- Email: [email protected]
Cytokines and postoperative delirium in older patients undergoing major elective surgery
Podium Presentations: Tuesday, July 21, 2015
6,000 of these subjects into the EPAD Longitudinal Cohort Study (LCS). This cohort will provide a trial ready cohort, provide data for pre-clinical disease models and risk stratification as well as run-in data of the highest quality for analyses of an intervention’s efficacy in the EPAD Proof-of-Concept trial. This adaptive trial will involve 1,500 subjects at any one time and be constructed to allow testing of drugs concurrently and in combination against a shared placebo group. Results: The Consortium has 36 partners working across 8 Work Plans. The final protocol for the EPAD-LCS will be delivered in Autumn 2015. Key methodological elements of this protocol in terms of subject selection, outcome measures and recruitment will be presented. Conclusions: In 2016 EPAD will provide an environment for the optimal testing of interventions at the PoC stage of development. The EPAD LCS is a critical element within the platform. The EPAD Consortium is also working with other IMI projects (EMIF and AETIONOMY) as part of the IMI-AD Platform and with the GAP Initiative to share knowledge, ideas and approaches for the secondary prevention of Alzheimer’s dementia. S3-02-03
RATIONALLY ITERATING NOVEL TRIALS DESIGNS
Lon S. Schneider, Keck School of Medicine of USC, Los Angeles, CA, USA. Contact e-mail: [email protected]
Abstract not available. S3-02-04
ETHICS IN ALZHEIMER’S DISEASE PREVENTION CLINICAL TRIAL DESIGN
Joshua D. Grill, University of California, Irvine, Irvine, CA, USA. Contact e-mail: [email protected]
Abstract not available. TUESDAY, JULY 21, 2015 FEATURED RESEARCH SESSIONS F3-01 THE IMPACT OF POSTOPERATIVE DELIRIUM ON COGNITIVE DECLINE: INFLAMMATION, NEUROPATHOLOGY, AND OUTCOMES F3-01-01
CYTOKINES AND POSTOPERATIVE DELIRIUM IN OLDER PATIENTS UNDERGOING MAJOR ELECTIVE SURGERY
P211
Sarinnapha (Fah) Vasunilashorn1, Edward Marcantonio2, 1Beth Israel Deaconess Medical Center, Boston, MA, USA; 2Harvard Medical School, Boston, MA, USA. Contact e-mail: [email protected] Background: A proinflammatory state has been associated with several age-associated conditions; however, the role of inflammation in delirium remains poorly characterized. Methods: We used the Successful Aging after Elective Surgery (SAGES) Study of 566 adults aged 70 undergoing major non-cardiac surgery (24% with delirium) to conduct a nested, matched, case-control study. Seventy-five pairs of delirium cases and non-delirious controls matched on age, sex, surgery type, baseline cognition, vascular comorbidity, Apolipoprotein E genotype were selected. Twelve cytokines were measured at 4 timepoints: preoperative (PREOP), postanesthesia care unit (PACU), postoperative day 2 (POD2) and 30 days later (POD1M). Non-parametric signed-rank tests evaluating median differences in cytokine levels between matched pairs were used to identify delirium-associated cytokines. Results: Match variables were similar in cases and controls. Compared to controls, cases had significantly higher IL-6 on POD2 (median difference [pg/ml] 39.35, p<.01), and IL-2 at all timepoints (0.99, 0.77, 1.07, 0.73 at PREOP, PACU, POD2, POD1M, respectively, p<.05). Conclusions: In this large, well-characterized cohort assessed at multiple timepoints, we observed an inflammatory signature for delirium involving elevated IL-6 at POD2 and elevated IL-2 at all timepoints. These two cytokines may be important disease and risk markers for delirium, respectively. Our findings support an emerging model of delirium in which certain individuals are primed for dysregulated inflammatory responses to a physiological stressor (major surgery), which may cross the blood brain barrier and lead to neuroinflammation and neuronal injury. This model may explain the relationship between short term delirium and long term cognitive decline after surgery. F3-01-02
THE NEUROCHEMISTRY OF DELIRIUM
Niccolo Terrando, Karolinska Institute, Stockholm, Sweden. Contact e-mail: [email protected] Background: Postoperative delirium often complicates recovery
from major surgery and associates with significant mortality, further co-morbidities, and increasing healthcare costs. Data from preclinical studies support the concept that neuroinflammation and activation of the innate immune system contribute to the pathophysiology of postoperative delirium. The impact of immune-
Table 1 Autopsied Mayo Clinic research participants who underwent antemortem PET and MRI within three years of death, and were classified as SNAP. *
PART
SNAP cases
Pathologic diagnosis
Final
Initial
Age
APOE
Braak tangle stage
Thai amyloid phase
Time (y)
PiB
FDG
HvA
1 2 3 4 5 6 7 8
Normal Normal/VaD FTLD/HpScI FTLD/HpScI CBD/AGD PSP PA/AG D TLBD/PA
Definite Definite Definite Definite Definite Possible Not met Not met
Definite Definite Definite Definite Not met Not met Not met Not met
85 76 66 76 79 83 65 88
23 23 33 33 23 24 34 33
II-III III 0 I III-IV III-IV II III
0 0 0 0 0 1 3 3
1.7 1.4 1.4 2.0 2.2 2.8 2.3 3.0
-
+ + + + + + + +
+ n/a + + + +
*PART was diagnosed based on Braak & Thai for initial classification, and significant co-existing pathology was used for final diagnosis. Acronyms: PET¼Positron emission tomography; MRI¼Magnetic resonance imaging; SNAP¼ Suspected Non-Alzheimer Pathophysiology; PART¼Primary age-related tauopathy; y¼Years; PiB¼11 C-Pittsburgh compound B; FDG¼18F-Fluorodeoxyglucose; HvA¼Hippocampal volume atrophy; VaD¼Vascular disease; FTLD¼Frontotemporal lobar degeneration; HpScl¼Hippocampal sclerosis; CBD¼Corticobasal degeneration; AGD¼Argyrophilic grains disease; PSP¼Progressive supranuclear palsy; PA¼Pathological aging; TLBD¼Transitional Lewy body disease.
6,000 of these subjects into the EPAD Longitudinal Cohort Study (LCS). This cohort will provide a trial ready cohort, provide data for pre-clinical disease models and risk stratification as well as run-in data of the highest quality for analyses of an intervention’s efficacy in the EPAD Proof-of-Concept trial. This adaptive trial will involve 1,500 subjects at any one time and be constructed to allow testing of drugs concurrently and in combination against a shared placebo group. Results: The Consortium has 36 partners working across 8 Work Plans. The final protocol for the EPAD-LCS will be delivered in Autumn 2015. Key methodological elements of this protocol in terms of subject selection, outcome measures and recruitment will be presented. Conclusions: In 2016 EPAD will provide an environment for the optimal testing of interventions at the PoC stage of development. The EPAD LCS is a critical element within the platform. The EPAD Consortium is also working with other IMI projects (EMIF and AETIONOMY) as part of the IMI-AD Platform and with the GAP Initiative to share knowledge, ideas and approaches for the secondary prevention of Alzheimer’s dementia. S3-02-03
RATIONALLY ITERATING NOVEL TRIALS DESIGNS
Lon S. Schneider, Keck School of Medicine of USC, Los Angeles, CA, USA. Contact e-mail: [email protected]
Abstract not available. S3-02-04
ETHICS IN ALZHEIMER’S DISEASE PREVENTION CLINICAL TRIAL DESIGN
Joshua D. Grill, University of California, Irvine, Irvine, CA, USA. Contact e-mail: [email protected]
Abstract not available. TUESDAY, JULY 21, 2015 FEATURED RESEARCH SESSIONS F3-01 THE IMPACT OF POSTOPERATIVE DELIRIUM ON COGNITIVE DECLINE: INFLAMMATION, NEUROPATHOLOGY, AND OUTCOMES F3-01-01
CYTOKINES AND POSTOPERATIVE DELIRIUM IN OLDER PATIENTS UNDERGOING MAJOR ELECTIVE SURGERY
P211
Sarinnapha (Fah) Vasunilashorn1, Edward Marcantonio2, 1Beth Israel Deaconess Medical Center, Boston, MA, USA; 2Harvard Medical School, Boston, MA, USA. Contact e-mail: [email protected] Background: A proinflammatory state has been associated with several age-associated conditions; however, the role of inflammation in delirium remains poorly characterized. Methods: We used the Successful Aging after Elective Surgery (SAGES) Study of 566 adults aged 70 undergoing major non-cardiac surgery (24% with delirium) to conduct a nested, matched, case-control study. Seventy-five pairs of delirium cases and non-delirious controls matched on age, sex, surgery type, baseline cognition, vascular comorbidity, Apolipoprotein E genotype were selected. Twelve cytokines were measured at 4 timepoints: preoperative (PREOP), postanesthesia care unit (PACU), postoperative day 2 (POD2) and 30 days later (POD1M). Non-parametric signed-rank tests evaluating median differences in cytokine levels between matched pairs were used to identify delirium-associated cytokines. Results: Match variables were similar in cases and controls. Compared to controls, cases had significantly higher IL-6 on POD2 (median difference [pg/ml] 39.35, p<.01), and IL-2 at all timepoints (0.99, 0.77, 1.07, 0.73 at PREOP, PACU, POD2, POD1M, respectively, p<.05). Conclusions: In this large, well-characterized cohort assessed at multiple timepoints, we observed an inflammatory signature for delirium involving elevated IL-6 at POD2 and elevated IL-2 at all timepoints. These two cytokines may be important disease and risk markers for delirium, respectively. Our findings support an emerging model of delirium in which certain individuals are primed for dysregulated inflammatory responses to a physiological stressor (major surgery), which may cross the blood brain barrier and lead to neuroinflammation and neuronal injury. This model may explain the relationship between short term delirium and long term cognitive decline after surgery. F3-01-02
THE NEUROCHEMISTRY OF DELIRIUM
Niccolo Terrando, Karolinska Institute, Stockholm, Sweden. Contact e-mail: [email protected] Background: Postoperative delirium often complicates recovery
from major surgery and associates with significant mortality, further co-morbidities, and increasing healthcare costs. Data from preclinical studies support the concept that neuroinflammation and activation of the innate immune system contribute to the pathophysiology of postoperative delirium. The impact of immune-
Table 1 Autopsied Mayo Clinic research participants who underwent antemortem PET and MRI within three years of death, and were classified as SNAP. *
PART
SNAP cases
Pathologic diagnosis
Final
Initial
Age
APOE
Braak tangle stage
Thai amyloid phase
Time (y)
PiB
FDG
HvA
1 2 3 4 5 6 7 8
Normal Normal/VaD FTLD/HpScI FTLD/HpScI CBD/AGD PSP PA/AG D TLBD/PA
Definite Definite Definite Definite Definite Possible Not met Not met
Definite Definite Definite Definite Not met Not met Not met Not met
85 76 66 76 79 83 65 88
23 23 33 33 23 24 34 33
II-III III 0 I III-IV III-IV II III
0 0 0 0 0 1 3 3
1.7 1.4 1.4 2.0 2.2 2.8 2.3 3.0
-
+ + + + + + + +
+ n/a + + + +
*PART was diagnosed based on Braak & Thai for initial classification, and significant co-existing pathology was used for final diagnosis. Acronyms: PET¼Positron emission tomography; MRI¼Magnetic resonance imaging; SNAP¼ Suspected Non-Alzheimer Pathophysiology; PART¼Primary age-related tauopathy; y¼Years; PiB¼11 C-Pittsburgh compound B; FDG¼18F-Fluorodeoxyglucose; HvA¼Hippocampal volume atrophy; VaD¼Vascular disease; FTLD¼Frontotemporal lobar degeneration; HpScl¼Hippocampal sclerosis; CBD¼Corticobasal degeneration; AGD¼Argyrophilic grains disease; PSP¼Progressive supranuclear palsy; PA¼Pathological aging; TLBD¼Transitional Lewy body disease.