Diabetic patients treated with metformin during early stages of Alzheimer's disease show a better integral performance: data from ADNI study

We evaluated the effect of the antidiabetic drug metformin on patients enrolled in the ADNI study considering patients with mild cognitive impairment (MCI) due to Alzheimer's disease (AD). Employing data from this observational study, we performed a principal component analysis focusing on the...

Full description

Autores:
Pomilio, Carlos
González Pérez, Nicolás
Calandri, Ismael
Crivelli, Lucía
Allegri, Ricardo
Sevlever, Gustavo
Saravia, Flavia
Tipo de recurso:
Article of investigation
Fecha de publicación:
2022
Institución:
Corporación Universidad de la Costa
Repositorio:
REDICUC - Repositorio CUC
Idioma:
eng
OAI Identifier:
oai:repositorio.cuc.edu.co:11323/10907
Acceso en línea:
https://hdl.handle.net/11323/10907
https://repositorio.cuc.edu.co
Palabra clave:
Alzheimer's disease
Metformin
Type 2 diabetes
Rights
openAccess
License
Atribución-NoComercial-SinDerivadas 4.0 Internacional (CC BY-NC-ND 4.0)
id RCUC2_6ba94fef2996606e450346d449d16146
oai_identifier_str oai:repositorio.cuc.edu.co:11323/10907
network_acronym_str RCUC2
network_name_str REDICUC - Repositorio CUC
repository_id_str
dc.title.eng.fl_str_mv Diabetic patients treated with metformin during early stages of Alzheimer's disease show a better integral performance: data from ADNI study
title Diabetic patients treated with metformin during early stages of Alzheimer's disease show a better integral performance: data from ADNI study
spellingShingle Diabetic patients treated with metformin during early stages of Alzheimer's disease show a better integral performance: data from ADNI study
Alzheimer's disease
Metformin
Type 2 diabetes
title_short Diabetic patients treated with metformin during early stages of Alzheimer's disease show a better integral performance: data from ADNI study
title_full Diabetic patients treated with metformin during early stages of Alzheimer's disease show a better integral performance: data from ADNI study
title_fullStr Diabetic patients treated with metformin during early stages of Alzheimer's disease show a better integral performance: data from ADNI study
title_full_unstemmed Diabetic patients treated with metformin during early stages of Alzheimer's disease show a better integral performance: data from ADNI study
title_sort Diabetic patients treated with metformin during early stages of Alzheimer's disease show a better integral performance: data from ADNI study
dc.creator.fl_str_mv Pomilio, Carlos
González Pérez, Nicolás
Calandri, Ismael
Crivelli, Lucía
Allegri, Ricardo
Sevlever, Gustavo
Saravia, Flavia
dc.contributor.author.none.fl_str_mv Pomilio, Carlos
González Pérez, Nicolás
Calandri, Ismael
Crivelli, Lucía
Allegri, Ricardo
Sevlever, Gustavo
Saravia, Flavia
dc.subject.proposal.eng.fl_str_mv Alzheimer's disease
Metformin
Type 2 diabetes
topic Alzheimer's disease
Metformin
Type 2 diabetes
description We evaluated the effect of the antidiabetic drug metformin on patients enrolled in the ADNI study considering patients with mild cognitive impairment (MCI) due to Alzheimer's disease (AD). Employing data from this observational study, we performed a principal component analysis focusing on the cognitive sphere by evaluating data from neuropsychological tests included in a modified version of the Alzheimer's Disease Cooperative Study-Preclinical Alzheimer Cognitive Composite (ADCS-PACC). Second, we included the levels of amyloid-beta, tau, and phosphorylated tau in CSF. We found that MCI metformin-treated patients were globally characterized as subjects with a better cognitive performance and CSF biomarkers profile than the mean population of MCI patients. On the other hand, control subjects and type 2 diabetes patients (T2D) were paired by age, gender, ApoE allele, and years of education, defining three groups: MCI, MCI + T2D, and MCI + T2D + metformin. We evaluated the effect of T2D and metformin treatment employing the PACC score and composites defined from standardized ADNI variables to evaluate the memory and learning function. We found that MCI + T2D patients had a worse cognitive performance than MCI patients, but this deleterious effect was not observed in MCI + T2D + metformin patients. These cognitive variations were associated with changes in cortical thickness and hippocampal volume. Finally, no differences were found in metabolic plasmatic parameters (glycemia, cholesterol, triglycerides). Our study-employing different strategies for data analysis from the global study ADNI-shows a beneficial effect of metformin treatment on cognitive performance, CSF biomarkers profile, and neuroanatomical measures in MCI due to AD patients.
publishDate 2022
dc.date.issued.none.fl_str_mv 2022
dc.date.accessioned.none.fl_str_mv 2024-03-21T14:50:04Z
dc.date.available.none.fl_str_mv 2024-03-21T14:50:04Z
dc.type.spa.fl_str_mv Artículo de revista
dc.type.coar.spa.fl_str_mv http://purl.org/coar/resource_type/c_2df8fbb1
dc.type.content.spa.fl_str_mv Text
dc.type.driver.spa.fl_str_mv info:eu-repo/semantics/article
dc.type.redcol.spa.fl_str_mv http://purl.org/redcol/resource_type/ART
dc.type.version.spa.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.coarversion.spa.fl_str_mv http://purl.org/coar/version/c_970fb48d4fbd8a85
format http://purl.org/coar/resource_type/c_2df8fbb1
status_str publishedVersion
dc.identifier.citation.spa.fl_str_mv Pomilio, C., Pérez, N.G., Calandri, I. et al. Diabetic patients treated with metformin during early stages of Alzheimer’s disease show a better integral performance: data from ADNI study. GeroScience 44, 1791–1805 (2022). https://doi-org.ezproxy.cuc.edu.co/10.1007/s11357-022-00568-6
dc.identifier.issn.spa.fl_str_mv 2509-2715
dc.identifier.uri.none.fl_str_mv https://hdl.handle.net/11323/10907
dc.identifier.doi.none.fl_str_mv 10.1007/s11357-022-00568-6
dc.identifier.instname.spa.fl_str_mv Corporación Universidad de la Costa
dc.identifier.reponame.spa.fl_str_mv REDICUC - Repositorio CUC
dc.identifier.repourl.spa.fl_str_mv https://repositorio.cuc.edu.co
identifier_str_mv Pomilio, C., Pérez, N.G., Calandri, I. et al. Diabetic patients treated with metformin during early stages of Alzheimer’s disease show a better integral performance: data from ADNI study. GeroScience 44, 1791–1805 (2022). https://doi-org.ezproxy.cuc.edu.co/10.1007/s11357-022-00568-6
2509-2715
10.1007/s11357-022-00568-6
Corporación Universidad de la Costa
REDICUC - Repositorio CUC
url https://hdl.handle.net/11323/10907
https://repositorio.cuc.edu.co
dc.language.iso.spa.fl_str_mv eng
language eng
dc.relation.ispartofjournal.spa.fl_str_mv GeroScience
dc.relation.references.spa.fl_str_mv 1. Abbatecola AM, Paolisso G, Lamponi M, Bandinelli S, Lauretani F, et al. Insulin resistance and executive dysfunction in older persons. Journal of the American Geriatrics Society. 2004;52:1713–8.
2. Andreasen N, Blennow K. Beta-amyloid (Abeta) protein in cerebrospinal fuid as a biomarker for Alzheimer’s disease. Peptides. 2002;23:1205–14.
3. Arai H, Terajima M, Miura M, Higuchi S, Muramatsu T, et al. Tau in cerebrospinal fuid: a potential diagnostic marker in Alzheimer’s disease. Ann Neurol. 1995;38:649–52.
4. Alzheimer’s Association. Alzheimer’s disease facts and fgures. 2018. https://www.alz.org/media/HomeOfce/ Facts%20and%20Figures/facts-and-fgures.pdf.
5. Bakkour A, Morris JC, Dickerson BC. The cortical signature of prodromal AD: regional thinning predicts mild AD dementia. Neurology. 2009;72:1048–55.
6. Bharath LP, Agrawal M, McCambridge G, Nicholas DA, Hasturk H, et al. Metformin enhances autophagy and normalizes mitochondrial function to alleviate aging-associated infammation. Cell metabolism. 2020;32:44-55 e6.
7. Biancardi VC, Son SJ, Ahmadi S, Filosa JA, Stern JE. Circulating angiotensin II gains access to the hypothalamus and brain stem during hypertension via breakdown of the blood-brain barrier. Hypertension. 2014;63:572–9.
8. Blennow K, Zetterberg H. Biomarkers for Alzheimer’s disease: current status and prospects for the future. J Intern Med. 2018;284:643–63.
9. Criado-Marrero M, Smith TM, Gould LA, Kim S, Penny HJ, et al. FKBP5 and early life stress afect the hippocampus by an age-dependent mechanism. Brain, behavior, & immunity - health. 2020;9:100143.
10. Chen J, Ou Y, Li Y, Hu S, Shao LW, Liu Y. Metformin extends C. elegans lifespan through lysosomal pathway. eLife 2017;6.
11. Chen Y, Zhao S, Fan Z, Li Z, Zhu Y, et al. Metformin attenuates plaque-associated tau pathology and reduces amyloid-beta burden in APP/PS1 mice. Alzheimer’s research & therapy. 2021;13:40.
12. Donohue MC, Sperling RA, Salmon DP, Rentz DM, Raman R, et al. The preclinical Alzheimer cognitive composite: measuring amyloid-related decline. JAMA Neurol. 2014;71:961–70.
13. Duarte AI, Moreira PI, Oliveira CR. Insulin in central nervous system: more than just a peripheral hormone. Journal of aging research. 2012;2012:384017.
14. Farr SA, Roesler E, Niehof ML, Roby DA, McKee A, Morley JE. Metformin improves learning and memory in the SAMP8 mouse model of Alzheimer’s disease. Journal of Alzheimer’s disease : JAD. 2019;68:1699–710.
15. Ghasemi R, Haeri A, Dargahi L, Mohamed Z, Ahmadiani A. Insulin in the brain: sources, localization and functions. Mol Neurobiol. 2013;47:145–71.
16. Han J, Li Y, Liu X, Zhou T, Sun H, et al. Metformin suppresses retinal angiogenesis and infammation in vitro and in vivo. PloS one. 2018;13:e0193031.
17. Ihara M, Saito S. Drug repositioning for Alzheimer’s disease: fnding hidden clues in old drugs. Journal of Alzheimer’s disease : JAD. 2020;74:1013–28.
18. Imfeld P, Bodmer M, Jick SS, Meier CR. Metformin, other antidiabetic drugs, and risk of Alzheimer’s disease: a population-based case-control study. J Am Geriatr Soc. 2012;60:916–21.
19. Jack CR Jr, Bennett DA, Blennow K, Carrillo MC, Dunn B, et al. NIA-AA research framework: toward a biological defnition of Alzheimer’s disease. Alzheimer’s Dementia. 2018;14:535–62.
20. Justice JN, Gubbi S, Kulkarni AS, Bartley JM, Kuchel GA, Barzilai N. A geroscience perspective on immune resilience and infectious diseases: a potential case for metformin. GeroScience. 2021;43:1093–112.
21. Kim D, Lee JE, Jung YJ, Lee AS, Lee S, et al. Metformin decreases high-fat diet-induced renal injury by regulating the expression of adipokines and the renal AMP-activated protein kinase/acetyl-CoA carboxylase pathway in mice. Int J Mol Med. 2013;32:1293–302.
22. Kinney JW, Bemiller SM, Murtishaw AS, Leisgang AM, Salazar AM, Lamb BT. Infammation as a central mechanism in Alzheimer’s disease. Alzheimers Dement (N Y). 2018;4:575–90.
23. Kivipelto M, Mangialasche F, Snyder HM, Allegri R, Andrieu S, et al. World-Wide FINGERS Network: a global approach to risk reduction and prevention of dementia. Alzheimer’s Dementia. 2020;16:1078–94.
24. Koenig AM, Mechanic-Hamilton D, Xie SX, Combs MF, Cappola AR, et al. Efects of the insulin sensitizer metformin in Alzheimer disease: pilot data from a randomized placebo-controlled crossover study. Alzheimer Dis Assoc Disord. 2017;31:107–13.
25. Lee S, Kang BM, Kim JH, Min J, Kim HS, et al. Real-time in vivo two-photon imaging study reveals decreased cerebro-vascular volume and increased bloodbrain barrier permeability in chronically stressed mice. Sci Rep. 2018;8:13064.
26. Li MZ, Zheng LJ, Shen J, Li XY, Zhang Q, et al. SIRT1 facilitates amyloid beta peptide degradation by upregulating lysosome number in primary astrocytes. Neural Regen Res. 2018;13:2005–13.
27. Liu X, Chhipa RR, Nakano I, Dasgupta B. The AMPK inhibitor compound C is a potent AMPK-independent antiglioma agent. Mol Cancer Ther. 2014;13:596–605.
28. Lv WS, Wen JP, Li L, Sun RX, Wang J, et al. The efect of metformin on food intake and its potential role in hypothalamic regulation in obese diabetic rats. Brain Res. 2012;1444:11–9.
29. Ma R, Yi B, Riker AI, Xi Y. Metformin and cancer immunity. Acta Pharmacol Sin. 2020;41:1403–9.
30. MacVicar BA, Newman EA. Astrocyte regulation of blood fow in the brain. Cold Spring Harbor Perspect Biol 2015;7.
31. Manaenko A, Chen H, Kammer J, Zhang JH, Tang J. Comparison Evans Blue injection routes: intravenous versus intraperitoneal, for measurement of blood-brain barrier in a mice hemorrhage model. J Neurosci Methods. 2011;195:206–10.
32. Markowicz-Piasecka M, Sikora J, Szydlowska A, Skupien A, Mikiciuk-Olasik E, Huttunen KM. Metformin - a future therapy for neurodegenerative diseases: Theme: Drug Discovery, Development and Delivery in Alzheimer’s Disease Guest Editor: Davide Brambilla. Pharm Res. 2017;34:2614–27.
33. Martin-Montalvo A, Mercken EM, Mitchell SJ, Palacios HH, Mote PL, et al. Metformin improves healthspan and lifespan in mice. Nat Commun. 2013;4:2192.
34. Moore EM, Mander AG, Ames D, Kotowicz MA, Carne RP, et al. Increased risk of cognitive impairment in patients with diabetes is associated with metformin. Diabetes Care. 2013;36:2981–7.
35. Ng TP, Feng L, Yap KB, Lee TS, Tan CH, Winblad B. Long-term metformin usage and cognitive function among older adults with diabetes. Journal of Alzheimer’s disease : JAD. 2014;41:61–8.
36. Ngandu T, Lehtisalo J, Solomon A, Levalahti E, Ahtiluoto S, et al. A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial. Lancet. 2015;385:2255–63.
37. Ping F, Jiang N, Li Y. Association between metformin and neurodegenerative diseases of observational studies: systematic review and meta-analysis. BMJ Open Diabetes Res Care 2020;8.
38. Ronaldson PT, Davis TP. Blood-brain barrier integrity and glial support: mechanisms that can be targeted for novel therapeutic approaches in stroke. Curr Pharm Des. 2012;18:3624–44.
39. Samaras K, Makkar S, Crawford JD, Kochan NA, Wen W, et al. Metformin use is associated with slowed cognitive decline and reduced incident dementia in older adults with type 2 diabetes: the Sydney Memory and Ageing Study. Diabetes Care. 2020;43:2691–701.
40. Soraya H, Clanachan AS, Rameshrad M, Maleki-Dizaji N, Ghazi-Khansari M, Garjani A. Chronic treatment with metformin suppresses toll-like receptor 4 signaling and attenuates left ventricular dysfunction following myocardial infarction. Eur J Pharmacol. 2014;737:77–84.
41. Stranahan AM, Arumugam TV, Cutler RG, Lee K, Egan JM, Mattson MP. Diabetes impairs hippocampal function through glucocorticoid-mediated efects on new and mature neurons. Nat Neurosci. 2008;11:309–17.
42. Vinuesa A, Bentivegna M, Calfa G, Filipello F, Pomilio C, et al. Early exposure to a high-fat diet impacts on hippocampal plasticity: implication of microglia-derived exosome-like extracellular vesicles. Mol Neurobiol. 2019;56:5075–94.
43. Wang YW, He SJ, Feng X, Cheng J, Luo YT, et al. Metformin: a review of its potential indications. Drug Des Dev Ther. 2017;11:2421–9.
44. White MD, Angiolini JF, Alvarez YD, Kaur G, Zhao ZW, et al. Long-lived binding of Sox2 to DNA predicts cell fate in the four-cell mouse embryo. Cell. 2016;165:75–87.
45. Yuan SY, Liu J, Zhou J, Lu W, Zhou HY, et al. AMPK mediates glucocorticoids stress-induced downregulation of the glucocorticoid receptor in cultured rat prefrontal cortical astrocytes. PloS one. 2016;11:e0159513.
dc.relation.citationendpage.spa.fl_str_mv 1805
dc.relation.citationstartpage.spa.fl_str_mv 1791
dc.relation.citationissue.spa.fl_str_mv 3
dc.relation.citationvolume.spa.fl_str_mv 44
dc.rights.eng.fl_str_mv The Author(s), under exclusive licence to American Aging Association 2022
dc.rights.license.spa.fl_str_mv Atribución-NoComercial-SinDerivadas 4.0 Internacional (CC BY-NC-ND 4.0)
dc.rights.uri.spa.fl_str_mv https://creativecommons.org/licenses/by-nc-nd/4.0/
dc.rights.accessrights.spa.fl_str_mv info:eu-repo/semantics/openAccess
dc.rights.coar.spa.fl_str_mv http://purl.org/coar/access_right/c_abf2
rights_invalid_str_mv Atribución-NoComercial-SinDerivadas 4.0 Internacional (CC BY-NC-ND 4.0)
The Author(s), under exclusive licence to American Aging Association 2022
https://creativecommons.org/licenses/by-nc-nd/4.0/
http://purl.org/coar/access_right/c_abf2
eu_rights_str_mv openAccess
dc.format.extent.spa.fl_str_mv 15 páginas
dc.format.mimetype.spa.fl_str_mv application/pdf
dc.publisher.spa.fl_str_mv Springer International Publishing AG
dc.publisher.place.spa.fl_str_mv Switzerland
dc.source.spa.fl_str_mv https://www-webofscience-com.ezproxy.cuc.edu.co/wos/woscc/full-record/WOS:000784956600001
institution Corporación Universidad de la Costa
bitstream.url.fl_str_mv https://repositorio.cuc.edu.co/bitstreams/14f31c2d-76c9-434b-ab30-7ddcb4face54/download
https://repositorio.cuc.edu.co/bitstreams/568d0f20-48f4-49c4-91c7-beb18961b481/download
https://repositorio.cuc.edu.co/bitstreams/8adf1b0f-e87e-4cf6-b14d-1d93a984cf93/download
https://repositorio.cuc.edu.co/bitstreams/11b2d907-fa5d-4ea8-91a1-5a7277f9af91/download
bitstream.checksum.fl_str_mv be636c3445431ebfa7f8ba7c2bf60240
2f9959eaf5b71fae44bbf9ec84150c7a
0965b2da184cf4b2fb1a9e8090bf34a1
65ec6fa465af64db32d5b263274a7bd9
bitstream.checksumAlgorithm.fl_str_mv MD5
MD5
MD5
MD5
repository.name.fl_str_mv Repositorio de la Universidad de la Costa CUC
repository.mail.fl_str_mv repdigital@cuc.edu.co
_version_ 1811760711214301184
spelling Atribución-NoComercial-SinDerivadas 4.0 Internacional (CC BY-NC-ND 4.0)The Author(s), under exclusive licence to American Aging Association 2022https://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2Pomilio, CarlosGonzález Pérez, NicolásCalandri, IsmaelCrivelli, LucíaAllegri, RicardoSevlever, GustavoSaravia, Flavia2024-03-21T14:50:04Z2024-03-21T14:50:04Z2022Pomilio, C., Pérez, N.G., Calandri, I. et al. Diabetic patients treated with metformin during early stages of Alzheimer’s disease show a better integral performance: data from ADNI study. GeroScience 44, 1791–1805 (2022). https://doi-org.ezproxy.cuc.edu.co/10.1007/s11357-022-00568-62509-2715https://hdl.handle.net/11323/1090710.1007/s11357-022-00568-6Corporación Universidad de la CostaREDICUC - Repositorio CUChttps://repositorio.cuc.edu.coWe evaluated the effect of the antidiabetic drug metformin on patients enrolled in the ADNI study considering patients with mild cognitive impairment (MCI) due to Alzheimer's disease (AD). Employing data from this observational study, we performed a principal component analysis focusing on the cognitive sphere by evaluating data from neuropsychological tests included in a modified version of the Alzheimer's Disease Cooperative Study-Preclinical Alzheimer Cognitive Composite (ADCS-PACC). Second, we included the levels of amyloid-beta, tau, and phosphorylated tau in CSF. We found that MCI metformin-treated patients were globally characterized as subjects with a better cognitive performance and CSF biomarkers profile than the mean population of MCI patients. On the other hand, control subjects and type 2 diabetes patients (T2D) were paired by age, gender, ApoE allele, and years of education, defining three groups: MCI, MCI + T2D, and MCI + T2D + metformin. We evaluated the effect of T2D and metformin treatment employing the PACC score and composites defined from standardized ADNI variables to evaluate the memory and learning function. We found that MCI + T2D patients had a worse cognitive performance than MCI patients, but this deleterious effect was not observed in MCI + T2D + metformin patients. These cognitive variations were associated with changes in cortical thickness and hippocampal volume. Finally, no differences were found in metabolic plasmatic parameters (glycemia, cholesterol, triglycerides). Our study-employing different strategies for data analysis from the global study ADNI-shows a beneficial effect of metformin treatment on cognitive performance, CSF biomarkers profile, and neuroanatomical measures in MCI due to AD patients.15 páginasapplication/pdfengSpringer International Publishing AGSwitzerlandhttps://www-webofscience-com.ezproxy.cuc.edu.co/wos/woscc/full-record/WOS:000784956600001Diabetic patients treated with metformin during early stages of Alzheimer's disease show a better integral performance: data from ADNI studyArtículo de revistahttp://purl.org/coar/resource_type/c_2df8fbb1Textinfo:eu-repo/semantics/articlehttp://purl.org/redcol/resource_type/ARTinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/version/c_970fb48d4fbd8a85GeroScience1. Abbatecola AM, Paolisso G, Lamponi M, Bandinelli S, Lauretani F, et al. Insulin resistance and executive dysfunction in older persons. Journal of the American Geriatrics Society. 2004;52:1713–8.2. Andreasen N, Blennow K. Beta-amyloid (Abeta) protein in cerebrospinal fuid as a biomarker for Alzheimer’s disease. Peptides. 2002;23:1205–14.3. Arai H, Terajima M, Miura M, Higuchi S, Muramatsu T, et al. Tau in cerebrospinal fuid: a potential diagnostic marker in Alzheimer’s disease. Ann Neurol. 1995;38:649–52.4. Alzheimer’s Association. Alzheimer’s disease facts and fgures. 2018. https://www.alz.org/media/HomeOfce/ Facts%20and%20Figures/facts-and-fgures.pdf.5. Bakkour A, Morris JC, Dickerson BC. The cortical signature of prodromal AD: regional thinning predicts mild AD dementia. Neurology. 2009;72:1048–55.6. Bharath LP, Agrawal M, McCambridge G, Nicholas DA, Hasturk H, et al. Metformin enhances autophagy and normalizes mitochondrial function to alleviate aging-associated infammation. Cell metabolism. 2020;32:44-55 e6.7. Biancardi VC, Son SJ, Ahmadi S, Filosa JA, Stern JE. Circulating angiotensin II gains access to the hypothalamus and brain stem during hypertension via breakdown of the blood-brain barrier. Hypertension. 2014;63:572–9.8. Blennow K, Zetterberg H. Biomarkers for Alzheimer’s disease: current status and prospects for the future. J Intern Med. 2018;284:643–63.9. Criado-Marrero M, Smith TM, Gould LA, Kim S, Penny HJ, et al. FKBP5 and early life stress afect the hippocampus by an age-dependent mechanism. Brain, behavior, & immunity - health. 2020;9:100143.10. Chen J, Ou Y, Li Y, Hu S, Shao LW, Liu Y. Metformin extends C. elegans lifespan through lysosomal pathway. eLife 2017;6.11. Chen Y, Zhao S, Fan Z, Li Z, Zhu Y, et al. Metformin attenuates plaque-associated tau pathology and reduces amyloid-beta burden in APP/PS1 mice. Alzheimer’s research & therapy. 2021;13:40.12. Donohue MC, Sperling RA, Salmon DP, Rentz DM, Raman R, et al. The preclinical Alzheimer cognitive composite: measuring amyloid-related decline. JAMA Neurol. 2014;71:961–70.13. Duarte AI, Moreira PI, Oliveira CR. Insulin in central nervous system: more than just a peripheral hormone. Journal of aging research. 2012;2012:384017.14. Farr SA, Roesler E, Niehof ML, Roby DA, McKee A, Morley JE. Metformin improves learning and memory in the SAMP8 mouse model of Alzheimer’s disease. Journal of Alzheimer’s disease : JAD. 2019;68:1699–710.15. Ghasemi R, Haeri A, Dargahi L, Mohamed Z, Ahmadiani A. Insulin in the brain: sources, localization and functions. Mol Neurobiol. 2013;47:145–71.16. Han J, Li Y, Liu X, Zhou T, Sun H, et al. Metformin suppresses retinal angiogenesis and infammation in vitro and in vivo. PloS one. 2018;13:e0193031.17. Ihara M, Saito S. Drug repositioning for Alzheimer’s disease: fnding hidden clues in old drugs. Journal of Alzheimer’s disease : JAD. 2020;74:1013–28.18. Imfeld P, Bodmer M, Jick SS, Meier CR. Metformin, other antidiabetic drugs, and risk of Alzheimer’s disease: a population-based case-control study. J Am Geriatr Soc. 2012;60:916–21.19. Jack CR Jr, Bennett DA, Blennow K, Carrillo MC, Dunn B, et al. NIA-AA research framework: toward a biological defnition of Alzheimer’s disease. Alzheimer’s Dementia. 2018;14:535–62.20. Justice JN, Gubbi S, Kulkarni AS, Bartley JM, Kuchel GA, Barzilai N. A geroscience perspective on immune resilience and infectious diseases: a potential case for metformin. GeroScience. 2021;43:1093–112.21. Kim D, Lee JE, Jung YJ, Lee AS, Lee S, et al. Metformin decreases high-fat diet-induced renal injury by regulating the expression of adipokines and the renal AMP-activated protein kinase/acetyl-CoA carboxylase pathway in mice. Int J Mol Med. 2013;32:1293–302.22. Kinney JW, Bemiller SM, Murtishaw AS, Leisgang AM, Salazar AM, Lamb BT. Infammation as a central mechanism in Alzheimer’s disease. Alzheimers Dement (N Y). 2018;4:575–90.23. Kivipelto M, Mangialasche F, Snyder HM, Allegri R, Andrieu S, et al. World-Wide FINGERS Network: a global approach to risk reduction and prevention of dementia. Alzheimer’s Dementia. 2020;16:1078–94.24. Koenig AM, Mechanic-Hamilton D, Xie SX, Combs MF, Cappola AR, et al. Efects of the insulin sensitizer metformin in Alzheimer disease: pilot data from a randomized placebo-controlled crossover study. Alzheimer Dis Assoc Disord. 2017;31:107–13.25. Lee S, Kang BM, Kim JH, Min J, Kim HS, et al. Real-time in vivo two-photon imaging study reveals decreased cerebro-vascular volume and increased bloodbrain barrier permeability in chronically stressed mice. Sci Rep. 2018;8:13064.26. Li MZ, Zheng LJ, Shen J, Li XY, Zhang Q, et al. SIRT1 facilitates amyloid beta peptide degradation by upregulating lysosome number in primary astrocytes. Neural Regen Res. 2018;13:2005–13.27. Liu X, Chhipa RR, Nakano I, Dasgupta B. The AMPK inhibitor compound C is a potent AMPK-independent antiglioma agent. Mol Cancer Ther. 2014;13:596–605.28. Lv WS, Wen JP, Li L, Sun RX, Wang J, et al. The efect of metformin on food intake and its potential role in hypothalamic regulation in obese diabetic rats. Brain Res. 2012;1444:11–9.29. Ma R, Yi B, Riker AI, Xi Y. Metformin and cancer immunity. Acta Pharmacol Sin. 2020;41:1403–9.30. MacVicar BA, Newman EA. Astrocyte regulation of blood fow in the brain. Cold Spring Harbor Perspect Biol 2015;7.31. Manaenko A, Chen H, Kammer J, Zhang JH, Tang J. Comparison Evans Blue injection routes: intravenous versus intraperitoneal, for measurement of blood-brain barrier in a mice hemorrhage model. J Neurosci Methods. 2011;195:206–10.32. Markowicz-Piasecka M, Sikora J, Szydlowska A, Skupien A, Mikiciuk-Olasik E, Huttunen KM. Metformin - a future therapy for neurodegenerative diseases: Theme: Drug Discovery, Development and Delivery in Alzheimer’s Disease Guest Editor: Davide Brambilla. Pharm Res. 2017;34:2614–27.33. Martin-Montalvo A, Mercken EM, Mitchell SJ, Palacios HH, Mote PL, et al. Metformin improves healthspan and lifespan in mice. Nat Commun. 2013;4:2192.34. Moore EM, Mander AG, Ames D, Kotowicz MA, Carne RP, et al. Increased risk of cognitive impairment in patients with diabetes is associated with metformin. Diabetes Care. 2013;36:2981–7.35. Ng TP, Feng L, Yap KB, Lee TS, Tan CH, Winblad B. Long-term metformin usage and cognitive function among older adults with diabetes. Journal of Alzheimer’s disease : JAD. 2014;41:61–8.36. Ngandu T, Lehtisalo J, Solomon A, Levalahti E, Ahtiluoto S, et al. A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial. Lancet. 2015;385:2255–63.37. Ping F, Jiang N, Li Y. Association between metformin and neurodegenerative diseases of observational studies: systematic review and meta-analysis. BMJ Open Diabetes Res Care 2020;8.38. Ronaldson PT, Davis TP. Blood-brain barrier integrity and glial support: mechanisms that can be targeted for novel therapeutic approaches in stroke. Curr Pharm Des. 2012;18:3624–44.39. Samaras K, Makkar S, Crawford JD, Kochan NA, Wen W, et al. Metformin use is associated with slowed cognitive decline and reduced incident dementia in older adults with type 2 diabetes: the Sydney Memory and Ageing Study. Diabetes Care. 2020;43:2691–701.40. Soraya H, Clanachan AS, Rameshrad M, Maleki-Dizaji N, Ghazi-Khansari M, Garjani A. Chronic treatment with metformin suppresses toll-like receptor 4 signaling and attenuates left ventricular dysfunction following myocardial infarction. Eur J Pharmacol. 2014;737:77–84.41. Stranahan AM, Arumugam TV, Cutler RG, Lee K, Egan JM, Mattson MP. Diabetes impairs hippocampal function through glucocorticoid-mediated efects on new and mature neurons. Nat Neurosci. 2008;11:309–17.42. Vinuesa A, Bentivegna M, Calfa G, Filipello F, Pomilio C, et al. Early exposure to a high-fat diet impacts on hippocampal plasticity: implication of microglia-derived exosome-like extracellular vesicles. Mol Neurobiol. 2019;56:5075–94.43. Wang YW, He SJ, Feng X, Cheng J, Luo YT, et al. Metformin: a review of its potential indications. Drug Des Dev Ther. 2017;11:2421–9.44. White MD, Angiolini JF, Alvarez YD, Kaur G, Zhao ZW, et al. Long-lived binding of Sox2 to DNA predicts cell fate in the four-cell mouse embryo. Cell. 2016;165:75–87.45. Yuan SY, Liu J, Zhou J, Lu W, Zhou HY, et al. AMPK mediates glucocorticoids stress-induced downregulation of the glucocorticoid receptor in cultured rat prefrontal cortical astrocytes. PloS one. 2016;11:e0159513.18051791344Alzheimer's diseaseMetforminType 2 diabetesPublicationORIGINALDiabetic patients treated with metformin during early stages of Alzheimer's disease show a better integral performance.pdfDiabetic patients treated with metformin during early stages of Alzheimer's disease show a better integral performance.pdfArtículoapplication/pdf1027836https://repositorio.cuc.edu.co/bitstreams/14f31c2d-76c9-434b-ab30-7ddcb4face54/downloadbe636c3445431ebfa7f8ba7c2bf60240MD51LICENSElicense.txtlicense.txttext/plain; charset=utf-814828https://repositorio.cuc.edu.co/bitstreams/568d0f20-48f4-49c4-91c7-beb18961b481/download2f9959eaf5b71fae44bbf9ec84150c7aMD52TEXTDiabetic patients treated with metformin during early stages of Alzheimer's disease show a better integral performance.pdf.txtDiabetic patients treated with metformin during early stages of Alzheimer's disease show a better integral performance.pdf.txtExtracted texttext/plain57592https://repositorio.cuc.edu.co/bitstreams/8adf1b0f-e87e-4cf6-b14d-1d93a984cf93/download0965b2da184cf4b2fb1a9e8090bf34a1MD53THUMBNAILDiabetic patients treated with metformin during early stages of Alzheimer's disease show a better integral performance.pdf.jpgDiabetic patients treated with metformin during early stages of Alzheimer's disease show a better integral performance.pdf.jpgGenerated Thumbnailimage/jpeg14968https://repositorio.cuc.edu.co/bitstreams/11b2d907-fa5d-4ea8-91a1-5a7277f9af91/download65ec6fa465af64db32d5b263274a7bd9MD5411323/10907oai:repositorio.cuc.edu.co:11323/109072024-09-17 10:45:21.048https://creativecommons.org/licenses/by-nc-nd/4.0/The Author(s), under exclusive licence to American Aging Association 2022open.accesshttps://repositorio.cuc.edu.coRepositorio de la Universidad de la Costa CUCrepdigital@cuc.edu.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

Publicaciones similares