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Exploratory mass spectrometry of cerebrospinal fluid from persons with autopsy-confirmed LATE-NC

BACKGROUND: Common neuropathologies associated with dementia include Alzheimer’s disease neuropathologic change (ADNC) and limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC). Biofluid proteomics provides a window into the pathobiology of dementia and the informatio...

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Autores principales: Gal, Jozsef, Vary, Calvin, Gartner, Carlos A., Jicha, Gregory A., Abner, Erin L., Ortega, Yulica S., Choucair, Ibrahim, Wilcock, Donna M., Nelson, Ruth, Nelson, Peter
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Journal Experts 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10479397/
https://www.ncbi.nlm.nih.gov/pubmed/37674727
http://dx.doi.org/10.21203/rs.3.rs-3252238/v1
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author Gal, Jozsef
Vary, Calvin
Gartner, Carlos A.
Jicha, Gregory A.
Abner, Erin L.
Ortega, Yulica S.
Choucair, Ibrahim
Wilcock, Donna M.
Nelson, Ruth
Nelson, Peter
author_facet Gal, Jozsef
Vary, Calvin
Gartner, Carlos A.
Jicha, Gregory A.
Abner, Erin L.
Ortega, Yulica S.
Choucair, Ibrahim
Wilcock, Donna M.
Nelson, Ruth
Nelson, Peter
author_sort Gal, Jozsef
collection PubMed
description BACKGROUND: Common neuropathologies associated with dementia include Alzheimer’s disease neuropathologic change (ADNC) and limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC). Biofluid proteomics provides a window into the pathobiology of dementia and the information from biofluid tests may help guide clinical management. METHODS: Participants were recruited from a longitudinal cohort of older adults at the University of Kentucky AD Research Center. A convenience sample of clinically obtained lumbar puncture cerebrospinal fluid (CSF) samples was analyzed from 29 older adults that had autopsy confirmation of the presence or absence of LATE-NC. Nine of the participants had autopsy-confirmed LATE-NC. Antemortem CSF specimens were analyzed in two separate processes: From one group, aliquots were depleted of highly abundant proteins using affinity spin columns. Tryptic digests of sample proteins were subjected to liquid chromatographic separation and mass spectrometry using an Eksigent Ekspert nanoLC 400 system in line with a Sciex 6600+ mass spectrometer. Protein identification was performed using Protein Pilot (Sciex, ver. 5) software, and relative quantification was performed using the SWATH processing microApp in PeakView and MarkerView software (Sciex), respectively. Following data analyses, additional studies were performed using western blots. RESULTS: A total of 830 proteins were identified in the samples depleted of abundant proteins, and 730 proteins were identified in the non-depleted samples. Whereas some dementia-related proteins were detected (Aβ peptide and α-synuclein protein), others were not (TDP-43, TMEM106B, and tau proteins). When the Bonferroni correction was applied to correct for multiple comparisons, only 4 proteins showed differential expression (LATE-NC vs non-LATE-NC) in the nondepleted samples (RBP4, MIF, IGHG3 and ITM2B), whereas none showed statistically different changes in the depleted samples. Post-hoc western blots confirmed that RBP4 expression was higher in the LATE-NC cases at the group level, but there was overlap between the levels of RBP4 in LATE-NC and non-LATE-NC cases. CONCLUSIONS: An exploratory assessment of CSF proteomes of autopsy-confirmed LATE-NC and non-LATE-NC cases from a community-based cohort failed to demonstrate a clear-cut proteomic fingerprint that distinguished the two groups. There was intriguing increase in RBP4 protein levels in CSF from LATE-NC cases. This may provide clues about pathogenetic mechanisms in LATE-NC.
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spelling pubmed-104793972023-09-06 Exploratory mass spectrometry of cerebrospinal fluid from persons with autopsy-confirmed LATE-NC Gal, Jozsef Vary, Calvin Gartner, Carlos A. Jicha, Gregory A. Abner, Erin L. Ortega, Yulica S. Choucair, Ibrahim Wilcock, Donna M. Nelson, Ruth Nelson, Peter Res Sq Article BACKGROUND: Common neuropathologies associated with dementia include Alzheimer’s disease neuropathologic change (ADNC) and limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC). Biofluid proteomics provides a window into the pathobiology of dementia and the information from biofluid tests may help guide clinical management. METHODS: Participants were recruited from a longitudinal cohort of older adults at the University of Kentucky AD Research Center. A convenience sample of clinically obtained lumbar puncture cerebrospinal fluid (CSF) samples was analyzed from 29 older adults that had autopsy confirmation of the presence or absence of LATE-NC. Nine of the participants had autopsy-confirmed LATE-NC. Antemortem CSF specimens were analyzed in two separate processes: From one group, aliquots were depleted of highly abundant proteins using affinity spin columns. Tryptic digests of sample proteins were subjected to liquid chromatographic separation and mass spectrometry using an Eksigent Ekspert nanoLC 400 system in line with a Sciex 6600+ mass spectrometer. Protein identification was performed using Protein Pilot (Sciex, ver. 5) software, and relative quantification was performed using the SWATH processing microApp in PeakView and MarkerView software (Sciex), respectively. Following data analyses, additional studies were performed using western blots. RESULTS: A total of 830 proteins were identified in the samples depleted of abundant proteins, and 730 proteins were identified in the non-depleted samples. Whereas some dementia-related proteins were detected (Aβ peptide and α-synuclein protein), others were not (TDP-43, TMEM106B, and tau proteins). When the Bonferroni correction was applied to correct for multiple comparisons, only 4 proteins showed differential expression (LATE-NC vs non-LATE-NC) in the nondepleted samples (RBP4, MIF, IGHG3 and ITM2B), whereas none showed statistically different changes in the depleted samples. Post-hoc western blots confirmed that RBP4 expression was higher in the LATE-NC cases at the group level, but there was overlap between the levels of RBP4 in LATE-NC and non-LATE-NC cases. CONCLUSIONS: An exploratory assessment of CSF proteomes of autopsy-confirmed LATE-NC and non-LATE-NC cases from a community-based cohort failed to demonstrate a clear-cut proteomic fingerprint that distinguished the two groups. There was intriguing increase in RBP4 protein levels in CSF from LATE-NC cases. This may provide clues about pathogenetic mechanisms in LATE-NC. American Journal Experts 2023-08-22 /pmc/articles/PMC10479397/ /pubmed/37674727 http://dx.doi.org/10.21203/rs.3.rs-3252238/v1 Text en https://creativecommons.org/licenses/by/4.0/This work is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/) , which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.
spellingShingle Article
Gal, Jozsef
Vary, Calvin
Gartner, Carlos A.
Jicha, Gregory A.
Abner, Erin L.
Ortega, Yulica S.
Choucair, Ibrahim
Wilcock, Donna M.
Nelson, Ruth
Nelson, Peter
Exploratory mass spectrometry of cerebrospinal fluid from persons with autopsy-confirmed LATE-NC
title Exploratory mass spectrometry of cerebrospinal fluid from persons with autopsy-confirmed LATE-NC
title_full Exploratory mass spectrometry of cerebrospinal fluid from persons with autopsy-confirmed LATE-NC
title_fullStr Exploratory mass spectrometry of cerebrospinal fluid from persons with autopsy-confirmed LATE-NC
title_full_unstemmed Exploratory mass spectrometry of cerebrospinal fluid from persons with autopsy-confirmed LATE-NC
title_short Exploratory mass spectrometry of cerebrospinal fluid from persons with autopsy-confirmed LATE-NC
title_sort exploratory mass spectrometry of cerebrospinal fluid from persons with autopsy-confirmed late-nc
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10479397/
https://www.ncbi.nlm.nih.gov/pubmed/37674727
http://dx.doi.org/10.21203/rs.3.rs-3252238/v1
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