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Sepsis-associated encephalopathy (SAE) is a significant cause of mortality in patients with sepsis. Despite extensive research, its exact cause remains unclear. Our previous research indicated a relationship between non-hepatic hyperammonemia (NHH) and SAE. This study aimed to investigate the relationship between NHH and SAE and the potential mechanisms causing cognitive impairment. In the in vivo experimental results, there were no significant abnormalities in the livers of mice with moderate cecal ligation and perforation (CLP); however, ammonia levels were elevated in the hippocampal tissue and serum. The ELISA study suggest that fecal microbiota transplantation in CLP mice can reduce ammonia levels. Reduction in ammonia levels improved cognitive dysfunction and neurological impairment in CLP mice through behavioral, neuroimaging, and molecular biology studies. Further studies have shown that ammonia enters the brain to regulate the expression of aquaporins-4 (AQP4) in astrocytes, which may be the mechanism underlying brain dysfunction in CLP mice. The results of the in vitro experiments showed that ammonia up-regulated AQP4 expression in astrocytes, resulting in astrocyte damage. The results of this study suggest that ammonia up-regulates astrocyte AQP4 expression through the gut-brain axis, which may be a potential mechanism for the occurrence of SAE., SCOPUS: ar.j, info:eu-repo/semantics/published

Delirium is a neuropsychiatric syndrome characterised by the acute onset of fluctuating cognitive disturbances including awareness and attention deficits, hallucinations, delusions, and circadian rhythm changes. Delirium is a common condition in hospitalised older adults that portends a poor prognosis and provokes many malign complications. Under-diagnosis is a problem in Delirium despite its prevalence. Delirium lacks any therapy that improves the natural history of the disorder: while antipsychotics are frequently used for symptoms, clear evidence of benefit is lacking and the superiority of any single agent over another is unknown. Once established then, Delirium’s course cannot be modified. Circadian rhythm disturbances are common in Delirium. Melatonin is a pineal gland hormone that contributes to circadian regulation, and secretion is perturbed in Delirium. Melatonin is available as an oral medication, approved for use in sleep disorders. Melatonin has been used to prevent Delirium onset but has not been evaluated for treatment of established Delirium. This thesis examined the prevalence and prevalence of under-diagnosis of Delirium, finding it large. The thesis examined melatonin for treatment of Delirium severity in hospitalised older patients. An effect on a comprehensive rating scale of Delirium symptoms was not found.

Sepsis-associated encephalopathy (SAE) remains a challenge for intensivists that is exacerbated by lack of an effective diagnostic tool and an unambiguous definition to properly identify SAE patients. Risk factors for SAE development include age, genetic factors as well as pre-existing neuropsychiatric conditions. Sepsis due to certain infection sites/origins might be more prone to encephalopathy development than other cases. Currently, ICU management of SAE is mainly based on non-pharmacological support. Pre-clinical studies have described the role of the alarmin high mobility group box 1 (HMGB1) in the complex pathogenesis of SAE. Although there are limited data available about the role of HMGB1 in neuroinflammation following sepsis, it has been implicated in other neurologic disorders, where its translocation from the nucleus to the extracellular space has been found to trigger neuroinflammatory reactions and disrupt the blood–brain barrier. Negating the inflammatory cascade, by targeting HMGB1, may be a strategy to complement non-pharmacologic interventions directed against encephalopathy. This review describes inflammatory cascades implicating HMGB1 and strategies for its use to mitigate sepsis-induced encephalopathy., SCOPUS: re.j, info:eu-repo/semantics/published

Sepsis-induced impairment of cerebral function is the result of the interaction of multiples factors.The findings of our studies show that the alteration in perfusion potentially plays a role in SAE dueto a disruption of the mechanisms of CBF regulation that negatively influence cortical function. Thealteration of these protective mechanisms is a dynamic process. We showed that CA becomesimpaired only in the late phases of sepsis and this in odds with previous literature. Therefore, in aclinical scenario, patients frequently present a shifted CA curve, due to other medical preexistingconditions, preventing a correct interpretation of CA parameters. Since methods to monitor CA inreal time are increasingly available, prospective randomized trials should be underwent to answer thequestion of whether individualizing perfusion pressure targets in septic patients has a positive effectover outcome. Some studies suggested that NVC might be less robust against a sepsis-inducedinflammation challenge. Accordingly, we showed that, already in early phases of sepsis, NVCbecomes less performant to sustain the seizure-induced increase in neuronal activity. Furthermore, inhealthy animals, recurring seizure might independently alter the control mechanisms of cerebralperfusion which become inadequate to balance the enormous metabolic needs of rapidly firingneurons resulting in a reduction in inter-ictal tissue oxygenation. Thus, the association of seizure andsepsis may be particularly dangerous in those patients presenting a prior condition known to alterNVC (such as subarachnoid haemorrhage, traumatic brain injury or ischemic stroke). We showed inour animal model that systemic inflammation does not trigger spontaneous seizures in a healthy brain.This finding was confirmed by clinical data of our highly selected patient cohort, since we do notrecord any spontaneous seizure. Sepsis won’t be a risk factor for seizure occurrence per se but,reducing seizure threshold, it may elicit them i, Doctorat en Sciences médicales (Médecine), info:eu-repo/semantics/nonPublished

Background Aging and pre-existing cognitive impairment are considered to be independent risk factors for sepsis-associated encephalopathy. This study aimed to investigate the manner in which aging and pre-existing cognitive dysfunction modified neuroinflammation, synaptic plasticity, and basal synaptic transmission during the acute phase of sepsis using Senescence-Accelerated Mice Prone 8 (SAMP8) and Senescence-Accelerated Resistant Mice 1 (SAMR1). Methods We used 6-month-old SAMP8 and SAMR1. Sepsis was induced using cecal ligation and puncture (CLP). The animal's hippocampi and blood were collected for subsequent investigations 24 h after surgery. Results Long-term potentiation (LTP) was impaired in the Shaffer-collateral (SC)-CA1 pathway of the hippocampus in SAMP8 without surgery compared to the age-matched SAMR1, which was reflective of cognitive dysfunction in SAMP8. CLP impaired the SC-CA1 LTP in SAMR1 compared to the sham-operated controls, but not in SAMP8. Moreover, CLP decreased the input-output curve and increased the paired-pulse ratio in SAMP8, suggesting the reduced probability of basal synaptic transmission due to sepsis. Immunohistochemical analysis revealed that CLP elevated IL-1 beta levels, especially in the hippocampi of SAMP8 with microglial activation. In vivo peripheral IL-1 receptor antagonist (IL-1ra) administration in the septic SAMP8 revealed that the neuroinflammation was not correlated with the peripheral elevation of IL-1 beta. Ex vivo IL-1ra administration to the hippocampus ameliorated LTP impairment in SAMR1 and the reduction in basal transmission in SAMP8 after sepsis. Conclusions The mechanism of the modulation of synaptic transmission and synaptic plasticity by the acute stage of sepsis differed between SAMR1 and SAMP8. These changes were related to centrally derived IL-1 receptor-mediated signaling and were accompanied by microglial activation, especially in SAMP8.

Alteration of the mechanisms of cerebral blood flow (CBF) regulation might contribute to the pathophysiology of sepsis-associated encephalopathy (SAE). However, previous clinical studies on dynamic cerebral autoregulation (dCA) in sepsis had several cofounders. Furthermore, little is known on the potential impairment of neurovascular coupling (NVC) in sepsis. The aim of our study was to determine the presence and time course of dCA and NVC alterations in a clinically relevant animal model and their potential impact on the development of SAE., SCOPUS: ar.j, info:eu-repo/semantics/published

Astroglial cells are involved in most if not in all pathologies of the brain. These cells can change the morpho-functional properties in response to pathology or innate changes of these cells can lead to pathologies. Overall pathological changes in astroglia are complex and diverse and often vary with different disease stages. We classify astrogliopathologies into reactive astrogliosis, astrodegeneration with astroglial atrophy and loss of function, and pathological remodelling of astrocytes. Such changes can occur in neurological, neurodevelopmental, metabolic and psychiatric disorders as well as in infection and toxic insults. Mutation in astrocyte-specific genes leads to specific pathologies, such as Alexander disease, which is a leukodystrophy. We discuss changes in astroglia in the pathological context and identify some molecular entities underlying pathology. These entities within astroglia may repent targets for novel therapeutic intervention in the management of brain pathologies.

We reassessed data from a previous study on the transcerebral net exchange of large neutral amino acids (LNAAs) using a novel mathematical model of blood–brain barrier (BBB) transport. The study included twelve healthy volunteers who received a 4-h intravenous lipopolysaccharide (LPS) infusion (total dose: 0·3 ng/kg), a human experimental model of the systemic inflammatory response during the early stages of sepsis. Cerebral blood flow and arterial-to-jugular venous LNAA concentrations were measured prior to and after LPS, and the BBB transport and brain extracellular concentrations of LNAAs were calculated. The arterial concentration and unidirectional cerebral influx of phenylalanine increased after LPS. The BBB transport of tyrosine was unaffected, while its concentration in the brain extracellular fluid increased. These findings suggest that LPS infusion leads to an increased cerebral uptake of phenylalanine, which is then metabolized to tyrosine. This may reflect a neuroprotective mechanism that ‘detoxifies’ excess intracerebral phenylalanine in the clinical setting of sepsis.

Sepsis-associated encephalopathy is a major complication during sepsis, and an effective treatment remains unknown. Although minocycline (MINO) has neuroprotective effects and is an attractive candidate for treating sepsis-associated encephalopathy, the effect of MINO on synaptic plasticity during sepsis is still unclear. In the present study, we investigated the effects of MINO on long-term potentiation (LTP) in the hippocampus in a cecal ligation and puncture (CLP) mouse model. We divided mice into four groups; sham + vehicle, sham + MINO (60 mg/kg, i.p. for 3 consecutive days before slice preparation), CLP + vehicle, and CLP + MINO. We tested LTP in the CA1 region of the hippocampus, using slices taken 24 h after surgery. Because MINO is also anti-inflammatory, LTP was analyzed following 30 min of IL-1 receptor antagonist (IL-1ra) perfusion. The endotoxin level in the blood was increased at 24 h after CLP operations regardless of MINO administrations, and LTP in the CLP + vehicle group mice was severely impaired (P < 0.05). High doses of MINO prevented the LTP impairment during sepsis in the CLP + MINO group. Interleukin (IL)-1ra administration ameliorated LTP impairment only in the CLP + vehicle group (P < 0.05); it had no additional effects on LTP in the CLP + MINO group. In conclusion, we have provided the first evidence that MINO prevents impaired LTP related to sepsis-induced encephalopathy in the mouse hippocampus, and that mechanisms associated with IL-1 receptor activity may be involved.

Sepsis-associated encephalopathy is a major complication during sepsis, and an effective treatment remains unknown. Although minocycline (MINO) has neuroprotective effects and is an attractive candidate for treating sepsis-associated encephalopathy, the effect of MINO on synaptic plasticity during sepsis is still unclear. In the present study, we investigated the effects of MINO on long-term potentiation (LTP) in the hippocampus in a cecal ligation and puncture (CLP) mouse model. We divided mice into four groups; sham + vehicle, sham + MINO (60 mg/kg, i.p. for 3 consecutive days before slice preparation), CLP + vehicle, and CLP + MINO. We tested LTP in the CA1 region of the hippocampus, using slices taken 24 h after surgery. Because MINO is also anti-inflammatory, LTP was analyzed following 30 min of IL-1 receptor antagonist (IL-1ra) perfusion. The endotoxin level in the blood was increased at 24 h after CLP operations regardless of MINO administrations, and LTP in the CLP + vehicle group mice was severely impaired (P < 0.05). High doses of MINO prevented the LTP impairment during sepsis in the CLP + MINO group. Interleukin (IL)-1ra administration ameliorated LTP impairment only in the CLP + vehicle group (P < 0.05); it had no additional effects on LTP in the CLP + MINO group. In conclusion, we have provided the first evidence that MINO prevents impaired LTP related to sepsis-induced encephalopathy in the mouse hippocampus, and that mechanisms associated with IL-1 receptor activity may be involved.

Sepsis-associated encephalopathy is a major complication during sepsis, and an effective treatment remains unknown. Although minocycline (MINO) has neuroprotective effects and is an attractive candidate for treating sepsis-associated encephalopathy, the effect of MINO on synaptic plasticity during sepsis is still unclear. In the present study, we investigated the effects of MINO on long-term potentiation (LTP) in the hippocampus in a cecal ligation and puncture (CLP) mouse model. We divided mice into four groups; sham + vehicle, sham + MINO (60 mg/kg, i.p. for 3 consecutive days before slice preparation), CLP + vehicle, and CLP + MINO. We tested LTP in the CA1 region of the hippocampus, using slices taken 24 h after surgery. Because MINO is also anti-inflammatory, LTP was analyzed following 30 min of IL-1 receptor antagonist (IL-1ra) perfusion. The endotoxin level in the blood was increased at 24 h after CLP operations regardless of MINO administrations, and LTP in the CLP + vehicle group mice was severely impaired (P < 0.05). High doses of MINO prevented the LTP impairment during sepsis in the CLP + MINO group. Interleukin (IL)-1ra administration ameliorated LTP impairment only in the CLP + vehicle group (P < 0.05); it had no additional effects on LTP in the CLP + MINO group. In conclusion, we have provided the first evidence that MINO prevents impaired LTP related to sepsis-induced encephalopathy in the mouse hippocampus, and that mechanisms associated with IL-1 receptor activity may be involved.

Sepsis-associated encephalopathy is a major complication during sepsis, and an effective treatment remains unknown. Although minocycline (MINO) has neuroprotective effects and is an attractive candidate for treating sepsis-associated encephalopathy, the effect of MINO on synaptic plasticity during sepsis is still unclear. In the present study, we investigated the effects of MINO on long-term potentiation (LTP) in the hippocampus in a cecal ligation and puncture (CLP) mouse model. We divided mice into four groups; sham + vehicle, sham + MINO (60 mg/kg, i.p. for 3 consecutive days before slice preparation), CLP + vehicle, and CLP + MINO. We tested LTP in the CA1 region of the hippocampus, using slices taken 24 h after surgery. Because MINO is also anti-inflammatory, LTP was analyzed following 30 min of IL-1 receptor antagonist (IL-1ra) perfusion. The endotoxin level in the blood was increased at 24 h after CLP operations regardless of MINO administrations, and LTP in the CLP + vehicle group mice was severely impaired (P < 0.05). High doses of MINO prevented the LTP impairment during sepsis in the CLP + MINO group. Interleukin (IL)-1ra administration ameliorated LTP impairment only in the CLP + vehicle group (P < 0.05); it had no additional effects on LTP in the CLP + MINO group. In conclusion, we have provided the first evidence that MINO prevents impaired LTP related to sepsis-induced encephalopathy in the mouse hippocampus, and that mechanisms associated with IL-1 receptor activity may be involved.

Purpose: To investigate heart rate and EEG variability and their coupling in patients with sepsis and determine their relationship to sepsis severity and severity of sepsis-Associated brain dysfunction. Methods: Fifty-Two patients with sepsis were prospectively identified, categorized as comatose (N = 30) and noncomatose (N = 22), and compared with 11 control subjects. In a 30-minute EEG and electrocardiogram recording, heart rate variability and EEG variability (measured by the variability of relative power in a modified alpha band = RAP) and their coupled oscillations were quantified using linear (least-square periodogram and magnitude square coherence) and nonlinear (Shannon entropy and mutual information) measures. These measures were compared between the three groups and correlated with outcome, adjusting for severity of sepsis. Results: Several measures of heart rate variability and EEG variability and of their coupled oscillations were significantly lower in patients with sepsis compared with controls and correlated with outcome. This correlation was not independent when adjusting for severity of sepsis. Conclusions: Sepsis is associated with lower variability of both heart rate and RAP on EEG and reduction of their coupled oscillations. This uncoupling is associated with the severity of encephalopathy. Combined EEG and electrocardiogram monitoring may be used to gain insight in underlying mechanisms of sepsis and quantify brainstem or thalamic dysfunction., SCOPUS: ar.j, info:eu-repo/semantics/published