VAMP-2 is a surrogate cerebrospinal fluid marker of Alzheimer-related cognitive impairment in adults with Down syndrome
Por:
Lleo, A, Carmona-Iragui, M, Videla, L, Fernandez, S, Benejam, B, Pegueroles, J, Barroeta, I, Altuna, M, Valldeneu, S, Xiao, MF, Xu, DS, Nunez-Llaves, R, Querol-Vilaseca, M, Sirisi, S, Bejanin, A, Iulita, MF, Clarimon, J, Blesa, R, Worley, P, Alcolea, D, Fortea, J, Belbin, O
Publicada:
28 jun 2021
Resumen:
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 A beta(42:40) ratio, CSF A beta(1-42), 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 A beta(42:40) (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.
Filiaciones:
Lleo, A:
Autonomous Univ Barcelona, Hosp Santa Creu & Sant Pau, Memory Unit, C Sant Quinti 77-79, Barcelona 08025, Spain
Autonomous Univ Barcelona, Hosp Santa Creu & Sant Pau, Biomed Res Inst Sant Pau IIB Sant Pau, Neurol Dept, C Sant Quinti 77-79, Barcelona 08025, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid 28031, Spain
Carmona-Iragui, M:
Autonomous Univ Barcelona, Hosp Santa Creu & Sant Pau, Memory Unit, C Sant Quinti 77-79, Barcelona 08025, Spain
Autonomous Univ Barcelona, Hosp Santa Creu & Sant Pau, Biomed Res Inst Sant Pau IIB Sant Pau, Neurol Dept, C Sant Quinti 77-79, Barcelona 08025, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid 28031, Spain
Fundacio Catalana Sindrome, Barcelona Med Ctr, Barcelona, Spain
Videla, L:
Autonomous Univ Barcelona, Hosp Santa Creu & Sant Pau, Memory Unit, C Sant Quinti 77-79, Barcelona 08025, Spain
Autonomous Univ Barcelona, Hosp Santa Creu & Sant Pau, Biomed Res Inst Sant Pau IIB Sant Pau, Neurol Dept, C Sant Quinti 77-79, Barcelona 08025, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid 28031, Spain
Fundacio Catalana Sindrome, Barcelona Med Ctr, Barcelona, Spain
Fernandez, S:
Fundacio Catalana Sindrome, Barcelona Med Ctr, Barcelona, Spain
Benejam, B:
Autonomous Univ Barcelona, Hosp Santa Creu & Sant Pau, Memory Unit, C Sant Quinti 77-79, Barcelona 08025, Spain
Autonomous Univ Barcelona, Hosp Santa Creu & Sant Pau, Biomed Res Inst Sant Pau IIB Sant Pau, Neurol Dept, C Sant Quinti 77-79, Barcelona 08025, Spain
Fundacio Catalana Sindrome, Barcelona Med Ctr, Barcelona, Spain
Pegueroles, J:
Autonomous Univ Barcelona, Hosp Santa Creu & Sant Pau, Memory Unit, C Sant Quinti 77-79, Barcelona 08025, Spain
Autonomous Univ Barcelona, Hosp Santa Creu & Sant Pau, Biomed Res Inst Sant Pau IIB Sant Pau, Neurol Dept, C Sant Quinti 77-79, Barcelona 08025, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid 28031, Spain
Barroeta, I:
Autonomous Univ Barcelona, Hosp Santa Creu & Sant Pau, Memory Unit, C Sant Quinti 77-79, Barcelona 08025, Spain
Autonomous Univ Barcelona, Hosp Santa Creu & Sant Pau, Biomed Res Inst Sant Pau IIB Sant Pau, Neurol Dept, C Sant Quinti 77-79, Barcelona 08025, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid 28031, Spain
Altuna, M:
Autonomous Univ Barcelona, Hosp Santa Creu & Sant Pau, Memory Unit, C Sant Quinti 77-79, Barcelona 08025, Spain
Autonomous Univ Barcelona, Hosp Santa Creu & Sant Pau, Biomed Res Inst Sant Pau IIB Sant Pau, Neurol Dept, C Sant Quinti 77-79, Barcelona 08025, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid 28031, Spain
Valldeneu, S:
Autonomous Univ Barcelona, Hosp Santa Creu & Sant Pau, Memory Unit, C Sant Quinti 77-79, Barcelona 08025, Spain
Autonomous Univ Barcelona, Hosp Santa Creu & Sant Pau, Biomed Res Inst Sant Pau IIB Sant Pau, Neurol Dept, C Sant Quinti 77-79, Barcelona 08025, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid 28031, Spain
Xiao, MF:
Johns Hopkins Univ, Sch Med, Solomon H Snyder Dept Neurosci, Baltimore, MD 21205 USA
Xu, DS:
Johns Hopkins Univ, Sch Med, Solomon H Snyder Dept Neurosci, Baltimore, MD 21205 USA
Nunez-Llaves, R:
Autonomous Univ Barcelona, Hosp Santa Creu & Sant Pau, Memory Unit, C Sant Quinti 77-79, Barcelona 08025, Spain
Autonomous Univ Barcelona, Hosp Santa Creu & Sant Pau, Biomed Res Inst Sant Pau IIB Sant Pau, Neurol Dept, C Sant Quinti 77-79, Barcelona 08025, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid 28031, Spain
Querol-Vilaseca, M:
Autonomous Univ Barcelona, Hosp Santa Creu & Sant Pau, Memory Unit, C Sant Quinti 77-79, Barcelona 08025, Spain
Autonomous Univ Barcelona, Hosp Santa Creu & Sant Pau, Biomed Res Inst Sant Pau IIB Sant Pau, Neurol Dept, C Sant Quinti 77-79, Barcelona 08025, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid 28031, Spain
Sirisi, S:
Autonomous Univ Barcelona, Hosp Santa Creu & Sant Pau, Memory Unit, C Sant Quinti 77-79, Barcelona 08025, Spain
Autonomous Univ Barcelona, Hosp Santa Creu & Sant Pau, Biomed Res Inst Sant Pau IIB Sant Pau, Neurol Dept, C Sant Quinti 77-79, Barcelona 08025, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid 28031, Spain
Bejanin, A:
Autonomous Univ Barcelona, Hosp Santa Creu & Sant Pau, Memory Unit, C Sant Quinti 77-79, Barcelona 08025, Spain
Autonomous Univ Barcelona, Hosp Santa Creu & Sant Pau, Biomed Res Inst Sant Pau IIB Sant Pau, Neurol Dept, C Sant Quinti 77-79, Barcelona 08025, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid 28031, Spain
Iulita, MF:
Autonomous Univ Barcelona, Hosp Santa Creu & Sant Pau, Memory Unit, C Sant Quinti 77-79, Barcelona 08025, Spain
Autonomous Univ Barcelona, Hosp Santa Creu & Sant Pau, Biomed Res Inst Sant Pau IIB Sant Pau, Neurol Dept, C Sant Quinti 77-79, Barcelona 08025, Spain
Clarimon, J:
Autonomous Univ Barcelona, Hosp Santa Creu & Sant Pau, Memory Unit, C Sant Quinti 77-79, Barcelona 08025, Spain
Autonomous Univ Barcelona, Hosp Santa Creu & Sant Pau, Biomed Res Inst Sant Pau IIB Sant Pau, Neurol Dept, C Sant Quinti 77-79, Barcelona 08025, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid 28031, Spain
Blesa, R:
Autonomous Univ Barcelona, Hosp Santa Creu & Sant Pau, Memory Unit, C Sant Quinti 77-79, Barcelona 08025, Spain
Autonomous Univ Barcelona, Hosp Santa Creu & Sant Pau, Biomed Res Inst Sant Pau IIB Sant Pau, Neurol Dept, C Sant Quinti 77-79, Barcelona 08025, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid 28031, Spain
Worley, P:
Johns Hopkins Univ, Sch Med, Solomon H Snyder Dept Neurosci, Baltimore, MD 21205 USA
Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA
Alcolea, D:
Autonomous Univ Barcelona, Hosp Santa Creu & Sant Pau, Memory Unit, C Sant Quinti 77-79, Barcelona 08025, Spain
Autonomous Univ Barcelona, Hosp Santa Creu & Sant Pau, Biomed Res Inst Sant Pau IIB Sant Pau, Neurol Dept, C Sant Quinti 77-79, Barcelona 08025, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid 28031, Spain
Fortea, J:
Autonomous Univ Barcelona, Hosp Santa Creu & Sant Pau, Memory Unit, C Sant Quinti 77-79, Barcelona 08025, Spain
Autonomous Univ Barcelona, Hosp Santa Creu & Sant Pau, Biomed Res Inst Sant Pau IIB Sant Pau, Neurol Dept, C Sant Quinti 77-79, Barcelona 08025, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid 28031, Spain
Belbin, O:
Autonomous Univ Barcelona, Hosp Santa Creu & Sant Pau, Memory Unit, C Sant Quinti 77-79, Barcelona 08025, Spain
Autonomous Univ Barcelona, Hosp Santa Creu & Sant Pau, Biomed Res Inst Sant Pau IIB Sant Pau, Neurol Dept, C Sant Quinti 77-79, Barcelona 08025, Spain
Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid 28031, Spain
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