VAMP-2 is a surrogate cerebrospinal fluid marker of Alzheimer-related cognitive impairment in adults with Down syndrome
Year: 2021
Type: article
Study design: Observational Study
Abstract: 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 Aβ42:40ratio, 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 recalladj.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.
Source: Alzheimer s Research & Therapy
Authors: Alberto Lleó, Maria Carmona-Iragui, Laura Videla, Susana Fernández, Bessy Benejam, Jordi Pegueroles, Isabel Barroeta, Miren Altuna, Silvia Valldeneu, Mei-Fang Xiao, Desheng Xu, Raúl Núñez-Llaves, Marta Querol-Vilaseca, Sònia Sirisi, Alexandre Bejanin, M. Florencia Iulita, Jordi Clarimón, Rafael Blesa, Paul Worley, Daniel Alcolea, Juan Fortea, Olivia Belbin
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,490
Funders: Fundación BBVA, Fundació la Marató de TV3, Fondation Jérôme Lejeune, Generalitat de Catalunya, Banco Bilbao Vizcaya Argentaria, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, National Institutes of Health, Agència de Gestió d'Ajuts Universitaris i de Recerca, Instituto de Salud Carlos III, European Regional Development Fund, Departament de Salut, Generalitat de Catalunya, National Institute on Aging, National Institute of Neurological Disorders and Stroke
Awards: G1075404386, G1087952636, G1228583376, Retinal Dehydrogenases, G1853423388, G2152553174, The Role of Inflammation and NGF Dysfunction in the Evolution of AlzheimerDisease Pathology in Down syndrome, G2677554862, G2681669101, De novo Synthesis and Memory, G3288897321, G425470326, G4484208813, G4509608868, Estudio del trazador de tomografía por emisión de positrones (PET) para Tau [18F]THK-5351 en pacientes con diferentes Taupatías, Utilidad diagnóstica de Aß42 y Aß42/40 en LCR y plasma para detectar amiloidosis cerebral y correlación con marcadores subrogados de producción de ß-amiloide en enf. de Alzheimer, G5277868701, Effects of Age-Related Changes in the Microenvironment on Patterns of Hematopoiesis, G5428408597, Estudio multimodal de nuevos biomarcadores sinápticos en cohortes de la enfermedad de Alzheimer y la demencia frontotemporal, G5935723808, Estudios longitudinales de RM magnética estructural, de difusión y funcional en la enfermedad de Alzheimer preclínica esporádica y asociada al síndrome de Down, G6368058359, G6523755466, G6555716666, G6567408650, G7093738275, Tau pathology in Down syndrome and Alzheimer's, Abordajes terapéuticos en leucemia mieloide crónica mediante CRISPR/CAS9, Estudio de biomarcadores bioquímicos y de imagen de angiopatía amiloide cerebral en el continuum de la enfermedad de Alzheimer esporádica y asociada al síndrome de Down, G8284279906, Biological Correlates of Alzheimer in Down Syndrome., G8712830647, Johns Hopkins Alzheimer's Disease Research Center, G931469340
OpenAlex ID: W3136903797