Academic literature on the topic 'Cerebral clearance'

The purpose of the present study was to estimate the relative contributions of degradation and brain-to-blood elimination processes to the clearance of microinjected human amyloid-β peptide(1-40) (hAβ(1-40)) from mouse cerebral cortex, using a solid-phase extraction method together with a newly developed ultraperformance liquid chromatography/tandem mass spectrometry (UPLC/MS/MS) quantitation method for intact hAβ(1-40). The clearance rate constant of hAβ(1-40) in mouse cerebral cortex was determined to be 3.21 × 10−2/min under conditions where the saturable brain-to-blood elimination process across the blood–brain barrier (BBB) was expected to be saturated. Thus, this clearance rate constant should mainly reflect degradation. The [125I]hAβ(1-40) elimination rate across the BBB under nonsaturating conditions was determined to be 1.48 × 10−2/min. Inhibition studies suggested that processes sensitive to insulin and phosphoramidon, which inhibit neprilysin, insulin-degrading enzyme, and endothelin-converting enzyme, are involved not only in degradation, but also in elimination of hAβ(1-40). In conclusion, our results suggest a dominant contribution of degradation to cerebral hAβ(1-40) clearance, and also indicate that a sequential process of degradation and elimination of degradation products is involved in cerebral hAβ(1-40) clearance.

Key Points Lactadherin promotes the clearance of circulating microvesicles through phagocytosis. Promoting microvesicle clearance prevents coagulopathy, reduces cerebral edema, and improves neurological function in severe TBI mice.

ObjectiveInitial hemorrhage burden is an independent predictor for delayed cerebral ischemia (DCI) in patients with aneurysmal subarachnoid hemorrhage (aSAH). However, the association between clot clearance and DCI still remains to be elucidated.MethodsQuantitative analysis of hemorrhage volume and clot clearance was made in 116 consecutive patients who were scanned within 24 h from onset. Cisternal plus intraventricular hemorrhage volume (CIHV) was calculated as clot volume from the initial scans and scans performed up to 7 days after onset. Clot clearance was calculated as a percentage of residual clot volume compared with the clot volume on the initial scan. Initial clot volume and clot clearance were dichotomized to evaluate the association with DCI.ResultsIncluded patients were aged 55.5±15.2 years with a female preponderance (65.5%, (76/116)). The group with higher initial clot volume (≥17.2 mL) had higher odds for DCI (OR 4.3, 95% CI 1.3 to 14.0, p=0.015). However, the rate of DCI was not different between high and low clot clearance groups (26.7% vs 31.0%, p=0.66). Clot clearance rate was similar in patients with and without DCI up to day 7 after onset.ConclusionsThe quantitative clot clearance rate is not an independent predictor for DCI.

Abstract The importance of cerebral ischemia produced by carotid clamping during carotid endarterectomy remains controversial. In an effort to determine the importance of cerebral ischemia during carotid endarterectomy. 369 patients undergoing 431 consecutive carotid endarterectomies were studied by Xenon-133 (133Xe) clearance and electroencephalogram (EEG) monitoring. None of the patients was shunted during the procedures. The severity of ischemia as indicated by 133 Xe clearance from the ipsilateral hemisphere during 20 to 30 minutes of carotid occlusion did not predict the appearance of complications in this group of patients (x2 = 1.417: P = 0.841). There was a highly significant relationship between the depth of cerebral ischemia as demonstrated by 133Xe clearance and the appearance of abnormalities on the EEG (x2 = 42.043, P < 0.0001). In the subgroup of patients developing abnormalities as shown by EEG. there was a negative correlation (x2 = 17.495; P < 0.002) between reduction in blood flow and the appearance of complications, in that the higher the blood flow during occlusion the more likely the patient developing EEG changes would develop complications.

Abstract Aquaporin-4 (AQP4) is located mainly in the astrocytic end-feet around cerebral blood vessels and regulates ion and water homeostasis in the brain. While deletion of AQP4 is shown to reduce amyloid-β (Aβ) clearance and exacerbate Aβ peptide accumulation in plaques and vessels of Alzheimer’s disease mouse models, the mechanism and clearing pathways involved are debated. Here, we investigated how inhibiting the function of AQP4 in healthy male C57BL/6 J mice impacts clearance of Aβ40, the more soluble Aβ isoform. Using two-photon in vivo imaging and visualizing vessels with Sulfurodamine 101 (SR101), we first showed that Aβ40 injected as a ≤ 0.5-μl volume in the cerebral cortex diffused rapidly in parenchyma and accumulated around blood vessels. In animals treated with the AQP4 inhibitor TGN-020, the perivascular Aβ40 accumulation was significantly (P < 0.001) intensified by involving four times more vessels, thus suggesting a generalized clearance defect associated with vessels. Increasing the injecting volume to ≥ 0.5 ≤ 1 μl decreased the difference of Aβ40-positive vessels observed in non-treated and AQP4 inhibitor-treated animals, although the difference was still significant (P = 0.001), suggesting that larger injection volumes could overwhelm intramural vascular clearance mechanisms. While both small and large vessels accumulated Aβ40, for the ≤ 0.5-μl volume group, the average diameter of the Aβ40-positive vessels tended to be larger in control animals compared with TGN-020-treated animals, although the difference was non-significant (P = 0.066). Using histopathology and ultrastructural microscopy, no vascular structural change was observed after a single massive dose of TGN-020. These data suggest that AQP4 deficiency is directly involved in impaired Aβ brain clearance via the peri-/para-vascular routes, and AQP4-mediated vascular clearance might counteract blood-brain barrier abnormalities and age-related vascular amyloidopathy.

Ammonia is a neurotoxic molecule that causes cerebral edema and encephalopathy. Ammonia is either produced in excess or poorly purified during severe hepatic insufficiency, poisoning, infection, and inborn errors of metabolism. During continuous renal replacement therapy, ammonia clearance is determined by the dialysate flow rate and the dialyzer surface area. Extra-renal blood purification for ammonia clearance has been studied in neonates with urea cycle disorders. Prognostic factors affecting patient outcome are thought to be the duration of coma, the patient’s clinical status prior to dialysis, and the ammonia removal rate. In this review, we discuss the various dialytic modalities used for ammonia clearance as well as the thresholds for initiating dialysis and the better strategy ensures rapid patient protection from cerebral edema and herniation induced by hyperammonemia.

L’espace extracellulaire entre les cellules du tissu nerveux (ECS) est le siège de flux moléculaires constants et essentiels à la physiologie cérébrale. Ces flux sont toutefois fortement dépendants de la grande complexité des surfaces cellulaires qui délimitent l’ECS et de l’enchevêtrement de ses constituants matriciels. Initialement considéré comme relativement immuable, l’ECS est en réalité très dynamique. Son volume accessible aux solutés représente 15 à 20 % du volume cérébral et sa structure réticulaire, qui entrave leurs flux moléculaires — contrainte appelée tortuosité — varient fortement à court et long termes en fonction de l’âge, du rythme circadien et de l’environnement. Cette plasticité de l’ECS joue un rôle majeur dans la clairance cérébrale et son altération semble être impliquée dans le vieillissement cérébral ainsi que dans le développement et la progression de protéinopathies. La pathogenèse de ces maladies, comme la maladie d’Alzheimer (MA) par exemple, repose sur l’agrégation de peptides toxiques qui s’accumulent dans le parenchyme cérébral et causent la mort neuronale. On ne sait pas encore si ce phénomène est une cause ou une conséquence de la baisse de la clairance cérébrale observée dans ces pathologies. Il est en revanche certain que la diminution de ces flux d’épuration contribue à entretenir la pathologie dans les deux cas. J’ai pensé qu’une manière de lutter contre la protéotoxicité pourrait être de préserver de façon durable des flux moléculaires efficaces dans l’ECS, en régulant ce qui peut concourir à entraver la progression des molécules, c’est-à-dire en diminuant sa tortuosité. Une approche consisterait à intervenir sur la forme des parois de l’ECS, notamment sur la morphologie des prolongements et des corps cellulaires, en agissant sur des régulateurs de la taille cellulaire. Un candidat intéressant est le récepteur de type 1 des facteurs de croissance insulinosemblables, IGF1R, impliqué dans le contrôle de la taille cellulaire, et dont le knockout (KO) neuronal confère aux neurones une résistance accrue aux stress hypoxiques et protéotoxiques d’une part, et une morphologie plus compacte d’autre part. En parallèle, notre équipe a montré que des souris modèles de la MA étaient protégées contre le déclin cognitif, la mort neuronale et l’accumulation d’espèces amyloïdes dans le parenchyme cérébral quand la signalisation IGF1R neuronale était supprimée. Gontier et al. ont notamment identifié la clairance cérébrale comme un acteur de cette neuroprotection. Ces données m’ont amenée à formuler l’hypothèse que la compaction de la morphologie neuronale due au KO d’IGF1R permet de réduire la tortuosité de l’ECS de sorte à faciliter les flux moléculaires et la clairance à long terme dans le parenchyme cérébral. J’étudie dans ma thèse la réponse fonctionnelle de l’ECS à une réduction volumique pérenne d’un de ses constituants majoritaires, la population neuronale. J’ai injecté par stéréotaxie des macromolécules paramagnétiques ou marquées par fluorescence directement dans le cortex de souris KO conditionnel inductible pour l’IGF1R neuronal (inIGF1RKO), et analysé in et ex vivo, par IRM et microscopie optique, leurs mouvements dans l’ECS. J’ai montré qu’une morphologie neuronale plus mince favorisait les flux moléculaires dans l’ECS en facilitant la diffusion des solutés et en réduisant sa tortuosité. J’ai prouvé que cet effet facilitateur était présent dès l’âge adulte et se maintenait tout au long de la vie et du vieillissement de la souris. Enfin, j’ai établi que ces changements neuromorphologiques contribuaient à renforcer la relation neurovasculaire par un rapprochement relatif des neurones et des vaisseaux. Dans l’ensemble, mon travail contribue à une meilleure compréhension des phénomènes de neuroprotection dépendants d’IGF-1 et identifie la morphologie neuronale comme un régulateur des flux moléculaires à travers l’ECS et comme une cible potentielle dans la prévention contre la protéotoxicité
Continuous interstitial molecular fluxes are essential to cerebral physiology. They occur in the extracellular space (ECS) of the brain that extends between all neural and glial cells. The efficiency of these fluxes depends on the extremely complex cell surfaces that delineate the ECS and on the entanglement of its matrix components. For many years, the ECS was considered to be rather unchanging and stable, but this compartment is in fact highly dynamic. The ECS volume fraction, defined as the space accessible to interstitial solute movements, represents 15 to 20% of the brain volume. Its reticular structure that hinders molecular fluxes is defined as tortuosity. These characteristics vary over time depending on age, circadian rhythm and environment. ECS plasticity is indeed a major determinant of cerebral clearance, and its alteration is thought to be involved in brain aging as well as in the development and progression of proteinopathies. Importantly, the pathogenesis of proteinopathies such as Alzheimer disease (AD) involves the intracerebral aggregation of toxic peptides that eventually accumulate in the brain parenchyma causing neuronal death. So far, we do not know whether these processes are responsible for defective cerebral clearance identified in proteinopathies, or if they result from it. Nonetheless, it is clear in both cases that reducing fluxes that eliminate waste metabolites contributes to maintaining and even exacerbating the disease. I thought that one way to fight proteotoxicity might consist in lastingly preserving effective molecular fluxes in the ECS. This could be achieved by diminishing ECS tortuosity, namely by regulating the cellular or molecular players that are physiologically limiting ECS solute movements in the brain. To this end, altering the morphology of the ECS walls, and in particular the morphology of cell bodies and processes by targeting cell size regulators, could be an innovative strategy to manipulate tortuosity. An interesting candidate is the insulin-like growth factor type 1 receptor (IGF1R) as it potently participates in the control of cell size. Knocking out this receptor in neurons leads to a noticeably compact neuronal morphology. IGF receptor is also strongly involved in the regulation of neuronal resistance to hypoxic and proteotoxic stresses. Our team showed previously that a mouse model of AD was protected against cognitive decline, neuronal loss and accumulation of amyloid species in the cerebral parenchyma when neuronal IGF1R signaling was suppressed. Importantly, Gontier et al. identified cerebral clearance as a functional player in this neuroprotection. Therefore, I hypothesized that the compaction of neuronal morphology resulting from neuronal IGF1R knockout could be sufficient to reduce ECS tortuosity, and thereby improve molecular fluxes and clearance in the cerebral parenchyma. My PhD work is thus focusing on the functional response of the ECS to a lasting reduction in neuronal cell volume. For that, I injected paramagnetic and fluorescently labeled macromolecules stereotactically in the cerebral cortex of inducible, neuronspecific IGF1R knockout mice (inIGF1RKO). I analyzed the macroscopic movements of these tracers in the ECS in vivo by MRI and by optical microscopy. I showed that a lean neuronal phenotype favors molecular fluxes in the ECS by facilitating diffusion and by reducing ECS tortuosity. I demonstrated that this facilitating effect existed in adult mutant mice at any age and was maintained throughout aging. I also established that neuromorphological changes contributed to strengthen the neurovascular relationship specifically by bringing the capillaries closer to the neurons. Altogether, my work contributes to a better understanding of the mechanisms underlying IGF-dependent neuroprotection. It identifies neuronal morphology as an important regulator of molecular flux through the ECS and as a potential target in the prevention of proteotoxic diseases

Nelle persone affette da Grave Cerebrolesione Acquisita la connessione al ventilatore meccanico è l’unica alternativa che permetta ai soggetti di raggiungere o mantenere una stabilità clinica. Il paziente è a rischio per sviluppo di ingombro secretivo periferico presentando un quadro fisiopatologico di tipo restrittivo.L’ingombro bronchiale profondo rappresenta perciò il punto di partenza per la riacquisizione del respiro spontaneo. L’obiettivo è reperire le evidenze scientifiche relative alle tecniche respiratorie di disostruzione bronco-polmonare e verificare se possono essere applicate al fine di ricercare una precoce acquisizione del respiro spontaneo nei soggetti affetti da GCLA. L’obiettivo, è anche quello di distinguere, le tecniche da utilizzare per le vie aeree prossimali e quelle per le vie aeree distali. La ricerca bibliografica è stata eseguita sulle seguenti banche dati medico-scientifiche: The Cochrane Library e PubMed. La valutazione della qualità metodologica viene effettuata attraverso la PRISMA checklist. Sono stati selezionati studi relativi alle tecniche di airways clearance in diverse patologie respiratorie. In 2 studi viene effettuata una revisione sistematica riguardante queste tecniche; uno stila delle linee guida per il trattamento di tre tipologie di pazienti; mentre gli altri 7 studi descrivono l’argomento in modo generale rappresentando però anch’essi un valido strumento informativo. La sintesi dei risultati dati dagli studi ci consente di considerare tecniche valide al raggiungimento della clearance tracheo-bronchiale nel GCLA le seguenti: Mechanical Insufflation-Exsufflation (MI-E), l’Intrapulmonary Percussive Ventilation (IPV), la Positive Espiratory Pressure (PEP). Queste tecniche possono essere applicate adattandole a persone non collaboranti, rispondendo comunque agli obiettivi prefissati. In questo modo la persona, recuperata una corretta clearance bronco-polmonare, può intraprendere un precoce percorso verso il respiro spontaneo.

Anaesthesia for children is tempered by changes that occur during both growth and development. Drug dose is affected by size and clearance maturation processes as well as the changing body composition that occurs with age. All organ systems undergo these maturation changes and most are complete within the first few years of life. Normal physiological variables in infancy and childhood are quite different from adults. The central nervous, cardiovascular, and respiratory systems are particularly important. Cerebral immaturity and plasticity impacts sensitivity to drugs, pain responses, and behaviour and increases potential harm from apoptosis with anaesthesia. The heart undergoes a transition from fetal to adult circulation during the first few weeks of life. Undiagnosed congenital defects are not uncommon. The neonate is very susceptible to conditions that trigger an increase in pulmonary vascular resistance, with reversion to fetal circulatory patterns. Respiratory anatomy and mechanics affect the propensity to apnoea, airway maintenance, artificial ventilation modalities, uptake of inhalational agents, and tracheal tube sizes. Metabolic rate and oxygen requirements increase with decreasing age. This physiology influences diverse aspects that include the rate of desaturation during apnoea, hypoglycaemia during starvation, cardiac output, drug metabolism, fluid requirements, and heat production or loss.

We report on a computational model used to study the reversal of flow direction inside the annular region between concentric micro-cylinders filled with an incompressible Newtonian fluid. The flow is induced by boundary deformations on the inner and outer cylinder surfaces due to forward-propagating transverse waves and their reflections. This microfluidic transport mechanism is postulated as a vital pathway for removal of beta-amyloid from the brain along sub-millimeter cerebral arteries, and failure of this clearance is associated with Alzheimer’s disease. We show that the direction of this annular flow depends on superposition of the peristaltic waves and their reflection waves. A control volume analysis is developed to predict the transport characteristics and compared with numerical solutions of the Navier-Stokes equations. The identified set of microfluidic parameters that leads to a net reverse flow will aid biologists in understanding why an aging brain becomes prone to beta-amyloid accumulation.