- Email: [email protected]
Prevention trials
P210
Podium Presentations: Tuesday, July 21, 2015
Background: We recently showed that brains of aged individuals who suffer from type-2 diabetes (T2D) with dementia accumulate large vascular deposits of amylin, a pancreatic hormone that has amyloidogenic and cytotoxic properties similar to the b-amyloid peptide. In an animal model, we demonstrated that the brain amylin deposition is associated with neuroinflammation and impaired exploratory drive, vestibulomotor function and long-term recognition memory. Here, we tested a possible immune response to the vascular amylin deposits in an animal model. Methods: Because rodent amylin is neither amyloidogenic nor cytotoxic, we used HIP rats (N¼30) that overexpress human amylin in the pancreas and develop diabetes at 10-12 months of age. Age- and glucose-matched UCD rats (N¼20) expressing only wild-type (WT) amylin were used as controls. The level of incorporated oligomerized amylin in vascular media was measured with an antibody specific for human amylin. Brain capillaries were investigated for inflammatory markers by western blot. In addition, smooth muscle cells (SMCs) were isolated from small diameter cerebral (pial) arteries and tested for the activation status of the receptor for advanced glycation endproducts (RAGE) by immunofluorescence. SMCs were also assayed for lipid peroxidation products using confocal microscopy analysis of the fluorescent probes C11-BODIPY581/591 and Liperfluo. Results: Brain capillaries from HIP rats display significant levels of incorporated human amylin that correlate with a w60% downregulation (P<0.005) of the anti-inflammatory cytokine IL-10. Elevated RAGE activation (by w50%; P<0.005) and lipid peroxidation (by 18%; P<0.05) were detected in SMCs from HIP rats compared to UCD rats. Moreover, incubation of WT rat SMCs with exogenous amylin oligomers (50 mM; 2 hours) increased lipid peroxidation by w45% (P<0.05) and RAGE activation level by w65% (P<0.005). Glucose increased the level of RAGE activation in a dose-dependent manner for a 2 hours incubation time. In contrast, incubation for the same duration with the highest glucose dose used (400 mg/dl) had no effect on the lipid peroxidation level. Conclusions: Present results suggest that neurological deficits in diabetes are likely involving an amylin-mediated inflammatory stress response in the vascular media. Future studies should focus on identifying clinically relevant therapeutic strategies to mitigate the amylin-mediated vascular pathology.
TUESDAY, JULY 21, 2015 SYMPOSIA S3-01 RE-EVALUATION OF MODIFIABLE LIFESTYLE FACTORS IN PREVENTION S3-01-01
PREVENTION REPORT FROM ALZHEIMER’S DISEASE INTERNATIONAL (ADI)
Martin J. Prince, King’s College London, London, United Kingdom. Contact e-mail: [email protected]
Abstract not available. S3-01-02
IS THERE A NEED FOR LARGER PREVENTION TRIALS?
Laura Fratiglioni, Aging Research Center, Karolinska Institutet & Stockholm University, Stockholm, Sweden. Contact e-mail: laura. [email protected]
Abstract not available.
S3-01-03
EXPERIENTIAL AND PSYCHOSOCIAL RISK FACTORS FOR DEMENTIA
David A. Bennett, Rush University Medical Center, Chicago, IL, USA. Contact e-mail: [email protected]
Abstract not available. S3-01-04
IS IT TIME TO GO BEYOND RANDOMIZED CONTROLLED TRIALS?
Kaarin J. Anstey, Centre for Research on Ageing, Health and Wellbeing, Dementia Collaborative Research Centre, Research School of Population Health, The Australian National University, Canberra, Australia. Contact e-mail: [email protected]
Abstract not available. TUESDAY, JULY 21, 2015 SYMPOSIA S3-02 NOVEL TRIAL DESIGN S3-02-01
QUANTIFYING THE PLACEBO EFFECT THROUGH MODELING AND SIMULATION
Klaus Romero1, Kaori Ito2, Brian Corrigan2, Richard J. Anziano2, Jon Neville3, Diane Stephenson1, Richard Lalonde2, CAMD AD Modeling and Simulation Team, 1Coalition Against Major Diseases, Critical Path Institute, Tucson, AZ, USA; 2Pfizer, Groton, CT, USA; 3Critical Path Institute, Tucson, AZ, USA. Contact e-mail: [email protected] Background: Understanding the magnitude, duration and variability of the placebo effect in longitudinal Alzheimer’s disease (AD) studies is critical in order to optimally design clinical trials and interpret their results. Standardized and integrated data, along with literature data, provide a platform to develop quantitative models for the placebo effect. Methods: The placebo response component from an FDA/EMA-endorsed drug-disease-trial model for AD, developed from ADNI, CAMD and the literature, is used to illustrate disease progression in the control groups from various case studies. Results: The case studies show how the varying placebo response in control arms has an impact in understanding the magnitude of drug effect in clinical trials. Relevant covariates like baseline disease severity are important factors to take into account when comparing outcomes between groups. Study duration, sample size and study design are important factors to consider when interpreting a trial’s results. These case studies show that failures in late-stage studies are not likely due to insufficient cognitive decline in the control groups. Conclusions: Meta-analytic approaches that integrate all available relevant data provide a quantitative understanding of placebo effect, disease progression and potential interpretation of treatment effects, which offers a useful tool to optimize trial design and interpretation. S3-02-02
PREVENTION TRIALS
Craig W. Ritchie, EPAD Consortium, University of Edinburgh, Edinburgh, United Kingdom. Contact e-mail: [email protected] Background: An ever-increasing understanding of neurodegenerative
disease processes preceding dementia coupled to a lack of success in developing disease modifying drugs for this condition have driven a need to undertake secondary prevention trials differently. To address this problem, a significant public-private partnership was developed by the European IMI (Innovative Medicines Initiative). Through this award, the EPAD (European Prevention of Alzheimer’s Dementia) Project was established. Methods: EPAD will draw together 24,000 subjects from existing cohorts and registers in Europe to then enter
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.
Podium Presentations: Tuesday, July 21, 2015
Background: We recently showed that brains of aged individuals who suffer from type-2 diabetes (T2D) with dementia accumulate large vascular deposits of amylin, a pancreatic hormone that has amyloidogenic and cytotoxic properties similar to the b-amyloid peptide. In an animal model, we demonstrated that the brain amylin deposition is associated with neuroinflammation and impaired exploratory drive, vestibulomotor function and long-term recognition memory. Here, we tested a possible immune response to the vascular amylin deposits in an animal model. Methods: Because rodent amylin is neither amyloidogenic nor cytotoxic, we used HIP rats (N¼30) that overexpress human amylin in the pancreas and develop diabetes at 10-12 months of age. Age- and glucose-matched UCD rats (N¼20) expressing only wild-type (WT) amylin were used as controls. The level of incorporated oligomerized amylin in vascular media was measured with an antibody specific for human amylin. Brain capillaries were investigated for inflammatory markers by western blot. In addition, smooth muscle cells (SMCs) were isolated from small diameter cerebral (pial) arteries and tested for the activation status of the receptor for advanced glycation endproducts (RAGE) by immunofluorescence. SMCs were also assayed for lipid peroxidation products using confocal microscopy analysis of the fluorescent probes C11-BODIPY581/591 and Liperfluo. Results: Brain capillaries from HIP rats display significant levels of incorporated human amylin that correlate with a w60% downregulation (P<0.005) of the anti-inflammatory cytokine IL-10. Elevated RAGE activation (by w50%; P<0.005) and lipid peroxidation (by 18%; P<0.05) were detected in SMCs from HIP rats compared to UCD rats. Moreover, incubation of WT rat SMCs with exogenous amylin oligomers (50 mM; 2 hours) increased lipid peroxidation by w45% (P<0.05) and RAGE activation level by w65% (P<0.005). Glucose increased the level of RAGE activation in a dose-dependent manner for a 2 hours incubation time. In contrast, incubation for the same duration with the highest glucose dose used (400 mg/dl) had no effect on the lipid peroxidation level. Conclusions: Present results suggest that neurological deficits in diabetes are likely involving an amylin-mediated inflammatory stress response in the vascular media. Future studies should focus on identifying clinically relevant therapeutic strategies to mitigate the amylin-mediated vascular pathology.
TUESDAY, JULY 21, 2015 SYMPOSIA S3-01 RE-EVALUATION OF MODIFIABLE LIFESTYLE FACTORS IN PREVENTION S3-01-01
PREVENTION REPORT FROM ALZHEIMER’S DISEASE INTERNATIONAL (ADI)
Martin J. Prince, King’s College London, London, United Kingdom. Contact e-mail: [email protected]
Abstract not available. S3-01-02
IS THERE A NEED FOR LARGER PREVENTION TRIALS?
Laura Fratiglioni, Aging Research Center, Karolinska Institutet & Stockholm University, Stockholm, Sweden. Contact e-mail: laura. [email protected]
Abstract not available.
S3-01-03
EXPERIENTIAL AND PSYCHOSOCIAL RISK FACTORS FOR DEMENTIA
David A. Bennett, Rush University Medical Center, Chicago, IL, USA. Contact e-mail: [email protected]
Abstract not available. S3-01-04
IS IT TIME TO GO BEYOND RANDOMIZED CONTROLLED TRIALS?
Kaarin J. Anstey, Centre for Research on Ageing, Health and Wellbeing, Dementia Collaborative Research Centre, Research School of Population Health, The Australian National University, Canberra, Australia. Contact e-mail: [email protected]
Abstract not available. TUESDAY, JULY 21, 2015 SYMPOSIA S3-02 NOVEL TRIAL DESIGN S3-02-01
QUANTIFYING THE PLACEBO EFFECT THROUGH MODELING AND SIMULATION
Klaus Romero1, Kaori Ito2, Brian Corrigan2, Richard J. Anziano2, Jon Neville3, Diane Stephenson1, Richard Lalonde2, CAMD AD Modeling and Simulation Team, 1Coalition Against Major Diseases, Critical Path Institute, Tucson, AZ, USA; 2Pfizer, Groton, CT, USA; 3Critical Path Institute, Tucson, AZ, USA. Contact e-mail: [email protected] Background: Understanding the magnitude, duration and variability of the placebo effect in longitudinal Alzheimer’s disease (AD) studies is critical in order to optimally design clinical trials and interpret their results. Standardized and integrated data, along with literature data, provide a platform to develop quantitative models for the placebo effect. Methods: The placebo response component from an FDA/EMA-endorsed drug-disease-trial model for AD, developed from ADNI, CAMD and the literature, is used to illustrate disease progression in the control groups from various case studies. Results: The case studies show how the varying placebo response in control arms has an impact in understanding the magnitude of drug effect in clinical trials. Relevant covariates like baseline disease severity are important factors to take into account when comparing outcomes between groups. Study duration, sample size and study design are important factors to consider when interpreting a trial’s results. These case studies show that failures in late-stage studies are not likely due to insufficient cognitive decline in the control groups. Conclusions: Meta-analytic approaches that integrate all available relevant data provide a quantitative understanding of placebo effect, disease progression and potential interpretation of treatment effects, which offers a useful tool to optimize trial design and interpretation. S3-02-02
PREVENTION TRIALS
Craig W. Ritchie, EPAD Consortium, University of Edinburgh, Edinburgh, United Kingdom. Contact e-mail: [email protected] Background: An ever-increasing understanding of neurodegenerative
disease processes preceding dementia coupled to a lack of success in developing disease modifying drugs for this condition have driven a need to undertake secondary prevention trials differently. To address this problem, a significant public-private partnership was developed by the European IMI (Innovative Medicines Initiative). Through this award, the EPAD (European Prevention of Alzheimer’s Dementia) Project was established. Methods: EPAD will draw together 24,000 subjects from existing cohorts and registers in Europe to then enter
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.