Electrocardiogram differences in cognitively unimpaired PSEN1-E280A carriers and non-carriers from the Alzheimer’s Prevention Initiative Autosomal-Dominant Alzheimer’s Disease Colombia Trial
Background: Some but not all studies have found compromised myocardial function and amyloid deposition, related or unrelated to amyloid-β pathology itself, in persons with late-onset Alzheimer’s Disease (AD). Other changes in QT interval, heart rate variability, and QRS voltages have been described...
- Autores:
-
Vásquez Botero, Daniel
Giraldo Chica, Margarita María
Jaramillo, Carlos J.
Acosta Baena, Natalia
Espinosa, Alejandro
Ramos Pérez, Claudia Patricia
Aguillón Niño, David Fernando
Aponte Restrepo, Claudia Patricia
Londoño, Jennifer
Ríos Romenets, Silvia
Lopera Restrepo, Francisco Javier
Malek Ahmadi, Michael H.
Hu, Nan
Su, Yi
Ehrhard, Patricia
Sink, Kaycee M.
Tariot, Pierre N.
Reiman, Eric M.
- Tipo de recurso:
- http://purl.org/coar/resource_type/c_6670
- Fecha de publicación:
- 2023
- Institución:
- Universidad de Antioquia
- Repositorio:
- Repositorio UdeA
- Idioma:
- eng
- OAI Identifier:
- oai:bibliotecadigital.udea.edu.co:10495/48426
- Acceso en línea:
- https://hdl.handle.net/10495/48426
- Palabra clave:
- Electrocardiografía
Electrocardiography
Enfermedad de Alzheimer
Alzheimer Disease
https://id.nlm.nih.gov/mesh/D004562
https://id.nlm.nih.gov/mesh/D000544
ODS 3: Salud y bienestar. Garantizar una vida sana y promover el bienestar de todos a todas las edades
- Rights
- openAccess
- License
- http://creativecommons.org/licenses/by-nc/4.0/
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Electrocardiogram differences in cognitively unimpaired PSEN1-E280A carriers and non-carriers from the Alzheimer’s Prevention Initiative Autosomal-Dominant Alzheimer’s Disease Colombia Trial |
| title |
Electrocardiogram differences in cognitively unimpaired PSEN1-E280A carriers and non-carriers from the Alzheimer’s Prevention Initiative Autosomal-Dominant Alzheimer’s Disease Colombia Trial |
| spellingShingle |
Electrocardiogram differences in cognitively unimpaired PSEN1-E280A carriers and non-carriers from the Alzheimer’s Prevention Initiative Autosomal-Dominant Alzheimer’s Disease Colombia Trial Electrocardiografía Electrocardiography Enfermedad de Alzheimer Alzheimer Disease https://id.nlm.nih.gov/mesh/D004562 https://id.nlm.nih.gov/mesh/D000544 ODS 3: Salud y bienestar. Garantizar una vida sana y promover el bienestar de todos a todas las edades |
| title_short |
Electrocardiogram differences in cognitively unimpaired PSEN1-E280A carriers and non-carriers from the Alzheimer’s Prevention Initiative Autosomal-Dominant Alzheimer’s Disease Colombia Trial |
| title_full |
Electrocardiogram differences in cognitively unimpaired PSEN1-E280A carriers and non-carriers from the Alzheimer’s Prevention Initiative Autosomal-Dominant Alzheimer’s Disease Colombia Trial |
| title_fullStr |
Electrocardiogram differences in cognitively unimpaired PSEN1-E280A carriers and non-carriers from the Alzheimer’s Prevention Initiative Autosomal-Dominant Alzheimer’s Disease Colombia Trial |
| title_full_unstemmed |
Electrocardiogram differences in cognitively unimpaired PSEN1-E280A carriers and non-carriers from the Alzheimer’s Prevention Initiative Autosomal-Dominant Alzheimer’s Disease Colombia Trial |
| title_sort |
Electrocardiogram differences in cognitively unimpaired PSEN1-E280A carriers and non-carriers from the Alzheimer’s Prevention Initiative Autosomal-Dominant Alzheimer’s Disease Colombia Trial |
| dc.creator.fl_str_mv |
Vásquez Botero, Daniel Giraldo Chica, Margarita María Jaramillo, Carlos J. Acosta Baena, Natalia Espinosa, Alejandro Ramos Pérez, Claudia Patricia Aguillón Niño, David Fernando Aponte Restrepo, Claudia Patricia Londoño, Jennifer Ríos Romenets, Silvia Lopera Restrepo, Francisco Javier Malek Ahmadi, Michael H. Hu, Nan Su, Yi Ehrhard, Patricia Sink, Kaycee M. Tariot, Pierre N. Reiman, Eric M. |
| dc.contributor.author.none.fl_str_mv |
Vásquez Botero, Daniel Giraldo Chica, Margarita María Jaramillo, Carlos J. Acosta Baena, Natalia Espinosa, Alejandro Ramos Pérez, Claudia Patricia Aguillón Niño, David Fernando Aponte Restrepo, Claudia Patricia Londoño, Jennifer Ríos Romenets, Silvia Lopera Restrepo, Francisco Javier Malek Ahmadi, Michael H. Hu, Nan Su, Yi Ehrhard, Patricia Sink, Kaycee M. Tariot, Pierre N. Reiman, Eric M. |
| dc.contributor.researchgroup.none.fl_str_mv |
Grupo de Neurociencias de Antioquia |
| dc.subject.decs.none.fl_str_mv |
Electrocardiografía Electrocardiography Enfermedad de Alzheimer Alzheimer Disease |
| topic |
Electrocardiografía Electrocardiography Enfermedad de Alzheimer Alzheimer Disease https://id.nlm.nih.gov/mesh/D004562 https://id.nlm.nih.gov/mesh/D000544 ODS 3: Salud y bienestar. Garantizar una vida sana y promover el bienestar de todos a todas las edades |
| dc.subject.meshuri.none.fl_str_mv |
https://id.nlm.nih.gov/mesh/D004562 https://id.nlm.nih.gov/mesh/D000544 |
| dc.subject.ods.none.fl_str_mv |
ODS 3: Salud y bienestar. Garantizar una vida sana y promover el bienestar de todos a todas las edades |
| description |
Background: Some but not all studies have found compromised myocardial function and amyloid deposition, related or unrelated to amyloid-β pathology itself, in persons with late-onset Alzheimer’s Disease (AD). Other changes in QT interval, heart rate variability, and QRS voltages have been described in the electrocardiogram (ECG), but those are not consistent between studies. We explored differences in several ECG measures in cognitively unimpaired (CU) Presenilin 1 (PSEN1)-E280A carriers and non-carriers from the Alzheimer’s Prevention Initiative Autosomal Dominant AD (API ADAD) Trial (NCT01998841). Method: The trial enrolled 252 CU 30–60-year-old participants. We included participants (144 PSEN1-E280A mutation carriers and 71 non-carriers) in these analyses who were enrolled in the trial during their first screening attempt. Baseline cardiovascular data and medical history were obtained by medical assessment and blood sample. Interval durations, QRS voltages of all leads, and the diagnosis were taken from baseline ECG. T-test, chi-square, correlation, and effect size were used in the data analysis. The p values in this are exploratory. Result: Mean age (years) for carriers was 36 and 43 for non-carriers. Years of education, sex, and clinical variables like body mass index, cholesterol, hemoglobin A1c, TSH, and previous cardiovascular disorders were similar between groups. There were no differences in the heart rate, PR, QRS, or corrected QT interval duration. Voltages in AVL and DI leads were lower in carriers than non-carriers with a low size of effect (0.42 vs. 0.50, p = 0.03; 0.64 vs. 0.71, p = 0.04, respectively), while the other ten leads and low voltage in any of the 12 derivates did not show any difference. There was also a negative and small correlation between voltage and age for DII, V6, and AVR (-0.146, -0.144, -0.137; p = 0.03,0.03,0.04; respectively). Conclusion: Our findings suggest no clinically significant difference in ECG parameters between PSEN1-E280A mutation carriers compared to non-carriers. Since intramyocardial deposits of amyloid-β are age-dependent, it is likely that there are low levels of these deposits in young CU individuals. Longitudinal studies with larger samples that include CU patients might identify ECG-related changes associated with amyloid-β cardiac deposits. |
| publishDate |
2023 |
| dc.date.issued.none.fl_str_mv |
2023 |
| dc.date.accessioned.none.fl_str_mv |
2025-11-27T01:30:03Z |
| dc.type.none.fl_str_mv |
Artículo de divulgación Poster de conferencia |
| dc.type.coar.fl_str_mv |
http://purl.org/coar/resource_type/c_c94f |
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http://purl.org/coar/resource_type/c_6670 |
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http://purl.org/redcol/resource_type/EC |
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Text |
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http://purl.org/coar/version/c_970fb48d4fbd8a85 |
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info:eu-repo/semantics/conferenceObject |
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info:eu-repo/semantics/publishedVersion |
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publishedVersion |
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1552-5260 |
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https://hdl.handle.net/10495/48426 |
| dc.identifier.doi.none.fl_str_mv |
10.1002/alz.064023 |
| dc.identifier.eissn.none.fl_str_mv |
1552-5279 |
| identifier_str_mv |
1552-5260 10.1002/alz.064023 1552-5279 |
| url |
https://hdl.handle.net/10495/48426 |
| dc.language.iso.none.fl_str_mv |
eng |
| language |
eng |
| dc.relation.ispartofjournalabbrev.none.fl_str_mv |
Alzheimers Dement. |
| dc.relation.citationendpage.none.fl_str_mv |
2 |
| dc.relation.citationissue.none.fl_str_mv |
2 |
| dc.relation.citationstartpage.none.fl_str_mv |
1 |
| dc.relation.citationvolume.none.fl_str_mv |
19 |
| dc.relation.ispartofjournal.none.fl_str_mv |
Alzheimer's & Dementia : The Journal of the Alzheimer's Association |
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http://creativecommons.org/licenses/by-nc/4.0/ |
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info:eu-repo/semantics/openAccess |
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Attribution-NonCommercial 4.0 International |
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http://purl.org/coar/access_right/c_abf2 |
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http://creativecommons.org/licenses/by-nc/4.0/ Attribution-NonCommercial 4.0 International http://purl.org/coar/access_right/c_abf2 |
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openAccess |
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2 páginas |
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application/pdf |
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Lat: 04 00 00 N degrees minutes Lat: 4.0000 decimal degrees Long: 072 00 00 W degrees minutes Long: -72.0000 decimal degrees |
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http://vocab.getty.edu/page/tgn/1000050 |
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Colombia |
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Wiley Open Access |
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Orlando, Estados Unidos |
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Wiley Open Access |
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Vásquez Botero, DanielGiraldo Chica, Margarita MaríaJaramillo, Carlos J.Acosta Baena, NataliaEspinosa, AlejandroRamos Pérez, Claudia PatriciaAguillón Niño, David FernandoAponte Restrepo, Claudia PatriciaLondoño, JenniferRíos Romenets, SilviaLopera Restrepo, Francisco JavierMalek Ahmadi, Michael H.Hu, NanSu, YiEhrhard, PatriciaSink, Kaycee M.Tariot, Pierre N.Reiman, Eric M.Grupo de Neurociencias de Antioquia2025-11-27T01:30:03Z20231552-5260https://hdl.handle.net/10495/4842610.1002/alz.0640231552-5279Background: Some but not all studies have found compromised myocardial function and amyloid deposition, related or unrelated to amyloid-β pathology itself, in persons with late-onset Alzheimer’s Disease (AD). Other changes in QT interval, heart rate variability, and QRS voltages have been described in the electrocardiogram (ECG), but those are not consistent between studies. We explored differences in several ECG measures in cognitively unimpaired (CU) Presenilin 1 (PSEN1)-E280A carriers and non-carriers from the Alzheimer’s Prevention Initiative Autosomal Dominant AD (API ADAD) Trial (NCT01998841). Method: The trial enrolled 252 CU 30–60-year-old participants. We included participants (144 PSEN1-E280A mutation carriers and 71 non-carriers) in these analyses who were enrolled in the trial during their first screening attempt. Baseline cardiovascular data and medical history were obtained by medical assessment and blood sample. Interval durations, QRS voltages of all leads, and the diagnosis were taken from baseline ECG. T-test, chi-square, correlation, and effect size were used in the data analysis. The p values in this are exploratory. Result: Mean age (years) for carriers was 36 and 43 for non-carriers. Years of education, sex, and clinical variables like body mass index, cholesterol, hemoglobin A1c, TSH, and previous cardiovascular disorders were similar between groups. There were no differences in the heart rate, PR, QRS, or corrected QT interval duration. Voltages in AVL and DI leads were lower in carriers than non-carriers with a low size of effect (0.42 vs. 0.50, p = 0.03; 0.64 vs. 0.71, p = 0.04, respectively), while the other ten leads and low voltage in any of the 12 derivates did not show any difference. There was also a negative and small correlation between voltage and age for DII, V6, and AVR (-0.146, -0.144, -0.137; p = 0.03,0.03,0.04; respectively). Conclusion: Our findings suggest no clinically significant difference in ECG parameters between PSEN1-E280A mutation carriers compared to non-carriers. Since intramyocardial deposits of amyloid-β are age-dependent, it is likely that there are low levels of these deposits in young CU individuals. Longitudinal studies with larger samples that include CU patients might identify ECG-related changes associated with amyloid-β cardiac deposits.COL00107442 páginasapplication/pdfengWiley Open AccessOrlando, Estados Unidoshttp://creativecommons.org/licenses/by-nc/4.0/info:eu-repo/semantics/openAccessAttribution-NonCommercial 4.0 Internationalhttp://purl.org/coar/access_right/c_abf2Electrocardiogram differences in cognitively unimpaired PSEN1-E280A carriers and non-carriers from the Alzheimer’s Prevention Initiative Autosomal-Dominant Alzheimer’s Disease Colombia TrialArtículo de divulgaciónPoster de conferenciahttp://purl.org/coar/resource_type/c_6670http://purl.org/coar/resource_type/c_c94fhttp://purl.org/redcol/resource_type/ECTexthttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/conferenceObjectinfo:eu-repo/semantics/publishedVersionElectrocardiografíaElectrocardiographyEnfermedad de AlzheimerAlzheimer Diseasehttps://id.nlm.nih.gov/mesh/D004562https://id.nlm.nih.gov/mesh/D000544ODS 3: Salud y bienestar. Garantizar una vida sana y promover el bienestar de todos a todas las edadesAlzheimers Dement.22119Alzheimer's & Dementia : The Journal of the Alzheimer's AssociationLat: 04 00 00 N degrees minutes Lat: 4.0000 decimal degrees Long: 072 00 00 W degrees minutes Long: -72.0000 decimal degreeshttp://vocab.getty.edu/page/tgn/1000050ColombiaPublicationORIGINALVasquezDaniel_2023_Electrocardiogram_Differences_Cognitively.pdfVasquezDaniel_2023_Electrocardiogram_Differences_Cognitively.pdfapplication/pdf92877https://bibliotecadigital.udea.edu.co/bitstreams/9c45a21b-b1af-4c30-b491-7edffe4738ff/download5397e6ef958b4a261dd89d8329b5bdc7MD51trueAnonymousREADCC-LICENSElicense_rdflicense_rdfapplication/rdf+xml; charset=utf-81025https://bibliotecadigital.udea.edu.co/bitstreams/888a68f7-3d41-4d62-9fb6-434872005fc9/downloadd93f5db78fcf73cec9795c8fea744a8bMD52falseAnonymousREADLICENSElicense.txtlicense.txttext/plain; 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