Exosome α-Synuclein Release in Plasma May be Associated With Postoperative Delirium in Hip Fracture Patients

Abstract

Background:Little is known about the underlying mechanisms of the similarities in the core features of postoperative delirium (POD) and α-synuclein (α-syn)-related cognitive disorders. We herein investigated associations between fluctuated levels of exosomal α-syn in the plasma and POD presentation in geriatric hip fracture patients. Methods:We conducted an observational, prospective, and 1:1 matched (on age older than 65, hip fracture diagnosis, American Society of Anesthesiologist' (ASA) physical status, duration of surgery, and intraoperative bleeding) case-control study: POD cases and non-POD controls were selected from the overall cohort by using Confusion Assessment Method (CAM). Delirium severity was measured by the Memorial Delirium Assessment Scale (MDAS). Plasma exosome levels of α-syn were examined preoperatively and at the time that POD was diagnosed, by using an established immunocapture technology based on a putative brain-cell-specific marker. Circulating concentrations of interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factorα (TNF-α) were also determined. The relationship between α-syn levels and POD risk, as well as the association between α-syn and MDAS scores and plasma cytokines, were assessed.Results: POD incidence was 8.4% (17/202). Postoperative α-syn were either elevated or lowered. As primary outcome variables, the change of α-syn in POD patients was significantly higher than non-POD ones (21.0 ± 29.3 pg.ml −1 vs.1.9 ± 20.0, P = 0.047). The α-syn alteration was positively correlated to MDAS (r = 0.436, P = 0.010) and the change of IL-6 (r = 0.383, P = 0.025).

Inhibition of α‐Synuclein Accumulation Improves Neuronal Apoptosis and Delayed Postoperative Cognitive Recovery in Aged Mice

“…Moreover, α -syn can also impair the NMDA receptor-mediated LTP, an enhanced synaptic activity, which is widely accepted to be related to memory formation [ 46 ]. Meanwhile, our preliminary studies [ 15 , 16 ] and others [ 17 , 18 ] have demonstrated that α -syn may also be associated with surgery-induced cognitive impairment. However, the exact association between α -syn accumulation and the mechanism of dNCR is not fully understood.…”

“…Aggregation and propagation of misfolded α -syn in the brain are involved in the pathogenesis of neurodegenerative diseases, especially in Parkinson's disease cases [ 13 , 14 ]. In our earlier work, we demonstrated that anesthesia and surgery increased α -syn oligomerization and disturbed neurotransmitter homeostasis in the hippocampus of aged rats, while exosome α -syn release into the plasma of postoperative delirium (POD) patients with hip fractures was significantly higher compared with non-POD cases [ 15 , 16 ]. In addition, an earlier study from another laboratory found elevated total α -syn expression in the cortex after 12 h, with attention deficit after 24 h in mice following anesthesia plus surgery [ 17 ].…”

The Potential Protective Effect of Mesencephalic Astrocyte-Derived Neurotrophic Factor on Post-Operative Delirium via Inhibiting Inflammation and Microglia Activation

“…The increase of pro-inflammatory factors like TNF-α, IL-1β and IL-6 is positively related to POD pathogenesis. 23–26 The up-regulated inflammatory response has been also demonstrated in POD animal model studies. 7 , 27 , 28 In this study, human recombinant MANF inhibited the surgery-induced inflammatory response in mice to decrease the surgery-induced increase of IL-1β, IL-6 and TNF-α in serum and pre-cortex of mice brain, suggesting that MANF up-regulation in circulation and brain might be a self-protective response to surgery.…”

The Role of Microglia in Perioperative Neurocognitive Disorders

“…The pathogenesis of PND is multifaceted, which might be associated with anesthesia, tissue damage, neuroinflammation, surgical stress, psychological stress, and so on. In human studies, patients who develop PND showed cerebrospinal fluid (CSF) and plasma pro-inflammatory cytokines increases after anesthesia and surgery (Ji et al, 2013 ; Hirsch et al, 2016 ; Yuan et al, 2020 ). The more pronounced changes in CSF cytokines compared to plasma for several cytokines (MCP, MIP-1α, MIP-1β) provide evidence for substantial inflammatory activity in the CNS (Hirsch et al, 2016 ).…”

“…The more pronounced changes in CSF cytokines compared to plasma for several cytokines (MCP, MIP-1α, MIP-1β) provide evidence for substantial inflammatory activity in the CNS (Hirsch et al, 2016 ). Since microglia are the macrophages of the CNS and play critical roles in neuroinflammatory disease (West et al, 2019 ), the significant alterations in some cytokines in CSF from patients indicate that microglia may be involved in PND in human (Helmy et al, 1999 ; Bromander et al, 2012 ; Hirsch et al, 2016 ; Yuan et al, 2020 ). Mounting evidence from animal studies suggests that microglia, like immune cells, are activated in the CNS and implicated in neuroinflammation and PND.…”