Abstract
BackgroundThere 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.MethodsWe 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.ResultsIn 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).ConclusionThese 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.
Highlights
Alzheimer’s disease (AD) is the leading cause of death in adults with Down syndrome (DS), with a cumulative incidence that exceeds 90% in the seventh decade [1,2,3,4]
Lleó et al Alzheimer's Research & Therapy (2021) 13:119. These data show proof-of-concept for cerebrospinal fluid (CSF) Vesicle-associated membrane protein-2 (VAMP-2) as a potential marker of synapse degeneration that correlates with CSF AD and axonal degeneration markers and cognitive performance
Several lines of evidence suggest that CSF VAMP-2 levels change as a function of AD as opposed to intellectual disability (ID): (a) the association between CSF VAMP-2 and age was independent of ID, (b) CSF VAMP-2 was comparable to controls in adults with DS negative for the CSF amyloid marker, (c) the findings reported here for this genetically determined form of AD
Summary
Alzheimer’s disease (AD) is the leading cause of death in adults with Down syndrome (DS), with a cumulative incidence that exceeds 90% in the seventh decade [1,2,3,4]. There is an urgent need for objective markers of AD-related cognitive impairment in people with DS to improve diagnosis, monitor disease progression, and assess response to disease-modifying therapies. Synaptic proteins that show AD-associated changes in biofluids are rapidly gaining attention as potential surrogate markers of AD-related synapse loss and may be informative markers of early AD-related cognitive dysfunction in adults with DS. 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. GluA4 and neuronal pentraxin 2 (NPTX2) showed limited potential as cerebrospinal fluid (CSF) markers of cognitive impairment in adults with DS. 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
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
