Regional Cerebral Blood Flow Research Articles

Unveiling connections between venous disruption and cerebral small vessel disease using diffusion tensor image analysis along perivascular space (DTI-ALPS): A 7-T MRI study.

Cerebral venous disruption is one of the characteristic findings in cerebral small vessel disease (CSVD), and its disruption may impede perivascular glymphatic drainage. And lower diffusivity along perivascular space (DTI-ALPS) index has been suggested to be with the presence and severity of CSVD. However, the relationships between venous disruption, DTI-ALPS index, and CSVD neuroimaging features remain unclear. To investigate the association between venous integrity and perivascular diffusion activity, and explore the mediating role of DTI-ALPS index between venous disruption and CSVD imaging features. In this cross-sectional study, 31 patients (mean age, 59.0 ± 9.9 years) were prospectively enrolled and underwent 7-T magnetic resonance (MR) imaging. DTI-ALPS index was measured to quantify the perivascular diffusivity. The visibility and continuity of deep medullary veins (DMVs) were evaluated based on a brain region-based visual score on high-resolution susceptibility-weighted imaging. White matter hyperintensity (WMH) and perivascular space (PVS) were assessed using qualitative and quantitative methods. Linear regression and mediation analysis were performed to analyze the relationships among DMV scores, DTI-ALPS index, and CSVD features. The DTI-ALPS index was significantly associated with the parietal DMV score (β = -0.573, p corrected = 0.004). Parietal DMV score was associated with WMH volume (β = 0.463, p corrected = 0.013) and PVS volume in basal ganglia (β = 0.415, p corrected = 0.028). Mediation analyses showed that DTI-ALPS index manifested a full mediating effect on the association between parietal DMV score and WMH (indirect effect = 0.115, Pm = 43.1%), as well as between parietal DMV score and PVS volume in basal ganglia (indirect effect = 0.161, Pm = 42.8%). Cerebral venous disruption is associated with glymphatic activity, and with WMH and PVS volumes. Our results suggest cerebral venous integrity may play a critical role in preserving perivascular glymphatic activity; while disruption of small veins may impair the perivascular diffusivity, thereby contributing to the development of WMH and PVS enlargement.

Magnetic resonance diffusion tensor imaging for detecting the cerebral microstructure changes in patients with CSVD -induced mild cognitive impairment.

Cerebral small vessel disease (CSVD)-induced mild cognitive impairment (MCI) has been linked to cognitive decline. Brain atrophy is considered the most common change in MCI patients, which can be measured by diffusion tensor imaging (DTI). The study aimed to explore the relationship between DTI parameters and cognitive function in CSVD patients with MCI. This retrospective analysis involved 185 patients with CSVD, comprising 87 cases with MCI and 98 cases without MCI (NMCI). Analyses of demographic and clinical characteristics were conducted. DTI-measured fractional anisotropy (FA) and mean diffusivity (MD) in the hippocampus and entorhinal cortex regions were examined. The diagnostic values were determined using receiver-operative-curve (ROC) analysis, with the Youden Index identifying optimum sensitivity and specificity. Correlations between Montreal cognitive assessment (MoCA) scores and FA or MD in MCI patients were further assessed. No significant differences were observed in demographic and clinical characteristics between MCI and NMCI groups (all p>0.05), except for diabetes prevalence (p=0.011). Notably, the ROC analysis highlighted the diagnostic potential of FA, showing the maximum area under the curve values (Hippocampus-Left: 0.76; Hippocampus-Right: 0.66; Entorhinal cortex-Left: 0.62; Entorhinal cortex-Right: 0.64). MD exhibited a significant negative correlation with MoCA scores (Hippocampus-Left: r=-0.58, p<0.001; Hippocampus-Right: r=-0.41, p<0.001; Entorhinal cortex-Left: r=-0.49, p<0.001; Entorhinal cortex-Right: r=-0.27, p<0.001), while FA showed a significant positive correlation (Hippocampus-Left: r=0.51, p<0.001; Hippocampus-Right: r=0.31, p=0.004; Entorhinal cortex-Left: r=0.35, p<0.001; Entorhinal cortex-Right: r=0.38, p<0.001). The study demonstrates the diagnostic value of DTI parameters in CSVD patients with MCI, emphasizing the associations between microstructural brain changes and cognitive function.

Impact of intracranial hypertension and cerebral perfusion pressure on spreading depolarization.

Spreading depolarization (SD) develops after stroke and traumatic brain injury and may contribute to secondary brain damage. These diseases are often accompanied by intracranial hypertension, but little is known about the effects of intracranial pressure (ICP) on SD. Here, we study the effect of increased ICP on hemodynamic and metabolic response to SD in rats. SDs were triggered at different ICPs and cerebral perfusion pressures (CPP). The regional cerebral blood flow (rCBF), partial pressure of brain tissue oxygen (PbtO2), cerebral extracellular glucose and lactate concentrations were recorded. Fluoro-Jade staining was used to quantify neuronal injury in cortex. At high ICP (50 mmHg) with low CPP (30 mmHg), rCBF and PbtO2 were monophasically decreased in contrast to a monophasically increased pattern under normal conditions. Neuronal death increased in both hemispheres but much more on the side where SDs were triggered. At high ICP (50 mmHg) with normal CPP (70 mmHg), CBF and metabolism during SD did not differ from baseline, and neuronal death did not increase even on the side of SD induction. These data suggest that maintaining CPP at 70 mmHg, even when the ICP is as high as 50 mmHg, preserves normal blood flow and metabolism during SD events and prevents neuronal degeneration.

Cerebral Cortical Vasodilation via Nicotinic Receptors by Heated Tobacco Product Aerosol Extract in Rats.

Smoking increases the risk of lung cancer due to a number of components of smoke. The use of novel heated tobacco products (HTPs), alternative to conventional combustion cigarettes, has increased in recent years. However, the in vivo biological effects of HTPs are poorly understood. This study aimed to clarify the acute effects of injecting aerosol extract prepared from an HTP on regional cerebral blood flow (rCBF) in rat cortex by comparing them to the effects of injecting smoke extract prepared from conventional combustible cigarettes. In urethane anesthetized rats, rCBF was measured using laser speckle contrast imaging simultaneously with arterial pressure. Both cigarette smoke extract and HTP aerosol extract, at a dose equivalent to 30 μg nicotine/kg, injected intravenously, increased cortical rCBF without changing arterial pressure. The magnitude and time course of the increased rCBF response to both extracts were similar throughout the cortical area, and the rCBF increases were all abolished by dihydro-β-erythroidine, an α4β2-preferring nicotinic acetylcholine receptor (nAChR) antagonist. In conclusion, our study demonstrated that the effect of injecting aerosol extract prepared from an HTP, an acute increase in cortical rCBF, is mediated via activation of α4β2-like neuronal nAChRs in the brain.

Quantitative modeling of lenticulostriate arteries on 7-T TOF-MRA for cerebral small vessel disease.

We developed a framework for segmenting and modeling lenticulostriate arteries (LSAs) on 7-T time-of-flight magnetic resonance angiography and tested its performance on cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) patients and controls. We prospectively included 29 CADASIL patients and 21 controls. The framework includes a small-patch convolutional neural network (SP-CNN) for fine segmentation, a random forest for modeling LSAs, and a screening model for removing wrong branches. The segmentation performance of our SP-CNN was compared to competitive networks. External validation with different resolution was performed on ten patients with aneurysms. Dice similarity coefficient (DSC) and Hausdorff distance (HD) between each network and manual segmentation were calculated. The modeling results of the centerlines, diameters, and lengths of LSAs were compared against manual labeling by four neurologists. The SP-CNN achieved higher DSC (92.741 ± 2.789, mean ± standard deviation) and lower HD (0.610 ± 0.141 mm) in the segmentation of LSAs. It also outperformed competitive networks in the external validation (DSC 82.6 ± 5.5, HD 0.829 ± 0.143 mm). The framework versus manual difference was lower than the manual inter-observer difference for the vessel length of primary branches (median -0.040 mm, interquartile range -0.209 to 0.059 mm) and secondary branches (0.202 mm, 0.016-0.537 mm), as well as for the offset of centerlines of primary branches (0.071 mm, 0.065-0.078 mm) and secondary branches (0.072, 0.064-0.080 mm), with p < 0.001 for all comparisons. Our framework for LSAs modeling/quantification demonstrated high reliability and accuracy when compared to manual labeling. NCT05902039 ( https://clinicaltrials.gov/study/NCT05902039?cond=NCT05902039 ). The proposed automatic segmentation and modeling framework offers precise quantification of the morphological parameters of lenticulostriate arteries. This innovative technology streamlines diagnosis and research of cerebral small vessel disease, eliminating the burden of manual labeling, facilitating cohort studies and clinical diagnosis. The morphology of LSAs is important in the diagnosis of CSVD but difficult to quantify. The proposed algorithm achieved the performance equivalent to manual labeling by neurologists. Our method can provide standardized quantitative results, reducing radiologists' workload in cohort studies.

Diagnosing Monogenic Stroke at Younger Age.

An increasing number of monogenic conditions underlying stroke are being identified. We explored the possibilities of increasing the diagnostic yield of monogenic stroke in a population under 56 years of age. Fifty probands ≤55 years at their first stroke episode were characterized clinically and investigated by whole genome sequencing. Probands had one or more of: (1) one or more first to second degree relatives with stroke under 60 years or same stroke-causing condition/disease; (2) no hypertension, hypercholesterolemia, diabetes, heart disease, or smoking; or (3) either multiple stroke episodes or multiple arterial dissections. Variants with minor allele frequency under 0.01, identified by using our stroke gene panels, were assessed. The stroke subtypes, including large artery atherosclerotic, large artery nonatherosclerotic (tortuosity, dolichoectasia, aneurysm, nonatherosclerotic dissection, or occlusion), cerebral small vessel disease, cardioembolic (arrhythmia, heart defect, or cardiomyopathy), coagulation dysfunctions (venous thrombosis, arterial thrombosis, or bleeding tendency), intracerebral hemorrhage, vascular malformations (cavernoma or arteriovenous malformations), metabolic disorders, or cryptogenic embolic, were used for genotype-phenotype correlation. In a final step, we combined genetic and clinical information to determine if the genetic variant likely was the cause of stroke in the patients. Whole genome sequencing of younger patients with stroke identified 17 clinically matching genetic variants in 15 of 50 (30%) patients, while a stronger clinical correlation with stroke was established in only 6 (12%) of them. Stroke-related genetic variants were identified in 4 of 5 (80%) patients with cardioembolic stroke subtype, 3 of 4 (75%) with intracerebral hemorrhage, 7 of 18 (39%) with cryptogenic embolic stroke, 1 of 6 (17%) with small vessel disease, and 3 of 15 (20%) of patients with nonatherosclerotic large artery stroke, including 1 of 11 (9%) with cervical dissection stroke. Careful clinical interpretation of whole genome data using stroke gene panels can detect monogenic causes of early stroke, allowing individualized follow-up and opening new possibilities for potential treatment.

Varicella zoster vasculopathy causing recurrent ischaemic strokes in an immunocompetent patient.

A 66-year-old woman reported 10 days of generalised weakness, falls and memory 'glitches'. She had developed left-sided ophthalmic herpes zoster 3 months before but was otherwise well. MR scan of brain showed acute left-sided ischaemic strokes and CT cerebral angiogram identified marked stenoses of the left anterior and middle cerebral arteries. We suspected varicella-zoster virus vasculopathy, confirmed by cerebrospinal fluid analysis. Initially she had further ischaemic strokes despite intravenous acyclovir, prednisone, aspirin and clopidogrel. However, after prolonged acyclovir and prednisone, there were no new infarcts though imaging of left anterior and middle cerebral artery vessel walls showed persistent inflammation. Varicella zoster vasculopathy can cause recurrent ischaemic strokes, even in immunocompetent people with no cardiovascular risk factors, and despite long-term antiviral therapy.

Therapeutic utility of Perfluorocarbon Oxygent in limiting the severity of subarachnoid hemorrhage in mice

Subarachnoid hemorrhage (SAH) is the deadliest form of hemorrhagic stroke; however, effective therapies are still lacking. Perfluorocarbons (PFCs) are lipid emulsion particles with great flexibility and their much smaller size as compared to red blood cells (RBCs) allows them to flow more efficiently within the blood circulation. Due to their ability to carry oxygen, a specific PFC-based emulsion, PFC-Oxygent, has been used as a blood substitute; however, its role in cerebral blood flow regulation is unknown. Adult C57BL/6 wildtype male mice were subjected to an endovascular perforation model of SAH followed by an intravenous (i.v.) injection of 9 ml/kg PFC-Oxygent or no treatment at 5 h after SAH. At 48 h after SAH, functional and anatomical outcomes were assessed. We found that SAH resulted in significant neurologic and motor deficits which were prevented by PFC-Oxygent treatment. We found that SAH-induced vasospasm, reduced RBC deformability, and augmented endothelial dysfunction were also restricted by PFC-Oxygent treatment. Moreover, mitochondrial activity and fusion proteins were also markedly decreased as assessed by oxidative phosphorylation (OXPHOS) after SAH. Interestingly, PFC-Oxygent treatment brought the mitochondrial activity close to the basal level. Moreover, SAH attenuated the level of phosphorylated AMP-activated protein kinase (pAMPK), whereas PFC treatment improved pAMPK levels. These data show the beneficial effects of PFC-Oxygent in limiting the severity of SAH. Further studies are needed to fully understand the mechanism through which PFC-Oxygent exerts its beneficial effects in limiting SAH severity.

Circulating MicroRNAs as potential biomarkers for cerebral collateral circulation in symptomatic carotid stenosis

Circulating MicroRNAs as potential biomarkers for cerebral collateral circulation in symptomatic carotid stenosis

Characterizing the role of the microbiota-gut-brain axis in cerebral small vessel disease: an integrative multi‑omics study

Characterizing the role of the microbiota-gut-brain axis in cerebral small vessel disease: an integrative multi‑omics study

Automatic segmentation and diameter measurement of deep medullary veins.

As one of the pathogenic factors of cerebral small vessel disease, venous collagenosis may result in the occlusion or stenosis of deep medullary veins (DMVs). Although numerous DMVs can be observed in susceptibility-weighted MRI images, their diameters are usually smaller than the MRI resolution, making it difficult to segment them and quantify their sizes. We aim to automatically segment DMVs and measure their diameters from gradient-echo images. A neural network model was trained for DMV segmentation based on the gradient-echo magnitude and phase images of 20 subjects at 7 T. The diameters of DMVs were obtained by fitting measured complex images with model images that accounted for the DMV-induced magnetic field and point spread function. A phantom study with graphite rods of different diameters was conducted to validate the proposed method. Simulation was carried out to evaluate the voxel-size dependence of measurement accuracy for a typical DMV size. The automatically segmented DMV masks had Dice similarity coefficients of 0.68 ± 0.03 (voxel level) and 0.83 ± 0.04 (cluster level). The fitted graphite-rod diameters closely matched their true values. In simulation, the fitted diameters closely matched the true value when voxel size was ≤ 0.45 mm, and 92.2% of DMVs had diameters between 90 μm and 200 μm with a peak at about 120 μm, which agreed well with an earlier ex vivo report. The proposed methods enabled efficient and quantitative study of DMVs, which may help illuminate the role of DMVs in the etiopathogenesis of cerebral small vessel disease.

Peripapillary vessels density is closely related to cerebral white matter hyperintensities: An OCTA study.

Chronic cerebral hypoperfusion triggers the development of white matter hyperintensities (WMHs), common in cerebral small vessel disease (CSVD). However, conventional imaging techniques cannot visualize cerebral small vessels. The retina, a direct extension of the central nervous system, has an unclear correlation with WMHs. This study employs Optical coherence tomographic angiography (OCTA) to investigate vascular changes in the retina and explore its correlation with WMHs, aiming to provide a new method for assessing perfusion in early ischemic brain WMHs. Forty-nine patients with WMHs were stratified into mild and moderate/severe WMHs groups based on MRI findings, utilizing the Fazekas and Scheltens scales. OCTA assessed fundus vessel microcirculation. Logistic regression analyzed the correlation between ocular fundus microcirculation and WMH severity and location. Additionally, ROC curves evaluated the diagnostic efficacy of each fundus vascular microcirculation index in determining WMH severity. After adjusting for multiple confounders, finding consistently indicated that the moderate/ severe WMHs group exhibited lower vessel density (VD) in the superior quadrant of the inner peripapillary region compared to the mild group [OR = 0.487, CI (0.255,0.929), p < 0.05]. ROC curves revealed that when combined with age, diabetes, and superior quadrant VD of the inner peripapillary region, specificity could be increased to 94.1%. Peripapillary vessel density correlates closely with the severity of cerebral WMHs. Early morphological changes due to chronic hypoperfusion may initiate from the inner layer of the optic disc, and OCTA could offer a novel method for evaluating blood perfusion in ischemic WMHs.

High-Salt Diet Accelerates Neuron Loss and Anxiety in APP/PS1 Mice Through Serpina3n

High salt (HS) consumption is an independent risk factor for neurodegenerative diseases such as dementia, stroke, and cerebral small vessel disease related to cognitive decline. Recently, Alzheimer’s disease-like pathology changes have been reported as consequences of a HS diet in wild-type (wt) mice. However, it has not been revealed how HS diets accelerate the progress of Alzheimer’s disease (AD) in APP/PS1 mice. Here, we fed APP/PS1 mice a HS diet or normal diet (ND) for six months; the effects of the HS/ND on wt mice were also observed. The results of our behavior test reveal that the HS diet exacerbates anxiety, β-amyloid overload, neuron loss, and synapse damage in the hippocampi of APP/PS1 mice; this was not observed in HS-treated wt mice. RNA sequencing shows that nearly all serpin family members were increased in the hippocampus of HS-treated APP/PS1 mice. Gene function analysis showed that a HS diet induces neurodegeneration, including axon dysfunction and neuro-ligand-based dysfunction, and regulates serine protein inhibitor activities. The mRNA and protein levels of Serpina3n were dramatically increased. Upregulated Serpina3n may be the key for β-amyloid aggregation and neuronal loss in the hippocampus of HS-treated APP/PS1 mice. Serpina3n inhibition attenuated the anxiety and increased the number of neurons in the hippocampal CA1(cornu ammonis) region of APP/PS1 mice. Our study provides novel insights into the mechanisms by which excessive HS diet deteriorates anxiety in AD mice. Therefore, decreasing daily dietary salt consumption constitutes a pivotal public health intervention for mitigating the progression of neuropathology, especially for old patients and those with neurodegenerative disease.

Emerging Role of Prefrontal Lobe Involving Visual Function in a Case with Whiplash-Associated Disorders

Whiplash, often resulting from vehicle accidents, can cause bony or soft tissue injuries leading to clinical symptoms related to the cervical spine or brain. However, diagnosing whiplash objectively is challenging, as acute phase abnormalities in the cervical spine or brain are difficult to detect through anatomic/ structural imaging. We present a case of a 54-year-old woman suffering from Whiplash-Associated Disorder (WAD) without abnormal structural abnormalities. Using brain perfusion single-photon emission computed tomography (SPECT) to measure regional cerebral blood flow, hypoperfusion was observed in the bilateral prefrontal regions and parietal/occipital lobes, which was associated with her visual impairment. We support the nociceptive-vascular hypothesis and propose an additional role for the prefrontal lobe in contributing to WAD in patients following whiplash injury. Further investigation is needed to monitor the effects of brain perfusion after treatment using SPECT.

Patient specific numerical hemodynamics for postoperative risk assessment: series case study of EC-IC cerebral bypass

Abstract The study is devoted to the hemodynamics during cerebral vascular bypass surgery for the treatment of cerebral aneurysms in two patients. The location, morphological characteristics and treatment approaches of the patients were similar, but different outcomes were observed as a result of the performed microsurgical procedures . Computational approach was used to analyze the hemodynamic differences of aneurysms, treated via extra-intra cranial (EC-IC) cerebral bypass shunt. The paper presents a new criterion based on the energy parameters of healthy compartment of cerebral circulation. The applied approach demonstrates a new effective method of preoperative risk modelling for medical decision-making.

ADVANCES IN CARE FOR PATIENTS WITH STROKE

Stroke is a medical emergency characterized by the sudden onset of neurological deficits, classified as either ischemic, caused by obstruction of blood flow, or hemorrhagic, due to the rupture of a cerebral vessel. It remains one of the leading causes of death and disability worldwide, with early diagnosis being crucial for improving patient outcomes. This study presents an integrative review of advancements in stroke care, emphasizing the importance of prompt treatment to reduce complications and enhance functional independence. The review analyzed 14 relevant studies from the last five years, sourced from databases like PubMed and Google Scholar. Key findings highlight the significance of rapid hospital arrival, early use of MRI to predict cognitive impairments, and clear communication regarding prognosis. The study also identified barriers in patient care flow, indicating a need for Continuing Education and improved coordination within the Emergency Care Network. Effective integration among healthcare professionals is essential to optimize care quality and rehabilitation outcomes for stroke patients.

Executive functions and processing speed in covert cerebral small vessel disease.

Executive dysfunction and slowed processing speed are central cognitive impairments in cerebral small vessel disease (cSVD). It is unclear whether the subcomponents of executive functions become equally affected and whether computerized tests are more sensitive in detecting early cognitive changes over traditional tests. The associations of specific executive abilities (cognitive flexibility, inhibitory control, working memory) and processing speed with white matter hyperintensities (WMHs) and Instrumental Activities of Daily Living (IADL) were examined. In the Helsinki Small Vessel Disease Study, 152 older individuals without stroke or dementia were assessed with brain magnetic resonance imaging and comprehensive neuropsychological evaluation. WMH volumes were obtained with automated segmentation. Executive functions and processing speed measures included established paper-and-pencil tests and the computer-based Flexible Attention Test (FAT), Simon task and Sustained Attention to Response Task. White matter hyperintensity volume and IADL were associated with multiple cognitive measures across subdomains independently of demographic factors. The highest effect sizes were observed for FAT numbers and number-letter tasks (tablet modifications from the Trail Making Test), FAT visuospatial span, Simon task and semantic verbal fluency. Some of the widely used tests such as Stroop inhibition, phonemic fluency and digit span were not significantly associated with either WMHs or IADL. Processing speed and executive function subcomponents are broadly related to functional abilities and WMH severity in covert cSVD, but the strength of associations within subdomains is heavily dependent on the assessment method. Digital tests providing precise measures of reaction times and response accuracy seem to outperform many of the conventional paper-and-pencil tests.

Deficiency of NLRP3 protects cerebral pericytes and attenuates Alzheimer’s pathology in tau-transgenic mice

IntroductionActivation of NLRP3-containing inflammasome, which is responsible for IL-1β maturation, has been shown to contribute to Alzheimer’s disease (AD)-associated pathogenesis in both APP- and tau-transgenic mice. However, effects of NLRP3 on pericytes and subsequent cerebrovascular pathology in AD remain unknown.MethodsNLRP3-deficient and wild-type AD animal models were generated by crossing human P301S tau-transgenic mice and Nlrp3 knockout mice. AD-associated neuroinflammation, tauopathy, vasculature and pericyte coverage in the brain were investigated using immunohistological and molecular biological methods. To investigate how NLRP3 regulates pericyte activation and survival, pericytes from the brains of Nlrp3 knockout and wild-type mice were cultured, treated with IL-1β and H2O2 at different concentrations and analyzed by confocal microscopy and flow cytometry after staining with fluorescently labelled phalloidin, annexin-V and PDGFRβ antibody.ResultsDeficiency of NLRP3 (1) reduced Iba-1, GFAP and AT8 antibody-immunoreactive phosphorylated tau-positive cells, without significantly altering transcription of inflammatory genes, (2) preserved cerebral vasculature and pericyte coverage and up-regulated Osteopontin gene transcription, and (3) improved cognitive function in tau-transgenic mice. In cell culture, NLRP3 deficiency prevented pericyte apoptosis. Treatment with IL-1β or H2O2 increased the expression of PDGFRβ in NLRP3-deficient pericytes, but decreased it in NLRP3 wild-type pericytes in a dose-dependent manner.DiscussionInhibition of NLRP3 can promote pericyte survival, improve cerebrovascular function, and attenuate AD pathology in the brain of tau-transgenic mice. Our study supports NLRP3 as a novel therapeutic target for Alzheimer’s patients.

Artificial intelligence and real decisions: predictive systems and generative AI vs. emotive-cognitive legal deliberations

IntroductionActivation of NLRP3-containing inflammasome, which is responsible for IL-1β maturation, has been shown to contribute to Alzheimer’s disease (AD)-associated pathogenesis in both APP- and tau-transgenic mice. However, effects of NLRP3 on pericytes and subsequent cerebrovascular pathology in AD remain unknown.MethodsNLRP3-deficient and wild-type AD animal models were generated by crossing human P301S tau-transgenic mice and Nlrp3 knockout mice. AD-associated neuroinflammation, tauopathy, vasculature and pericyte coverage in the brain were investigated using immunohistological and molecular biological methods. To investigate how NLRP3 regulates pericyte activation and survival, pericytes from the brains of Nlrp3 knockout and wild-type mice were cultured, treated with IL-1β and H2O2 at different concentrations and analyzed by confocal microscopy and flow cytometry after staining with fluorescently labelled phalloidin, annexin-V and PDGFRβ antibody.ResultsDeficiency of NLRP3 (1) reduced Iba-1, GFAP and AT8 antibody-immunoreactive phosphorylated tau-positive cells, without significantly altering transcription of inflammatory genes, (2) preserved cerebral vasculature and pericyte coverage and up-regulated Osteopontin gene transcription, and (3) improved cognitive function in tau-transgenic mice. In cell culture, NLRP3 deficiency prevented pericyte apoptosis. Treatment with IL-1β or H2O2 increased the expression of PDGFRβ in NLRP3-deficient pericytes, but decreased it in NLRP3 wild-type pericytes in a dose-dependent manner.DiscussionInhibition of NLRP3 can promote pericyte survival, improve cerebrovascular function, and attenuate AD pathology in the brain of tau-transgenic mice. Our study supports NLRP3 as a novel therapeutic target for Alzheimer’s patients.

The role of surgery in recurrent local cerebral metastases: a multi-institutional retrospective analysis.

Local recurrent brain metastases are defined as lesions that recur in the brain at the same site after a previous local therapy. In patients already submitted to surgery, a second operation may be potentially challenging due to scar formation, infiltration of cerebral vessels or eloquent brain areas and local effect of previous radiotherapy. The aim of this study is to retrospectively review the results and complications of a second surgical treatment in a series of local recurrent lesions and to review the literature on this topic. 37 patients submitted to surgery for a local, histologically confirmed, recurrent brain metastases between 2000 and 2022 were retrospectively analyzed with respect to the following parameters: age, histology, anatomic location, time to recurrence, previous radiotherapy, size of recurrent tumors, preoperative and postoperative Karnofsky Performance Status(KPS) score, recursive partitioning analysis (RPA) class and graded prognostic assessment (GPA) score, surgery-related complications and the presence of further cerebral metastases. Overall survival (OS) was calculated using the Kaplan-Meier method. A multivariate Cox proportional hazard model was developed using stepwise regression (forwards selection) with predictive variables that were significant in the univariate analyses. A significant improvement of post-operative KPS status was obtained after second surgery. At multivariate analysis better results in terms of OS were achieved in patients with a pre-operative KPS ≥ 70 and in patients who had received radiotherapy after the initial surgery. No significant postoperative complications related to previous treatments were observed. Surgical resection of local recurrent brain metastases may improve patients ́ neurologic conditions allowing more time for systemic therapies to act with a low incidence of surgery-related morbidity and mortality. However, careful patient selection with a fair pre-operative clinical status seems mandatory to achieve the best post-operative results, since uniform treatment-paradigms cannot be established yet, due to the highly heterogeneous patient cohort.