Statins and brain dysfunction: a hypothesis to reduce the burden of cognitive impairment in patients who are critically ill.
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ABSTRACT:
SUBMITTER: Morandi A
PROVIDER: S-EPMC3168859 | biostudies-other | 2011 Sep
REPOSITORIES: biostudies-other
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Project description:The use or misuse of statins in critically ill patients recently attracted the attention of intensive care clinicians. Indeed, statins are probably the most common chronic treatment before critical illness and some recent experimental and clinical data demonstrated their beneficial effects during sepsis, acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), or after aneurismal subarachnoidal hemorrhage (aSAH). Due to the heterogeneity of current studies and the lack of well-designed prospective studies, definitive conclusions for systematic and large-scale utilization in intensive care units cannot be drawn from the published evidence. Furthermore, the extent of statins side effects in critically ill patients is still unknown. For the intensive care clinician, it is a matter of individually identifying the patient who can benefit from this therapy according to the current literature. The purpose of this review is to describe the mechanisms of actions of statins and to synthesize the clinical data that underline the relevant effects of statins in the particular setting of critical care, in an attempt to guide the clinician through his daily practice.
| S-EPMC3488539 | biostudies-other
Project description:Terblanche and colleagues add to the ongoing controversy over the role, if any, for statins in patients with sepsis. The authors note that statins fail to prevent progression to organ dysfunction in critically ill patients. However, like most publications, the study is retrospective and stimulates the controversy but fails to resolve it. The time has come for robust randomized controlled clinical trials.
| S-EPMC3219346 | biostudies-literature
Project description:The brainstem conveys sensory and motor inputs between the spinal cord and the brain, and contains nuclei of the cranial nerves. It controls the sleep-wake cycle and vital functions via the ascending reticular activating system and the autonomic nuclei, respectively. Brainstem dysfunction may lead to sensory and motor deficits, cranial nerve palsies, impairment of consciousness, dysautonomia, and respiratory failure. The brainstem is prone to various primary and secondary insults, resulting in acute or chronic dysfunction. Of particular importance for characterizing brainstem dysfunction and identifying the underlying etiology are a detailed clinical examination, MRI, neurophysiologic tests such as brainstem auditory evoked potentials, and an analysis of the cerebrospinal fluid. Detection of brainstem dysfunction is challenging but of utmost importance in comatose and deeply sedated patients both to guide therapy and to support outcome prediction. In the present review, we summarize the neuroanatomy, clinical syndromes, and diagnostic techniques of critical illness-associated brainstem dysfunction for the critical care setting.
| S-EPMC6945639 | biostudies-literature
Project description:Critically ill patients are highly susceptible to hospital-acquired infection. Neutrophil function in critical illness remains poorly understood.To characterize and define mechanisms of peripheral blood neutrophil (PBN) dysfunction in critically ill patients. To determine whether the inflamed lung contributes additional phagocytic impairment.Prospective collection of blood and bronchoalveolar lavage fluid from patients with suspected ventilator-associated pneumonia and from age- and sex-matched volunteers; laboratory analysis of neutrophil functions.Seventy-two patients and 21 volunteers were included. Phagocytic capacity of PBNs was 36% lower in patients than in volunteers (P < 0.0001). From several biologically plausible candidates only activated complement was significantly associated with impaired PBN phagocytosis (P < 0.0001). Phagocytosis was negatively correlated with serum C3a and positively correlated with expression of C5a receptor type 1 (CD88) on PBNs. C5a recapitulated impaired PBN phagocytosis and significantly down-regulated CD88 expression in vitro. C5a-mediated phagocytic impairment was prevented by blocking either CD88 or phosphoinositide 3-kinase, and completely reversed by granulocyte-macrophage colony-stimulating factor. C5a also impaired killing of Pseudomonas aeruginosa by, and migration of, PBNs, indicating that effects were not restricted to phagocytosis. Bronchoalveolar lavage fluid leukocytes from patients also demonstrated significantly impaired function, and lavage supernatant reduced phagocytosis in healthy neutrophils by 43% (P = 0.0001). However, lavage fluid did not affect CD88 expression and lavage-mediated impairment of phagocytosis was not blocked by anti-CD88 antibody.Critically ill patients have significant dysfunction of PBNs, which is mediated predominantly by activated complement. Further, profound complement-independent neutrophil dysfunction occurs in the inflamed lung.
| S-EPMC2948533 | biostudies-other
Project description:IntroductionMultiple organ dysfunction (MOD) is a common pathway to morbidity and death in critically ill children. Defining organ dysfunction is challenging, as we lack a complete understanding of the complex pathobiology. Current pediatric organ dysfunction criteria assign the same diagnostic value-the same "weight"- to each organ system. While each organ dysfunction in isolation contributes to the outcome, there are likely complex interactions between multiple failing organs that are not simply additive.ObjectiveDetermine whether certain combinations of organ system dysfunctions have a significant interaction associated with higher risk of morbidity or mortality in critically ill children.MethodsWe conducted a retrospective observational cohort study of critically ill children at two large academic medical centers from 2010 and 2018. Patients were included in the study if they had at least two organ dysfunctions by day 3 of PICU admission based on the Pediatric Organ Dysfunction Information Update Mandate (PODIUM) criteria. Mortality was described as absolute number of deaths and mortality rate. Combinations of two pediatric organ dysfunctions were analyzed with interaction terms as independent variables and mortality or persistent MOD as the dependent variable in logistic regression models.ResultsOverall, 7,897 patients met inclusion criteria and 446 patients (5.6%) died. The organ dysfunction interactions that were significantly associated with the highest absolute number of deaths were cardiovascular + endocrinologic, cardiovascular + neurologic, and cardiovascular + respiratory. Additionally, the interactions associated with the highest mortality rates were liver + cardiovascular, respiratory + hematologic, and respiratory + renal. Among patients with persistent MOD, the most common organ dysfunctions with significant interaction terms were neurologic + respiratory, hematologic + immunologic, and endocrinologic + respiratory. Further analysis using classification and regression trees (CART) demonstrated that the absence of respiratory and liver dysfunction was associated with the lowest likelihood of mortality.Implications and future directionsCertain combinations of organ dysfunctions are associated with a higher risk of persistent MOD or death. Notably, the three most common organ dysfunction interactions were associated with 75% of the mortality in our cohort. Critically ill children with MOD presenting with these combinations of organ dysfunctions warrant further study.
| S-EPMC9081807 | biostudies-literature
Project description:Importance:Evidence shows that sleep dysfunction and β-amyloid (Aβ) deposition work synergistically to impair brain function in individuals with normal cognition, increasing the risk of developing dementia later in life. However, whether Aβ continues to play an integral role in sleep dysfunction after the onset of cognitive decline in individuals with dementia is unclear. Objective:To determine whether Aβ deposition in the brain is associated with subjective measures of sleep quality and cognition in elderly individuals with cognitive disorders. Design, Setting, and Participants:A nested survey study was conducted at the Cognitive Disorders and Comprehensive Alzheimer Disease Center of Thomas Jefferson University Hospital in Philadelphia, Pennsylvania. Participants included patients aged 65 years and older with cognitive disorders verified by neuropsychological testing. Eligible participants were identified from a referral center-based sample of patients who underwent fluorine 18-labeled florbetaben positron emission tomography imaging at Thomas Jefferson University Hospital as part of the multicenter Imaging Dementia-Evidence for Amyloid Scanning study. Data collection and analysis occurred between November 2018 and March 2019. Main Outcomes and Measures:Sleep quality was measured via responses to sleep questionnaires, Aβ deposition was measured via fluorine 18-labeled florbetaben positron emission tomography, and cognition was measured via Mini-Mental State Examination (MMSE) performance. Results:Of the 67 eligible participants, 52 (77.6%) gave informed consent to participate in the study. Of the 52 enrolled participants (mean [SD] age, 76.6 [7.4] years), 27 (51.9%) were women. Daytime sleepiness was associated with Aβ deposition in the brainstem (B = 0.0063; 95% CI, 0.001 to 0.012; P = .02), but not MMSE performance (B = -0.01; 95% CI, -0.39 to 0.37; P = .96). The number of nocturnal awakenings was associated with Aβ deposition in the precuneus (B = 0.11; 95% CI, 0.06 to 0.17; P < .001) and poor MMSE performance (B = -2.13; 95% CI, -3.13 to -1.13; P < .001). Mediation analysis demonstrated an indirect association between Aβ deposition and poor MMSE performance that relied on nocturnal awakenings as an intermediary (B = -3.99; 95% CI, -7.88 to -0.83; P = .01). Conclusions and Relevance:Nighttime sleep disruption may mediate the association between Aβ and cognitive impairment, suggesting that there is an underlying sleep-dependent mechanism that links Aβ burden in the brain to cognitive decline. Further elucidation of this mechanism may improve understanding of disease processes associated with Aβ accumulation.
| S-EPMC6806437 | biostudies-literature
Project description:Cerebral malaria (CM) is the most severe manifestation of Plasmodium falciparum infection in children and non-immune adults. Previous work has documented a persistent cognitive impairment in children who survive an episode of CM that is mimicked in animal models of the disease. Potential therapeutic interventions for this complication have not been investigated, and are urgently needed. HMG-CoA reductase inhibitors (statins) are widely prescribed for cardiovascular diseases. In addition to their effects on the inhibition of cholesterol synthesis, statins have pleiotropic immunomodulatory activities. Here we tested if statins would prevent cognitive impairment in a murine model of cerebral malaria. Six days after infection with Plasmodium berghei ANKA (PbA) mice displayed clear signs of CM and were treated with chloroquine, or chloroquine and lovastatin. Intravital examination of pial vessels of infected animals demonstrated a decrease in functional capillary density and an increase in rolling and adhesion of leukocytes to inflamed endothelium that were reversed by treatment with lovastatin. In addition, oedema, ICAM-1, and CD11b mRNA levels were reduced in lovastatin-treated PbA-infected mice brains. Moreover, HMOX-1 mRNA levels are enhanced in lovastatin-treated healthy and infected brains. Oxidative stress and key inflammatory chemokines and cytokines were reduced to non-infected control levels in animals treated with lovastatin. Fifteen days post-infection cognitive dysfunction was detected by a battery of cognition tests in animals rescued from CM by chloroquine treatment. In contrast, it was absent in animals treated with lovastatin and chloroquine. The outcome was similar in experimental bacterial sepsis, suggesting that statins have neuroprotective effects in severe infectious syndromes in addition to CM. Statin treatment prevents neuroinflammation and blood brain barrier dysfunction in experimental CM and related conditions that are associated with cognitive sequelae, and may be a valuable adjuvant therapeutic agent for prevention of cognitive impairment in patients surviving an episode of CM.
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Project description:Background: Platelet hyperactivity is deleterious in coronary artery disease (CAD), requiring lifelong antiplatelet therapy, and is associated with worse cognitive outcomes. Upon activation, platelets release Brain-Derived Neurotrophic Factor (BDNF), a neurotrophin protective against cognitive decline. Given these apparently opposing effects of platelet activation on cognitive health, we investigated whether BDNF levels intercede in the relationship between platelet activation and cognitive function; and whether this relationship is moderated by the presence of CAD. Methods: In this cross-sectional study, 1,280 participants with (n = 673) and without CAD (n = 607) completed the Montreal Cognitive Assessment (MoCA). Plasma BDNF and soluble P-selectin (a marker of platelet activity) levels were assessed using multiplex flow cytometry. Results: In a mediation model, platelet activity was correlated with higher plasma BDNF concentrations (b = 0.53, p < 0.0001). The relationship between sP-selectin and BDNF concentrations was stronger for individuals without CAD (b = 0.71, p < 0.0001) than for CAD participants (b = 0.43, p < 0.0001; p interaction <0.0001). Higher BDNF concentrations were associated with higher MoCA scores (b = 0.26, p = 0.03). The overall effect of platelet activity on cognitive performance was non-significant (total effect: b = -0.12, p = 0.13), and became significant when accounting for BDNF as a mediating factor (direct effect: b = -0.26, p = 0.01). This resulted in a positive indirect effect of platelet activity (via BDNF) on MoCA scores (b = 0.14, CI 95% 0.02-0.30), that was smaller in CAD participants than in non-CAD participants [Δ -0.07 (95% CI -0.14 to -0.01)]. Conclusions: BDNF released from activated platelets could be a mitigating factor in a negative association between platelet activity and cognitive function.
| S-EPMC8452906 | biostudies-literature
Project description:We previously found that subjects with amnestic mild cognitive impairment exhibit a pro-inflammatory immune profile in the cerebrospinal fluid similar to multiple sclerosis, a central nervous system autoimmune disease. We therefore hypothesized that early neuroinflammation would reflect increases in brain amyloid burden during amnestic mild cognitive impairment.Cerebrospinal fluid and blood samples were collected from 24 participants with amnestic mild cognitive impairment (12 men, 12 women; 66?±?6 years; 0.5 Clinical Dementia Rating) enrolled in the AETMCI study. Analyses of cerebrospinal fluid and blood included immune profiling by multi-parameter flow cytometry, genotyping for apolipoprotein (APO)?, and quantification of cytokine and immunoglobin levels. Amyloid (A)? deposition was determined by 18F-florbetapir positron emission tomography. Spearman rank order correlations were performed to assess simple linear correlation for parameters including amyloid imaging, central and peripheral immune cell populations, and protein cytokine levels.Soluble A?42 in the cerebrospinal fluid declined as A? deposition increased overall and in the precuneous and posterior cingulate cortices. Lymphocyte profiling revealed a significant decline in T cell populations in the cerebrospinal fluid, specifically CD4+ T cells, as A? deposition in the posterior cingulate cortex increased. In contrast, increased A? burden correlated positively with increased memory B cells in the cerebrospinal fluid, which was exacerbated in APO?4 carriers. For peripheral circulating lymphocytes, only B cell populations decreased with A? deposition in the precuneous cortex, as peripheral T cell populations did not correlate with changes in brain amyloid burden.Elevations in brain A? burden associate with a shift from T cells to memory B cells in the cerebrospinal fluid of subjects with amnestic mild cognitive impairment in this exploratory cohort. These data suggest the presence of cellular adaptive immune responses during A? accumulation, but further study needs to determine whether lymphocyte populations contribute to, or result from, A? dysregulation during memory decline on a larger cohort collected at multiple centers.AETMCI NCT01146717.
| S-EPMC5530920 | biostudies-literature
Project description:Novel coronavirus spread rapidly around the world infecting millions of people. It was thus declared a pandemic. This new virus damages the lungs. In the most severe cases, it leads to acute respiratory failure that requires intensive care treatment. However, many clinical reports have listed different neurological symptoms, leading to increased interest in the neurological involvement of COVID-19. Various pathophysiological mechanisms have been proposed to explain these neurological aspects. Direct viral invasion of the nervous system, systemic cytokine storm and severe hypoxemia are key factors in the development of symptoms. Critically ill patients present several additional risk factors for nervous system damage. Reasons for these include deep sedation and extended muscular paralysis, bed rest for several days, and the inability to receive proper physical rehabilitation. After ICU treatment, COVID-19 patients generally require an extensive rehabilitation program. However, distancing restrictions mean that in many cases physiotherapists are unable to enter ICUs, delaying the process of rehabilitation. The role of telemedicine should be considered as an adjunctive tool in the rehabilitation of critically ill COVID-19 patients.
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