{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2024,9,1]],"date-time":"2024-09-01T07:52:33Z","timestamp":1725177153005},"reference-count":29,"publisher":"Hindawi Limited","license":[{"start":{"date-parts":[[2019,2,3]],"date-time":"2019-02-03T00:00:00Z","timestamp":1549152000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Computational and Mathematical Methods in Medicine"],"published-print":{"date-parts":[[2019,2,3]]},"abstract":"Background<\/jats:italic>. Alzheimer\u2019s disease (AD) is a major public health concern, and there is an urgent need to better understand its complex biology and develop effective therapies. AD progression can be tracked in patients through validated imaging and spinal fluid biomarkers of pathology and neuronal loss. We still, however, lack a coherent quantitative model that explains how these biomarkers interact and evolve over time. Such a model could potentially help identify the major drivers of disease in individual patients and simulate response to therapy prior to entry in clinical trials. A current theory of AD biomarker progression, known as the dynamic biomarker cascade model, hypothesizes AD biomarkers evolve in a sequential but temporally overlapping manner. A computational model incorporating assumptions about the underlying biology of this theory and its variations would be useful to test and refine its accuracy with longitudinal biomarker data from clinical trials. Methods<\/jats:italic>. We implemented a causal model to simulate time-dependent biomarker data under the descriptive assumptions of the dynamic biomarker cascade theory. We modeled pathologic biomarkers (beta-amyloid and tau), neuronal loss biomarkers, and cognitive impairment as nonlinear first-order ordinary differential equations (ODEs) to include amyloid-dependent and nondependent neurodegenerative cascades. We tested the feasibility of the model by adjusting its parameters to simulate three specific natural history scenarios in early-onset autosomal dominant AD and late-onset AD and determine whether computed biomarker trajectories agreed with current assumptions of AD biomarker progression. We also simulated the effects of antiamyloid therapy in late-onset AD. Results<\/jats:italic>. The computational model of early-onset AD demonstrated the initial appearance of amyloid, followed by biomarkers of tau and neurodegeneration and the onset of cognitive decline based on cognitive reserve, as predicted by the prior literature. Similarly, the late-onset AD computational models demonstrated the first appearance of amyloid or nonamyloid-related tauopathy, depending on the magnitude of comorbid pathology, and also closely matched the biomarker cascades predicted by the prior literature. Forward simulation of antiamyloid therapy in symptomatic late-onset AD failed to demonstrate any slowing in progression of cognitive decline, consistent with prior failed clinical trials in symptomatic patients. Conclusions<\/jats:italic>. We have developed and computationally implemented a mathematical causal model of the dynamic biomarker cascade theory in AD. We demonstrate the feasibility of this model by simulating biomarker evolution and cognitive decline in early- and late-onset natural history scenarios, as well as in a treatment scenario targeted at core AD pathology. Models resulting from this causal approach can be further developed and refined using patient data from longitudinal biomarker studies and may in the future play a key role in personalizing approaches to treatment.<\/jats:p>","DOI":"10.1155\/2019\/6216530","type":"journal-article","created":{"date-parts":[[2019,2,3]],"date-time":"2019-02-03T23:35:01Z","timestamp":1549236901000},"page":"1-8","source":"Crossref","is-referenced-by-count":36,"title":["Computational Causal Modeling of the Dynamic Biomarker Cascade in Alzheimer\u2019s Disease"],"prefix":"10.1155","volume":"2019","author":[{"ORCID":"http:\/\/orcid.org\/0000-0003-2596-217X","authenticated-orcid":true,"given":"Jeffrey R.","family":"Petrella","sequence":"first","affiliation":[{"name":"Department of Radiology, Duke University Health System, Durham, NC, USA"}]},{"given":"Wenrui","family":"Hao","sequence":"additional","affiliation":[{"name":"Department of Mathematics, Penn State University, State College, PA, USA"}]},{"given":"Adithi","family":"Rao","sequence":"additional","affiliation":[{"name":"Department of Radiology, Duke University Health System, Durham, NC, USA"}]},{"given":"P. Murali","family":"Doraiswamy","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Duke University Health System, Durham, NC, USA"}]}],"member":"98","reference":[{"key":"1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2016.04.008"},{"key":"2","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2013.37"},{"key":"3","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(09)70299-6"},{"key":"4","doi-asserted-by":"publisher","DOI":"10.1016\/s1474-4422(12)70291-0"},{"key":"5","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000002923"},{"key":"6","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2013.12.003"},{"key":"7","doi-asserted-by":"publisher","DOI":"10.1186\/alzrt269"},{"key":"8","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1202753"},{"key":"9","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2012.07.059"},{"key":"10","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awu176"},{"key":"11","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2017.05.062"},{"key":"12","doi-asserted-by":"publisher","DOI":"10.1186\/s12918-016-0348-2"},{"key":"13","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2017.02.058"},{"key":"14","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-170405"},{"key":"15","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms11934"},{"key":"16","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2018.06.028"},{"key":"17","doi-asserted-by":"publisher","DOI":"10.1038\/ng1934"},{"key":"18","doi-asserted-by":"publisher","DOI":"10.1017\/S1041610209009405"},{"key":"19","doi-asserted-by":"publisher","DOI":"10.4155\/cli.12.93"},{"key":"20","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2005.06.003"},{"key":"21","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2013.10.003"},{"key":"22","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2016.06.049"},{"key":"23","doi-asserted-by":"publisher","DOI":"10.1212\/wnl.0b013e3182840bbe"},{"key":"24","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-12289-2_8"},{"key":"25","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(13)70044-9"},{"key":"26","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2012.01.062"},{"key":"27","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2014.03.043"},{"key":"28","doi-asserted-by":"publisher","DOI":"10.1002\/hbm.20775"},{"key":"29","first-page":"347","volume-title":"Systems biology in medicine and drug development","year":"2013"}],"container-title":["Computational and Mathematical Methods in Medicine"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/downloads.hindawi.com\/journals\/cmmm\/2019\/6216530.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/downloads.hindawi.com\/journals\/cmmm\/2019\/6216530.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/downloads.hindawi.com\/journals\/cmmm\/2019\/6216530.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2019,2,3]],"date-time":"2019-02-03T23:35:04Z","timestamp":1549236904000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.hindawi.com\/journals\/cmmm\/2019\/6216530\/"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,2,3]]},"references-count":29,"alternative-id":["6216530","6216530"],"URL":"https:\/\/doi.org\/10.1155\/2019\/6216530","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/313353","asserted-by":"object"}]},"ISSN":["1748-670X","1748-6718"],"issn-type":[{"value":"1748-670X","type":"print"},{"value":"1748-6718","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,2,3]]}}}