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Pre-existing weakness is critical for the occurrence of postoperative cognitive dysfunction in mice of the same age.

ABSTRACT: Occurrence of postoperative cognitive dysfunction (POCD) is age-dependent and heterogenous. Factors deciding the occurrence of POCD in patients of the same age undergone same surgeries remain unclear. Here we investigated the effects of pre-existing weakness on the occurrence of POCD in mice of the same age. Pre-existing weakness of mice was induced by intraperitoneal injection of lipopolysaccharide (8mg/kg) and was evaluated by physical frailty index (by open field test), neuroinflammation level (by Iba1 immunostaining and inflammatory factors TNF-α and IL-1β), and neuronal activity (by p-CREB immunostaining). POCD was induced by partial hepatolobectomy and was evaluated by puzzle box test and Morris water maze test. The brains were collected to detect the levels of neuroinflammation, synaptophysin and NMDA receptor subunits NR2A, NR2B and NR1 (by western blot), and oxidative stress (by Dihydroethidium). Compared to the normal adult mice of the same age, LPS pretreated mice had increased physical frailty index, higher levels of neuroinflammation, and lower neuronal activity. Partial hepatolobectomy induced obvious impairments in executive function, learning and memory in LPS pretreated mice after surgery, but not in normal mice of the same age. Partial hepatolobectomy also induced heightened neuroinflammation, obvious loss of NMDA receptor subunits, strong oxidative stress in LPS pretreated mice on the 1st and 3rd postoperative day. However, the POCD-associated pathological changes didn't occur in normal mice of the same age after surgery. These results suggest that pre-existing weakness is critical for the occurrence of POCD in mice of the same age.

SUBMITTER: Tang Y

PROVIDER: S-EPMC5546624 | biostudies-other | 2017

REPOSITORIES: biostudies-other

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Project description:BackgroundSurgery can lead to significant muscle loss, which increases recovery time and associates with increased mortality. Muscle loss is not uniform, with some patients losing significant muscle mass and others losing relatively little, and is likely to be accompanied by marked changes in circulating metabolites and proteins. Determining these changes may help understand the variability and identify novel therapeutic approaches or markers of muscle wasting.MethodsTo determine the association between muscle loss and circulating metabolites, we studied 20 male patients (median age, 70.5, interquartile range, 62.5-75) undergoing aortic surgery. Muscle mass was determined before and 7 days after surgery and blood samples were taken before surgery, and 1, 3, and 7 days after surgery. The circulating metabolome and proteome were determined using commercial services (Metabolon and SomaLogic).ResultsTen patients lost more than 10% of the cross-sectional area of the rectus femoris (RFCSA ) and were defined as wasting. Metabolomic analysis showed that 557 circulating metabolites were altered following surgery (q < 0.05) in the whole cohort and 104 differed between wasting and non-wasting patients (q < 0.05). Weighted genome co-expression network analysis, identified clusters of metabolites, both before and after surgery, that associated with muscle mass and function (r = -0.72, p = 6 × 10-4 with RFCSA on Day 0, P = 3 × 10-4 with RFCSA on Day 7 and r = -0.73, P = 5 × 10-4 with hand-grip strength on Day 7). These clusters were mainly composed of acyl carnitines and dicarboxylates indicating that pre-existing mitochondrial dysfunction contributes to muscle loss following surgery. Surgery elevated cortisol to the same extent in wasting and non-wasting patients, but the cortisol:cortisone ratio was higher in the wasting patients (Day 3 P = 0.043 and Day 7 P = 0.016). Wasting patients also showed a greater increase in circulating nucleotides 3 days after surgery. Comparison of the metabolome with inflammatory markers identified by SOMAscan® showed that pre-surgical mitochondrial dysfunction was associated with growth differentiation factor 15 (GDF-15) (r = 0.79, P = 2 × 10-4 ) and that GDF-15, interleukin (IL)-8), C-C motif chemokine 23 (CCL-23), and IL-15 receptor subunit alpha (IL-15RA) contributed to metabolic changes in response to surgery.ConclusionsWe show that pre-existing mitochondrial dysfunction and reduced cortisol inactivation contribute to muscle loss following surgery. The data also implicate GDF-15 and IL-15RA in mitochondrial dysfunction.

Project description:Multi-morbidity is common among older adults; however, for many aging-related diseases there is no information for U.S. elderly population on how earlier-manifested disease affects the risk of another disease manifested later during patient's lifetime. Quantitative evaluation of risks of cancer and non-cancer diseases for older adults with pre-existing conditions is performed using the Surveillance, Epidemiology, and End Results (SEER) Registry data linked to the Medicare Files of Service Use (MFSU). Using the SEER-Medicare data containing individual records for 2,154,598 individuals, we empirically evaluated age patterns of incidence of age-associated diseases diagnosed after the onset of earlier manifested disease and compared these patterns with those in general population. Individual medical histories were reconstructed using information on diagnoses coded in MFSU, dates of medical services/procedures, and Medicare enrollment/disenrollment. More than threefold increase of subsequent diseases risk was observed for 15 disease pairs, majority of them were i) diseases of the same organ and/or system (e.g., Parkinson disease for patients with Alzheimer disease, HR=3.77, kidney cancer for patients with renal failure, HR=3.28) or ii) disease pairs with primary diseases being fast-progressive cancers (i.e., lung, kidney, and pancreas), e.g., ulcer (HR=4.68) and melanoma (HR=4.15) for patients with pancreatic cancer. Lower risk of subsequent disease was registered for 20 disease pairs, mostly among patients with Alzheimer's or Parkinson's disease, e.g., decreased lung cancer risk among patients with Alzheimer's (HR=0.64) and Parkinson's (HR=0.60) disease. Synergistic and antagonistic dependences in geriatric disease risks were observed among US elderly confirming known and detecting new associations of wide spectrum of age-associated diseases. The results can be used in optimization of screening, prevention and treatment strategies of chronic diseases among U.S. elderly population.

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Pre-existing weakness is critical for the occurrence of postoperative cognitive dysfunction in mice of the same age.

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