Biomarkers for dementia in Latin American countries: gaps and opportunities

Limited knowledge on dementia biomarkers in Latin American and Caribbean (LAC) countries remains a serious barrier. Here, we reported a survey to explore the ongoing work, needs, interests, potential barriers, and opportunities for future studies related to biomarkers. The results show that neuroima...

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Autores:
Parra, Mario A.
Orellana, Paulina
Leon, Tomas
Cabello G., Victoria
Henriquez, Fernando
Gómez, Rodrigo
Avalos, Constanza
Damian, Andrés
Slachevsky, Andrea
Ibáñez, Agustín
Zetterberg, Henrik
Tijms, Betty M.
Yokoyama, Jennifer S.
Piña-Escudero, Stefanie D.
Nicholas Cochran, J.
Matallana, Diana L.
Acosta, Daisy
Allegri, Ricardo Francisco
Arias-Suárez, Bianca P.
Barra, Bernardo
Behrens, Maria Isabel
Brucki, Sonia M. D.
Busatto, Geraldo
Caramelli, Paulo
Castro-Suarez, Sheila
Contreras, Valeria
Custodio, Nilton
Dansilio, Sergio
De la Cruz-Puebla, Myriam
Cruz de Souza, Leonardo
Diaz, Monica M.
Duque, Lissette
Farías, Gonzalo A.
Ferreira, Sergio T.
Magrath Guimet, Nahuel
Kmaid, Ana
Lira, David
Lopera, Francisco
Mar Meza, Beatriz
Miotto, Eliane C.
Nitrini, Ricardo
Núñez, Alberto
O’Neill, Santiago
Ochoa, John
Pintado-Caipa, Maritza
França Resende, Elisa de Paula
Risacher, Shannon
Rojas, Luz Angela
Sabaj, Valentina
Schilling, Lucas
Sellek, Allis F.
Sosa, Ana
Takada, Leonel T.
Teixeira, Antonio L.
Unaucho-Pilalumbo, Martha
Duran-Aniotz, Claudia
Tipo de recurso:
Article of investigation
Fecha de publicación:
2023
Institución:
Corporación Universidad de la Costa
Repositorio:
REDICUC - Repositorio CUC
Idioma:
eng
OAI Identifier:
oai:repositorio.cuc.edu.co:11323/10349
Acceso en línea:
https://hdl.handle.net/11323/10349
https://repositorio.cuc.edu.co/
Palabra clave:
Dementia
Latin American
Biomarkers
Rights
openAccess
License
Atribución-NoComercial-SinDerivadas 4.0 Internacional (CC BY-NC-ND 4.0)
id RCUC2_130bf15b085cae1303e45c0f18fd910d
oai_identifier_str oai:repositorio.cuc.edu.co:11323/10349
network_acronym_str RCUC2
network_name_str REDICUC - Repositorio CUC
repository_id_str
dc.title.eng.fl_str_mv Biomarkers for dementia in Latin American countries: gaps and opportunities
title Biomarkers for dementia in Latin American countries: gaps and opportunities
spellingShingle Biomarkers for dementia in Latin American countries: gaps and opportunities
Dementia
Latin American
Biomarkers
title_short Biomarkers for dementia in Latin American countries: gaps and opportunities
title_full Biomarkers for dementia in Latin American countries: gaps and opportunities
title_fullStr Biomarkers for dementia in Latin American countries: gaps and opportunities
title_full_unstemmed Biomarkers for dementia in Latin American countries: gaps and opportunities
title_sort Biomarkers for dementia in Latin American countries: gaps and opportunities
dc.creator.fl_str_mv Parra, Mario A.
Orellana, Paulina
Leon, Tomas
Cabello G., Victoria
Henriquez, Fernando
Gómez, Rodrigo
Avalos, Constanza
Damian, Andrés
Slachevsky, Andrea
Ibáñez, Agustín
Zetterberg, Henrik
Tijms, Betty M.
Yokoyama, Jennifer S.
Piña-Escudero, Stefanie D.
Nicholas Cochran, J.
Matallana, Diana L.
Acosta, Daisy
Allegri, Ricardo Francisco
Arias-Suárez, Bianca P.
Barra, Bernardo
Behrens, Maria Isabel
Brucki, Sonia M. D.
Busatto, Geraldo
Caramelli, Paulo
Castro-Suarez, Sheila
Contreras, Valeria
Custodio, Nilton
Dansilio, Sergio
De la Cruz-Puebla, Myriam
Cruz de Souza, Leonardo
Diaz, Monica M.
Duque, Lissette
Farías, Gonzalo A.
Ferreira, Sergio T.
Magrath Guimet, Nahuel
Kmaid, Ana
Lira, David
Lopera, Francisco
Mar Meza, Beatriz
Miotto, Eliane C.
Nitrini, Ricardo
Núñez, Alberto
O’Neill, Santiago
Ochoa, John
Pintado-Caipa, Maritza
França Resende, Elisa de Paula
Risacher, Shannon
Rojas, Luz Angela
Sabaj, Valentina
Schilling, Lucas
Sellek, Allis F.
Sosa, Ana
Takada, Leonel T.
Teixeira, Antonio L.
Unaucho-Pilalumbo, Martha
Duran-Aniotz, Claudia
dc.contributor.author.none.fl_str_mv Parra, Mario A.
Orellana, Paulina
Leon, Tomas
Cabello G., Victoria
Henriquez, Fernando
Gómez, Rodrigo
Avalos, Constanza
Damian, Andrés
Slachevsky, Andrea
Ibáñez, Agustín
Zetterberg, Henrik
Tijms, Betty M.
Yokoyama, Jennifer S.
Piña-Escudero, Stefanie D.
Nicholas Cochran, J.
Matallana, Diana L.
Acosta, Daisy
Allegri, Ricardo Francisco
Arias-Suárez, Bianca P.
Barra, Bernardo
Behrens, Maria Isabel
Brucki, Sonia M. D.
Busatto, Geraldo
Caramelli, Paulo
Castro-Suarez, Sheila
Contreras, Valeria
Custodio, Nilton
Dansilio, Sergio
De la Cruz-Puebla, Myriam
Cruz de Souza, Leonardo
Diaz, Monica M.
Duque, Lissette
Farías, Gonzalo A.
Ferreira, Sergio T.
Magrath Guimet, Nahuel
Kmaid, Ana
Lira, David
Lopera, Francisco
Mar Meza, Beatriz
Miotto, Eliane C.
Nitrini, Ricardo
Núñez, Alberto
O’Neill, Santiago
Ochoa, John
Pintado-Caipa, Maritza
França Resende, Elisa de Paula
Risacher, Shannon
Rojas, Luz Angela
Sabaj, Valentina
Schilling, Lucas
Sellek, Allis F.
Sosa, Ana
Takada, Leonel T.
Teixeira, Antonio L.
Unaucho-Pilalumbo, Martha
Duran-Aniotz, Claudia
dc.subject.proposal.eng.fl_str_mv Dementia
Latin American
Biomarkers
topic Dementia
Latin American
Biomarkers
description Limited knowledge on dementia biomarkers in Latin American and Caribbean (LAC) countries remains a serious barrier. Here, we reported a survey to explore the ongoing work, needs, interests, potential barriers, and opportunities for future studies related to biomarkers. The results show that neuroimaging is the most used biomarker (73%), followed by genetic studies (40%), peripheral fluids biomarkers (31%), and cerebrospinal fluid biomarkers (29%). Regarding barriers in LAC, lack of funding appears to undermine the implementation of biomarkers in clinical or research settings, followed by insufficient infrastructure and training. The survey revealed that despite the above barriers, the region holds a great potential to advance dementia biomarkers research. Considering the unique contributions that LAC could make to this growing field, we highlight the urgent need to expand biomarker research. These insights allowed us to propose an action plan that addresses the recommendations for a biomarker framework recently proposed by regional experts.
publishDate 2023
dc.date.accessioned.none.fl_str_mv 2023-07-31T14:25:50Z
dc.date.available.none.fl_str_mv 2023-07-31T14:25:50Z
dc.date.issued.none.fl_str_mv 2023
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
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dc.identifier.citation.spa.fl_str_mv Yonatan Sanz Perl, Sol Fittipaldi, Cecilia Gonzalez Campo, Sebastián Moguilner, Josephine Cruzat, Matias E Fraile-Vazquez, Rubén Herzog, Morten L Kringelbach, Gustavo Deco, Pavel Prado, Agustin Ibanez, Enzo Tagliazucchi, Model-based whole-brain perturbational landscape of neurodegenerative diseases, eLife, 10.7554/eLife.83970, 12, (2023).
dc.identifier.issn.spa.fl_str_mv 552-5260
dc.identifier.uri.none.fl_str_mv https://hdl.handle.net/11323/10349
dc.identifier.doi.none.fl_str_mv 10.7554/eLife.83970
dc.identifier.eissn.spa.fl_str_mv 1552-5279
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 Yonatan Sanz Perl, Sol Fittipaldi, Cecilia Gonzalez Campo, Sebastián Moguilner, Josephine Cruzat, Matias E Fraile-Vazquez, Rubén Herzog, Morten L Kringelbach, Gustavo Deco, Pavel Prado, Agustin Ibanez, Enzo Tagliazucchi, Model-based whole-brain perturbational landscape of neurodegenerative diseases, eLife, 10.7554/eLife.83970, 12, (2023).
552-5260
10.7554/eLife.83970
1552-5279
Corporación Universidad de la Costa
REDICUC – Repositorio CUC
url https://hdl.handle.net/11323/10349
https://repositorio.cuc.edu.co/
dc.language.iso.spa.fl_str_mv eng
language eng
dc.relation.ispartofjournal.spa.fl_str_mv Alzheimer's and Dementia
dc.relation.references.spa.fl_str_mv 1. Baez S, Ibanez A. Dementia in Latin America: an Emergent Silent Tsunami. Front Aging Neurosci. 2016;8:253.
2. Parra MA, Baez S, Allegri R, et al. Dementia in Latin America: assessing the present and envisioning the future. Neurology. 2018;90:222-231.
3. Parra MA, Baez S, Sedeno L, et al. Dementia in Latin America: paving the way toward a regional action plan. Alzheimers Dement. 2021;17:295-313.
4. Nitrini R, Barbosa MT, Dozzi Brucki SM, Yassuda MS, Caramelli P. Current trends and challenges on dementia management and research in Latin America. J Glob Health. 2020;10:010362.
5. Manes F. The huge burden of dementia in Latin America. Lancet Neurol. 2016;15:29.
6. Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP. The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement. 2013;9:63-75.e2.
7. Nitrini R, Bottino CM, Albala C, et al. Prevalence of dementia in Latin America: a collaborative study of population-based cohorts. Int Psychogeriatr. 2009;21:622-630.
8. Wolters FJ, Chibnik LB, Waziry R, et al. Twenty-seven-year time trends in dementia incidence in Europe and the United States: the Alzheimer Cohorts Consortium. Neurology. 2020;95:e519-e531.
9. Prince MJ, Wimo A, Guerchet MM, Ali GC, Wu Y-T, Prina M. World alzheimer report 2015 – The global impact of dementia: an analysis of prevalence, incidence, costs and trends. London: Alzheimer’s Disease International, 2015. 84 p.
10. World Bank. List of economies. June 2020. https://www.hupo. org/resources/Documents/HPP/World%20Bank%20list%20of% 20economies%20(June%202020).pdf
11. Jack CR, Jr, Bennett DA, Blennow K, et al. NIA-AA research framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018;14:535-562.
12. Sperling RA, Aisen PS, Beckett LA, et al. Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7:280- 292.
13. Dubois B, Feldman HH, Jacova C, et al. Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS-ADRDA criteria. Lancet Neurol. 2007;6:734-746.
14. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s disease: report of the NINCDSADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology. 1984;34:939-944.
15. El Kadmiri N, Said N, Slassi I, El Moutawakil B, Nadifi S. Biomarkers for Alzheimer disease: classical and novel candidates’ review. Neuroscience. 2018;370:181-190.
16. Blennow K, Hampel H. CSF markers for incipient Alzheimer’s disease. Lancet Neurol. 2003;2:605-613.
17. Burger nee Buch K, Padberg F, Nolde T, et al. Cerebrospinal fluid tau protein shows a better discrimination in young old (<70 years) than in old old patients with Alzheimer’s disease compared with controls. Neurosci Lett. 1999;277:21-24.
18. Hampel H, Buerger K, Zinkowski R, et al. Measurement of phosphorylated tau epitopes in the differential diagnosis of Alzheimer disease: a comparative cerebrospinal fluid study. Arch Gen Psychiatry. 2004;61:95-102.
19. Hampel H, Burger K, Teipel SJ, Bokde AL, Zetterberg H, Blennow K. Core candidate neurochemical and imaging biomarkers of Alzheimer’s disease. Alzheimers Dement. 2008;4:38-48.
20. Mattsson N, Zetterberg H, Hansson O, et al. CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment. JAMA. 2009;302:385-393.
21. Bobinski M, de Leon MJ, Wegiel J, et al. The histological validation of post mortem magnetic resonance imaging-determined hippocampal volume in Alzheimer’s disease. Neuroscience. 2000;95:721- 725.
22. Zarow C, Vinters HV, EllisWG, et al. Correlates of hippocampal neuron number in Alzheimer’s disease and ischemic vascular dementia. Ann Neurol. 2005;57:896-903.
23. Silverman DH, Small GW, Chang CY, et al. Positron emission tomography in evaluation of dementia: regional brain metabolism and long-term outcome. JAMA. 2001;286:2120-2127.
24. de Leon MJ, Convit A, Wolf OT, et al. Prediction of cognitive decline in normal elderly subjects with 2-[(18)F]fluoro-2-deoxy-Dglucose/poitron-emission tomography (FDG/PET). Proc Natl Acad Sci U S A. 2001;98:10966-10971.
25. Drzezga A, Lautenschlager N, Siebner H, et al. Cerebral metabolic changes accompanying conversion of mild cognitive impairment into Alzheimer’s disease: a PET follow-up study. Eur J Nucl Med Mol Imaging. 2003;30:1104-1113.
26. Koychev I, Gunn RN, Firouzian A, et al. PET tau and amyloidbeta burden in mild Alzheimer’s disease: divergent relationship with age, cognition, and cerebrospinal fluid biomarkers. J Alzheimers Dis. 2017;60:283-293.
27. Ossenkoppele R, Smith R, Ohlsson T, et al. Associations between tau, Abeta, and cortical thickness with cognition in Alzheimer disease. Neurology. 2019;92:e601-e612.
28. Aschenbrenner AJ, Gordon BA, Benzinger TLS, Morris JC, Hassenstab JJ. Influence of tau PET, amyloid PET, and hippocampal volume on cognition in Alzheimer disease. Neurology. 2018;91:e859-e866.
29. Jack CR, Jr, Bennett DA, Blennow K, et al. A/T/N: an unbiased descriptive classification scheme for Alzheimer disease biomarkers. Neurology. 2016;87:539-547.
30. Irizarry MC. Biomarkers of Alzheimer disease in plasma. NeuroRx. 2004;1:226-234.
31. Thambisetty M, Lovestone S. Blood-based biomarkers of Alzheimer’s disease: challenging but feasible. Biomark Med. 2010;4:65-79.
32. Lista S, Faltraco F, Prvulovic D, Hampel H. Blood and plasma-based proteomic biomarker research in Alzheimer’s disease. Prog Neurobiol. 2013;101-102:1-17.
33. Zetterberg H, Schott JM. Blood biomarkers for Alzheimer’s disease and related disorders. Acta Neurol Scand. 2022;146(1):51- 55.
34. Zetterberg H, Blennow K. Moving fluid biomarkers for Alzheimer’s disease from research tools to routine clinical diagnostics. Mol Neurodegener. 2021;16:10.
35. van der Flier WM, Scheltens P. Epidemiology and risk factors of dementia. J Neurol Neurosurg Psychiatry. 2005;76(Suppl 5):v2-7.
36. Goate A. Segregation of a missense mutation in the amyloid betaprotein precursor gene with familial Alzheimer’s disease. J Alzheimers Dis. 2006;9:341-347.
37. Cruts M, Hendriks L, Van Broeckhoven C. The presenilin genes: a new gene family involved in Alzheimer disease pathology. Hum Mol Genet. 1996;5 Spec No: 1449-55.
38. Levy-Lahad E, Wasco W, Poorkaj P, et al. Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science. 1995;269:973- 977.
39. DeJesus-Hernandez M, Mackenzie IR, Boeve BF, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011;72:245- 256.
40. Baker M, Mackenzie IR, Pickering-Brown SM, et al. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature. 2006;442:916-919.
41. Poorkaj P, Bird TD, Wijsman E, et al. Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol. 1998;43:815-825.
42. Saunders AM, Strittmatter WJ, Schmechel D, et al. Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer’s disease. Neurology. 1993;43:1467-1472.
43. Duran-Aniotz C, Orellana P, Leon Rodriguez T, et al. Systematic review: genetic, neuroimaging, and fluids biomarkers for frontotemporal dementia across Latin America countries. Front Neurol. 2021;12:663407.
44. Sexton C, Snyder HM, Chandrasekaran L, Worley S, Carrillo MC. Expanding representation of low and middle income countries in global dementia research: commentary from the Alzheimer’s. Association Front Neurol. 2021;12:633777.
45. Tutor CA, Frias L. Development of PET in Latin America Experience of the first PET-Cyclotron Center. World J Nucl Med. 2002;1:219.
46. Allegri RF, Chrem Mendez P, Calandri I, et al. Prognostic value of ATN Alzheimer biomarkers: 60-month follow-up results from the Argentine Alzheimer’s Disease Neuroimaging Initiative. Alzheimers Dement (Amst). 2020;12:e12026.
47. Allegri RF, Chrem Mendez P, Russo MJ, et al. Biomarkers of Alzheimer’s disease in mild cognitive impairment: experience in a memory clinic from Latin America. Neurologia (Engl Ed). 2021;36:201- 208.
48. Cecchini MA, Yassuda MS, Squarzoni P, et al. Deficits in short-term memory binding are detectable in individuals with brain amyloid deposition in the absence of overt neurodegeneration in the Alzheimer’s disease continuum. Brain Cogn. 2021;152:105749.
49. Damian A, Portugal F, Niell N, et al. Clinical impact of PET with (18)FFDG and (11)C-PIB in patients with dementia in a developing country. Front Neurol. 2021;12:630958.
50. Faria DP, Duran FL, Squarzoni P, et al. Topography of 11C-Pittsburgh compound B uptake in Alzheimer’s disease: a voxel-based investigation of cortical and white matter regions. Braz J Psychiatry. 2019;41:101- 111.
51. Coutinho AM, Busatto GF, de Gobbi Porto FH, et al. Brain PET amyloid and neurodegeneration biomarkers in the context of the 2018 NIA-AA research framework: an individual approach exploring clinicalbiomarker mismatches and sociodemographic parameters. Eur J Nucl Med Mol Imaging. 2020;47:2666-2680.
52. de Souza GS, Andrade MA, Borelli WV, et al. Amyloid-beta PET classification on cognitive aging stages using the centiloid scale. Mol Imaging Biol. 2022;24:394-403.
53. Hansen EO, Dias NS, Burgos ICB, et al. Millipore xMap(R) Luminex (HATMAG-68K): an accurate and cost-effective method for evaluating Alzheimer’s biomarkers in cerebrospinal fluid. Front Psychiatry. 2021;12:716686.
54. Madeira C, Lourenco MV, Vargas-Lopes C, et al. d-serine levels in Alzheimer’s disease: implications for novel biomarker development. Transl Psychiatry. 2015;5:e561.
55. Lourenco MV, Ribeiro FC, Sudo FK, et al. Cerebrospinal fluid irisin correlates with amyloid-beta, BDNF, and cognition in Alzheimer’s disease. Alzheimers Dement (Amst). 2020;12:e12034.
56. Lourenco MV, Ribeiro FC, Santos LE, et al. Cerebrospinal fluid neurotransmitters, cytokines, and chemokines in Alzheimer’s and lewy body diseases. J Alzheimers Dis. 2021;82:1067-1074.
57. Madeira C, Vargas-Lopes C, Brandao CO, et al. Elevated glutamate and glutamine levels in the cerebrospinal fluid of patients with probable Alzheimer’s disease and depression. Front Psychiatry. 2018;9: 561.
58. Reiman EM, Quiroz YT, Fleisher AS, et al. Brain imaging and fluid biomarker analysis in young adults at genetic risk for autosomal dominant Alzheimer’s disease in the presenilin 1 E280A kindred: a case-control study. Lancet Neurol. 2012;11:1048-1056.
59. Hampel H, O’Bryant SE, Molinuevo JL, et al. Blood-based biomarkers for Alzheimer disease: mapping the road to the clinic. Nat Rev Neurol. 2018;14:639-652.
60. Ibanez A, Parra MA, Butler C, Latin A, the Caribbean Consortium on D. The Latin America and the Caribbean Consortium on Dementia (LAC-CD): from networking to research to implementation science. J Alzheimers Dis. 2021;82:S379-S394.
61. Ibanez A, Yokoyama JS, Possin KL, et al. The multi-partner consortium to expand dementia Research in Latin America (ReDLat): driving multicentric research and implementation science. Front Neurol. 2021;12:631722.
62. Reyes-Pablo AE, Campa-Cordoba BB, Luna-Viramontes NI, et al. National dementia BioBank: a strategy for the diagnosis and study of neurodegenerative diseases in Mexico. J Alzheimers Dis. 2020;76:853- 862.
63. Zetterberg H, Bendlin BB. Biomarkers for Alzheimer’s diseasepreparing for a new era of disease-modifying therapies. Mol Psychiatry. 2021;26:296-308.
64. Thijssen EH, La Joie R, Wolf A, et al. Diagnostic value of plasma phosphorylated tau181 in Alzheimer’s disease and frontotemporal lobar degeneration. Nat Med. 2020;26:387-397.
65. Khan TK, Alkon DL. Peripheral biomarkers of Alzheimer’s disease. J Alzheimers Dis. 2015;44:729-744.
66. Ogonowski N, Salcidua S, Leon T, et al. Systematic review: microRNAs as potential biomarkers in mild cognitive impairment diagnosis. Front Aging Neurosci. 2021;13:807764.
67. Alawode DOT, Heslegrave AJ, Ashton NJ, et al. Transitioning from cerebrospinal fluid to blood tests to facilitate diagnosis and disease monitoring in Alzheimer’s disease. J Intern Med. 2021;290:583- 601.
68. Wojsiat J, Laskowska-Kaszub K, Mietelska-Porowska A, Wojda U. Search for Alzheimer’s disease biomarkers in blood cells: hypothesesdriven approach. Biomark Med. 2017;11:917-931.
69. O’Bryant SE, Mielke MM, Rissman RA, et al. Blood-based biomarkers in Alzheimer disease: current state of the science and a novel collaborative paradigm for advancing from discovery to clinic. Alzheimers Dement. 2017;13:45-58.
70. Teunissen CE, Verberk IMW, Thijssen EH, et al. Blood-based biomarkers for Alzheimer’s disease: towards clinical implementation. Lancet Neurol. 2022;21:66-77.
71. Ashton NJ, Kiddle SJ, Graf J, et al. Blood protein predictors of brain amyloid for enrichment in clinical trials. Alzheimers Dement (Amst). 2015;1:48-60.
72. Cummings J, Feldman HH, Scheltens P. The “rights” of precision drug development for Alzheimer’s disease. Alzheimers Res Ther. 2019;11:76.
73. Slachevsky A, Zitko P, Martinez-Pernia D, et al. GERO Cohort Protocol, Chile, 2017-2022: community-based cohort of functional decline in subjective cognitive complaint elderly. BMC Geriatr. 2020;20:505.
74. Magaki S, Yong WH, Khanlou N, Tung S, Vinters HV. Comorbidity in dementia: update of an ongoing autopsy study. J Am Geriatr Soc. 2014;62:1722-1728.
75. Gullett JM, Albizu A, Fang R, et al. Baseline neuroimaging predicts decline to dementia from amnestic mild cognitive impairment. Front Aging Neurosci. 2021;13:758298.
76. Shiino A, Shirakashi Y, Ishida M, Tanigaki K, Japanese Alzheimer’s Disease Neuroimaging I. Machine learning of brain structural biomarkers for Alzheimer’s disease (AD) diagnosis, prediction of disease progression, and amyloid beta deposition in the Japanese population. Alzheimers Dement (Amst). 2021;13:e12246.
77. Zhou Y, Song Z, Han X, Li H, Tang X. Prediction of Alzheimer’s disease progression based on magnetic resonance imaging. ACS Chem Neurosci. 2021;12:4209-4223.
78. Di Tella S, Cabinio M, Isernia S, et al. Neuroimaging biomarkers predicting the efficacy of multimodal rehabilitative intervention in the Alzheimer’s Dementia Continuum Pathology. Front Aging Neurosci. 2021;13:735508.
79. Menon MC, Murphy B, Heeger PS. Moving biomarkers toward clinical implementation in kidney transplantation. J Am Soc Nephrol. 2017;28:735-7347.
80. Teunissen CE, Otto M, Engelborghs S, et al. White paper by the Society for CSF Analysis and Clinical Neurochemistry: overcoming barriers in biomarker development and clinical translation. Alzheimers Res Ther. 2018;10:30.
81. Bachli MB, Sedeno L, Ochab JK, et al. Evaluating the reliability of neurocognitive biomarkers of neurodegenerative diseases across countries: a machine learning approach. Neuroimage. 2020;208:116456.
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spelling Atribución-NoComercial-SinDerivadas 4.0 Internacional (CC BY-NC-ND 4.0)© 2022 The Authors. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.https://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2Parra, Mario A.Orellana, PaulinaLeon, TomasCabello G., VictoriaHenriquez, FernandoGómez, RodrigoAvalos, ConstanzaDamian, AndrésSlachevsky, AndreaIbáñez, AgustínZetterberg, HenrikTijms, Betty M.Yokoyama, Jennifer S.Piña-Escudero, Stefanie D.Nicholas Cochran, J.Matallana, Diana L.Acosta, DaisyAllegri, Ricardo FranciscoArias-Suárez, Bianca P.Barra, BernardoBehrens, Maria IsabelBrucki, Sonia M. D.Busatto, GeraldoCaramelli, PauloCastro-Suarez, SheilaContreras, ValeriaCustodio, NiltonDansilio, SergioDe la Cruz-Puebla, MyriamCruz de Souza, LeonardoDiaz, Monica M.Duque, LissetteFarías, Gonzalo A.Ferreira, Sergio T.Magrath Guimet, NahuelKmaid, AnaLira, DavidLopera, FranciscoMar Meza, BeatrizMiotto, Eliane C.Nitrini, RicardoNúñez, AlbertoO’Neill, SantiagoOchoa, JohnPintado-Caipa, MaritzaFrança Resende, Elisa de PaulaRisacher, ShannonRojas, Luz AngelaSabaj, ValentinaSchilling, LucasSellek, Allis F.Sosa, AnaTakada, Leonel T.Teixeira, Antonio L.Unaucho-Pilalumbo, MarthaDuran-Aniotz, Claudia2023-07-31T14:25:50Z2023-07-31T14:25:50Z2023Yonatan Sanz Perl, Sol Fittipaldi, Cecilia Gonzalez Campo, Sebastián Moguilner, Josephine Cruzat, Matias E Fraile-Vazquez, Rubén Herzog, Morten L Kringelbach, Gustavo Deco, Pavel Prado, Agustin Ibanez, Enzo Tagliazucchi, Model-based whole-brain perturbational landscape of neurodegenerative diseases, eLife, 10.7554/eLife.83970, 12, (2023).552-5260https://hdl.handle.net/11323/1034910.7554/eLife.839701552-5279Corporación Universidad de la CostaREDICUC – Repositorio CUChttps://repositorio.cuc.edu.co/Limited knowledge on dementia biomarkers in Latin American and Caribbean (LAC) countries remains a serious barrier. Here, we reported a survey to explore the ongoing work, needs, interests, potential barriers, and opportunities for future studies related to biomarkers. The results show that neuroimaging is the most used biomarker (73%), followed by genetic studies (40%), peripheral fluids biomarkers (31%), and cerebrospinal fluid biomarkers (29%). Regarding barriers in LAC, lack of funding appears to undermine the implementation of biomarkers in clinical or research settings, followed by insufficient infrastructure and training. The survey revealed that despite the above barriers, the region holds a great potential to advance dementia biomarkers research. Considering the unique contributions that LAC could make to this growing field, we highlight the urgent need to expand biomarker research. These insights allowed us to propose an action plan that addresses the recommendations for a biomarker framework recently proposed by regional experts.15 páginasapplication/pdfengJohn Wiley & Sons Inc.United Stateshttps://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.12757Biomarkers for dementia in Latin American countries: gaps and opportunitiesArtículo 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_970fb48d4fbd8a85Latin AmericaAlzheimer's and Dementia1. Baez S, Ibanez A. Dementia in Latin America: an Emergent Silent Tsunami. Front Aging Neurosci. 2016;8:253.2. Parra MA, Baez S, Allegri R, et al. Dementia in Latin America: assessing the present and envisioning the future. Neurology. 2018;90:222-231.3. Parra MA, Baez S, Sedeno L, et al. Dementia in Latin America: paving the way toward a regional action plan. Alzheimers Dement. 2021;17:295-313.4. Nitrini R, Barbosa MT, Dozzi Brucki SM, Yassuda MS, Caramelli P. Current trends and challenges on dementia management and research in Latin America. J Glob Health. 2020;10:010362.5. Manes F. The huge burden of dementia in Latin America. Lancet Neurol. 2016;15:29.6. Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP. The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement. 2013;9:63-75.e2.7. Nitrini R, Bottino CM, Albala C, et al. Prevalence of dementia in Latin America: a collaborative study of population-based cohorts. Int Psychogeriatr. 2009;21:622-630.8. Wolters FJ, Chibnik LB, Waziry R, et al. Twenty-seven-year time trends in dementia incidence in Europe and the United States: the Alzheimer Cohorts Consortium. Neurology. 2020;95:e519-e531.9. Prince MJ, Wimo A, Guerchet MM, Ali GC, Wu Y-T, Prina M. World alzheimer report 2015 – The global impact of dementia: an analysis of prevalence, incidence, costs and trends. London: Alzheimer’s Disease International, 2015. 84 p.10. World Bank. List of economies. June 2020. https://www.hupo. org/resources/Documents/HPP/World%20Bank%20list%20of% 20economies%20(June%202020).pdf11. Jack CR, Jr, Bennett DA, Blennow K, et al. NIA-AA research framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018;14:535-562.12. Sperling RA, Aisen PS, Beckett LA, et al. Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7:280- 292.13. Dubois B, Feldman HH, Jacova C, et al. Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS-ADRDA criteria. Lancet Neurol. 2007;6:734-746.14. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s disease: report of the NINCDSADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology. 1984;34:939-944.15. El Kadmiri N, Said N, Slassi I, El Moutawakil B, Nadifi S. Biomarkers for Alzheimer disease: classical and novel candidates’ review. Neuroscience. 2018;370:181-190.16. Blennow K, Hampel H. CSF markers for incipient Alzheimer’s disease. Lancet Neurol. 2003;2:605-613.17. Burger nee Buch K, Padberg F, Nolde T, et al. Cerebrospinal fluid tau protein shows a better discrimination in young old (<70 years) than in old old patients with Alzheimer’s disease compared with controls. Neurosci Lett. 1999;277:21-24.18. Hampel H, Buerger K, Zinkowski R, et al. Measurement of phosphorylated tau epitopes in the differential diagnosis of Alzheimer disease: a comparative cerebrospinal fluid study. Arch Gen Psychiatry. 2004;61:95-102.19. Hampel H, Burger K, Teipel SJ, Bokde AL, Zetterberg H, Blennow K. Core candidate neurochemical and imaging biomarkers of Alzheimer’s disease. Alzheimers Dement. 2008;4:38-48.20. Mattsson N, Zetterberg H, Hansson O, et al. CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment. JAMA. 2009;302:385-393.21. Bobinski M, de Leon MJ, Wegiel J, et al. The histological validation of post mortem magnetic resonance imaging-determined hippocampal volume in Alzheimer’s disease. Neuroscience. 2000;95:721- 725.22. Zarow C, Vinters HV, EllisWG, et al. Correlates of hippocampal neuron number in Alzheimer’s disease and ischemic vascular dementia. Ann Neurol. 2005;57:896-903.23. Silverman DH, Small GW, Chang CY, et al. Positron emission tomography in evaluation of dementia: regional brain metabolism and long-term outcome. JAMA. 2001;286:2120-2127.24. de Leon MJ, Convit A, Wolf OT, et al. Prediction of cognitive decline in normal elderly subjects with 2-[(18)F]fluoro-2-deoxy-Dglucose/poitron-emission tomography (FDG/PET). Proc Natl Acad Sci U S A. 2001;98:10966-10971.25. Drzezga A, Lautenschlager N, Siebner H, et al. Cerebral metabolic changes accompanying conversion of mild cognitive impairment into Alzheimer’s disease: a PET follow-up study. Eur J Nucl Med Mol Imaging. 2003;30:1104-1113.26. Koychev I, Gunn RN, Firouzian A, et al. PET tau and amyloidbeta burden in mild Alzheimer’s disease: divergent relationship with age, cognition, and cerebrospinal fluid biomarkers. J Alzheimers Dis. 2017;60:283-293.27. Ossenkoppele R, Smith R, Ohlsson T, et al. Associations between tau, Abeta, and cortical thickness with cognition in Alzheimer disease. Neurology. 2019;92:e601-e612.28. Aschenbrenner AJ, Gordon BA, Benzinger TLS, Morris JC, Hassenstab JJ. Influence of tau PET, amyloid PET, and hippocampal volume on cognition in Alzheimer disease. Neurology. 2018;91:e859-e866.29. Jack CR, Jr, Bennett DA, Blennow K, et al. A/T/N: an unbiased descriptive classification scheme for Alzheimer disease biomarkers. Neurology. 2016;87:539-547.30. Irizarry MC. Biomarkers of Alzheimer disease in plasma. NeuroRx. 2004;1:226-234.31. Thambisetty M, Lovestone S. Blood-based biomarkers of Alzheimer’s disease: challenging but feasible. Biomark Med. 2010;4:65-79.32. Lista S, Faltraco F, Prvulovic D, Hampel H. Blood and plasma-based proteomic biomarker research in Alzheimer’s disease. Prog Neurobiol. 2013;101-102:1-17.33. Zetterberg H, Schott JM. Blood biomarkers for Alzheimer’s disease and related disorders. Acta Neurol Scand. 2022;146(1):51- 55.34. Zetterberg H, Blennow K. Moving fluid biomarkers for Alzheimer’s disease from research tools to routine clinical diagnostics. Mol Neurodegener. 2021;16:10.35. van der Flier WM, Scheltens P. Epidemiology and risk factors of dementia. J Neurol Neurosurg Psychiatry. 2005;76(Suppl 5):v2-7.36. Goate A. Segregation of a missense mutation in the amyloid betaprotein precursor gene with familial Alzheimer’s disease. J Alzheimers Dis. 2006;9:341-347.37. Cruts M, Hendriks L, Van Broeckhoven C. The presenilin genes: a new gene family involved in Alzheimer disease pathology. Hum Mol Genet. 1996;5 Spec No: 1449-55.38. Levy-Lahad E, Wasco W, Poorkaj P, et al. Candidate gene for the chromosome 1 familial Alzheimer’s disease locus. Science. 1995;269:973- 977.39. DeJesus-Hernandez M, Mackenzie IR, Boeve BF, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011;72:245- 256.40. Baker M, Mackenzie IR, Pickering-Brown SM, et al. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature. 2006;442:916-919.41. Poorkaj P, Bird TD, Wijsman E, et al. Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol. 1998;43:815-825.42. Saunders AM, Strittmatter WJ, Schmechel D, et al. Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer’s disease. Neurology. 1993;43:1467-1472.43. Duran-Aniotz C, Orellana P, Leon Rodriguez T, et al. Systematic review: genetic, neuroimaging, and fluids biomarkers for frontotemporal dementia across Latin America countries. Front Neurol. 2021;12:663407.44. Sexton C, Snyder HM, Chandrasekaran L, Worley S, Carrillo MC. Expanding representation of low and middle income countries in global dementia research: commentary from the Alzheimer’s. Association Front Neurol. 2021;12:633777.45. Tutor CA, Frias L. Development of PET in Latin America Experience of the first PET-Cyclotron Center. World J Nucl Med. 2002;1:219.46. Allegri RF, Chrem Mendez P, Calandri I, et al. Prognostic value of ATN Alzheimer biomarkers: 60-month follow-up results from the Argentine Alzheimer’s Disease Neuroimaging Initiative. Alzheimers Dement (Amst). 2020;12:e12026.47. Allegri RF, Chrem Mendez P, Russo MJ, et al. Biomarkers of Alzheimer’s disease in mild cognitive impairment: experience in a memory clinic from Latin America. Neurologia (Engl Ed). 2021;36:201- 208.48. Cecchini MA, Yassuda MS, Squarzoni P, et al. Deficits in short-term memory binding are detectable in individuals with brain amyloid deposition in the absence of overt neurodegeneration in the Alzheimer’s disease continuum. Brain Cogn. 2021;152:105749.49. Damian A, Portugal F, Niell N, et al. Clinical impact of PET with (18)FFDG and (11)C-PIB in patients with dementia in a developing country. Front Neurol. 2021;12:630958.50. Faria DP, Duran FL, Squarzoni P, et al. Topography of 11C-Pittsburgh compound B uptake in Alzheimer’s disease: a voxel-based investigation of cortical and white matter regions. Braz J Psychiatry. 2019;41:101- 111.51. Coutinho AM, Busatto GF, de Gobbi Porto FH, et al. Brain PET amyloid and neurodegeneration biomarkers in the context of the 2018 NIA-AA research framework: an individual approach exploring clinicalbiomarker mismatches and sociodemographic parameters. Eur J Nucl Med Mol Imaging. 2020;47:2666-2680.52. de Souza GS, Andrade MA, Borelli WV, et al. Amyloid-beta PET classification on cognitive aging stages using the centiloid scale. Mol Imaging Biol. 2022;24:394-403.53. Hansen EO, Dias NS, Burgos ICB, et al. Millipore xMap(R) Luminex (HATMAG-68K): an accurate and cost-effective method for evaluating Alzheimer’s biomarkers in cerebrospinal fluid. Front Psychiatry. 2021;12:716686.54. Madeira C, Lourenco MV, Vargas-Lopes C, et al. d-serine levels in Alzheimer’s disease: implications for novel biomarker development. Transl Psychiatry. 2015;5:e561.55. Lourenco MV, Ribeiro FC, Sudo FK, et al. Cerebrospinal fluid irisin correlates with amyloid-beta, BDNF, and cognition in Alzheimer’s disease. Alzheimers Dement (Amst). 2020;12:e12034.56. Lourenco MV, Ribeiro FC, Santos LE, et al. Cerebrospinal fluid neurotransmitters, cytokines, and chemokines in Alzheimer’s and lewy body diseases. J Alzheimers Dis. 2021;82:1067-1074.57. Madeira C, Vargas-Lopes C, Brandao CO, et al. Elevated glutamate and glutamine levels in the cerebrospinal fluid of patients with probable Alzheimer’s disease and depression. Front Psychiatry. 2018;9: 561.58. Reiman EM, Quiroz YT, Fleisher AS, et al. Brain imaging and fluid biomarker analysis in young adults at genetic risk for autosomal dominant Alzheimer’s disease in the presenilin 1 E280A kindred: a case-control study. Lancet Neurol. 2012;11:1048-1056.59. Hampel H, O’Bryant SE, Molinuevo JL, et al. Blood-based biomarkers for Alzheimer disease: mapping the road to the clinic. Nat Rev Neurol. 2018;14:639-652.60. Ibanez A, Parra MA, Butler C, Latin A, the Caribbean Consortium on D. The Latin America and the Caribbean Consortium on Dementia (LAC-CD): from networking to research to implementation science. J Alzheimers Dis. 2021;82:S379-S394.61. Ibanez A, Yokoyama JS, Possin KL, et al. The multi-partner consortium to expand dementia Research in Latin America (ReDLat): driving multicentric research and implementation science. Front Neurol. 2021;12:631722.62. Reyes-Pablo AE, Campa-Cordoba BB, Luna-Viramontes NI, et al. National dementia BioBank: a strategy for the diagnosis and study of neurodegenerative diseases in Mexico. J Alzheimers Dis. 2020;76:853- 862.63. Zetterberg H, Bendlin BB. Biomarkers for Alzheimer’s diseasepreparing for a new era of disease-modifying therapies. Mol Psychiatry. 2021;26:296-308.64. Thijssen EH, La Joie R, Wolf A, et al. Diagnostic value of plasma phosphorylated tau181 in Alzheimer’s disease and frontotemporal lobar degeneration. Nat Med. 2020;26:387-397.65. Khan TK, Alkon DL. Peripheral biomarkers of Alzheimer’s disease. J Alzheimers Dis. 2015;44:729-744.66. Ogonowski N, Salcidua S, Leon T, et al. Systematic review: microRNAs as potential biomarkers in mild cognitive impairment diagnosis. Front Aging Neurosci. 2021;13:807764.67. Alawode DOT, Heslegrave AJ, Ashton NJ, et al. Transitioning from cerebrospinal fluid to blood tests to facilitate diagnosis and disease monitoring in Alzheimer’s disease. J Intern Med. 2021;290:583- 601.68. Wojsiat J, Laskowska-Kaszub K, Mietelska-Porowska A, Wojda U. Search for Alzheimer’s disease biomarkers in blood cells: hypothesesdriven approach. Biomark Med. 2017;11:917-931.69. O’Bryant SE, Mielke MM, Rissman RA, et al. Blood-based biomarkers in Alzheimer disease: current state of the science and a novel collaborative paradigm for advancing from discovery to clinic. Alzheimers Dement. 2017;13:45-58.70. Teunissen CE, Verberk IMW, Thijssen EH, et al. Blood-based biomarkers for Alzheimer’s disease: towards clinical implementation. Lancet Neurol. 2022;21:66-77.71. Ashton NJ, Kiddle SJ, Graf J, et al. Blood protein predictors of brain amyloid for enrichment in clinical trials. Alzheimers Dement (Amst). 2015;1:48-60.72. Cummings J, Feldman HH, Scheltens P. The “rights” of precision drug development for Alzheimer’s disease. Alzheimers Res Ther. 2019;11:76.73. Slachevsky A, Zitko P, Martinez-Pernia D, et al. GERO Cohort Protocol, Chile, 2017-2022: community-based cohort of functional decline in subjective cognitive complaint elderly. BMC Geriatr. 2020;20:505.74. Magaki S, Yong WH, Khanlou N, Tung S, Vinters HV. Comorbidity in dementia: update of an ongoing autopsy study. J Am Geriatr Soc. 2014;62:1722-1728.75. Gullett JM, Albizu A, Fang R, et al. Baseline neuroimaging predicts decline to dementia from amnestic mild cognitive impairment. Front Aging Neurosci. 2021;13:758298.76. Shiino A, Shirakashi Y, Ishida M, Tanigaki K, Japanese Alzheimer’s Disease Neuroimaging I. Machine learning of brain structural biomarkers for Alzheimer’s disease (AD) diagnosis, prediction of disease progression, and amyloid beta deposition in the Japanese population. Alzheimers Dement (Amst). 2021;13:e12246.77. Zhou Y, Song Z, Han X, Li H, Tang X. Prediction of Alzheimer’s disease progression based on magnetic resonance imaging. ACS Chem Neurosci. 2021;12:4209-4223.78. Di Tella S, Cabinio M, Isernia S, et al. Neuroimaging biomarkers predicting the efficacy of multimodal rehabilitative intervention in the Alzheimer’s Dementia Continuum Pathology. Front Aging Neurosci. 2021;13:735508.79. Menon MC, Murphy B, Heeger PS. Moving biomarkers toward clinical implementation in kidney transplantation. J Am Soc Nephrol. 2017;28:735-7347.80. Teunissen CE, Otto M, Engelborghs S, et al. White paper by the Society for CSF Analysis and Clinical Neurochemistry: overcoming barriers in biomarker development and clinical translation. Alzheimers Res Ther. 2018;10:30.81. Bachli MB, Sedeno L, Ochab JK, et al. Evaluating the reliability of neurocognitive biomarkers of neurodegenerative diseases across countries: a machine learning approach. Neuroimage. 2020;208:116456.735721219DementiaLatin AmericanBiomarkersPublicationORIGINALBiomarkers for dementia in Latin American countries. Gaps and opportunities.pdfBiomarkers for dementia in Latin American countries. Gaps and opportunities.pdfArtículoapplication/pdf1855941https://repositorio.cuc.edu.co/bitstreams/90ec73fd-7e2a-4438-bf1d-bf54ac4b330b/download0902d9b0a080a6dd0a24921d803dcc58MD51LICENSElicense.txtlicense.txttext/plain; charset=utf-814828https://repositorio.cuc.edu.co/bitstreams/64019a00-7cc8-4194-9d72-a467de3b1070/download2f9959eaf5b71fae44bbf9ec84150c7aMD52TEXTBiomarkers for dementia in Latin American countries. Gaps and opportunities.pdf.txtBiomarkers for dementia in Latin American countries. Gaps and opportunities.pdf.txtExtracted texttext/plain79824https://repositorio.cuc.edu.co/bitstreams/85076597-073d-49a1-8522-c9883614d02b/download76e24f9715a12c616349c32cb7555768MD53THUMBNAILBiomarkers for dementia in Latin American countries. Gaps and opportunities.pdf.jpgBiomarkers for dementia in Latin American countries. Gaps and opportunities.pdf.jpgGenerated Thumbnailimage/jpeg17172https://repositorio.cuc.edu.co/bitstreams/ba58e3b2-5d10-403e-a6f2-9096e697109d/download219fef58720082e7ad9c93984e51612cMD5411323/10349oai:repositorio.cuc.edu.co:11323/103492024-09-17 10:48:42.447https://creativecommons.org/licenses/by-nc-nd/4.0/© 2022 The Authors. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.open.accesshttps://repositorio.cuc.edu.coRepositorio de la Universidad de la Costa 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ada en las Obras Colectivas.

b.	Distribuir copias o fonogramas de las Obras, exhibirlas públicamente, ejecutarlas públicamente y/o ponerlas a disposición pública, incluyéndolas como incorporadas en Obras Colectivas, según corresponda.

c.	Distribuir copias de las Obras Derivadas que se generen, exhibirlas públicamente, ejecutarlas públicamente y/o ponerlas a disposición pública.
Los derechos mencionados anteriormente pueden ser ejercidos en todos los medios y formatos, actualmente conocidos o que se inventen en el futuro. Los derechos antes mencionados incluyen el derecho a realizar dichas modificaciones en la medida que sean técnicamente necesarias para ejercer los derechos en otro medio o formatos, pero de otra manera usted no está autorizado para realizar obras derivadas. Todos los derechos no otorgados expresamente por el Licenciante quedan por este medio reservados, incluyendo pero sin limitarse a aquellos que se mencionan en las secciones 4(d) y 4(e).

4. Restricciones.
La licencia otorgada en la anterior Sección 3 está expresamente sujeta y limitada por las siguientes restricciones:

a.	Usted puede distribuir, exhibir públicamente, ejecutar públicamente, o poner a disposición pública la Obra sólo bajo las condiciones de esta Licencia, y Usted debe incluir una copia de esta licencia o del Identificador Universal de Recursos de la misma con cada copia de la Obra que distribuya, exhiba públicamente, ejecute públicamente o ponga a disposición pública. No es posible ofrecer o imponer ninguna condición sobre la Obra que altere o limite las condiciones de esta Licencia o el ejercicio de los derechos de los destinatarios otorgados en este documento. No es posible sublicenciar la Obra. Usted debe mantener intactos todos los avisos que hagan referencia a esta Licencia y a la cláusula de limitación de garantías. Usted no puede distribuir, exhibir públicamente, ejecutar públicamente, o poner a disposición pública la Obra con alguna medida tecnológica que controle el acceso o la utilización de ella de una forma que sea inconsistente con las condiciones de esta Licencia. Lo anterior se aplica a la Obra incorporada a una Obra Colectiva, pero esto no exige que la Obra Colectiva aparte de la obra misma quede sujeta a las condiciones de esta Licencia. Si Usted crea una Obra Colectiva, previo aviso de cualquier Licenciante debe, en la medida de lo posible, eliminar de la Obra Colectiva cualquier referencia a dicho Licenciante o al Autor Original, según lo solicitado por el Licenciante y conforme lo exige la cláusula 4(c).

b.	Usted no puede ejercer ninguno de los derechos que le han sido otorgados en la Sección 3 precedente de modo que estén principalmente destinados o directamente dirigidos a conseguir un provecho comercial o una compensación monetaria privada. El intercambio de la Obra por otras obras protegidas por derechos de autor, ya sea a través de un sistema para compartir archivos digitales (digital file-sharing) o de cualquier otra manera no será considerado como estar destinado principalmente o dirigido directamente a conseguir un provecho comercial o una compensación monetaria privada, siempre que no se realice un pago mediante una compensación monetaria en relación con el intercambio de obras protegidas por el derecho de autor.

c.	Si usted distribuye, exhibe públicamente, ejecuta públicamente o ejecuta públicamente en forma digital la Obra o cualquier Obra Derivada u Obra Colectiva, Usted debe mantener intacta toda la información de derecho de autor de la Obra y proporcionar, de forma razonable según el medio o manera que Usted esté utilizando: (i) el nombre del Autor Original si está provisto (o seudónimo, si fuere aplicable), y/o (ii) el nombre de la parte o las partes que el Autor Original y/o el Licenciante hubieren designado para la atribución (v.g., un instituto patrocinador, editorial, publicación) en la información de los derechos de autor del Licenciante, términos de servicios o de otras formas razonables; el título de la Obra si está provisto; en la medida de lo razonablemente factible y, si está provisto, el Identificador Uniforme de Recursos (Uniform Resource Identifier) que el Licenciante especifica para ser asociado con la Obra, salvo que tal URI no se refiera a la nota sobre los derechos de autor o a la información sobre el licenciamiento de la Obra; y en el caso de una Obra Derivada, atribuir el crédito identificando el uso de la Obra en la Obra Derivada (v.g., "Traducción Francesa de la Obra del Autor Original," o "Guión Cinematográfico basado en la Obra original del Autor Original"). Tal crédito puede ser implementado de cualquier forma razonable; en el caso, sin embargo, de Obras Derivadas u Obras Colectivas, tal crédito aparecerá, como mínimo, donde aparece el crédito de cualquier otro autor comparable y de una manera, al menos, tan destacada como el crédito de otro autor comparable.

d.	Para evitar toda confusión, el Licenciante aclara que, cuando la obra es una composición musical:

i.	Regalías por interpretación y ejecución bajo licencias generales. El Licenciante se reserva el derecho exclusivo de autorizar la ejecución pública o la ejecución pública digital de la obra y de recolectar, sea individualmente o a través de una sociedad de gestión colectiva de derechos de autor y derechos conexos (por ejemplo, SAYCO), las regalías por la ejecución pública o por la ejecución pública digital de la obra (por ejemplo Webcast) licenciada bajo licencias generales, si la interpretación o ejecución de la obra está primordialmente orientada por o dirigida a la obtención de una ventaja comercial o una compensación monetaria privada.

ii.	Regalías por Fonogramas. El Licenciante se reserva el derecho exclusivo de recolectar, individualmente o a través de una sociedad de gestión colectiva de derechos de autor y derechos conexos (por ejemplo, los consagrados por la SAYCO), una agencia de derechos musicales o algún agente designado, las regalías por cualquier fonograma que Usted cree a partir de la obra (“versión cover”) y distribuya, en los términos del régimen de derechos de autor, si la creación o distribución de esa versión cover está primordialmente destinada o dirigida a obtener una ventaja comercial o una compensación monetaria privada.

e.	Gestión de Derechos de Autor sobre Interpretaciones y Ejecuciones Digitales (WebCasting). Para evitar toda confusión, el Licenciante aclara que, cuando la obra sea un fonograma, el Licenciante se reserva el derecho exclusivo de autorizar la ejecución pública digital de la obra (por ejemplo, webcast) y de recolectar, individualmente o a través de una sociedad de gestión colectiva de derechos de autor y derechos conexos (por ejemplo, ACINPRO), las regalías por la ejecución pública digital de la obra (por ejemplo, webcast), sujeta a las disposiciones aplicables del régimen de Derecho de Autor, si esta ejecución pública digital está primordialmente dirigida a obtener una ventaja comercial o una compensación monetaria privada.

5. Representaciones, Garantías y Limitaciones de Responsabilidad.
A MENOS QUE LAS PARTES LO ACORDARAN DE OTRA FORMA POR ESCRITO, EL LICENCIANTE OFRECE LA OBRA (EN EL ESTADO EN EL QUE SE ENCUENTRA) “TAL CUAL”, SIN BRINDAR GARANTÍAS DE CLASE ALGUNA RESPECTO DE LA OBRA, YA SEA EXPRESA, IMPLÍCITA, LEGAL O CUALQUIERA OTRA, INCLUYENDO, SIN LIMITARSE A ELLAS, GARANTÍAS DE TITULARIDAD, COMERCIABILIDAD, ADAPTABILIDAD O ADECUACIÓN A PROPÓSITO DETERMINADO, AUSENCIA DE INFRACCIÓN, DE AUSENCIA DE DEFECTOS LATENTES O DE OTRO TIPO, O LA PRESENCIA O AUSENCIA DE ERRORES, SEAN O NO DESCUBRIBLES (PUEDAN O NO SER ESTOS DESCUBIERTOS). ALGUNAS JURISDICCIONES NO PERMITEN LA EXCLUSIÓN DE GARANTÍAS IMPLÍCITAS, EN CUYO CASO ESTA EXCLUSIÓN PUEDE NO APLICARSE A USTED.

6. Limitación de responsabilidad.
A MENOS QUE LO EXIJA EXPRESAMENTE LA LEY APLICABLE, EL LICENCIANTE NO SERÁ RESPONSABLE ANTE USTED POR DAÑO ALGUNO, SEA POR RESPONSABILIDAD EXTRACONTRACTUAL, PRECONTRACTUAL O CONTRACTUAL, OBJETIVA O SUBJETIVA, SE TRATE DE DAÑOS MORALES O PATRIMONIALES, DIRECTOS O INDIRECTOS, PREVISTOS O IMPREVISTOS PRODUCIDOS POR EL USO DE ESTA LICENCIA O DE LA OBRA, AUN CUANDO EL LICENCIANTE HAYA SIDO ADVERTIDO DE LA POSIBILIDAD DE DICHOS DAÑOS. ALGUNAS LEYES NO PERMITEN LA EXCLUSIÓN DE CIERTA RESPONSABILIDAD, EN CUYO CASO ESTA EXCLUSIÓN PUEDE NO APLICARSE A USTED.

7. Término.

a.	Esta Licencia y los derechos otorgados en virtud de ella terminarán automáticamente si Usted infringe alguna condición establecida en ella. Sin embargo, los individuos o entidades que han recibido Obras Derivadas o Colectivas de Usted de conformidad con esta Licencia, no verán terminadas sus licencias, siempre que estos individuos o entidades sigan cumpliendo íntegramente las condiciones de estas licencias. Las Secciones 1, 2, 5, 6, 7, y 8 subsistirán a cualquier terminación de esta Licencia.

b.	Sujeta a las condiciones y términos anteriores, la licencia otorgada aquí es perpetua (durante el período de vigencia de los derechos de autor de la obra). No obstante lo anterior, el Licenciante se reserva el derecho a publicar y/o estrenar la Obra bajo condiciones de licencia diferentes o a dejar de distribuirla en los términos de esta Licencia en cualquier momento; en el entendido, sin embargo, que esa elección no servirá para revocar esta licencia o que deba ser otorgada , bajo los términos de esta licencia), y esta licencia continuará en pleno vigor y efecto a menos que sea terminada como se expresa atrás. La Licencia revocada continuará siendo plenamente vigente y efectiva si no se le da término en las condiciones indicadas anteriormente.

8. Varios.

a.	Cada vez que Usted distribuya o ponga a disposición pública la Obra o una Obra Colectiva, el Licenciante ofrecerá al destinatario una licencia en los mismos términos y condiciones que la licencia otorgada a Usted bajo esta Licencia.

b.	Si alguna disposición de esta Licencia resulta invalidada o no exigible, según la legislación vigente, esto no afectará ni la validez ni la aplicabilidad del resto de condiciones de esta Licencia y, sin acción adicional por parte de los sujetos de este acuerdo, aquélla se entenderá reformada lo mínimo necesario para hacer que dicha disposición sea válida y exigible.

c.	Ningún término o disposición de esta Licencia se estimará renunciada y ninguna violación de ella será consentida a menos que esa renuncia o consentimiento sea otorgado por escrito y firmado por la parte que renuncie o consienta.

d.	Esta Licencia refleja el acuerdo pleno entre las partes respecto a la Obra aquí licenciada. No hay arreglos, acuerdos o declaraciones respecto a la Obra que no estén especificados en este documento. El Licenciante no se verá limitado por ninguna disposición adicional que pueda surgir en alguna comunicación emanada de Usted. Esta Licencia no puede ser modificada sin el consentimiento mutuo por escrito del Licenciante y Usted.
