Decision letter for "Accelerated brain aging in sepsis survivors with cognitive long‐term impairment"

Introduction: Sepsis results in dysregulated inflammation, coagulation, and metabolism, which may contribute to increased cardiovascular disease (CVD) risk. We conducted a systematic review and meta-analysis to determine the association between sepsis and subsequent long-term CVD events. Methods: MEDLINE, Embase, and the Cochrane Controlled Trials Register and Database of Systematic Reviews were searched from inception to May 2020 to identify observational studies of adult sepsis survivors (defined by diagnostic codes or consensus definitions) measuring long-term CV outcomes. The primary outcome was a composite of myocardial infarction, CV death, and stroke. Random-effects models estimated the pooled cumulative incidence and adjusted hazard ratios of CV events relative to hospital or population controls. Odds ratios were included as risk ratios assuming <10% incidence in non-septic controls, and risk ratios were taken as hazard ratios (HR) assuming no censoring. Outcomes were analyzed at maximum follow-up (primary analysis) and stratified by time (<1 year, 1-2 years, and >2 years) since sepsis. Results: Of 11,235 abstracts screened, 25 studies (22 cohort studies, 2 case-crossover studies, and 1 case-control) involving 1,949,793 sepsis survivors were included. The pooled cumulative incidence of CVD events was 9% (95% CI; 5-14%). Sepsis was associated with an increased risk (HR 1.59, 95% CI 1.37-1.86) of CVD events at maximum follow-up ( Figure ); between-study heterogeneity was substantial (I 2 =97.3%). There was no significant difference when comparing studies using population and hospital controls. Significantly elevated risk was observed up to 5 years following sepsis. Conclusions: Sepsis survivors experience an approximately 50% increased risk of CVD events, which may persist for years following the index episode. These results highlight a potential unmet need for early cardiac risk stratification and optimization in sepsis survivors.

Download Full-text

Effects of Long-Term Treatment with a Blend of Highly Purified Olive Secoiridoids on Cognition and Brain ATP Levels in Aged NMRI Mice

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/4070935 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 9

Author(s):

Martina Reutzel ◽

Rekha Grewal ◽

Carmina Silaidos ◽

Jens Zotzel ◽

Stefan Marx ◽

...

Keyword(s):

Mitochondrial Dysfunction ◽

Citrate Synthase ◽

Brain Aging ◽

Mrna Levels ◽

Nmri Mice ◽

Aged Mice ◽

Atp Levels ◽

Long Term Treatment ◽

The Brain

Aging represents a major risk factor for developing neurodegenerative diseases such as Alzheimer’s disease (AD). As components of the Mediterranean diet, olive polyphenols may play a crucial role in the prevention of AD. Since mitochondrial dysfunction acts as a final pathway in both brain aging and AD, respectively, the effects of a mixture of highly purified olive secoiridoids were tested on cognition and ATP levels in a commonly used mouse model for brain aging. Over 6 months, female NMRI mice (12 months of age) were fed with a blend containing highly purified olive secoiridoids (POS) including oleuropein, hydroxytyrosol and oleurosid standardized for 50 mg oleuropein/kg diet (equivalent to 13.75 mg POS/kg b.w.) or the study diet without POS as control. Mice aged 3 months served as young controls. Behavioral tests showed deficits in cognition in aged mice. Levels of ATP and mRNA levels of NADH-reductase, cytochrome-c-oxidase, and citrate synthase were significantly reduced in the brains of aged mice indicating mitochondrial dysfunction. Moreover, gene expression of Sirt1, CREB, Gap43, and GPx-1 was significantly reduced in the brain tissue of aged mice. POS-fed mice showed improved spatial working memory. Furthermore, POS restored brain ATP levels in aged mice which were significantly increased. Our results show that a diet rich in purified olive polyphenols has positive long-term effects on cognition and energy metabolism in the brain of aged mice.

Download Full-text

Targeting the Blood-Brain Barrier to Prevent Sepsis-Associated Cognitive Impairment

Journal of Central Nervous System Disease ◽

10.1177/1179573519840652 ◽

2019 ◽

Vol 11 ◽

pp. 117957351984065 ◽

Cited By ~ 23

Author(s):

Divine C Nwafor ◽

Allison L Brichacek ◽

Afroz S Mohammad ◽

Jessica Griffith ◽

Brandon P Lucke-Wold ◽

...

Keyword(s):

Cognitive Impairment ◽

Blood Brain Barrier ◽

Immune Cell ◽

The United States ◽

Brain Barrier ◽

Blood Brain ◽

Systemic Inflammatory Disease ◽

Sepsis Survivors ◽

The Brain

Sepsis is a systemic inflammatory disease resulting from an infection. This disorder affects 750 000 people annually in the United States and has a 62% rehospitalization rate. Septic symptoms range from typical flu-like symptoms (eg, headache, fever) to a multifactorial syndrome known as sepsis-associated encephalopathy (SAE). Patients with SAE exhibit an acute altered mental status and often have higher mortality and morbidity. In addition, many sepsis survivors are also burdened with long-term cognitive impairment. The mechanisms through which sepsis initiates SAE and promotes long-term cognitive impairment in septic survivors are poorly understood. Due to its unique role as an interface between the brain and the periphery, numerous studies support a regulatory role for the blood-brain barrier (BBB) in the progression of acute and chronic brain dysfunction. In this review, we discuss the current body of literature which supports the BBB as a nexus which integrates signals from the brain and the periphery in sepsis. We highlight key insights on the mechanisms that contribute to the BBB’s role in sepsis which include neuroinflammation, increased barrier permeability, immune cell infiltration, mitochondrial dysfunction, and a potential barrier role for tissue non-specific alkaline phosphatase (TNAP). Finally, we address current drug treatments (eg, antimicrobials and intravenous immunoglobulins) for sepsis and their potential outcomes on brain function. A comprehensive understanding of these mechanisms may enable clinicians to target specific aspects of BBB function as a therapeutic tool to limit long-term cognitive impairment in sepsis survivors.

Download Full-text

Older Sepsis Survivors Suffer Persistent Disability Burden and Poor Long‐Term Survival

Journal of the American Geriatrics Society ◽

10.1111/jgs.16435 ◽

2020 ◽

Vol 68 (9) ◽

pp. 1962-1969 ◽

Cited By ~ 3

Author(s):

Robert T. Mankowski ◽

Stephen D. Anton ◽

Gabriela L. Ghita ◽

Babette Brumback ◽

Michael C. Cox ◽

...

Keyword(s):

Term Survival ◽

Long Term Survival ◽

Sepsis Survivors ◽

Persistent Disability

Download Full-text

Ascorbic Acid Mitigates D-galactose-Induced Brain Aging by Increasing Hippocampal Neurogenesis and Improving Memory Function

Nutrients ◽

10.3390/nu11010176 ◽

2019 ◽

Vol 11 (1) ◽

pp. 176 ◽

Cited By ~ 14

Author(s):

Sung Nam ◽

Misun Seo ◽

Jin-Seok Seo ◽

Hyewhon Rhim ◽

Sang-Soep Nahm ◽

...

Keyword(s):

Ascorbic Acid ◽

Cellular Proliferation ◽

Brain Aging ◽

Memory Function ◽

Interleukin 1 ◽

Hippocampal Neurogenesis ◽

Adult Brain ◽

Normal Brain ◽

Long Term Treatment

Ascorbic acid is essential for normal brain development and homeostasis. However, the effect of ascorbic acid on adult brain aging has not been determined. Long-term treatment with high levels of D-galactose (D-gal) induces brain aging by accumulated oxidative stress. In the present study, mice were subcutaneously administered with D-gal (150 mg/kg/day) for 10 weeks; from the seventh week, ascorbic acid (150 mg/kg/day) was orally co-administered for four weeks. Although D-gal administration alone reduced hippocampal neurogenesis and cognitive functions, co-treatment of ascorbic acid with D-gal effectively prevented D-gal-induced reduced hippocampal neurogenesis through improved cellular proliferation, neuronal differentiation, and neuronal maturation. Long-term D-gal treatment also reduced expression levels of synaptic plasticity-related markers, i.e., synaptophysin and phosphorylated Ca2+/calmodulin-dependent protein kinase II, while ascorbic acid prevented the reduction in the hippocampus. Furthermore, ascorbic acid ameliorated D-gal-induced downregulation of superoxide dismutase 1 and 2, sirtuin1, caveolin-1, and brain-derived neurotrophic factor and upregulation of interleukin 1 beta and tumor necrosis factor alpha in the hippocampus. Ascorbic acid-mediated hippocampal restoration from D-gal-induced impairment was associated with an enhanced hippocampus-dependent memory function. Therefore, ascorbic acid ameliorates D-gal-induced impairments through anti-oxidative and anti-inflammatory effects, and it could be an effective dietary supplement against adult brain aging.

Download Full-text