Cerebrospinal fluid profile of NPTX2 supports role of Alzheimer's disease-related inhibitory circuit dysfunction in adults with Down syndrome.
Alzheimer’s disease
Biomarker
Cerebrospinal fluid
Cortical atrophy
Down syndrome
GluA4
Glucose metabolism
Inhibitory circuits
Neuronal Pentraxin-2
Journal
Molecular neurodegeneration
ISSN: 1750-1326
Titre abrégé: Mol Neurodegener
Pays: England
ID NLM: 101266600
Informations de publication
Date de publication:
17 08 2020
17 08 2020
Historique:
received:
05
03
2020
accepted:
10
08
2020
entrez:
19
8
2020
pubmed:
19
8
2020
medline:
27
8
2021
Statut:
epublish
Résumé
Alzheimer's disease (AD) is the major cause of death in adults with Down syndrome (DS). There is an urgent need for objective markers of AD in the DS population to improve early diagnosis and monitor disease progression. NPTX2 has recently emerged as a promising cerebrospinal fluid (CSF) biomarker of Alzheimer-related inhibitory circuit dysfunction in sporadic AD patients. The objective of this study was to evaluate NPTX2 in the CSF of adults with DS and to explore the relationship of NPTX2 to CSF levels of the PV interneuron receptor, GluA4, and existing AD biomarkers (CSF and neuroimaging). This is a cross-sectional, retrospective study of adults with DS with asymptomatic AD (aDS, n = 49), prodromal AD (pDS, n = 18) and AD dementia (dDS, n = 27). Non-trisomic controls (n = 34) and patients with sporadic AD dementia (sAD, n = 40) were included for comparison. We compared group differences in CSF NPTX2 according to clinical diagnosis and degree of intellectual disability. We determined the relationship of CSF NPTX2 levels to age, cognitive performance (CAMCOG, free and cued selective reminding, semantic verbal fluency), CSF levels of a PV-interneuron marker (GluA4) and core AD biomarkers; CSF Aβ Compared to controls, mean CSF NPTX2 levels were lower in DS at all AD stages; aDS (0.6-fold, adj.p < 0.0001), pDS (0.5-fold, adj.p < 0.0001) and dDS (0.3-fold, adj.p < 0.0001). This reduction was similar to that observed in sporadic AD (0.5-fold, adj.p < 0.0001). CSF NPTX2 levels were not associated with age (p = 0.6), intellectual disability (p = 0.7) or cognitive performance (all p > 0.07). Low CSF NPTX2 levels were associated with low GluA4 in all clinical groups; controls (r Low levels of CSF NPTX2, a protein implicated in inhibitory circuit function, is common to sporadic and genetic forms of AD. CSF NPTX2 represents a promising CSF surrogate marker of early AD-related changes in adults with DS.
Sections du résumé
BACKGROUND
Alzheimer's disease (AD) is the major cause of death in adults with Down syndrome (DS). There is an urgent need for objective markers of AD in the DS population to improve early diagnosis and monitor disease progression. NPTX2 has recently emerged as a promising cerebrospinal fluid (CSF) biomarker of Alzheimer-related inhibitory circuit dysfunction in sporadic AD patients. The objective of this study was to evaluate NPTX2 in the CSF of adults with DS and to explore the relationship of NPTX2 to CSF levels of the PV interneuron receptor, GluA4, and existing AD biomarkers (CSF and neuroimaging).
METHODS
This is a cross-sectional, retrospective study of adults with DS with asymptomatic AD (aDS, n = 49), prodromal AD (pDS, n = 18) and AD dementia (dDS, n = 27). Non-trisomic controls (n = 34) and patients with sporadic AD dementia (sAD, n = 40) were included for comparison. We compared group differences in CSF NPTX2 according to clinical diagnosis and degree of intellectual disability. We determined the relationship of CSF NPTX2 levels to age, cognitive performance (CAMCOG, free and cued selective reminding, semantic verbal fluency), CSF levels of a PV-interneuron marker (GluA4) and core AD biomarkers; CSF Aβ
RESULTS
Compared to controls, mean CSF NPTX2 levels were lower in DS at all AD stages; aDS (0.6-fold, adj.p < 0.0001), pDS (0.5-fold, adj.p < 0.0001) and dDS (0.3-fold, adj.p < 0.0001). This reduction was similar to that observed in sporadic AD (0.5-fold, adj.p < 0.0001). CSF NPTX2 levels were not associated with age (p = 0.6), intellectual disability (p = 0.7) or cognitive performance (all p > 0.07). Low CSF NPTX2 levels were associated with low GluA4 in all clinical groups; controls (r
CONCLUSIONS
Low levels of CSF NPTX2, a protein implicated in inhibitory circuit function, is common to sporadic and genetic forms of AD. CSF NPTX2 represents a promising CSF surrogate marker of early AD-related changes in adults with DS.
Identifiants
pubmed: 32807227
doi: 10.1186/s13024-020-00398-0
pii: 10.1186/s13024-020-00398-0
pmc: PMC7433053
doi:
Substances chimiques
Biomarkers
0
Nerve Tissue Proteins
0
neuronal pentraxin
0
C-Reactive Protein
9007-41-4
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
46Subventions
Organisme : NIA NIH HHS
ID : P30 AG066507
Pays : United States
Organisme : NINDS NIH HHS
ID : R35 NS097966
Pays : United States
Organisme : NIA NIH HHS
ID : R21 AG056974
Pays : United States
Références
Front Hum Neurosci. 2012 May 01;6:107
pubmed: 22557957
Nat Neurosci. 2010 Sep;13(9):1090-7
pubmed: 20729843
Neuroimage. 2014 May 15;92:225-36
pubmed: 24361666
Alzheimers Dement. 2017 Nov;13(11):1251-1260
pubmed: 28463681
Lancet. 2020 Jun 27;395(10242):1988-1997
pubmed: 32593336
Prog Clin Biol Res. 1989;317:247-67
pubmed: 2532369
Proc Natl Acad Sci U S A. 2000 Sep 26;97(20):11050-5
pubmed: 10984517
Neuroimage. 2016 May 15;132:334-343
pubmed: 26915497
J Neurosci. 2012 Nov 14;32(46):16265-73
pubmed: 23152610
Neuron. 2007 Feb 15;53(4):591-604
pubmed: 17296559
J Alzheimers Dis. 2018;61(2):717-728
pubmed: 29226868
Neuroimage Clin. 2017 Nov 06;17:263-271
pubmed: 29159043
Mult Scler Int. 2011;2011:246412
pubmed: 22096631
J Alzheimers Dis. 2017;58(3):909-918
pubmed: 28527215
Elife. 2017 Mar 23;6:
pubmed: 28440221
Alzheimers Dement (N Y). 2019 Dec 09;5:871-882
pubmed: 31853477
Ann Neurol. 1985 Mar;17(3):278-82
pubmed: 3158266
Genome Res. 2006 Sep;16(9):1136-48
pubmed: 16899659
Bioinformatics. 2014 Sep 1;30(17):2524-6
pubmed: 24794931
Neuron. 2015 Mar 18;85(6):1257-72
pubmed: 25754824
Lancet Neurol. 2018 Oct;17(10):860-869
pubmed: 30172624
J Alzheimers Dis. 2017;55(4):1489-1496
pubmed: 27858714
Neurology. 2015 Aug 18;85(7):626-33
pubmed: 26180139
Alzheimers Dement (N Y). 2019 Oct 14;5:597-609
pubmed: 31650016
Lancet Neurol. 2014 Jun;13(6):614-29
pubmed: 24849862
J Neurol Neurosurg Psychiatry. 2020 Jun;91(6):612-621
pubmed: 32273328
J Intellect Disabil Res. 2014 Jan;58(1):61-70
pubmed: 23902161
Nat Rev Neurosci. 2016 Dec;17(12):777-792
pubmed: 27829687
Neuron. 2003 Mar 27;37(6):925-37
pubmed: 12670422
N Engl J Med. 2012 Aug 30;367(9):795-804
pubmed: 22784036
Neuron. 2013 Sep 4;79(5):887-902
pubmed: 24012003
Neurobiol Aging. 2011 Jul;32(7):1207-18
pubmed: 19660834
Brain. 2018 Aug 1;141(8):2457-2474
pubmed: 29945247
Alzheimers Dement. 2011 May;7(3):263-9
pubmed: 21514250
Mol Cell Proteomics. 2019 Mar;18(3):546-560
pubmed: 30606734
Rev Neurol. 2013 Oct 16;57(8):337-46
pubmed: 24081888
JAMA Neurol. 2019 Feb 1;76(2):152-160
pubmed: 30452522
Neuroscience. 1997 Oct;80(4):1113-25
pubmed: 9284064