Conserved YKL-40 changes in mice and humans after postoperative delirium

David-Bercholz, Jennifer; Acker, Leah; Caceres, Ana I.; Wu, Pau Yen; Goenka, Saanvi; Franklin, Nathan O; Rodriguiz, Ramona M.; Wetsel, William C.; Devinney, Michael J.; Wright, Mary Cooter; Zetterberg, Henrik; Yang, Ting; Berger, Miles; Terrando, Niccolò

doi:10.1016/j.bbih.2022.100555

Cited by 6 publications

(5 citation statements)

References 47 publications

(66 reference statements)

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“…Our data are also compatible with the idea that blood–brain barrier dysfunction may simply be a marker of greater overall brain dysfunction after surgery, and that this greater overall brain dysfunction leads to delirium without a causal role for blood–brain barrier dysfunction itself. Nonetheless, our results are similar to results from mouse models of perioperative neurocognitive disorders, in which postoperative blood–brain barrier dysfunction has been demonstrated following orthopedic surgery and has been associated with delirium‐like behavioral changes 35–37 . Moreover, in these animal studies, delirium‐like behavioral changes are prevented when blood–brain barrier dysfunction is reduced by administration of netrin‐1, a protein that upregulates endothelial tight junction proteins to increase blood–brain barrier integrity 38 …”

Section: Discussionsupporting

confidence: 86%

“…Nonetheless, our results are similar to results from mouse models of perioperative neurocognitive disorders, in which postoperative bloodbrain barrier dysfunction has been demonstrated following orthopedic surgery and has been associated with deliriumlike behavioral changes. [35][36][37] Moreover, in these animal studies, delirium-like behavioral changes are prevented when blood-brain barrier dysfunction is reduced by administration of netrin-1, a protein that upregulates endothelial tight junction proteins to increase blood-brain barrier integrity. 38 Two other lines of evidence also suggest that it is biologically plausible for blood-brain barrier dysfunction to play an etiologic role in delirium.…”

Section: Discussionmentioning

confidence: 99%

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Role of Blood–Brain Barrier Dysfunction in Delirium following Non‐cardiac Surgery in Older Adults

Devinney,

Wong,

Wright

et al. 2023

Annals of Neurology

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ObjectiveAlthough animal models suggest a role for blood‐brain barrier dysfunction in postoperative delirium‐like behavior, its role in postoperative delirium and postoperative recovery in humans is unclear. Thus, we evaluated the role of blood‐brain barrier dysfunction in postoperative delirium and hospital length of stay among older surgery patients.MethodsCognitive testing, delirium assessment, and cerebrospinal fluid and blood sampling were prospectively performed before and after non‐cardiac, non‐neurologic surgery. Blood‐brain barrier dysfunction was assessed using the cerebrospinal fluid‐to‐plasma albumin ratio (CPAR).ResultsOf 207 patients (median age 68, 45% female) with complete CPAR and delirium data, 26 (12.6%) developed postoperative delirium. Overall, CPAR increased from before to 24‐hours after surgery (median change 0.28, [IQR] [‐0.48, 1.24]; Wilcoxon p=0.001). Preoperative to 24‐hour postoperative change in CPAR was greater among patients who developed delirium vs those who did not (median [IQR] 1.31 [0.004, 2.34] vs 0.19 [‐0.55, 1.08]; p=0.003). In a multivariable model adjusting for age, baseline cognition, and surgery type, preoperative to 24‐hour postoperative change in CPAR was independently associated with delirium occurrence (per CPAR increase of 1, OR = 1.30, [95% CI 1.03‐1.63]; p=0.026) and increased hospital length of stay (IRR = 1.15 [95% CI 1.09‐1.22]; p<0.001)InterpretationPostoperative increases in blood‐brain barrier permeability are independently associated with increased delirium rates and postoperative hospital length of stay. Although these findings do not establish causality, studies are warranted to determine whether interventions to reduce postoperative blood‐brain barrier dysfunction would reduce postoperative delirium rates and hospital length of stay.This article is protected by copyright. All rights reserved.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Role of Blood–Brain Barrier Dysfunction in Delirium following Non‐cardiac Surgery in Older Adults

Devinney,

Wong,

Wright

et al. 2023

Annals of Neurology

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“…Fan Wang (MIT) and used as recently reported. 12 , 13 Briefly, Fos-TRAP2 transgenic mice (Fostm2.1[icre/ERT2]Luo/J) were crossed to Ai14 tdTomato reporter mice (B6.Cg-Gt(ROSA)26Sortm14(CAG-tdTomato))Hze/J to obtain the double heterozygous (Fos-TRAP2; Ai14) mice used in the experiments described in this study (The Jackson Laboratory, Strains #030,323 and #007,914). In Fos-TRAP2; Ai14 double transgenic mice, neuronal activation and subsequent c-Fos induction results in the expression of CreER, which enters the nucleus in response to 4-hydroxytamoxifen (4-OHT) injection and causes recombination.…”

Section: Methodsmentioning

confidence: 99%

Vagus nerve stimulation rescues persistent pain following orthopedic surgery in adult mice

Wu,

Caceres,

Chen

et al. 2024

Pain

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Postoperative pain is a major clinical problem imposing a significant burden on patients and society. In a survey 2 years after orthopedic surgery, 57% of patients reported persisting postoperative pain. However, only limited progress has been made in the development of safe and effective therapies to prevent the onset and chronification of pain after orthopedic surgery. We established a tibial fracture mouse model that recapitulates clinically relevant orthopedic trauma surgery, which causes changes in neuropeptide levels in dorsal root ganglia and sustained neuroinflammation in the spinal cord. Here, we monitored extended pain behavior in this model, observing chronic bilateral hindpaw mechanical allodynia in both male and female C57BL/6J mice that persisted for >3 months after surgery. We also tested the analgesic effects of a novel, minimally invasive, bioelectronic approach to percutaneously stimulate the vagus nerve (termed percutaneous vagus nerve stimulation [pVNS]). Weekly pVNS treatment for 30 minutes at 10 Hz for 3 weeks after the surgery strongly reduced pain behaviors compared with untreated controls. Percutaneous vagus nerve stimulation also improved locomotor coordination and accelerated bone healing. In the dorsal root ganglia, vagal stimulation inhibited the activation of glial fibrillary acidic protein-positive satellite cells but without affecting microglial activation. Overall, these data provide novel evidence supportive of the use of pVNS to prevent postoperative pain and inform translational studies to test antinociceptive effects of bioelectronic medicine in the clinic.

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“…For example, leveraging clinical specimens and established biomarkers from wellphenotyped human cohorts can be combined with preclinical models to further clarify the role of specific biomarkers involved in delirium. 64 In addition, clinical studies may identify genetic predispositions to inform model creation and distinguish among mechanistic subtypes or mechanism-phenotype associations. When revealed, effective pharmacological treatments for delirium in humans or treatments that disrupt the delirium-neurodegeneration link present powerful opportunities for validating models that may ultimately have clinical benefit.…”

Section: Realistic Goals For Preclinical Modelsmentioning

confidence: 99%

“…Lastly, although current murine delirium models have illustrated moderate utility, improvement within the models requires further cross validation between clinical and preclinical research. For example, leveraging clinical specimens and established biomarkers from well‐phenotyped human cohorts can be combined with preclinical models to further clarify the role of specific biomarkers involved in delirium 64 . In addition, clinical studies may identify genetic predispositions to inform model creation and distinguish among mechanistic subtypes or mechanism‐phenotype associations.…”

Section: Introductionmentioning

confidence: 99%

Preclinical and translational models for delirium: Recommendations for future research from the NIDUS delirium network

Vasunilashorn

Lunardi

Newman

et al. 2023

Alzheimer's & Dementia

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Delirium is a common, morbid, and costly syndrome that is closely linked to Alzheimer's disease (AD) and AD-related dementias (ADRD) as a risk factor and outcome. Human studies of delirium have advanced our knowledge of delirium incidence and prevalence, risk factors, biomarkers, outcomes, prevention, and management. However, understanding of delirium neurobiology remains limited. Preclinical and translational models for delirium, while challenging to develop, could advance our knowledge of delirium neurobiology and inform the development of new prevention and treatment approaches. We discuss the use of preclinical and translational animal models in delirium, focusing on (1) a review of current animal models, (2) challenges and strategies for replicating elements of human delirium in animals, and (3) the utility of biofluid, neurophysiology, and neuroimaging translational markers in animals. We conclude with recommendations for the development and validation of preclinical and translational models for delirium, with the goal of advancing awareness in this important field.

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Conserved YKL-40 changes in mice and humans after postoperative delirium

Cited by 6 publications

References 47 publications

Role of Blood–Brain Barrier Dysfunction in Delirium following Non‐cardiac Surgery in Older Adults

Role of Blood–Brain Barrier Dysfunction in Delirium following Non‐cardiac Surgery in Older Adults

Vagus nerve stimulation rescues persistent pain following orthopedic surgery in adult mice

Preclinical and translational models for delirium: Recommendations for future research from the NIDUS delirium network

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