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A biomarker of synapse loss, an early event in Alzheimer's disease (AD) pathophysiology that precedes neuronal death and symptom onset, would be a much-needed prognostic biomarker. With direct access to the brain interstitial fluid, the cerebrospinal fluid (CSF) is a potential source of synapse-derived proteins. In this study, we aimed to identify and validate novel CSF biomarkers of synapse loss in AD. Discovery: Combining shotgun proteomics of the CSF with an exhaustive search of the literature and public databases, we identified 251 synaptic proteins, from which we selected 22 for further study. Verification: Twelve proteins were discarded because of poor detection by Selected Reaction Monitoring (SRM). We confirmed the specific expression of 9 of the remaining proteins (Calsynytenin-1, GluR2, GluR4, Neurexin-2A, Neurexin-3A, Neuroligin-2, Syntaxin-1B, Thy-1, Vamp-2) at the human synapse using Array Tomography microscopy and biochemical fractionation methods. Exploration: Using SRM, we monitored these 9 synaptic proteins (20 peptides) in a cohort of CSF from cognitively normal controls and subjects in the pre-clinical and clinical AD stages (n = 80). Compared with controls, peptides from 8 proteins were elevated 1.3 to 1.6-fold (p < 0.04) in prodromal AD patients. Validation: Elevated levels of a GluR4 peptide at the prodromal stage were replicated (1.3-fold, p = 0.04) in an independent cohort (n = 60). Moreover, 7 proteins were reduced at preclinical stage 1 (0.6 to 0.8-fold, p < 0.04), a finding that was replicated (0.7 to 0.8-fold, p < 0.05) for 6 proteins in a third cohort (n = 38). In a cross-cohort meta-analysis, 6 synaptic proteins (Calsyntenin-1, GluR4, Neurexin-2A, Neurexin-3A, Syntaxin-1B and Thy-1) were reduced 0.8-fold (p < 0.05) in preclinical AD, changes that precede clinical symptoms and CSF markers of neurodegeneration. Therefore, these proteins could have clinical value for assessing disease progression, especially in preclinical stages of AD. This work was supported by the following research grants: Fondos de Investigaciones Sanitarias (PI15/00058, PI14/01561, PI18/000327) from the “Fondo Europeo de Desarrollo Regional (FEDER)”, Unión Europea, “Una manera de hacer Europa” and the “Instituto de Salud Carlos III, Ministerio de Economia y Competitividad, Gobierno de España” (ISCIII). Additional funding came from the “Departament de Salut, Generalitat de Cataluña - Pla Estratègic de Recerca i Innovació en Salut (PERIS) 2016 –2020, 2017–2019” (SLT002/16/00408, 2017SGR547), “Programa 1 Enfermedad de Alzheimer y otras demencias degenerativas” from the Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), the “Fundació Bancaria La Caixa” (4560/6393) and “La Marató” organized by the television channel, TV3 (20142610). OB is supported by the Miguel Servet program (CP13/00091) from the ISCIII and FEDER. AB is supported by the Ministerio de Economia y Competitividad, Gobierno de España and FEDER (BFU2012-34398 and BFU2015-69717-P), by the Career Integration Grant from the European Union (ref. 304111, Marie Curie Actions), by the Ramón y Cajal Fellowship (ref. RYC-2011-08391) from the Ministerio de Economia y Competitividad, Gobierno de España and by the CERCA Programme from the Generalitat de Catalunya. RN-L is supported by the research grant from the Generalitat de Catalunya (PERIS SLT/2381/2016/00099). The proteomics analyses were performed in the CRG/UPF Proteomics Unit which is part of the Proteored, PRB3 and is supported by grant PT17/0019, of the PE IDi 2013–2016, funded by ISCIII and ERDF

El Test de Recuerdo Verbal Selectivo (TRVS) es una de las pruebas más extensamente utilizadas para la evaluación del aprendizaje y la memoria verbales. Sin embargo, este test ha sido construido principalmente para evaluar a pacientes de habla inglesa, no existiendo todavía ninguna versión española que pueda ser utilizada para evaluar a pacientes de habla hispana. Para solventar este problema, se construyeron dos versiones españolas del Test de Recuerdo Verbal Selectivo administrándose a 48 sujetos sanos, 19-31 años, en dos sesiones separadas. Encontramos que las respuestas de los sujetos a las dos versiones fueron comparables, excepto para un índice. Todas las variables sobre ambas formas presentaron correlaciones positivas significativas. También se estudió la fiabilidad test-retest para cada orden, encontrándose que el orden 2 (en el que la forma 2 se administró primero) fue más fiable que el orden 1 (donde la forma 1 se administró primero). The Selective Reminding procedure has become a widely used test for evaluating verbal learning and memory. However, since this test was mainly devised for use in English speaking individuals, disadvantages could appear when translations of the test are applied to Spanish speaking patients. To overcome these difficulties, two Spanish versions of the Verbal Selective Reminding Test were devised and administered to 48 healthy individuals, 19-31 years in age, in two separate sessions. We found that performances on the two forms were comparable, except for one measure. All the variables on both forms yielded significant positive correlations. We also examined test-retest reliability separately for both possible orders, with Order 2 (Form 2 administered first) being more reliable than Order 1 (Form 1 administered first).

274 p. Alzheimer gaixotasuna egungo dementziarik sarriena da eta gehhienbat 65 urtetik Aurreraematen da. Azken dauten arabera, prebalentzia asko handitzen ari da eta etorkizunean asko handitzeaespero da, edozein osasun/gizarte sistema kolokan jartzeraino.Gauza jakina da, sintomak hasi baino urte batzuk lehenago garun mailan aldaketak gertatzen direla etahortaz, sintomak hasi aurretik biomarkatzaileen bitartez gaixotasuna detektatu eta gerora modugoiztiarrean tratatu edo eta prebenitu daitekeela uste da.Arrisku faktore kardiobaskularrek (AFKB) garun mailan duten eragina oso ikertua izan da azkenurteetan, eta mekanimoa gauza ezezaguna bada ere, erlazioaren existentzia baieztatua izan da.Tesi honek ikerketa zientifikoari eransten dion berria, laginak likido zefalorrakideoarekin (LZR)izan direla, orain arte publikatu ez dena.Lortutako emaitzen arabera, hipertentsio arteriala eta Alzheimer gaixotasunaren LZRbiomarkarkatzaileak asaldatuak izatea erlazionatuta daude. Eta gainontzeko AFKBekin erlazio estua ezbada ikusi ere, garrantzia handia dutela ondorioztatu da, faktore guztien artean dagoen erlazioagatik.