Cerebrovascular Alterations Research Articles

SKYQUANT 3D: Quantifying Vascular Anatomy With an Open-Source Workflow for Comprehensive Analysis of Volumetric Optoacoustic Angiography Data.

Efficient visualization of the vascular system is of key importance in biomedical research into tumor angiogenesis, cerebrovascular alterations, and other angiopathies. Optoacoustic (OA) angiography offers a promising solution combining molecular optical contrast with high resolution and deep penetration of ultrasound. However, its hybrid nature implies complex data collection and processing workflows, with significant variability in methodologies across developers and users. To streamline interoperability, we introduce SKYQUANT 3D, a Python-based set of instructions for the Thermo Fisher Scientific Amira/Avizo 3D Visualization & Analysis Software. Our workflow simplifies the batch processing of volumetric optoacoustic angiography images, extracting meaningful quantitative information while also providing statistical analysis and graphical representation of the results. Quantification performance of SKYQUANT 3D is demonstrated using functional preclinical and clinical in vivo 3D OA angiographic tests involving ambient temperature variations and repositioning of the imaged limb.

Super-resolution ultrasound imaging reveals temporal cerebrovascular changes with disease progression in female 5×FAD mouse model of Alzheimer's disease: correlation with pathological impairments

Vascular dysfunction is closely associated with the progression of Alzheimer's disease (AD). A critical research gap exists that no studies have explored the invivo temporal changes of cerebrovascular alterations with AD progression in mouse models, encompassing both structure and flow dynamics at micron-scale resolution across the early, middle, and late stages of the disease. In this study, ultrasound localisation microscopy (ULM) was applied to image the cerebrovascular alterations of the transgenic female 5×FAD mouse model across different stages of disease progression: early (4 months), moderate (7 months), and late (12 months). Age-matched non-transgenic (non-Tg) littermates were used as controls. Immunohistology examinations were performed to evaluate the influence of disease progression on the β-amyloid (Aβ) load and microvascular alterations, including morphological changes and the blood-brain barrier (BBB) leakage. Our findings revealed a significant decline in both vascular density and flow velocity in the retrosplenial cortex of 5×FAD mice at an early stage, which subsequently became more pronounced in the visual cortex and hippocampus as the disease progressed. Additionally, we observed a reduction in vascular length preceding diminished flow velocities in cortical penetrating arterioles during the early stages. The quantification of vascular metrics derived from ULM imaging showed significant correlations with those obtained from vascular histological images. Immunofluorescence staining identified early vascular abnormalities in the retrosplenial cortex. As the disease advanced, there was an exacerbation of Aβ accumulation and BBB disruption in a regionally variable manner. The vascular changes observed through ULM imaging exhibited a negative correlation with amyloid load and were associated with the compromise of the BBB integrity. Through high-resolution, invivo imaging of cerebrovasculature, this study reveals significant spatiotemporal dysfunction in cerebrovascular dynamics accompanying disease progression in a mouse model of AD, enhancing our understanding of its pathophysiology. This study is supported by grants from National Key Research and Development Program of China (2020YFA0908800), National Natural Science Foundation of China (12074269, 82272014, 82327804, 62071310), Shenzhen Basic Science Research (20220808185138001, JCYJ20220818095612027, JCYJ20210324093006017), STI 2030-Major Projects (2021ZD0200500) and Guangdong Natural Science Foundation (2024A1515012591, 2024A1515011342).

Assessment of cerebrovascular alterations induced by inflammatory response and oxidative–nitrative stress after traumatic intracranial hypertension and a potential mitigation strategy

The rapid perfusion of cerebral arteries leads to a significant increase in intracranial blood volume, exposing patients with traumatic brain injury to the risk of diffuse brain swelling or malignant brain herniation during decompressive craniectomy. The microcirculation and venous system are also involved in this process, but the precise mechanisms remain unclear. A physiological model of extremely high intracranial pressure was created in rats. This development triggered the TNF-α/NF-κB/iNOS axis in microglia, and released many inflammatory factors and reactive oxygen species/reactive nitrogen species, generating an excessive amount of peroxynitrite. Subsequently, the capillary wall cells especially pericytes exhibited severe degeneration and injury, the blood–brain barrier was disrupted, and a large number of blood cells were deposited within the microcirculation, resulting in a significant delay in the recovery of the microcirculation and venous blood flow compared to arterial flow, and this still persisted after decompressive craniectomy. Infliximab is a monoclonal antibody bound to TNF-α that effectively reduces the activity of TNF-α/NF-κB/iNOS axis. Treatment with Infliximab resulted in downregulation of inflammatory and oxidative–nitrative stress related factors, attenuation of capillary wall cells injury, and relative reduction of capillary hemostasis. These improved the delay in recovery of microcirculation and venous blood flow.

Hypotension with neurovascular changes and cognitive dysfunction: An epidemiological, pathobiological, and treatment review.

Hypotension is a leading cause of age-related cognitive impairment. The available literature evidences that vascular factors are associated with dementia and that hypotension alters cerebral perfusion flow and can aggravate the neurodegeneration of Alzheimer's disease (AD). Despite the discovery of biomarkers and the recent progress made in neurovascular biology, epidemiology, and brain imaging, some key issues remain largely unresolved: the potential mechanisms underlying the neural deterioration observed in AD, the effect of cerebrovascular alterations on cognitive deficits, and the positive effects of hypotension treatment on cognition. Therefore, further well-designed studies are needed to unravel the potential association between hypotension and cognitive dysfunction and reveal the potential benefits of hypotension treatment for AD patients. Here, we review the current epidemiological, pathobiological, and treatment-related literature on neurovascular changes and hypotension-related cognitive dysfunction and highlight the unsettled but imminent issues that warrant future research endeavors.

Cerebrovascular Conductance Responses to Carbon Dioxide are Attenuated by the Presence of Hypertension in Patients with Atrial Fibrillation

The cerebral vasculature is highly sensitive to carbon dioxide (CO2) and cerebrovascular CO2 reactivity (CVRCO2) is widely used to index cerebral vascular health. Some studies have shown that both atrial fibrillation (AF) and hypertension (HTN) are independently associated with reduced CVRCO2. However, it is unknown if these effects on CVRCO2 are synergistic when AF and HTN are present together. In this study we tested the hypothesis that CVRCO2 was lower in patients with both AF and HTN (AF+HTN) compared to normotensive patients with AF. Transcranial Doppler ultrasound was used to measure middle cerebral artery blood velocity (MCA Vm) in AF (n=31) and AF+HTN (n=57) during stepped increases and decreases in end-tidal carbon dioxide (PETCO2). The ratio of MCA Vm and mean arterial pressure (MAP) was defined as cerebrovascular conductance index (CVCi). CVRCO2 was taken as the linear slope for MCA Vm and MCA CVCi versus PETCO2. As expected, baseline MAP was higher in AF+HTN than AF (107±9 vs. 98±9 mmHg, respectively; p<0.001). Baseline MCA Vm was numerically lower in AF+HTN than AF, but this did not reach statistical significance (50 [44-60] vs. 52 [45-63] cm.s−1, respectively; p=0.075), while baseline CVCi was lower in AF+HTN compared to AF (0.46 [0.42-0.57] vs. 0.54 [0.44-0.63] cm.s−1.mmHg−1; p<0.001). MCA Vm CVRCO2 was not different between groups (1.70 [1.47-2.19] and 1.74 [1.54-2.52] cm/s/mmHg−2 for AF+HTN and AF, respectively; p=0.221), whereas MCA CVCi CVRCO2 was 13% lower in AF+HTN compared to AF (0.013 ± 0.004 vs. 0.015 ± 0.005 cm.s.mmHg−2; p=0.047). Stepwise linear regression analysis identified that cardiac rhythm during data acquisition (AF or normal sinus rhythm) was a predictor of baseline MCA CVCi and MCA CVCi CVRCO2. In summary, our results demonstrate impaired MCA CVCi CVRCO2 in AF+HTN and suggest that the presence of HTN worsens cerebrovascular function in AF. Such cerebrovascular alterations may be important for the development of cognitive decline and diminished brain health in AF. Funding provided by Bristol-Myers Squibb/Pfizer Alliance Project Grant (CV185-481), British Heart Foundation Project Grant (PG/15/45/31579) and the National Institute of Health Research Clinical Research Network (NIHR CRN). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Intravoxel incoherent motion as a surrogate marker of perfused vascular density in rat brain.

Intravoxel incoherent motion (IVIM) MRI has emerged as a valuable technique for the assessment of tissue characteristics and perfusion. However, there is limited knowledge about the relationship between IVIM-derived measures and changes at the level of the vascular network. In this study, we investigated the potential use of IVIM MRI as a noninvasive tool for measuring changes in cerebral vascular density. Variations in quantitative immunohistochemical measurements of the vascular density across different regions in the rat brain (cortex, corpus callosum, hippocampus, thalamus, and hypothalamus) were related to the pseudo-diffusion coefficient D* and the flowing blood fraction f in healthy Wistar rats. We assessed whether region-wise differences in the vascular density are reflected by variations in the IVIM measurements and found a significant positive relationship with the pseudo-diffusion coefficient (p < 0.05, β = 0.24). The effect of cerebrovascular alterations, such as blood-brain barrier (BBB) disruption on the perfusion-related IVIM parameters, is not well understood. Therefore, we investigated the effect of BBB disruption on the IVIM measures in a rat model of metabolic and vascular comorbidities (ZSF1 obese rat) and assessed whether this affects the relationship between the cerebral vascular density and the noninvasive IVIM measurements. We observed increased vascular permeability without detecting any differences in diffusivity, suggesting that BBB leakage is present before changes in the tissue integrity. We observed no significant difference in the relationship between cerebral vascular density and the IVIM measurements in our model of comorbidities compared with healthy normotensive rats.

Neural stem cell-derived exosomes regulate cell proliferation, migration, and cell death of brain microvascular endothelial cells via the miR-9/Hes1 axis under hypoxia.

Our previous study found that mouse embryonic neural stem cell (NSC)-derived exosomes (EXOs) regulated NSC differentiation via the miR-9/Hes1 axis. However, the effects of EXOs on brain microvascular endothelial cell (BMEC) dysfunction via the miR-9/Hes1 axis remain unknown. Therefore, the current study aimed to determine the effects of EXOs on BMEC proliferation, migration, and death via the miR-9/Hes1 axis. Immunofluorescence, quantitative real-time polymerase chain reaction, cell counting kit-8 assay, wound healing assay, calcein-acetoxymethyl/propidium iodide staining, and hematoxylin and eosin staining were used to determine the role and mechanism of EXOs on BMECs. EXOs promoted BMEC proliferation and migration and reduced cell death under hypoxic conditions. The overexpression of miR-9 promoted BMEC proliferation and migration and reduced cell death under hypoxic conditions. Moreover, miR-9 downregulation inhibited BMEC proliferation and migration and also promoted cell death. Hes1 silencing ameliorated the effect of amtagomiR-9 on BMEC proliferation and migration and cell death. Hyperemic structures were observed in the regions of the hippocampus and cortex in hypoxia-induced mice. Meanwhile, EXO treatment improved cerebrovascular alterations. NSC-derived EXOs can promote BMEC proliferation and migration and reduce cell death via the miR-9/Hes1 axis under hypoxic conditions. Therefore, EXO therapeutic strategies could be considered for hypoxia-induced vascular injury.

Repetitive head trauma and apoE4 induce chronic cerebrovascular alterations that impair tau elimination from the brain

Repetitive mild traumatic brain injuries (r-mTBI) sustained in the military or contact sports have been associated with the accumulation of extracellular tau in the brain, which may contribute to the pathogenesis of neurodegenerative tauopathies. The expression of the apolipoprotein E4 (apoE4) isoform has been associated with higher levels of tau in the brain, and worse clinical outcomes after r-mTBI, though the influence of apoE genotype on extracellular tau dynamics in the brain is poorly understood. We recently demonstrated that extracellular tau can be eliminated across blood-brain barrier (BBB), which is progressively impaired following r-mTBI. The current studies investigated the influence of repetitive mild TBI (r-mTBI) and apoE genotype on the elimination of extracellular solutes from the brain. Following intracortical injection of biotin-labeled tau into humanized apoE-Tr mice, the levels of exogenous tau residing in the brain of apoE4 mice were elevated compared to other isoforms, indicating reduced tau elimination. Additionally, we found exposure to r-mTBI increased tau residence in apoE2 mice, similar to our observations in E2FAD animals. Each of these findings may be the result of diminished tau efflux via LRP1 at the BBB, as LRP1 inhibition significantly reduced tau uptake in endothelial cells and decreased tau transit across an in vitro model of the BBB (basolateral-to-apical). Notably, we showed that injury and apoE status, (particularly apoE4) resulted in chronic alterations in BBB integrity, pericyte coverage, and AQP4 polarization. These aberrations coincided with an atypical reactive astrocytic gene signature indicative of diminished CSF-ISF exchange. Our work found that CSF movement was reduced in the chronic phase following r-mTBI (>18 months post injury) across all apoE genotypes. In summary, we show that apoE genotype strongly influences cerebrovascular homeostasis, which can lead to age-dependent deficiencies in the elimination of toxic proteins from the brain, like tau, particularly in the aftermath of head trauma.

Association between vertebral artery dominance and basilar artery curvature in migraineurs: an anatomical magnetic resonance imaging study.

Numerous studies demonstrate a link between cerebrovascular alterations and migraine pathogenesis. We investigated the association between migraine and vertebral artery dominance (VAD), basilar artery (BA) curvature, and elongation. This cross-sectional MRI study included 74 migraine patients and 74 control subjects aged between 18 and 55 years. Diameters of the intracranial part of the vertebral artery (VA) and BA, height of the BA bifurcation, and total lateral displacement of the BA were measured. In addition, we investigated the directional relationship between VAD and BA curvature. There were no statistically significant differences between the groups regarding VA and BA diameters and total lateral displacement of the BA. The height of the BA bifurcation was found to be significantly higher in migraine patients compared to controls (p = 0.002). The left-side VAD was more frequent in migraine patients compared to control subjects (60.8% (45/74) vs 41.9% (31/74), p = 0.001). In migraine patients, particularly those with aura (MwA) patients, with left-side VAD, the rate of BA displacement to the right side is significantly higher than those with right-side VAD or non-VAD (p = 0.022). Also, we found that total lateral displacement of the BA is correlated with VA asymmetry in patients with MwA (r = 0.538, p = 0.007). VAD and its opposite-directional relationship with the lateral displacement of the BA may be associated with migraine pathophysiology. Together with aging, this association may contribute to changes in the vertebrobasilar system (VBS) geometry which may result in increased risk for posterior circulation infarction (PCI) in migraineurs.

Basic Science and Pathogenesis - Part 1.

Cerebrovascular alterations and innate immune activation are key features of Alzheimer's disease (AD). However, the mechanisms that link blood-brain barrier disruption to neurodegeneration are poorly understood and well-defined druggable targets at the neurovascular interface are limited. We identified the blood coagulation factor fibrinogen as necessary and sufficient for the induction of pathogenic neuroinflammation in neurologic diseases1. Fibrinogen induces spine elimination and promotes cognitive deficits in AD mouse models mediated by oxidative stress induction in microglia2, 3. Volume imaging in cleared mouse and human AD brains combined with repetitive in vivo two-photon imaging showed focal fibrinogen deposits associated with loss of dendritic spines independent of amyloid plaques. We developed a first-in-class fibrin-targeting immunotherapy to selectively inhibit fibrin-induced inflammation without interfering with its beneficial coagulation effects4. Fibrin-targeting immunotherapy entered the CNS, bound to fibrin, and inhibited amyloid-driven neurotoxicity and neurotoxic inflammatory gene programs in AD mice. Thus, fibrinogen links cerebrovascular damage with immune-mediated neurodegeneration and fibrin therapeutics may have important therapeutic implications inhibiting vascular-driven neurodegeneration in AD and related conditions. 1. Petersen et al., Nat Rev Neurosci. 2018, 19:283-301 2. Merlini et al. Neuron 2019, 101:1099-1108 3. Mendiola et al. Nat Immunol 2020, 21:513-524 4. Ryu et al. Nat Immunol 2018, 19:1212-1223.

Altered BOLD Signal Fluctuations in precuneus relate to inflammatory markers and vascular risk in the AD spectrum

AbstractBackgroundInflammation, vascular disease and Alzheimer’s Disease (AD) appear to be closely linked. We recently showed that increased vascular risk relates to certain inflammatory profiles in CSF in the DELCODE cohort (Hayek et al, AAIC 2022). Moreover, we found cerebrovascular alterations in posterior‐midline regions including precuneus in subjects at risk for AD and with cognitive impairment relative to controls (Behrenbruch et al). Here, we examined the contributions of vascular risk and related inflammatory markers to alterations in resting‐state fMRI BOLD fluctuations that are sensitive to cerebrovascular reactivity (CVR)—a proposed marker of cerebrovascular dysfunction.MethodLeveraging resting‐state fMRI BOLD signal, we mapped voxel‐wise relative CVR (rCVR), using mean global signal as regressor, and the relative coefficient of variation (rCV). See Figure 1 for methodological details. We derived average rCV/rCVR from the precuneus as region of interest. Inflammation‐related CSF markers and AD markers (ptau181 and Aß42/40) from CSF were available in 205 subjects with rCVR/rCV maps. A Principal component (PC) analysis on 16 inflammation‐related CSF markers previously revealed 4 PCs. PC2 and PC3 were related to higher vascular risk scores (covering hypertension, diabetes and abnormal fat metabolism based on medical reports). We used linear regression models to assess how inflammation PC scores and AD biomarkers related to precuneus rCVR or rCV (controlling for age, sex, site, education and mean framewise displacement). We also tested if rCVR/rCV was related to vascular risk or memory.ResultLower precuneus rCVR was predicted by higher values of the inflammatory component PC2 (mainly driven by markers CRP, C1q and FactorB), with no additional effect of other PCs or AD markers. Lower precuneus rCV was predicted by higher values of the inflammatory component PC3 (mainly driven by IP10, MCP1, MIF, CRP, C4) and by higher ptau. Lower precuneus rCVR was also related to higher vascular risk. Lower rCVR and rCV related to worse memory. Figure 2 shows supplementary correlations of individual inflammation markers.ConclusionLower rCVR and rCV in the precuneus that are thought to reflect vascular dysfunction, relate to higher vascular‐risk related inflammatory markers beyond AD pathology. Their concurrent dynamics requires further investigation to understand their unique contributions to microvascular pathology.

Altered BOLD Signal Fluctuations in precuneus relate to inflammatory markers and vascular risk in the AD spectrum

AbstractBackgroundInflammation, vascular disease and Alzheimer’s Disease (AD) appear to be closely linked. We recently showed that increased vascular risk relates to certain inflammatory profiles in CSF in the DELCODE cohort (Hayek et al, AAIC 2022). Moreover, we found cerebrovascular alterations in posterior‐midline regions including precuneus in subjects at risk for AD and with cognitive impairment relative to controls (Behrenbruch et al). Here, we examined the contributions of vascular risk and related inflammatory markers to alterations in resting‐state fMRI BOLD fluctuations that are sensitive to cerebrovascular reactivity (CVR)—a proposed marker of cerebrovascular dysfunction.MethodLeveraging resting‐state fMRI BOLD signal, we mapped voxel‐wise relative CVR (rCVR), using mean global signal as regressor, and the relative coefficient of variation (rCV). See Figure 1 for methodological details. We derived average rCV/rCVR from the precuneus as region of interest. Inflammation‐related CSF markers and AD markers (ptau181 and Aβ42/40) from CSF were available in 205 subjects with rCVR/rCV maps. A Principal component (PC) analysis on 16 inflammation‐related CSF markers previously revealed 4 PCs. PC2 and PC3 were related to higher vascular risk scores (covering hypertension, diabetes and abnormal fat metabolism based on medical reports). We used linear regression models to assess how inflammation PC scores and AD biomarkers related to precuneus rCVR or rCV (controlling for age, sex, site, education and mean framewise displacement). We also tested if rCVR/rCV was related to vascular risk or memory.ResultLower precuneus rCVR was predicted by higher values of the inflammatory component PC2 (mainly driven by markers CRP, C1q and FactorB), with no additional effect of other PCs or AD markers. Lower precuneus rCV was predicted by higher values of the inflammatory component PC3 (mainly driven by IP10, MCP1, MIF, CRP, C4) and by higher ptau. Lower precuneus rCVR was also related to higher vascular risk. Lower rCVR and rCV related to worse memory. Figure 2 shows supplementary correlations of individual inflammation markers.ConclusionLower rCVR and rCV in the precuneus that are thought to reflect vascular dysfunction, relate to higher vascular‐risk related inflammatory markers beyond AD pathology. Their concurrent dynamics requires further investigation to understand their unique contributions to microvascular pathology.

Neurovascular crosstalk and cerebrovascular alterations: an underestimated therapeutic target in autism spectrum disorders.

Normal brain development, function, and aging critically depend on unique characteristics of the cerebrovascular system. Growing evidence indicated that cerebrovascular defects can have irreversible effects on the brain, and these defects have been implicated in various neurological disorders, including autism spectrum disorder (ASD). ASD is a neurodevelopmental disorder with heterogeneous clinical manifestations and anatomical changes. While extensive research has focused on the neural abnormalities underlying ASD, the role of brain vasculature in this disorder remains poorly understood. Indeed, the significance of cerebrovascular contributions to ASD has been consistently underestimated. In this work, we discuss the neurovascular crosstalk during embryonic development and highlight recent findings on cerebrovascular alterations in individuals with ASD. We also discuss the potential of vascular-based therapy for ASD. Collectively, these investigations demonstrate that ASD can be considered a neurovascular disease.

Beneficial effects of empagliflozin and liraglutide on the cerebral microcirculation of diabetic rats.

This study aimed to evaluate the effects of the antidiabetics liraglutide, a GLP-1 analog, and empagliflozin, an SGLT-2 inhibitor, on the brain microcirculation of diabetic rats. Type 2 diabetes mellitus (DM) was experimentally induced in male Wistar rats by combining a high-fat diet and a low dose of streptozotocin (35 mg/kg). Liraglutide (100 μg/kg s.c.) and empagliflozin (10 mg/kg, oral) were administered for 5 weeks. Body weight was monitored periodically. Oral glucose tolerance, fasting glycemia, and blood triglycerides were evaluated after the treatments. Endothelial-leukocyte interactions in the brain microcirculation and structural capillary density were assessed. DM rats presented metabolic and cerebrovascular alterations. Liraglutide treatment decreased body weight and blood triglycerides of DM rats. Empagliflozin treatment improved glucose tolerance but only the combination therapy significantly reduced fasting blood glucose. Both treatments and their combination reduced leukocyte adhesion into the endothelium of brain venules. However, empagliflozin was more effective in preventing DM-induced microvascular rarefaction. These findings suggest that chronic treatment with SGLT2 inhibitors and GLP-1 receptor agonists may serve as potential therapeutic approaches to prevent microvascular complications associated with diabetes.

Proteomics identifies lipocalin-2 in neonatal inflammation associated with cerebrovascular alteration in mice and preterm infants

Staphylococcus (S.) epidermidis is the most common nosocomial coagulase-negative staphylococci infection in preterm infants. Clinical signs of infection are often unspecific and novel markers to complement diagnosis are needed. We investigated proteomic alterations in mouse brain after S.epidermidis infection and in preterm infant blood. We identified lipocalin-2 (LCN2) as a crucial protein associated with cerebrovascular changes and astrocyte reactivity in mice. We further proved that LCN2 protein expression was associated with endothelial cells but not astrocyte reactivity. By combining network analysis and differential expression approaches, we identified LCN2 linked to blood C-reactive protein levels in preterm infants born <28weeks of gestation. Blood LCN2 levels were associated with similar alterations of cytokines and chemokines in both infected mice and human preterm infants with increased levels of C-reactive protein. This experimental and clinical study suggests that LCN2 may be a marker of preterm infection/inflammation associated with cerebrovascular changes and neuroinflammation.

16p11.2 haploinsufficiency reduces mitochondrial biogenesis in brain endothelial cells and alters brain metabolism in adult mice

Neurovascular abnormalities in mouse models of 16p11.2 deletion autism syndrome are reminiscent of alterations reported in murine models of glucose transporter deficiency, including reduced brain angiogenesis and behavioral alterations. Yet, whether cerebrovascular alterations in 16p11.2df/+ mice affect brain metabolism is unknown. Here, we report that anesthetized 16p11.2df/+ mice display elevated brain glucose uptake, a phenomenon recapitulated in mice with endothelial-specific 16p11.2 haplodeficiency. Awake 16p11.2df/+ mice display attenuated relative fluctuations of extracellular brain glucose following systemic glucose administration. Targeted metabolomics on cerebral cortex extracts reveals enhanced metabolic responses to systemic glucose in 16p11.2df/+ mice that also display reduced mitochondria number in brain endothelial cells. This is not associated with changes in mitochondria fusion or fission proteins, but 16p11.2df/+ brain endothelial cells lack the splice variant NT-PGC-1α, suggesting defective mitochondrial biogenesis. We propose that altered brain metabolism in 16p11.2df/+ mice is compensatory to endothelial dysfunction, shedding light on previously unknown adaptative responses.

Using Mean Arterial Pressure in Hypertension Diagnosis versus Using Either Systolic or Diastolic Blood Pressure Measurements.

Hypertension is a severe and highly prevalent disease. It is considered a leading contributor to mortality worldwide. Diagnosis guidelines for hypertension use systolic and diastolic blood pressure (BP) together. Mean arterial pressure (MAP), which refers to the average of the arterial blood pressure through a single cardiac cycle, can be an alternative index that may capture the overall exposure of the person to a heightened pressure. A clinical hypothesis, however, suggests that in patients over 50 years old in age, systolic BP may be more predictive of adverse events, while in patients under 50 years old, diastolic BP may be slightly more predictive. In this study, we investigated the correlation between cerebrovascular changes, (impacted by hypertension), and MAP, systolic BP, and diastolic BP separately. Several experiments were conducted using real and synthetic magnetic resonance angiography (MRA) data, along with corresponding BP measurements. Each experiment employs the following methodology: First, MRA data were processed to remove noise, bias, or inhomogeneity. Second, the cerebrovasculature was delineated for MRA subjects using a 3D adaptive region growing connected components algorithm. Third, vascular features (changes in blood vessel's diameters and tortuosity) that describe cerebrovascular alterations that occur prior to and during the development of hypertension were extracted. Finally, feature vectors were constructed, and data were classified using different classifiers, such as SVM, KNN, linear discriminant, and logistic regression, into either normotensives or hypertensives according to the cerebral vascular alterations and the BP measurements. The initial results showed that MAP would be more beneficial and accurate in identifying the cerebrovascular impact of hypertension (accuracy up to 95.2%) than just using either systolic BP (accuracy up to 89.3%) or diastolic BP (accuracy up to 88.9%). This result emphasizes the pathophysiological significance of MAP and supports prior views that this simple measure may be a superior index for the definition of hypertension and research on hypertension.

Cerebral chronic hypoperfusion in mice causes premature aging of the cerebrovasculature

Chronic cerebral hypoperfusion (CCH) is the main characteristic of an aged brain showing cerebrovascular alterations. Our previous study that the morphological changes in the pial arteries accompany a decrease in the cerebral blood flow in aged mouse brains, and it raises the question of whether artificial CCH can induce the same changes in brain vessel morphology. Here, we examined the effect of CCH on cerebrovascular morphology. Using a microcoil-induced chronic cerebral hypoperfusion (MCH) model, we induced CCH for 8 and 12 weeks. The cerebrovasculature morphology was evaluated using three-dimensional vessel analysis and compared with that of aging mice. We found the morphological changes in brain vessels of MCH mice, indicating that the CCH can induce cerebrovascular alteration. However, the changes in brain vessel morphology in the MCH mice were different in detail from those in the aging mice. Aging mice showed an increase in vessel tortuosity and thinned string vessels; MCH mice mainly showed thinned string vessels. This suggests that CCH may be a cause of age-related cerebrovascular alterations.

Cerebrovascular Function in Migraine Patients during, their Interictal Period, Compared to Normal Healthy Controls

Background: Migraine is a debilitating neurovascular disorder which primarily impacts the working age population. The aim of the study was to determine if transient hemodynamic alterations during each migraine attack translates into cerebrovascular alterations, during migraineurs interictal period. A secondary hypothesis was to determine if there was any relationship between vascular hemodynamics and either the severity or frequency of migraine attacks.Methods: We recruited 29 volunteers: 13 migraineurs (mean age 28±8.8 years; 12 female and 1 male) and 16 age-matched controls (mean age 26.6±6.9; 9 female and 7 male). Volunteers were classified as migraine sufferer or not (control group). All individuals underwent a detailed ophthalmic examination by a qualified optometrist and a Migraine Disability Assessment. Cerebral blood velocity measurements for the Middle Cerebral Artery (MCA) and Vertebral Artery (VA) were obtained using Colour Doppler Imaging using the Hitachi Aloka Noblus ultrasound system. The investigators were blind to the migraine diagnosis.Results: During their interictal period migraineurs appear to have no significant difference in any hemodynamic parameter, for either their MCA and VA, when compared to normal healthy controls. Neither was a significant relationship between Migraine Disability Assessment Scores and any vascular parameter reported.Conclusion: This study found nil cerebrovascular alterations which could be measured in migraineurs compared to normal healthy controls, during their interictal period.

How does APOE genotype moderate the relationship between physical activity and Alzheimer’s disease risk? A novel integrative model

AbstractBackgroundEvidence suggests that physical activity (PA) confers protection against Alzheimer’s disease (AD), while the Apolipoprotein E (APOE) ε4 allele represents the greatest genetic risk factor. Extensive research has thus far failed to establish whether frequent PA can mitigate the increased AD risk associated with APOE ε4. Studies looking at various AD‐related traits (e.g., amyloid beta burden or cortical atrophy) might show diverse results because the biological pathways involved are differentially influenced by PA, APOE ε4 carriage and their interaction. In order to bridge these discrepancies, the aim of this theoretical article is to propose a novel model of how PA and APOE ε4 carriage, independently and in combination, may alter well‐established molecular mechanisms underlying AD pathogenesis.MethodAvailable literature was searched to investigate how PA and APOE ε4 carriage, independently and in combination, may alter several molecular pathways involved in AD pathogenesis. The reviewed mechanisms include amyloid beta (Aβ) and tau deposition and clearance, neuronal resilience and neurogenesis, lipid function and cerebrovascular alterations, brain immune response, and glucose metabolism.ResultWe have identified potential pathways through which the beneficial effects of PA might offset some of the detrimental outcomes of APOE ε4 carriage. Nonetheless, PA does not seem to be able to entirely prevent or revert the noxious effects of genetic risk. Our integrative model includes evidence‐based and theoretical synergistic interactions across mechanisms, and a proposal of testable hypotheses for future studies.ConclusionPA influences a wide array of molecular targets involved in AD neuropathology. A better understanding of where, when and most importantly, how, PA decreases AD risk in the presence of the APOE ε4 allele is essential to formulate combined therapeutic approaches.