- Email: [email protected]
FROM BIG DATA TO SMART DATA: THE ROLE OF METABOLOMICS IN GENERATING ACTIONABLE KNOWLEDGE IN ALZHEIMER’S DISEASE FOR PERSONALIZED TREATMENT
P544
Podium Presentations: Monday, July 17, 2017
and genotypes on clinical response is important in optimizing clinical trial design as imbalance in the pharmacodynamic interactions between treatment arms can reduce clinical effect size. Combining humanized mechanism-based modeling with information from metabolomics has the capacity to further improve this predictive approach and ultimately increase the probability of success in clinical trials. MONDAY, JULY 17, 2017 FEATURED RESEARCH SESSION F2-02 THE CHANGING NATURE OF DEMENTIA AND COGNITIVE IMPAIRMENT ACROSS TWO GENERATIONS: IMPLICATIONS FOR THE FUTURE — EVIDENCE FROM THE COGNITIVE FUNCTION AGEING STUDIES I AND II Figure 1. Association of a ratio GCDCA:CDCA profile with brain structure using whole brain surface-based analysis using two independent cohorts: (a) ADNI-1 (discovery sample) and (b) ADNI-GO-2 (replication sample). Whole-brain cortical thickness analysis demonstrated the identification and replication of brain regions, especially bilateral temporal lobes, significantly associated with bile acid levels. Higher levels were associated with more structural atrophy or reduced cortical thickness. Statistical maps computed using SurfStat were thresholded using random field theory (RFT) as a multiple testing correction at p-corrected < 0.05.
with AD-related structural and functional neuroimaging phenotypes. Our results provide further support that bile acid signaling machinery is most likely implicated in neurodegenerative diseases.
F2-01-04
FROM BIG DATA TO SMART DATA: THE ROLE OF METABOLOMICS IN GENERATING ACTIONABLE KNOWLEDGE IN ALZHEIMER’S DISEASE FOR PERSONALIZED TREATMENT
Hugo Geerts, In Silico Biosciences, Berwyn, PA, USA. Contact e-mail: [email protected] Background: Recent technological advances are creating large data-
bases based on deep phenotyping, such as metabolomics. At the same time, individual clinical progression is very different from AD patient to AD patient. The next challenge is to generate actionable knowledge in terms of novel drug discovery and development and public health guidelines, especially with regard to personalized treatment. A concrete and immediate useful objective for clinical trial design is to study the pharmacodynamic impact of comedications and genotypes on clinical response. Methods: We propose to use a combination of traditional bio-informatics approaches with a mechanism-based Quantitative Systems Pharmacology (QSP) modeling of relevant neuronal circuits that drive cognitive outcome. Metabolomics data allow for documenting changes in relevant intracellular pathways; for instance, changes in neurotransmitter or precursor/metabolite levels can have a direct effect on firing dynamics in brain networks and clinical outcome. Results: The QSP platform has shown its predictive value by correctly predicting an unexpected clinical outcome of 3 novel drugs, just based on the preclinical pharmacology. When applied to the impact of b-amyloid changes to ADAS-Cog, the model predicts that the impact of COMTVal158Met can be more than 3 points on ADAS-Cog and that the APOE genotype does not affect the cognitive trajectory despite its differential effect on b-amyloid. In general, the SLC6A4 5-HTT LPR genotype has a complex non-linear interaction with b-amyloid and both memantine’s beneficial effect and its synergy with donepezil is dependent upon the patient’s Abeta load and disease state in a nonmonotonic way. Conclusions: Estimating the impact of comedications
F2-02-01
THE IMPACT OF INCIDENCE PRIOR TO DEATH ON THE INCIDENCE OF DEMENTIA IN INDIVIDUALS AGED 65 YEARS AND OLDER
Carol Brayne1, Fiona Matthews2, Cognitive Function and Ageing Study, 1 University of Cambridge, Cambridge, United Kingdom; 2Newcastle University, Newcastle upon Tyne, United Kingdom. Contact e-mail: [email protected] Background: Recent population studies of dementia from Europe and
the US suggest that dementia risk at specific ages in some societies might be lower for current older people than those from earlier generations however existing models do not adjust for changes in mortality. Methods: Between 1989 and 1994 investigators carried out baseline interviews in populations aged 65 years and over in six geographically defined areas of England and Wales. Three of these sites (CFAS I) were selected to provide comparison sites for an entirely new study – the Cognitive Function and Ageing Study II (CFAS II) in which populations aged 65 and over were recruited from the same geographical areas two decades after CFAS I using the same geographical boundaries, sampling and approach methods. For both CFAS I and II a two year follow-up was conducted in order to estimate incidence. Full likelihood modelling and multiple imputation were used to adjust for study design, non-response and longitudinal attrition, with those individuals who died by the second wave the number of incident cases of dementia at death were also included. Results: Even with mortality changes the incidence across the two decades had dropped by 20% (95% CI 0%40%). This drop was driven by a reduction in men at all ages. These findings suggest that in the UK in addition to the 210,000 incident cases per year, 74,000 in men and 135,000 in women, there are an additional estimated 97,000 cases occurring in individuals who die very rapidly between the two year screening stages. Conclusions: Prevalence is a function of incidence and mortality. Incidence has declined; mortality will also be tracked to establish whether the improvement seen is associated with higher or lower mortality for people once they do develop the dementia syndrome. Our findings therefore have considerable implications for policies related to mitigation of the impact of dementia on current and future societies around the world.
F2-02-02
THE CHANGING FACE OF MILD COGNITIVE IMPAIRMENT (MCI) AND MILD DEMENTIA
Connor Richardson1, Fiona Matthews1, Louise Robinson1, Blossom C. M. Stephan1, Cognitive Function and Ageing Study, 1 Newcastle University, Newcastle upon Tyne, United Kingdom. Contact e-mail: [email protected]
Podium Presentations: Monday, July 17, 2017
and genotypes on clinical response is important in optimizing clinical trial design as imbalance in the pharmacodynamic interactions between treatment arms can reduce clinical effect size. Combining humanized mechanism-based modeling with information from metabolomics has the capacity to further improve this predictive approach and ultimately increase the probability of success in clinical trials. MONDAY, JULY 17, 2017 FEATURED RESEARCH SESSION F2-02 THE CHANGING NATURE OF DEMENTIA AND COGNITIVE IMPAIRMENT ACROSS TWO GENERATIONS: IMPLICATIONS FOR THE FUTURE — EVIDENCE FROM THE COGNITIVE FUNCTION AGEING STUDIES I AND II Figure 1. Association of a ratio GCDCA:CDCA profile with brain structure using whole brain surface-based analysis using two independent cohorts: (a) ADNI-1 (discovery sample) and (b) ADNI-GO-2 (replication sample). Whole-brain cortical thickness analysis demonstrated the identification and replication of brain regions, especially bilateral temporal lobes, significantly associated with bile acid levels. Higher levels were associated with more structural atrophy or reduced cortical thickness. Statistical maps computed using SurfStat were thresholded using random field theory (RFT) as a multiple testing correction at p-corrected < 0.05.
with AD-related structural and functional neuroimaging phenotypes. Our results provide further support that bile acid signaling machinery is most likely implicated in neurodegenerative diseases.
F2-01-04
FROM BIG DATA TO SMART DATA: THE ROLE OF METABOLOMICS IN GENERATING ACTIONABLE KNOWLEDGE IN ALZHEIMER’S DISEASE FOR PERSONALIZED TREATMENT
Hugo Geerts, In Silico Biosciences, Berwyn, PA, USA. Contact e-mail: [email protected] Background: Recent technological advances are creating large data-
bases based on deep phenotyping, such as metabolomics. At the same time, individual clinical progression is very different from AD patient to AD patient. The next challenge is to generate actionable knowledge in terms of novel drug discovery and development and public health guidelines, especially with regard to personalized treatment. A concrete and immediate useful objective for clinical trial design is to study the pharmacodynamic impact of comedications and genotypes on clinical response. Methods: We propose to use a combination of traditional bio-informatics approaches with a mechanism-based Quantitative Systems Pharmacology (QSP) modeling of relevant neuronal circuits that drive cognitive outcome. Metabolomics data allow for documenting changes in relevant intracellular pathways; for instance, changes in neurotransmitter or precursor/metabolite levels can have a direct effect on firing dynamics in brain networks and clinical outcome. Results: The QSP platform has shown its predictive value by correctly predicting an unexpected clinical outcome of 3 novel drugs, just based on the preclinical pharmacology. When applied to the impact of b-amyloid changes to ADAS-Cog, the model predicts that the impact of COMTVal158Met can be more than 3 points on ADAS-Cog and that the APOE genotype does not affect the cognitive trajectory despite its differential effect on b-amyloid. In general, the SLC6A4 5-HTT LPR genotype has a complex non-linear interaction with b-amyloid and both memantine’s beneficial effect and its synergy with donepezil is dependent upon the patient’s Abeta load and disease state in a nonmonotonic way. Conclusions: Estimating the impact of comedications
F2-02-01
THE IMPACT OF INCIDENCE PRIOR TO DEATH ON THE INCIDENCE OF DEMENTIA IN INDIVIDUALS AGED 65 YEARS AND OLDER
Carol Brayne1, Fiona Matthews2, Cognitive Function and Ageing Study, 1 University of Cambridge, Cambridge, United Kingdom; 2Newcastle University, Newcastle upon Tyne, United Kingdom. Contact e-mail: [email protected] Background: Recent population studies of dementia from Europe and
the US suggest that dementia risk at specific ages in some societies might be lower for current older people than those from earlier generations however existing models do not adjust for changes in mortality. Methods: Between 1989 and 1994 investigators carried out baseline interviews in populations aged 65 years and over in six geographically defined areas of England and Wales. Three of these sites (CFAS I) were selected to provide comparison sites for an entirely new study – the Cognitive Function and Ageing Study II (CFAS II) in which populations aged 65 and over were recruited from the same geographical areas two decades after CFAS I using the same geographical boundaries, sampling and approach methods. For both CFAS I and II a two year follow-up was conducted in order to estimate incidence. Full likelihood modelling and multiple imputation were used to adjust for study design, non-response and longitudinal attrition, with those individuals who died by the second wave the number of incident cases of dementia at death were also included. Results: Even with mortality changes the incidence across the two decades had dropped by 20% (95% CI 0%40%). This drop was driven by a reduction in men at all ages. These findings suggest that in the UK in addition to the 210,000 incident cases per year, 74,000 in men and 135,000 in women, there are an additional estimated 97,000 cases occurring in individuals who die very rapidly between the two year screening stages. Conclusions: Prevalence is a function of incidence and mortality. Incidence has declined; mortality will also be tracked to establish whether the improvement seen is associated with higher or lower mortality for people once they do develop the dementia syndrome. Our findings therefore have considerable implications for policies related to mitigation of the impact of dementia on current and future societies around the world.
F2-02-02
THE CHANGING FACE OF MILD COGNITIVE IMPAIRMENT (MCI) AND MILD DEMENTIA
Connor Richardson1, Fiona Matthews1, Louise Robinson1, Blossom C. M. Stephan1, Cognitive Function and Ageing Study, 1 Newcastle University, Newcastle upon Tyne, United Kingdom. Contact e-mail: [email protected]