The Role of Inflammation after Surgery for Elders (RISE) study: Examination of [11C]PBR28 binding and exploration of its link to post-operative delirium

Katsumi, Yuta; Racine, Annie M.; Torrado‐Carvajal, Angel; Loggia, Marco L.; Hooker, Jacob M.; Greve, Douglas N.; Hightower, B. G.; Catana, Ciprian; Cavallari, Michele; Arnold, Steven E.; Fong, Tamara G.; Vasunilashorn, Sarinnapha; Marcantonio, Edward R.; Schmitt, Eva M.; Xu, Guoquan; Libermann, Towia A.; Barrett, Lisa Feldman; Inouye, Sharon K.; Dickerson, Bradford C.; Touroutoglou, Alexandra; Collins, Jessica

doi:10.1016/j.nicl.2020.102346

Cited by 19 publications

(17 citation statements)

References 96 publications

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“…No significant relationship was identified between post-operative delirium and [ 11 C]PBR28 binding, possibly related to the small number (n = 6) of delirium cases in the sample. 34 Prior studies have found a significant association between reduced CSF Aβ 42 and increased t-tau with delirium status in adjusted analyses among patients without dementia, supporting the notion that preclinical AD brain pathology may play a role in delirium pathophysiology. 9 A recent study of older hip fracture patients found a higher than expected prevalence of positive ATN biomarkers (89% of patients who had no cognitive impairment), suggesting that a large proportion of individuals with hip fracture may have preclinical or prodromal AD; furthermore, the investigators hypothesized that postoperative delirium may also be due to brain vulnerability reflected by underlying AD pathology as well.…”

Section: Discussionmentioning

confidence: 76%

“…In prior work in RISE, we examined [ 11 C]PBR28 positron emission tomography (PET) as a measure of neuroinflammation, but we unexpectedly found that PBR28 binding in the brain was globally downregulated at 1 month following major orthopedic surgery, suggesting a paradoxical downregulation of the isotope binding in the brain. No significant relationship was identified between post‐operative delirium and [ 11 C]PBR28 binding, possibly related to the small number ( n = 6) of delirium cases in the sample 34 …”

Section: Discussionmentioning

confidence: 90%

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Association of CSF Alzheimer's disease biomarkers with postoperative delirium in older adults

Fong

Vasunilashorn

Gou

et al. 2021

A&D Transl Res & Clin Interv

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Introduction The interaction between delirium and dementia is complex. We examined if Alzheimer's disease (AD) biomarkers in patients without clinical dementia are associated with increased risk of postoperative delirium, and whether AD biomarkers demonstrate a graded association with delirium severity. Methods Participants ( n = 59) were free of clinical dementia, age 70 years, and scheduled for elective total knee or hip arthroplasties. Cerebrospinal fluid (CSF) was collected at the time of induction for spinal anesthesia. CSF AD biomarkers were measured by enzyme‐linked immunosorbent assay (ELISA) (ADX/Euroimmun); cut points for amyloid, tau, and neurodegeneration (ATN) biomarker status were A = amyloid beta (Aβ) 42 <175 pg/mL or Aβ 42/40 ratio <0.07; T = p‐tau >80 pg/mL; and N = t‐tau >700 pg/mL. Confusion Assessment Method (CAM) and CAM‐Severity (CAM‐S) were rated daily post‐operatively for delirium and delirium severity, respectively. Results Aβ 42 , tau, and p‐tau mean pg/mL (SD) were 361.5 (326.1), 618.3 (237.1), and 97.1 (66.1), respectively, for those with delirium, and 550.4 (291.6), 518.3 (213.5), and 54.6 (34.5), respectively, for those without delirium. Thirteen participants (22%) were ATN positive. Delirium severity by peak CAM‐S [mean difference (95% confidence interval)] was 1.48 points higher (0.29‐2.67), P = 0.02 among the ATN positive. Delirium in the ATN‐positive group trended toward but did not reach statistical significance (23% vs. 7%, p = 0.10). Peak CAM‐S [mean (SD)] in the delirium group was 7 (2.8) compared to no delirium group 2.5 (1.3), but when groups were further classified by ATN status, an incremental effect on delirium severity was observed, such that patients who were both ATN and delirium negative had the lowest mean (SD) peak CAM‐S scores of 2.5 (1.3) points, whereas those who were ATN and delirium positive had CAM‐S scores of 8.7 (2.3) points; other groups (either ATN or delirium positive) had intermediate CAM‐S scores. Discussion The presence of AD biomarkers adds important information in predicting delirium severity. Future studies are needed to confirm this relationship and to better understand the role of AD biomarkers, even in pre‐clinical phase, in delirium.

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Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 90%

Association of CSF Alzheimer's disease biomarkers with postoperative delirium in older adults

Fong

Vasunilashorn

Gou

et al. 2021

A&D Transl Res & Clin Interv

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“…In animal models [ 14 , 19 , 20 , 37 , 38 ] as well as human studies [ 39 , 40 ], ibuprofen is successfully shown to reduce systemic as well as neuroinflammation. Since we [ 25 ] and others [ 6 ] strongly indicated a role for (neuro)inflammation in the development of POCD, we anticipated that ibuprofen would inhibit (neuro)inflammation and improve cognitive performance.…”

Section: Discussionmentioning

confidence: 99%

“…In young rats, hippocampus-dependent memory was shown specifically sensitive to the effects of surgery [ 11 , 12 , 25 , 39 , 40 ]. Accordingly, ibuprofen improved hippocampus-dependent spatial memory in young rats.…”

Section: Discussionmentioning

confidence: 99%

Acute pre-operative ibuprofen improves cognition in a rat model for postoperative cognitive dysfunction

Oberman

Haan

Leeuwen

et al. 2021

J Neuroinflammation

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Background Inflammation is considered a key factor in the development of postoperative cognitive dysfunction (POCD). Therefore, we hypothesized that pre-operative anti-inflammatory treatment with ibuprofen would inhibit POCD in our rat-model. Methods Male Wistar rats of 3 or 23 months old received a single injection of ibuprofen (15 mg/kg i.p.) or were control handled before abdominal surgery. Timed blood and fecal samples were collected for analyses of inflammation markers and gut microbiome changes. Behavioral testing was performed from 9 to 14 days after surgery, in the open field, novel object- and novel location-recognition tests and Morris water maze. Neuroinflammation and neurogenesis were assessed by immune histochemistry after sacrifice on postoperative day 14. Results Ibuprofen improved short-term spatial memory in the novel location recognition test, and increased hippocampal neurogenesis. However, these effects were associated with increased hippocampal microglia activity. Whereas plasma cytokine levels (IL1-β, IL6, IL10, and TNFα) were not significantly affected, VEGF levels increased and IFABP levels decreased after ibuprofen. Long-term memory in the Morris water maze was not significantly improved by ibuprofen. The gut microbiome was neither significantly affected by surgery nor by ibuprofen treatment. In general, effects in aged rats appeared similar to those in young rats, though less pronounced. Conclusion A single injection of ibuprofen before surgery improved hippocampus-associated short-term memory after surgery and increased neurogenesis. However, this favorable outcome seemed not attributable to inhibition of (neuro)inflammation. Potential contributions of intestinal and blood-brain barrier integrity need further investigation. Although less pronounced compared to young rats, effects in aged rats indicate that even elderly individuals could benefit from ibuprofen treatment.

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“…It also underscores the value of considering other modalities for measuring neuroinflammation, including [ 11 C] PBR28 on PET imaging. In the RISE study, we recently reported that between the baseline and PO1MO time points, inflammation measured by [ 11 C] PBR28 on PET imaging decreased [ 28 ]. Technical issues with PBR28, as described in the manuscript, may explain this surprising result.…”

Section: Discussionmentioning

confidence: 99%

Plasma and cerebrospinal fluid inflammation and the blood-brain barrier in older surgical patients: the Role of Inflammation after Surgery for Elders (RISE) study

Vasunilashorn

Ngo

Dillon

et al. 2021

J Neuroinflammation

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Background Our understanding of the relationship between plasma and cerebrospinal fluid (CSF) remains limited, which poses an obstacle to the identification of blood-based markers of neuroinflammatory disorders. To better understand the relationship between peripheral and central nervous system (CNS) markers of inflammation before and after surgery, we aimed to examine whether surgery compromises the blood-brain barrier (BBB), evaluate postoperative changes in inflammatory markers, and assess the correlations between plasma and CSF levels of inflammation. Methods We examined the Role of Inflammation after Surgery for Elders (RISE) study of adults aged ≥ 65 who underwent elective hip or knee surgery under spinal anesthesia who had plasma and CSF samples collected at baseline and postoperative 1 month (PO1MO) (n = 29). Plasma and CSF levels of three inflammatory markers previously identified as increasing after surgery were measured using enzyme-linked immunosorbent assay: interleukin-6 (IL-6), C-reactive protein (CRP), and chitinase 3-like protein (also known as YKL-40). The integrity of the BBB was computed as the ratio of CSF/plasma albumin levels (Qalb). Mean Qalb and levels of inflammation were compared between baseline and PO1MO. Spearman correlation coefficients were used to determine the correlation between biofluids. Results Mean Qalb did not change between baseline and PO1MO. Mean plasma and CSF levels of CRP and plasma levels of YKL-40 and IL-6 were higher on PO1MO relative to baseline, with a disproportionally higher increase in CRP CSF levels relative to plasma levels (CRP tripled in CSF vs. increased 10% in plasma). Significant plasma-CSF correlations for CRP (baseline r = 0.70 and PO1MO r = 0.89, p < .01 for both) and IL-6 (PO1MO r = 0.48, p < .01) were observed, with higher correlations on PO1MO compared with baseline. Conclusions In this elective surgical sample of older adults, BBB integrity was similar between baseline and PO1MO, plasma-CSF correlations were observed for CRP and IL-6, plasma levels of all three markers (CRP, IL-6, and YKL-40) increased from PREOP to PO1MO, and CSF levels of only CRP increased between the two time points. Our identification of potential promising plasma markers of inflammation in the CNS may facilitate the early identification of patients at greatest risk for neuroinflammation and its associated adverse cognitive outcomes.

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The Role of Inflammation after Surgery for Elders (RISE) study: Examination of [11C]PBR28 binding and exploration of its link to post-operative delirium

Cited by 19 publications

References 96 publications

Association of CSF Alzheimer's disease biomarkers with postoperative delirium in older adults

Association of CSF Alzheimer's disease biomarkers with postoperative delirium in older adults

Acute pre-operative ibuprofen improves cognition in a rat model for postoperative cognitive dysfunction

Plasma and cerebrospinal fluid inflammation and the blood-brain barrier in older surgical patients: the Role of Inflammation after Surgery for Elders (RISE) study

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