitoring patients after surgery greatly contribute to overall success rates. A collaborative approach among healthcare professionals ensures a multidisciplinary strategy during the period emphasizing effective communication. This comprehensive approach aims for outcomes in dealing with challenging rAAAs while considering advancements in research and clinical practices.

Assessment of developmental toxicity and the potential mode of action underlying single and binary exposure to estrogenic endocrine disrupting chemicals in zebrafish (Danio rerio)

The current study investigated the effect of single and binary exposure to distinct xenoestrogens, including diethylstilbestrol (DES) and zearalenone (ZEN), on zebrafish embryos subjected to continuous exposure for 4 days starting from 4 h post fertilization. Noteworthy impact on cumulative mortality, hatchability, spinal and tail curvature, pericardial edema, and reduction in blood circulation were observed in DES-treated embryos, with lower incidence and intensity shown for ZEN at the same nominal concentration (3 μM). An interactive effect was seen for the combined exposure to DES and ZEN, in which deformities and circulatory failure mediated by DES were mitigated by co-treatment with low concentrations of ZEN. Similarly, ZEN-induced spinal and tail curvature, pericardial edema, and blood flow reduction declined dramatically following DES co-exposure at low concentrations. A significant counteracting effect has been observed against DES- and ZEN-induced developmental anomalies following co-treatment with an estrogen receptor (ER) antagonist, fulvestrant (FUL). The assessment of the aromatase gene (CYP19A1b) showed that DES strongly upregulated mRNA expression of CYP19A1b with a lower EC50 (1.1 × 10−3 nM) than a natural estrogen, 17β-estradiol (2.5 nM). Similarly, ZEN induced CYP19A1b mRNA expression with an EC50 of 57 nM. Exposure to 10 or 20 μM FUL inhibited the expression of CYP19A1b induced by a single treatment of DES or ZEN. Overall, the competitive action against ER could be the main mechanism underlying the developmental toxicity induced by DES and ZEN.

Late-onset non-obstructive mesenteric ischemia (NOMI) resulting from delayed absorption of overdosed antihypertensive drugs: An autopsy case report.

Non-obstructive mesenteric ischemia (NOMI) is caused by reduced blood flow to the intestines without physical occlusion in the mesenteric artery. Previous reports show that drug overdose occasionally induces late-onset NOMI; however, in most cases, the reason for the delayed onset is unclear. Here, we present an autopsy case of late-onset NOMI that was induced by a drug overdose. An 80-year-old man was admitted to the intensive care unit because of severe hypotension after an overdose of antihypertensive drugs. He received vasopressor therapy and continuous hemodiafiltration dialysis; however, gastrointestinal decontamination was not performed. He began to recover but developed acute mesenteric ischemia on the evening of day 4 and died on day 5. Autopsy showed discontinuous submucosal bleeding from the duodenum to the colon; there was no thrombus in the mesenteric artery, which led to a diagnosis of NOMI. In the stomach, there was 250mL of reddish-brown fluid with a muddy brown substance. Histologic examination revealed ischemic necrosis in the small intestine. Quantitative analysis of serum collected during hospitalization revealed that nifedipine and cilostazol levels had peaked on day 3 of hospitalization. The formulation of nifedipine was a controlled-release tablet, and the low water solubility of cilostazol may have caused the tablets to adhere and remain in the stomach. Therefore, the drugs had been released into the blood stream several days after hospitalization, leading to delayed-onset NOMI. In cases of overdose, it is crucial to consider the formulation and properties of the involved drugs when determining medical treatment.

Spreading depolarization suppression from inter-astrocytic gap junction blockade assessed with multimodal imaging and a novel wavefront detection scheme

Spreading depolarizations (SDs) are an enigmatic and ubiquitous co-morbidity of neural dysfunction. SDs are propagating waves of local field depolarization and increased extracellular potassium. They increase the metabolic demand on brain tissue, resulting in changes in tissue blood flow, and are associated with adverse neurological consequences including stroke, epilepsy, neurotrauma, and migraine. Their occurrence is associated with poor patient prognosis through mechanisms which are only partially understood. Here we show in vivo that two (structurally dissimilar) drugs, which suppress astroglial gap junctional communication, can acutely suppress SDs. We found that mefloquine hydrochloride (MQH), administered IP, slowed the propagation of the SD potassium waveform and intermittently led to its suppression. The hemodynamic response was similarly delayed and intermittently suppressed. Furthermore, in instances where SD led to transient tissue swelling, MQH reduced observable tissue displacement. Administration of meclofenamic acid (MFA) IP was found to reduce blood flow, both proximal and distal, to the site of SD induction, preceding a large reduction in the amplitude of the SD-associated potassium wave. We introduce a novel image processing scheme for SD wavefront localization under low-contrast imaging conditions permitting full-field wavefront velocity mapping and wavefront parametrization. We found that MQH administration delayed SD wavefront's optical correlates. These two clinically used drugs, both gap junctional blockers found to distinctly suppress SDs, may be of therapeutic benefit in the various brain disorders associated with recurrent SDs.

Clinical experience with postpartum treatment of a patient with arteriovenous malformation of uterine vessels

Uterine arteriovenous malformation is a rare vascular dysplasia where the uterine veins communicate with the branches of arteries of varying calibers. Patient K., a 37-years-old patient, presented with genital tract bleeding. Her medical history included operative labor at 37 weeks with dichorionic diamniotic twins, with the placental site on the posterior uterine wall exhibited firm attachment. The uterine cavity walls were scraped, and the bleeding vessel in the placental site was sutured. The blood loss amounted to 750 mL, and reinfusion was conducted. Fourteen days after giving birth, a heavy bloody discharge with blood clots from the genital tract occurred. The blood tests revealed no abnormalities. Echography detected multiple tubular structures that were anechoic on the posterior wall of the uterus, from the endometrium to the serosa, with the CDC mode blood flow. Magnetic resonance angiography revealed hypervascularization with premature arteriovenous discharge. Superselective embolization was performed on uterine artery afferents, and complete blood flow reduction was achieved, leading to the cessation of bleeding. On postoperative day 17, the patient experienced considerable bloody discharge from the genital tract, causing the hemoglobin level to decrease to 88 g/L. The presence of an arteriovenous malformation in the uterine vessels accompanied by ineffective embolization necessitated uterine extirpation. The postoperative phase was uneventful, and the patient was discharged from the hospital in satisfactory condition, with no evidence of anemia (hemoglobin, 115 g/L).

Sex, Endothelial Cell Functions, and Peripheral Artery Disease.

Peripheral artery disease (PAD) is caused by blocked arteries due to atherosclerosis and/or thrombosis which reduce blood flow to the lower limbs. It results in major morbidity, including ischemic limb, claudication, and amputation, with patients also suffering a heightened risk of heart attack, stroke, and death. Recent studies suggest women have a higher prevalence of PAD than men, and with worse outcomes after intervention. In addition to a potential unconscious bias faced by women with PAD in the health system, with underdiagnosis, and lower rates of guideline-based therapy, fundamental biological differences between men and women may be important. In this review, we highlight sexual dimorphisms in endothelial cell functions and how they may impact PAD pathophysiology in women. Understanding sex-specific mechanisms in PAD is essential for the development of new therapies and personalized care for patients with PAD.

Worsening Symptoms Is Associated with Larger Cerebral Blood Flow Abnormalities during Tilt-Testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).

Background and Objectives: During tilt testing, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients experience an abnormal reduction in cerebral blood flow (CBF). The relationship between this CBF reduction and symptom severity has not been examined in detail. Our hypothesis was that ME/CFS severity is related to the degree of the CBF reduction during tilt testing. Materials and Methods: First, from our database, we selected ME/CFS patients who had undergone assessments of ME/CFS symptomatology and tilt tests on the same day, one at the first visit and the second during a follow-up. The change in symptomatology was related to the change in CBF during the tilt test. Second, we combined the data of two previously published studies (n = 219), where disease severity as defined by the 2011 international consensus criteria (ICC) was available but not published. Results: 71 patients were retested because of worsening symptoms. The ICC disease severity distribution (mild-moderate-severe) changed from 51/45/4% at visit-1 to 1/72/27% at follow-up (p < 0.0001). The %CBF reduction changed from initially 19% to 31% at follow-up (p < 0.0001). Of 39 patients with stable disease, the severity distribution was similar at visit-1 (36/51/13%) and at follow-up (33/49/18%), p = ns. The %CBF reduction remained unchanged: both 24%, p = ns. The combined data of the two previously published studies showed that patients with mild, moderate, and severe disease had %CBF reductions of 25, 29, and 33%, respectively (p < 0.0001). Conclusions: Disease severity and %CBF reduction during tilt testing are highly associated in ME/CFS: a more severe disease is related to a larger %CBF reduction. The data suggest a causal relationship where a larger CBF reduction leads to worsening symptoms.

Bridge to Better Care: Investigating Transient Ischemic Attack (TIA) Management Expertise Among Primary Healthcare Providers in Al-Ahsa, Saudi Arabia.

Introduction Transient ischemic attacks (TIAs) are brief episodes of neurological impairment caused by reduced blood flow to the brain, spinal cord, or retina, typically lasting under an hour. Recent advances in neuroimaging suggest that some TIAs may actually be small strokes with resolved symptoms. This study focuses on assessing the knowledge and management of TIAs among primary care physicians and nurses in Al-Ahsa, Saudi Arabia. Methodology This isa cross-sectional study, conducted in Al-Ahsa, Saudi Arabia, during the period July to August 2023. Data were collected using an electronic questionnaire and was analyzed using IBM SPSS Statistics for Windows, version 27.0.1 (released 2020, IBM Corp., Armonk, New York, United States). Results Among the participants, 64.0% correctly identified TIA as an ischemic neurological deficit. However, only 20.2% provided correct responses for all TIA symptoms. Regarding diagnostic tests, 47.4% acknowledged the need for neuroimaging immediately after TIA, while 17.5% recognized the importance of ultrasonography of the supra-aortic trunks. In terms of TIA management, 38.6% preferred referral to the emergency service, and 41.2% correctly perceived the risk of TIA recurrence as similar to that of established cerebral ischemic stroke. Significant disparities were observed in the recognition of TIA symptoms, with physicians outperforming nurses, particularly in identifying motor deficits (82.4% vs. 65.2%) and speech alterations (86.8% vs. 76.1%, p = 0.004). However, nurses exhibited better knowledge in recognizing the need for a neuroimaging test (48.5% vs. 45.7%, p = 0.849) and the urgency of conducting a transcranial Doppler (TCD) (19.1% vs. 23.9%, p = 0.641). Conclusion A considerable proportion of healthcare providers demonstrate a good understanding of TIA definition and management. However, the lack of significant predictors for good knowledge and attitude suggests the need for more comprehensive strategies to enhance TIA management expertise across healthcare professionals.

Cerebral blood flow and white matter alterations in adults with phenylketonuria

BackgroundPhenylketonuria (PKU) represents a congenital metabolic defect that disrupts the process of converting phenylalanine (Phe) into tyrosine. Earlier investigations have revealed diminished cognitive performance and changes in brain structure and function (including the presence of white matter lesions) among individuals affected by PKU. However, there exists limited understanding regarding cerebral blood flow (CBF) and its potential associations with cognition, white matter lesions, and metabolic parameters in patients with PKU, which we therefore aimed to investigate in this study. MethodArterial spin labeling perfusion MRI was performed to measure CBF in 30 adults with early-treated classical PKU (median age 35.5 years) and 59 healthy controls (median age 30.0 years). For all participants, brain Phe levels were measured with 1H spectroscopy, and white matter lesions were rated by two neuroradiologists on T2 weighted images. White matter integrity was examined with diffusion tensor imaging (DTI). For patients only, concurrent plasma Phe levels were assessed after an overnight fasting period. Furthermore, past Phe levels were collected to estimate historical metabolic control. On the day of the MRI, each participant underwent a cognitive assessment measuring IQ and performance in executive functions, attention, and processing speed. ResultsNo significant group difference was observed in global CBF between patients and controls (F (1, 87) = 3.81, p = 0.054). Investigating CBF on the level of cerebral arterial territories, reduced CBF was observed in the left middle and posterior cerebral artery (MCA and PCA), with the most prominent reduction of CBF in the anterior subdivision of the MCA (F (1, 87) = 6.15, p = 0.015, surviving FDR correction). White matter lesions in patients were associated with cerebral blood flow reduction in the affected structure. Particularly, patients with lesions in the occipital lobe showed significant CBF reductions in the left PCA (U = 352, p = 0.013, surviving FDR correction). Additionally, axial diffusivity measured with DTI was positively associated with CBF in the ACA and PCA (surviving FDR correction). Cerebral blood flow did not correlate with cognitive performance or metabolic parameters. ConclusionThe relationship between cerebral blood flow and white matter indicates a complex interplay between vascular health and white matter alterations in patients with PKU. It highlights the importance of considering a multifactorial model when investigating the impact of PKU on the brain.

Outcomes of Lithotripsy in Severely Calcified Coronary Artery Disease: A Systematic Review and Meta-analysis

BackgroundSeverely calcified coronary artery disease can cause reduced blood flow to the heart, leading to serious cardiac conditions. Intracoronary lithotripsy (ICL) has been developed to improve outcomes for patients with heavily calcified lesions. This study aims to summarize the existing evidence on the effectiveness and safety of intravascular lithotripsy (IVL) for severely calcified coronary artery disease. MethodsWe comprehensively searched PubMed, Cochrane Central Register of Controlled Trials, Web of Science, and Scopus, from their inception up to April 1, 2023, with a restricted search strategy. The R version 4.2.3 was utilized using Metafor package for analysis. To determine the study's heterogeneity, the indices tau2 and I2, as well as Cochran's Q test, were employed. ResultsA total of 17 studies, comprising 2488 observations, were included in the analysis. IVL is a treatment option for patients with severely calcified coronary artery disease. The percentage stenosis reduction showed a mean reduction of 15.0548% (95% CI: 8.310 to 21.79), with high heterogeneity observed among studies. The occurrence of cardiovascular-related events showed a proportion of 0.015 (95% CI: 0.0046-0.0254) and significant heterogeneity. ConclusionThese findings suggest that IVL is an effective treatment option, but further studies are needed to better understand its efficacy and safety.

Faktor-Faktor yang Mempengaruhi Kejadian Hipertensi pada Ibu Hamil Di Rumah Sakit Umum Aliyah Kota Kendari Tahun 2022

Hypertension is a manifestation of disturbances in the hemodynamics of the High blood pressure in pregnancy can reduce blood flow to the placenta, which will affect the supply of oxygen and nutrients to the baby. This can slow the growth of the baby and increase the risk during delivery. Pregnancy Hypertension ranks as the ninth disease at Aliyah Kendari Hospital with a prevalence that increases every year, namely 13% in 2019, 15.2% in 2020, 14% in 2021, and 15.5% in 2022 which has an impact on increasing miscarriage in the first trimester and sudden fetal death (stillbirth). This study aims to determine the factors associated with hypertension in pregnant women at the hospital. Aliyah Kendari City. This research was conducted at Aliyah Hospital, Kendari City in 2022. The research was conducted with a cross-sectional design. The population in this study were pregnant women at Aliyah Hospital, Kendari City during January-June 2022. The sampling technique used a random sampling system, namely by randomizing the patient's medical record number. The type of data in this study used secondary data from medical record data January-June 2022 by collecting data using form sheets and checklist sheets. Data analysis technique using chi-square analysis. Based on the bivariate analysis, it showed that there was a significant relationship between age (p value = 0.000, PR = 3.020), obesity (p value = 0.000, PR = 8.718), family history of hypertension (p value = 0.000, PR = 2.918), parity (p value = 0.000, PR = 2.181), working mother status (p value = 0.003, PR = 1.358). The suggestion of this research is that hospitals can further improve education about hypertension in pregnancy.

Predictive stroke risk model with vision transformer-based Doppler features.

Acute stroke is the leading cause of death and disability globally, with an estimated 16 million cases each year. The progression of carotid stenosis reduces blood flow to the intracranial vasculature, causing stroke. Early recognition of ischemic stroke is crucial for disease treatment and management. A computer-aided diagnosis (CAD) system was proposed in this study to rapidly evaluate ischemic stroke in carotid color Doppler (CCD). Based on the ground truth from the clinical examination report, the vision transformer (ViT) features extracted from all CCD images (513 stroke and 458 normal images) were combined in machine learning classifiers to generate the likelihood of ischemic stroke for each image. The pretrained weights from ImageNet reduced the time-consuming training process. The accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve were calculated to evaluate the stroke prediction model. The chi-square test, DeLongtest, and Bonferroni correction for multiple comparisons were applied to deal with the type-I error. Only p values equal to or less than 0.00125 were considered to be statistically significant. The proposed CAD system achieved an accuracy of 89%, a sensitivity of 94%, a specificity of 84%, and an area under the receiver operating characteristic curve of 0.95, outperforming the convolutional neural networks AlexNet (82%, p<0.001), Inception-v3 (78%, p<0.001), ResNet101 (84%, p<0.001), and DenseNet201 (85%, p<0.01). The computational time in model training was only 30 s, which would be efficient and practical in clinical use. The experiment shows the promising use of CCD images in stroke estimation. Using the pretrained ViT architecture, the image features can be automatically and efficiently generated without human intervention. The proposed CAD system provides a rapid and reliable suggestion for diagnosing ischemic stroke.

Cognitive status modifies the association between elevated cerebrospinal fluid phosphorylated tau and longitudinal cerebral blood flow changes over a 7‐year follow‐up period

AbstractBackgroundAlzheimer’s disease (AD) is associated with widespread reductions in cerebral blood flow (CBF), but the precise link between AD pathology and CBF is unclear. Hypoperfusion is a late‐stage event associated with tau, but not amyloid, pathology. We assessed whether baseline levels of cerebrospinal fluid (CSF)‐measured core AD pathology [β‐amyloid42 (Aβ42), phosphorylated tau (p‐tau)] related to CBF changes over a 7‐year period and if associations differed by baseline cognitive status.MethodsVanderbilt Memory and Aging Project participants free of clinical dementia or stroke at enrollment [n = 153, 72±6 years, 37% mild cognitive impairment (MCI), 33% female] underwent lumbar puncture to obtain CSF at study entry and serial multimodal 3T brain magnetic resonance imaging over a 7‐year follow‐up period (mean = 5.4 years). Enzyme‐linked immunosorbent assays quantified CSF Aβ42 and p‐tau181. Pseudo‐continuous arterial spin‐labeling captured CBF in total and lobar grey matter regions of interest (ROI). Linear mixed‐effects models related biomarker x time to longitudinal CBF variables adjusting for baseline age and cognitive status, sex, race/ethnicity, education, Framingham Stroke Risk Profile (minus age), ROI volume, APOE‐ε4 status, and time. Models were repeated testing a cognitive status x biomarker x time interaction term.ResultsIn main effect models, neither CSF Aβ42 (p‐values&gt;0.31) nor p‐tau (p‐values&gt;0.28) related to CBF outcomes. Aβ42 did not interact with cognitive status on CBF outcomes (p‐values&gt;0.37), but p‐tau interacted with baseline cognitive status on longitudinal frontal, temporal, parietal, occipital, and total grey matter CBF trajectories (p‐values&lt;0.005). Among cognitively unimpaired participants, higher p‐tau was associated with slower reductions in frontal (β = 0.01, p = 0.03), parietal (β = 0.01, p = 0.04), occipital (β = 0.01, p = 0.02), and total grey matter CBF (β = 0.01, p = 0.04). Among individuals with MCI, higher p‐tau was associated with faster reductions in frontal (β = ‐0.03, p = 0.008), temporal (β = ‐0.02, p = 0.01), parietal (β = ‐0.04, p = 0.002), occipital (β = ‐0.03, p = 0.0004), and total grey matter CBF (β = ‐0.03, p = 0.005).ConclusionsResults linking CSF p‐tau to CBF decline in MCI support the theory that grey matter hypoperfusion is a later‐stage event tied to neurofibrillary tangle pathology. Associations between higher p‐tau and slower rates of CBF decline among cognitively unimpaired individuals warrants further investigation. Funding: R01‐AG034962, K24‐AG046373, F31‐AG079640, T32‐AG058524, P20‐AG068082

Higher baseline cerebrospinal fluid platelet‐derived growth factor receptor‐β levels are associated with slower reductions in longitudinal cerebral blood flow among cognitively unimpaired individuals

AbstractBackgroundCerebrospinal fluid (CSF) platelet‐derived growth factor receptor‐β (PDGFR‐β) is an emerging biomarker hypothesized to reflect pericyte damage. CSF PDGFR‐β levels are increased in Alzheimer’s disease (AD), but it is unknown if pericyte injury contributes to cerebrovascular changes common in AD. We examined if PDGFR‐β relates to changes in cerebral blood flow (CBF) and white matter injury in older adults.MethodVanderbilt Memory and Aging Project participants (n = 152, baseline age 73±7 years, 43% mild cognitive impairment [MCI]) underwent baseline lumbar puncture and serial brain MRI over a 7‐year (5.5±2.3) follow‐up period. CSF PDGFR‐β concentrated was measured by immunoassay. MRI included pseudo‐continuous arterial spin‐labeling to quantify CBF, T2‐FLAIR to quantify white matter hyperintensities (WMHs), and diffusion tensor imaging (DTI) to quantify white matter microstructural integrity. Ordinary least squares regression and linear mixed‐effects models related baseline CSF PDGFR‐β to baseline and longitudinal whole brain and regional CBF, WMH, and DTI metrics, adjusting for baseline demographic variables, modified Framingham Stroke Risk Profile, cognitive status, apolipoprotein‐ε4 status, and regional tissue volume. Longitudinal models adjusted for follow‐up time. Follow‐up models tested a CSF PDGFR‐β x cognitive status interaction.ResultIn main models, higher CSF PDGFR‐β levels were cross‐sectionally associated with lower mean diffusivity (indicating better microstructural integrity) in white matter tracts in the frontal, temporal, parietal, and occipital lobes (p‐values&lt;0.03) but were unrelated to WMHs (p‐values&gt;0.18). Models investigating associations with longitudinal white matter variables were null (p‐values&gt;0.35). CSF PDGFR‐β cross‐sectionally interacted with diagnosis on temporal lobe CBF, such that higher CSF PDGFR‐β related to higher CBF in MCI participants (p = 0.01). In longitudinal models, baseline CSF PDGFR‐β interacted with cognitive status on whole brain and occipital lobe CBF (p‐values&lt;0.04). Stratified models showed higher baseline CSF PDGFR‐β related slower reductions in longitudinal CBF in whole brain (p = 0.02), frontal (p = 0.04), temporal (p = 0.02), parietal (p = 0.01), and occipital lobes (p = 0.008) in cognitively unimpaired participants only.ConclusionAmong older adults, higher CSF PDGFR‐β levels are associated with better white matter integrity at study entry and predict slower reductions in longitudinal CBF among cognitively unimpaired individuals. Results suggest that higher PDGFR‐β levels may reflect subclinical vascular remodeling that provides protection to future cerebrovascular compromise.

Transient ischemic stroke triggers sustained damage of the choroid plexus blood-CSF barrier.

Neuroinflammation is a pathological event associated with many neurological disorders, including dementia and stroke. The choroid plexus (ChP) is a key structure in the ventricles of the brain that secretes cerebrospinal fluid (CSF), forms a blood-CSF barrier, and responds to disease conditions by recruiting immune cells and maintaining an immune microenvironment in the brain. Despite these critical roles, the exact structural and functional changes to the ChP over post-stroke time remain to be elucidated. We induced ischemic stroke in C57BL/6J mice via transient middle cerebral artery occlusion which led to reduction of cerebral blood flow and infarct stroke. At 1-7 days post-stroke, we detected time-dependent increase in the ChP blood-CSF barrier permeability to albumin, tight-junction damage, and dynamic changes of SPAK-NKCC1 protein complex, a key ion transport regulatory system for CSF production and clearance. A transient loss of SPAK protein complex but increased phosphorylation of the SPAK-NKCC1 complex was observed in both lateral ventricle ChPs. Most interestingly, stroke also triggered elevation of proinflammatory Lcn2 mRNA and its protein as well as infiltration of anti-inflammatory myeloid cells in ChP at day 5 post-stroke. These findings demonstrate that ischemic strokes cause significant damage to the ChP blood-CSF barrier, contributing to neuroinflammation in the subacute stage.

Ameliorative potential of thymoquinone in four vessel occlusion induced vascular dementia in rats

AbstractBackgroundVascular dementia (VaD) is a common type of dementia caused by reduction of blood flow to the brain via deprivation of brain cellular oxygen and nutrients supply. At present VaD is the second most occurring type of dementia in older adults and stoke patients. Around 55 million people have dementia globally. As per WHO survey is expected to rise to 78 million in 2030 and triple by 2050. Generally Hypo perfusion and thromboembolic events reduces the cerebral blood flow to the brain which leads to oxidative stress, hypoxia and inflammation further it causes mitochondrial dysfunction results in VaD. The current treatment for VaD relieves various unwanted side effects. However, the specific medicines with more potent and high efficacy are not explored yet. Neuro‐inflammation and oxidative stress has been widely correlated to be involved in the pathogenesis of VaD. Therefore, finding new therapeutic targets or drugs for VaD treatment is vital. Some of the herbal moieties and synthetic derivatives are reported to prevent cognitive disorders via amelioration of neurovascular disorders.MethodMale Wistar Albino Rats (weight, 150 to 180 g), Cerebral hypo perfusion (CPH) was done in rats to create hypoxia in order to induce VaD, after the CPH all animals were treated with Thymoquinone (TQ (5 and 10mg/kg)). Invitro study of mast cell degranulation, Behavioral assessments; Biochemical markers and Histopathological evaluation.Result4VO cause the potential neurovascular damage leads to significant changes in learning and memory functions along with the alteration of psychosocial and neuromotor functions. Besides, Four vessel occlusion (4VO) induces the bio‐molecular changes in hippocampus. Treatment of TQ shown significant (p &lt; 0.05) ameliorative effect against 4VO induced cerebrovascular injury, cognitive impairments, neuroinflammation in rats. It is also comparable with the reference compound donepezil treatment. In the present study, it also showed the cognitive dysfunction with alteration of learning and memory functions. And, it also psychosocial behavior.ConclusionOur findings suggested that TQ may be use as a future medicine for metabolic and neurotoxic associated neurovascular disorders due to its potential anti‐oxidative, anti‐lipid peroxidative, anti‐inflammatory, and acetylcholinesterase inhibitory actions.

SARS‐CoV‐2 infection worsens Vascular Dementia (VaD)‐associated neuropathology in mice

AbstractBackgroundVascular Dementia (VaD) is the second leading cause of dementia behind Alzheimer’s disease (AD) and has a profound association with the morbidity and mortality of COVID‐19. Recent evidence demonstrates that preexisting vascular dementia is associated with increased COVID‐19 incidence and worsened outcomes after COVID‐19 infection. Collectively, these observations suggest that vascular pathology in VaD such as blood‐brain barrier (BBB) disruption, directly contributes to this association. Previously we and others have demonstrated that SARS‐CoV‐2 binds to the vascular integrin α5β1 receptor and that inhibition of α5β1 integrin with the clinically‐validated peptide ATN‐161 can improve acute SARS‐CoV‐2 infection and reduce SARS‐CoV‐2‐mediated vascular disruption. Furthermore, we have previously demonstrated that ATN‐161 reduces BBB disruption in models of brain ischemia (stroke) and VaD‐modeled chronic bilateral carotid artery stenosis (BCAS), which models reduced blood flow, BBB disruption, neuroinflammation, white matter damage and cognitive decline in VaD. In the present study, we tested the hypothesis that experimental VaD worsens COVID‐19‐associated neuroinflammation and exacerbates subsequent neurovascular damage, which may be targeted therapeutically by ATN‐161.Method10‐week‐old wild‐type (WT) BALB/c male mice were infected with 2×105 PFU mouse‐adapted (MA10) SARS‐CoV‐2 or mock infection 1‐week after BCAS surgery to model the effects of preexisting VaD in mice and subsequent SARS‐CoV‐2 infection. Body weight was monitored daily. The brain was isolated 3‐days post‐infection (dpi) and analyzed for immunohistochemical and mRNA expression of selected markers of neuroinflammation and immune response.ResultBCAS+SARS‐CoV‐2 infected mice exhibited a significant reduction in body weight at 3 dpi compared with the BCAS+mock infected group. Immunohistochemical analysis demonstrated a significant increase in α5 integrin signal in the cortex. SARS‐CoV‐2 infection after BCAS worsened brain and vascular inflammation and glial activation, indicated by increased Iba‐1 (microglia) and GFAP (astrocyte) immunofluorescence and brain (proinflammatory) IL‐1β cytokine transcript levels. Lastly, SARS‐CoV‐2 infection worsens white matter (myelin) integrity as measured by myelin basic protein (MBP) immunofluorescence.ConclusionSARS‐CoV‐2 aggravated VaD‐associated morbidity indicated by elevated white matter damage, glial activation, and neuroinflammation along with increased integrin α5 expression. Integrin α5β1 could, therefore, be a therapeutic target for improving both acute SARS‐CoV‐2 infection, and VaD post‐COVID morbidity and cognitive decline.

The retina in Alzheimer’s disease: Anatomy and Pathology

AbstractGrowing evidence suggests that Alzheimer’s disease (AD) pathology is not confined to the brain but also appears in the neurosensory retina. Perceived as an extension of the brain, the retina is visible directly and noninvasively at the vascular, cellular and molecular resolution. Aβ accumulation, vascular amyloidosis, hyperphosphorylated (p)tau, microgliosis, astrogliosis, Müller glia changes, abnormal electroretinography patterns, and neuronal degeneration have all been described in the postmortem retina of AD patients, including in early‐stage cases. Although a few studies were unable to consistently repeat these findings, increased proportion of positive studies from subsequent histological, biochemical, and imaging studies validated the original findings. Several studies further provided data suggesting that the brain and retina follow a similar trajectory during AD progression, potentially due to their common embryonic origin and anatomical proximity. A host of retinal vascular abnormalities including reduced blood flow, foveal avascular zone and arteriole‐to‐venule ratio were observed by in vivo fundus imaging, optical coherence tomography (OCT) or OCT‐angiopathy in preclinical, prodromal and clinical AD patients. Further, retinal vascular platelet‐derived growth factor receptor‐β (PDGFRβ) expression and pericyte loss have been associated with retinal vascular amyloidosis and cerebral amyloid angiopathy in mild cognitively impaired (MCI) and AD patients. A recent proteomics profiling study revealed common molecular signatures in the AD retina and brain, with enriched pathways related to inflammation, vascular and photoreceptor vulnerability. Novel imaging techniques, such as curcumin fluorescence, have correlated increases in retinal amyloid burden with brain amyloid PET load and hippocampal atrophy in patients, and together with vascular changes predicted cognitive deficits. This perspective provides an overview on the evidence of AD pathology in the retina and current gaps in knowledge. Future studies exploring retinal pathology in AD and other neurodegenerative diseases may fundamentally contribute to the development of validated retinal biomarkers for improved noninvasive disease diagnosis and monitoring.