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Projeto de investigação
ERA-NET for establishing synergies between the Joint Programming on Neurodegenerative Diseases Research and Horizon 2020
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Stratifying the presymptomatic phase of genetic frontotemporal dementia by Serum NfL and pNfH: a longitudinal multicentre study
Publication . Wilke, Carlo; Reich, Selina; Swieten, John C.; Borroni, Barbara; Sanchez‐Valle, Raquel; Moreno, Fermin; Laforce, Robert; Graff, Caroline; Galimberti, Daniela; Rowe, James B.; Masellis, Mario; Tartaglia, Maria C.; Finger, Elizabeth; Vandenberghe, Rik; De Mendonça, Alexandre; Tagliavini, Fabrizio; Santana, Isabel; Ducharme, Simon; Butler, Chris R.; Gerhard, Alexander; Levin, Johannes; Danek, Adrian; Otto, Markus; Frisoni, Giovanni; Ghidoni, Roberta; Sorbi, Sandro; Bocchetta, Martina; Todd, Emily; Kuhle, Jens; Barro, Christian; Afonso, Sónia; Almeida, Maria Rosario; Anderl‐Straub, Sarah; Andersson, Christin; Antonell, Anna; Archetti, Silvana; Arighi, Andrea; Balasa, Mircea; Barandiaran, Myriam; Bargalló, Nuria; Bartha, Robart; Bender, Benjamin; Benussi, Alberto; Benussi, Luisa; Bessi, Valentina; Binetti, Giuliano; Black, Sandra; Borrego‐Ecija, Sergi; Bras, Jose; Bruffaerts, Rose; Cañada, Marta; Cantoni, Valentina; Caroppo, Paola; Cash, David; Castelo-Branco, Miguel; Convery, Rhian; Cope, Thomas; Di Fede, Giuseppe; Díez, Alina; Duro, Diana; Fenoglio, Chiara; Ferrari, Camilla; Ferreira, Catarina B.; Fox, Nick; Freedman, Morris; Fumagalli, Giorgio; Gabilondo, Alazne; Gasparotti, Roberto; Gauthier, Serge; Gazzina, Stefano; Giaccone, Giorgio; Gorostidi, Ana; Greaves, Caroline; Guerreiro, Rita; Heller, Carolin; Hoegen, Tobias; Indakoetxea, Begoña; Jelic, Vesna; Jiskoot, Lize; Karnath, Hans‐Otto; Keren, Ron; Langheinrich, Tobias; Leitão, Maria João; Lladó, Albert; Lombardi, Gemma; Loosli, Sandra; Maruta, Carolina; Mead, Simon; Meeter, Lieke; Miltenberger-Miltenyi, Gabriel; Minkelen, Rick; Mitchell, Sara; Moore, Katrina; Nacmias, Benedetta; Nicholas, Jennifer; Öijerstedt, Linn; Olives, Jaume; Ourselin, Sebastien; Padovani, Alessandro; Panman, Jessica; Papma, Janne M.; Peakman, Georgia; Pievani, Michela; Pijnenburg, Yolande; Polito, Cristina; Premi, Enrico; Prioni, Sara; Prix, Catharina; Rademakers, Rosa; Redaelli, Veronica; Rittman, Tim; Rogaeva, Ekaterina; Rosa‐Neto, Pedro; Rossi, Giacomina; Rosser, Martin; Santiago, Beatriz; Scarpini, Elio; Schönecker, Sonja; Seelaar, Harro; Semler, Elisa; Shafei, Rachelle; Shoesmith, Christen; Tábuas‐Pereira, Miguel; Tainta, Mikel; Taipa, Ricardo; Tang‐Wai, David; Thomas, David L.; Thompson, Paul; Thonberg, Hakan; Timberlake, Carolyn; Tiraboschi, Pietro; Van Damme, Philip; Vandenbulcke, Mathieu; Veldsman, Michele; Verdelho, Ana; Villanua, Jorge; Warren, Jason; Woollacott, Ione; Wlasich, Elisabeth; Zetterberg, Henrik; Zulaica, Miren; Rohrer, Jonathan D.; Synofzik, Matthis
Objective: Although the presymptomatic stages of frontotemporal dementia (FTD) provide a unique chance to delay or even prevent neurodegeneration by early intervention, they remain poorly defined. Leveraging a large multicenter cohort of genetic FTD mutation carriers, we provide a biomarker-based stratification and biomarker cascade of the likely most treatment-relevant stage within the presymptomatic phase: the conversion stage.
Methods: We longitudinally assessed serum levels of neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) in the Genetic FTD Initiative (GENFI) cohort (n = 444), using single-molecule array technique. Subjects comprised 91 symptomatic and 179 presymptomatic subjects with mutations in the FTD genes C9orf72, GRN, or MAPT, and 174 mutation-negative within-family controls.
Results: In a biomarker cascade, NfL increase preceded the hypothetical clinical onset by 15 years and concurred with brain atrophy onset, whereas pNfH increase started close to clinical onset. The conversion stage was marked by increased NfL, but still normal pNfH levels, while both were increased at the symptomatic stage. Intra-individual change rates were increased for NfL at the conversion stage and for pNfH at the symptomatic stage, highlighting their respective potential as stage-dependent dynamic biomarkers within the biomarker cascade. Increased NfL levels and NfL change rates allowed identification of presymptomatic subjects converting to symptomatic disease and capture of proximity-to-onset. We estimate stage-dependent sample sizes for trials aiming to decrease neurofilament levels or change rates.
Interpretation: Blood NfL and pNfH provide dynamic stage-dependent stratification and, potentially, treatment response biomarkers in presymptomatic FTD, allowing demarcation of the conversion stage. The proposed biomarker cascade might pave the way towards a biomarker-based precision medicine approach to genetic FTD.
Novel players in the aging synapse: impact on cognition
Publication . Temido Ferreira, Mariana; Coelho, Joana E; Pousinha, Paula; Lopes, Luisa V.
While neuronal loss has long been considered as the main contributor to age-related cognitive decline, these alterations are currently attributed to gradual synaptic dysfunction driven by calcium dyshomeostasis and alterations in ionotropic/metabotropic receptors. Given the key role of the hippocampus in encoding, storage, and retrieval of memory, the morpho- and electrophysiological alterations that occur in the major synapse of this network-the glutamatergic-deserve special attention. We guide you through the hippocampal anatomy, circuitry, and function in physiological context and focus on alterations in neuronal morphology, calcium dynamics, and plasticity induced by aging and Alzheimer's disease (AD). We provide state-of-the art knowledge on glutamatergic transmission and discuss implications of these novel players for intervention. A link between regular consumption of caffeine-an adenosine receptor blocker-to decreased risk of AD in humans is well established, while the mechanisms responsible have only now been uncovered. We review compelling evidence from humans and animal models that implicate adenosine A2A receptors (A2AR) upsurge as a crucial mediator of age-related synaptic dysfunction. The relevance of this mechanism in patients was very recently demonstrated in the form of a significant association of the A2AR-encoding gene with hippocampal volume (synaptic loss) in mild cognitive impairment and AD. Novel pathways implicate A2AR in the control of mGluR5-dependent NMDAR activation and subsequent Ca2+ dysfunction upon aging. The nature of this receptor makes it particularly suited for long-term therapies, as an alternative for regulating aberrant mGluR5/NMDAR signaling in aging and disease, without disrupting their crucial constitutive activity.
A new protocol for whole-brain biodistribution analysis of AAVs by tissue clearing, light-sheet microscopy and semi-automated spatial quantification
Publication . Lopes, Miguel M.; Paysan, Jacques; Rino, José; Lopes, Sara M.; Pereira de Almeida, Luís; Cortes, Luísa; Nobre, Rui Jorge
Recombinant adeno-associated virus (rAAV) has become one of the most promising gene delivery systems for both in vitro and in vivo applications. However, a key challenge is the lack of suitable imaging technologies to evaluate delivery, biodistribution and tropism of rAAVs and efficiently monitor disease amelioration promoted by AAV-based therapies at a whole-organ level with single-cell resolution. Therefore, we aimed to establish a new pipeline for the biodistribution analysis of natural and new variants of AAVs at a whole-brain level by tissue clearing and light-sheet fluorescence microscopy (LSFM). To test this platform, neonatal C57BL/6 mice were intravenously injected with rAAV9 encoding EGFP and, after sacrifice, brains were processed by standard immunohistochemistry and a recently released aqueous-based clearing procedure. This clearing technique required no dedicated equipment and rendered highly cleared brains, while simultaneously preserving endogenous fluorescence. Moreover, three-dimensional imaging by LSFM allowed the quantitative analysis of EGFP at a whole-brain level, as well as the reconstruction of Purkinje cells for the retrieval of valuable morphological information inaccessible by standard immunohistochemistry. In conclusion, the pipeline herein described takes the AAVs to a new level when coupled to LSFM, proving its worth as a bioimaging tool in tropism and gene therapy studies.
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Entidade financiadora
European Commission
Programa de financiamento
H2020
Número da atribuição
643417