TY - JOUR
T1 - VAMP-2 is a surrogate cerebrospinal fluid marker of Alzheimer-related cognitive impairment in adults with Down syndrome
AU - Lleó, Alberto
AU - Carmona-Iragui, Maria
AU - Videla, Laura
AU - Fernández, Susana
AU - Benejam, Bessy
AU - Pegueroles, Jordi
AU - Barroeta, Isabel
AU - Altuna, Miren
AU - Valldeneu, Silvia
AU - Xiao, Mei Fang
AU - Xu, Desheng
AU - Núñez-Llaves, Raúl
AU - Querol-Vilaseca, Marta
AU - Sirisi, Sònia
AU - Bejanin, Alexandre
AU - Iulita, M. Florencia
AU - Clarimón, Jordi
AU - Blesa, Rafael
AU - Worley, Paul
AU - Alcolea, Daniel
AU - Fortea, Juan
AU - Belbin, Olivia
N1 - Funding Information:
This work was supported by the Fundació Catalana Síndrome de Down and Fundació Víctor Grífols i Lucas and research grants from Institute of Health Carlos III (ISCIII), Spain (PI18/00327 to OB, PI18/00435 to DA, INT19/00016 to DA, PI17/01019 to JF; PI16/01825 to RB; PI17/01895 to AL and PI18/0335 to MC-I and CIBERNED Program 1, Alzheimer Disease to AL and SIGNAL study, www.signal.es ), and the National Institutes of Health, US (NIA grants R01AG056850-01A1, R21AG056974 and R01AG061566 to JF). This work has also been supported by the Fundació La Marató de TV3 (20141210 to JF and 044412 to RB), the Fundació Bancaria Obra Social La Caixa (DABNI project to RB), Fundación BBVA (to AL) and by the Department of Health, Generalitat de Catalunya PERIS (SLT006/17/125 to DA, SLT002/16/00099 to RNL, SLT006/17/00119 to JF 2017) and SGR (2017 SGR 547 to JC) programs and partly funded by Fondo Europeo de Desarrollo Regional (FEDER), Unión Europea, “Una manera de hacer Europa.” OB is funded by the Miguel Servet Fellowhsip grant from the Institute of Health Carlos III (ISCIII, CP18/00011), Spain, and M.F I is supported by the Jérôme Lejeune Foundation, France. PW, DS, and MX were supported by R35NS097966.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - 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 Aβ42:40 ratio, CSF Aβ1-42, CSF p-tau, and CSF NFL. P values were adjusted for multiple testing. 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 Aβ42:40 (adj.p =.0001), p-tau (adj.p <.0001), and NFL (adj.p <.0001). Compared to controls, mean VAMP-2 levels were lower in asymptomatic adults with DS only (adj.p =.02). CSF levels of Neurexin-3A, Thy-1, Neurexin-2A, Calysntenin-1, Neuroligin-2, GluA4, and Syntaxin-1B all strongly correlated with NPTX2 (p <.0001), which was the only synaptic protein to show reduced CSF levels in DS at all AD stages compared to controls (adj.p <.002). 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.
AB - 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 Aβ42:40 ratio, CSF Aβ1-42, CSF p-tau, and CSF NFL. P values were adjusted for multiple testing. 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 Aβ42:40 (adj.p =.0001), p-tau (adj.p <.0001), and NFL (adj.p <.0001). Compared to controls, mean VAMP-2 levels were lower in asymptomatic adults with DS only (adj.p =.02). CSF levels of Neurexin-3A, Thy-1, Neurexin-2A, Calysntenin-1, Neuroligin-2, GluA4, and Syntaxin-1B all strongly correlated with NPTX2 (p <.0001), which was the only synaptic protein to show reduced CSF levels in DS at all AD stages compared to controls (adj.p <.002). 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.
KW - Alzheimer’s disease
KW - Biomarker
KW - Cognitive decline
KW - Down syndrome
KW - Synapse
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U2 - 10.1186/s13195-021-00861-0
DO - 10.1186/s13195-021-00861-0
M3 - Article
C2 - 34183050
AN - SCOPUS:85109371447
SN - 1465-5411
VL - 13
JO - Alzheimer's Research and Therapy
JF - Alzheimer's Research and Therapy
IS - 1
M1 - 119
ER -