VAMP-2 is a surrogate cerebrospinal fluid marker of Alzheimer-related cognitive impairment in adults with Down syndrome.
Alzheimer’s disease
Biomarker
Cognitive decline
Down syndrome
Synapse
Journal
Alzheimer's research & therapy
ISSN: 1758-9193
Titre abrégé: Alzheimers Res Ther
Pays: England
ID NLM: 101511643
Informations de publication
Date de publication:
28 06 2021
28 06 2021
Historique:
received:
17
03
2021
accepted:
14
06
2021
entrez:
29
6
2021
pubmed:
30
6
2021
medline:
14
8
2021
Statut:
epublish
Résumé
There is an urgent need for objective markers of Alzheimer's disease (AD)-related cognitive impairment in people with Down syndrome (DS) to improve diagnosis, monitor disease progression, and assess response to disease-modifying therapies. Previously, GluA4 and neuronal pentraxin 2 (NPTX2) showed limited potential as cerebrospinal fluid (CSF) markers of cognitive impairment in adults with DS. Here, we compare the CSF profile of a panel of synaptic proteins (Calsyntenin-1, Neuroligin-2, Neurexin-2A, Neurexin-3A, Syntaxin-1B, Thy-1, VAMP-2) to that of NPTX2 and GluA4 in a large cohort of subjects with DS across the preclinical and clinical AD continuum and explore their correlation with cognitive impairment. We quantified the synaptic panel proteins by selected reaction monitoring in CSF from 20 non-trisomic cognitively normal controls (mean age 44) and 80 adults with DS grouped according to clinical AD diagnosis (asymptomatic, prodromal AD or AD dementia). We used regression analyses to determine CSF changes across the AD continuum and explored correlations with age, global cognitive performance (CAMCOG), episodic memory (modified cued-recall test; mCRT) and CSF biomarkers, CSF Aβ In adults with DS, VAMP-2 was the only synaptic protein to correlate with episodic memory (delayed recall adj.p = .04) and age (adj.p = .0008) and was the best correlate of CSF Aβ These data show proof-of-concept for CSF VAMP-2 as a potential marker of synapse degeneration that correlates with CSF AD and axonal degeneration markers and cognitive performance.
Sections du résumé
BACKGROUND
There is an urgent need for objective markers of Alzheimer's disease (AD)-related cognitive impairment in people with Down syndrome (DS) to improve diagnosis, monitor disease progression, and assess response to disease-modifying therapies. Previously, GluA4 and neuronal pentraxin 2 (NPTX2) showed limited potential as cerebrospinal fluid (CSF) markers of cognitive impairment in adults with DS. Here, we compare the CSF profile of a panel of synaptic proteins (Calsyntenin-1, Neuroligin-2, Neurexin-2A, Neurexin-3A, Syntaxin-1B, Thy-1, VAMP-2) to that of NPTX2 and GluA4 in a large cohort of subjects with DS across the preclinical and clinical AD continuum and explore their correlation with cognitive impairment.
METHODS
We quantified the synaptic panel proteins by selected reaction monitoring in CSF from 20 non-trisomic cognitively normal controls (mean age 44) and 80 adults with DS grouped according to clinical AD diagnosis (asymptomatic, prodromal AD or AD dementia). We used regression analyses to determine CSF changes across the AD continuum and explored correlations with age, global cognitive performance (CAMCOG), episodic memory (modified cued-recall test; mCRT) and CSF biomarkers, CSF Aβ
RESULTS
In adults with DS, VAMP-2 was the only synaptic protein to correlate with episodic memory (delayed recall adj.p = .04) and age (adj.p = .0008) and was the best correlate of CSF Aβ
CONCLUSION
These data show proof-of-concept for CSF VAMP-2 as a potential marker of synapse degeneration that correlates with CSF AD and axonal degeneration markers and cognitive performance.
Identifiants
pubmed: 34183050
doi: 10.1186/s13195-021-00861-0
pii: 10.1186/s13195-021-00861-0
pmc: PMC8240298
doi:
Substances chimiques
Amyloid beta-Peptides
0
Biomarkers
0
Peptide Fragments
0
VAMP2 protein, human
0
Vesicle-Associated Membrane Protein 2
0
tau Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
119Subventions
Organisme : NIA NIH HHS
ID : P30 AG066507
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG013566
Pays : United States
Organisme : NIA NIH HHS
ID : R21 AG056974
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG056480
Pays : United States
Références
Mol Neurodegener. 2020 Jun 18;15(1):36
pubmed: 32552841
Nat Neurosci. 2010 Sep;13(9):1090-7
pubmed: 20729843
Brain Behav Immun. 2016 Nov;58:201-208
pubmed: 27444967
Acta Neuropathol. 2018 Feb;135(2):213-226
pubmed: 29273900
Lancet Neurol. 2018 Oct;17(10):860-869
pubmed: 30172624
Alzheimers Dement (Amst). 2020 Jun 28;12(1):e12047
pubmed: 32613076
J Intellect Disabil Res. 2002 Sep;46(Pt 6):472-83
pubmed: 12354318
Ann Clin Transl Neurol. 2019 Sep;6(9):1815-1824
pubmed: 31464088
PLoS One. 2015 Oct 21;10(10):e0140868
pubmed: 26488171
Mol Neurodegener. 2011 Aug 26;6(1):63
pubmed: 21871088
Mult Scler Int. 2011;2011:246412
pubmed: 22096631
Mol Cell Proteomics. 2019 Mar;18(3):546-560
pubmed: 30606734
Proc Natl Acad Sci U S A. 2016 Feb 16;113(7):E922-31
pubmed: 26839408
Ann Neurol. 1991 Oct;30(4):572-80
pubmed: 1789684
Brain Behav. 2020 Oct;10(10):e01779
pubmed: 32748547
Mol Neurodegener. 2020 Aug 17;15(1):46
pubmed: 32807227
Alzheimers Dement (N Y). 2019 Dec 09;5:871-882
pubmed: 31853477
Science. 2002 Oct 25;298(5594):789-91
pubmed: 12399581
Neurobiol Aging. 2013 Jun;34(6):1653-61
pubmed: 23273601
Bioinformatics. 2014 Sep 1;30(17):2524-6
pubmed: 24794931
Nat Biotechnol. 2010 Dec;28(12):1248-50
pubmed: 21139605
Lancet. 2020 Jun 27;395(10242):1988-1997
pubmed: 32593336
Neuron. 1997 Nov;19(5):1087-94
pubmed: 9390521
BMC Neurosci. 2011 Nov 17;12:118
pubmed: 22094010
Neurology. 2015 Aug 18;85(7):626-33
pubmed: 26180139
Alzheimers Dement (N Y). 2019 Oct 14;5:597-609
pubmed: 31650016
J Alzheimers Dis. 2010;22(1):285-94
pubmed: 20847406
J Neurol Neurosurg Psychiatry. 2020 Jun;91(6):612-621
pubmed: 32273328
J Intellect Disabil Res. 2014 Jan;58(1):61-70
pubmed: 23902161
J Alzheimers Dis. 2018;61(2):717-728
pubmed: 29226868
Brain. 2014 Sep;137(Pt 9):2578-87
pubmed: 25012223
Am J Intellect Dev Disabil. 2015 Nov;120(6):481-9
pubmed: 26505869
Rev Neurol. 2013 Oct 16;57(8):337-46
pubmed: 24081888
JAMA Neurol. 2019 Feb 1;76(2):152-160
pubmed: 30452522