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- Heston, M. B., et al.
(författare)
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Gut inflammation associated with age and Alzheimer's disease pathology: a human cohort study
- 2023
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Ingår i: Scientific Reports. - 2045-2322. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Age-related disease may be mediated by low levels of chronic inflammation ("inflammaging"). Recent work suggests that gut microbes can contribute to inflammation via degradation of the intestinal barrier. While aging and age-related diseases including Alzheimer's disease (AD) are linked to altered microbiome composition and higher levels of gut microbial components in systemic circulation, the role of intestinal inflammation remains unclear. To investigate whether greater gut inflammation is associated with advanced age and AD pathology, we assessed fecal samples from older adults to measure calprotectin, an established marker of intestinal inflammation which is elevated in diseases of gut barrier integrity. Multiple regression with maximum likelihood estimation and Satorra-Bentler corrections were used to test relationships between fecal calprotectin and clinical diagnosis, participant age, cerebrospinal fluid biomarkers of AD pathology, amyloid burden measured using 11C-Pittsburgh compound B positron emission tomography (PiB PET) imaging, and performance on cognitive tests measuring executive function and verbal learning and recall. Calprotectin levels were elevated in advanced age and were higher in participants diagnosed with amyloid-confirmed AD dementia. Additionally, among individuals with AD dementia, higher calprotectin was associated with greater amyloid burden as measured with PiB PET. Exploratory analyses indicated that calprotectin levels were also associated with cerebrospinal fluid markers of AD, and with lower verbal memory function even among cognitively unimpaired participants. Taken together, these findings suggest that intestinal inflammation is linked with brain pathology even in the earliest disease stages. Moreover, intestinal inflammation may exacerbate the progression toward AD.
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| 3. |
- Thorstenson, J. C., et al.
(författare)
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Diet and APOE as moderators of the relationship between trimethylamine N-oxide and biomarkers of Alzheimer's disease and glial activation
- 2021
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 17
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Dietary patterns appear to impact cognitive trajectories in aging, and gut microbiota have been implicated in Alzheimer's disease (AD) pathogenesis, potentially as modulators of neuroinflammation early in the disease. Diets featuring low meat and dairy consumption have been linked to reduced AD risk, and recently, the gut microbial metabolite trimethylamine N-oxide (TMAO) was found in cerebrospinal fluid (CSF) and linked to CSF biomarkers of AD. Because TMAO is largely derived from dietary sources of choline, carnitine, and betaine, we examined whether these precursors drive the association between TMAO and sTREM2, a marker for glial activation. Additionally, TMAO has been found to inhibit cholesterol metabolism, a strong risk factor for AD, which is further dysregulated by the APOE4 allele. Therefore, we aimed to determine whether TMAO-glial activation relationships are moderated by APOE4 carrier status. METHOD: Participants from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center provided CSF samples (n=570, Table 1). sTREM2 and YKL-40 biomarkers were measured with the exploratory Roche NeuroToolKit assays, a panel of robust prototype immunoassays (Roche Diagnostics International Ltd). TMAO, carnitine, choline, and betaine relative abundance were obtained using Metabolon's UHPLC-MS/MS metabolomics platform. A subset of participants (n=159) completed the MIND diet questionnaire. Metabolite and biomarker levels were log-transformed for analysis; models were adjusted for age, sex, and APOE4 carrier status. Linear regression tested associations between intake of TMAO precursor-containing foods (red meat, butter, cheese, fish) and CSF levels of each TMAO precursor. Path analysis with Satorra-Bentler adjustments tested whether TMAO mediated precursor-biomarker relationships. Linear regression tested whether APOE4 carrier status moderated TMAO-biomarker relationships. RESULT: Red meat and cheese consumption predicted levels of CSF carnitine (βs=0.009, -0.017; ps=0.0609, 0.0007; Figure 1 A, B; respectively). TMAO mediated the relationship between carnitine and sTREM2, although effects were marginal; several individual relationships throughout both path models showed strong associations (Tables 2, 3; Figures 2, 3). APOE4 carrier status did not significantly moderate TMAO-glial activation relationships. CONCLUSION: This study suggests that CSF carnitine reflects dietary intake, and may drive the TMAO-sTREM2 association previously identified. Future studies in animal models are required to confirm these results mechanistically. © 2021 the Alzheimer's Association.
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| 4. |
- Prowle, John R., et al.
(författare)
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Postoperative acute kidney injury in adult non-cardiac surgery : joint consensus report of the Acute Disease Quality Initiative and PeriOperative Quality Initiative
- 2021
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Ingår i: Nature Reviews Nephrology. - : Springer Nature. - 1759-5061 .- 1759-507X. ; 17:9, s. 605-618
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Forskningsöversikt (refereegranskat)abstract
- The development of acute kidney injury (AKI) after major non-cardiac surgery is associated with substantial long-term morbidity and mortality. This joint Consensus Statement from the Acute Disease Quality Initiative and the PeriOperative Quality Initiative provides recommendations for the definition, prevention and management of postoperative AKI. Postoperative acute kidney injury (PO-AKI) is a common complication of major surgery that is strongly associated with short-term surgical complications and long-term adverse outcomes, including increased risk of chronic kidney disease, cardiovascular events and death. Risk factors for PO-AKI include older age and comorbid diseases such as chronic kidney disease and diabetes mellitus. PO-AKI is best defined as AKI occurring within 7 days of an operative intervention using the Kidney Disease Improving Global Outcomes (KDIGO) definition of AKI; however, additional prognostic information may be gained from detailed clinical assessment and other diagnostic investigations in the form of a focused kidney health assessment (KHA). Prevention of PO-AKI is largely based on identification of high baseline risk, monitoring and reduction of nephrotoxic insults, whereas treatment involves the application of a bundle of interventions to avoid secondary kidney injury and mitigate the severity of AKI. As PO-AKI is strongly associated with long-term adverse outcomes, some form of follow-up KHA is essential; however, the form and location of this will be dictated by the nature and severity of the AKI. In this Consensus Statement, we provide graded recommendations for AKI after non-cardiac surgery and highlight priorities for future research.
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