{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T22:18:39Z","timestamp":1789683519284,"version":"4.0.1"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,3,21]],"date-time":"2024-03-21T00:00:00Z","timestamp":1710979200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Almost all individuals with Down\u2019s syndrome (DS) show the characteristic neuropathological features of Alzheimer\u2019s disease (AD) by the age of 40, yet not every individual with DS experiences symptoms of AD later in life. Similar to neurotypical developing subjects, AD in people with DS lasts for a long preclinical phase in which biomarkers follow a predictable order of changes. Hence, a prolonged asymptomatic period precedes the onset of dementia, underscoring the importance of identifying new biomarkers for the early detection and monitoring of cognitive decline in individuals with DS. Blood-based biomarkers may offer an alternative non-invasive strategy for the detection of peripheral biological alterations paralleling nervous system pathology in an early phase of the AD continuum. In the last few years, a strong neurobiological link has been demonstrated between the deficit of transforming growth factor-\u03b21 (TGF-\u03b21) levels, an anti-inflammatory cytokine endowed with neuroprotective activity, and early pro-inflammatory processes in the AD brain. In this clinical prospective observational study, we found significant lower plasma TGF-\u03b21 concentrations at the first neuropsychological evaluation (baseline = T0) both in young adult DS individuals (19\u201335\u00a0years) and older DS subjects without AD (35\u201360\u00a0years) compared to age- and sex-matched healthy controls. Interestingly, we found that the lower TGF-\u03b21 plasma concentrations at T0 were strongly correlated with the following cognitive decline at 12 months. In addition, in young individuals with DS, we found, for the first time, a negative correlation between low TGF-\u03b21 concentrations and high TNF-\u03b1 plasma concentrations, a pro-inflammatory cytokine that is known to be associated with cognitive impairment in DS individuals with AD. Finally, adopting an <jats:italic>ex vivo<\/jats:italic> approach, we found that TGF-\u03b21 concentrations were reduced in parallel both in the plasma and in the peripheral blood mononuclear cells (PBMCs) of DS subjects, and interestingly, therapeutic concentrations of fluoxetine (FLX) applied to cultured PBMCs (1\u00a0\u00b5M for 24\u00a0h) were able to rescue TGF-\u03b21 concentrations in the culture media from DS PBMCs, suggesting that FLX, a selective serotonin reuptake inhibitor (SSRI) endowed with neuroprotective activity, might rescue TGF-\u03b21 concentrations in DS subjects at higher risk to develop cognitive decline.<\/jats:p>","DOI":"10.3389\/fphar.2024.1379965","type":"journal-article","created":{"date-parts":[[2024,3,21]],"date-time":"2024-03-21T05:02:15Z","timestamp":1710997335000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Low TGF-\u03b21 plasma levels are associated with cognitive decline in Down syndrome"],"prefix":"10.3389","volume":"15","author":[{"given":"Margherita","family":"Grasso","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annamaria","family":"Fidilio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"L\u2019Episcopo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marilena","family":"Recupero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Concetta","family":"Barone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Giulia","family":"Bacalini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Benatti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Concetta","family":"Giambirtone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Caruso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donatella","family":"Greco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santo","family":"Di Nuovo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corrado","family":"Romano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raffaele","family":"Ferri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serafino","family":"Buono","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. Claudio","family":"Cuello","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna M. C.","family":"Blom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabio","family":"Tascedda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pier Vincenzo","family":"Piazza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael","family":"De La Torre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filippo","family":"Caraci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,3,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"718426","DOI":"10.3389\/fnagi.2021.718426","article-title":"Innate immune system activation and neuroinflammation in down syndrome and neurodegeneration: therapeutic targets or partners?","volume":"13","author":"Ahmed","year":"2021","journal-title":"Front. Aging Neurosci."},{"key":"B2","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/s0167-4943(01)00117-0","article-title":"Cognitive assessment of severe dementia: the test for severe impairment (TSI)","volume":"7","author":"Appollonio","year":"2001","journal-title":"Arch. Gerontol. Geriatr. Suppl."},{"key":"B3","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.nbd.2013.11.010","article-title":"Fluoxetine in adulthood normalizes GABA release and rescues hippocampal synaptic plasticity and spatial memory in a mouse model of Down syndrome","volume":"63","author":"Begenisic","year":"2014","journal-title":"Neurobiol. Dis."},{"key":"B4","doi-asserted-by":"publisher","first-page":"8769","DOI":"10.1523\/JNEUROSCI.0534-10.2010","article-title":"Early pharmacotherapy restores neurogenesis and cognitive performance in the Ts65Dn mouse model for Down syndrome","volume":"30","author":"Bianchi","year":"2010","journal-title":"J. Neurosci."},{"key":"B5","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1016\/j.nbd.2008.01.007","article-title":"TGF-beta 1 protects against Abeta-neurotoxicity via the phosphatidylinositol-3-kinase pathway","volume":"30","author":"Caraci","year":"2008","journal-title":"Neurobiol. Dis."},{"key":"B6","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.ejphar.2017.10.004","article-title":"Searching for new pharmacological targets for the treatment of Alzheimer's disease in Down syndrome","volume":"817","author":"Caraci","year":"2017","journal-title":"Eur. J. Pharmacol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1007\/s00441-011-1230-6","article-title":"Dysfunction of TGF-\u03b21 signaling in Alzheimer's disease: perspectives for neuroprotection","volume":"347","author":"Caraci","year":"2012","journal-title":"Cell Tissue Res."},{"key":"B8","doi-asserted-by":"publisher","first-page":"374","DOI":"10.1016\/j.phrs.2018.02.007","article-title":"Neurobiological links between depression and AD: the role of TGF-\u03b21 signaling as a new pharmacological target","volume":"130","author":"Caraci","year":"2018","journal-title":"Pharmacol. Res."},{"key":"B9","doi-asserted-by":"publisher","first-page":"389","DOI":"10.3389\/fphar.2016.00389","article-title":"Fluoxetine prevents a\u03b21-42-induced toxicity via a paracrine signaling mediated by transforming-growth-factor-\u03b21","volume":"7","author":"Caraci","year":"2016","journal-title":"Front. Pharmacol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"605","DOI":"10.1016\/S1474-4422(21)00129-0","article-title":"Diagnostic and prognostic performance and longitudinal changes in plasma neurofilament light chain concentrations in adults with Down syndrome: a cohort study","volume":"20","author":"Carmona-Iragui","year":"2021","journal-title":"Lancet Neurol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"256","DOI":"10.1016\/j.expneurol.2006.02.005","article-title":"Fluoxetine rescues deficient neurogenesis in hippocampus of the Ts65Dn mouse model for Down syndrome","volume":"200","author":"Clark","year":"2006","journal-title":"Exp. Neurol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"601","DOI":"10.3390\/brainsci10090601","article-title":"Investigating gait, movement, and coordination in children with neurodevelopmental disorders: is there a role for motor abnormalities in atypical neurodevelopment?","volume":"10","author":"Colizzi","year":"2020","journal-title":"Brain Sci."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.pneurobio.2010.01.003","article-title":"Communication breaks-Down: from neurodevelopment defects to cognitive disabilities in Down syndrome","volume":"91","author":"Contestabile","year":"2010","journal-title":"Prog. Neurobiol."},{"key":"B14","volume-title":"Leiter-3 leiter international scale-thirth edition (di Roid, miller, pomplun, koch). Adattamento italiano. Manuale","author":"Cornoldi","year":"2016"},{"key":"B15","doi-asserted-by":"publisher","first-page":"8219","DOI":"10.3390\/ijms13078219","article-title":"The neuroprotective functions of transforming growth factor beta proteins","volume":"13","author":"Dobolyi","year":"2012","journal-title":"Int. J. Mol. Sci."},{"key":"B16","doi-asserted-by":"publisher","first-page":"439","DOI":"10.2174\/1567205013666151116124912","article-title":"Lymphocytes in Alzheimer's disease pathology: altered signaling pathways","volume":"13","author":"Esteras","year":"2016","journal-title":"Curr. Alzheimer Res."},{"key":"B17","doi-asserted-by":"publisher","first-page":"e14","DOI":"10.1002\/gps.4730","article-title":"Amyloid is essential but insufficient for Alzheimer causation: addition of subcellular cofactors is required for dementia","volume":"33","author":"Fessel","year":"2018","journal-title":"Int. J. Geriatr. Psychiatry"},{"key":"B18","doi-asserted-by":"publisher","first-page":"860","DOI":"10.1016\/S1474-4422(18)30285-0","article-title":"Plasma and CSF biomarkers for the diagnosis of Alzheimer's disease in adults with Down syndrome: a cross-sectional study","volume":"17","author":"Fortea","year":"2018","journal-title":"Lancet Neurol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1988","DOI":"10.1016\/S0140-6736(20)30689-9","article-title":"Clinical and biomarker changes of Alzheimer's disease in adults with Down syndrome: a cross-sectional study","volume":"395","author":"Fortea","year":"2020","journal-title":"Lancet"},{"key":"B20","doi-asserted-by":"publisher","first-page":"e12903","DOI":"10.1111\/acel.12903","article-title":"Accelerated bio-cognitive aging in Down syndrome: state of the art and possible deceleration strategies","volume":"18","author":"Franceschi","year":"2019","journal-title":"Aging Cell"},{"key":"B21","doi-asserted-by":"publisher","first-page":"635","DOI":"10.1007\/s00281-020-00804-1","article-title":"Down syndrome, accelerated aging and immunosenescence","volume":"42","author":"Gensous","year":"2020","journal-title":"Semin. Immunopathol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1515\/revneuro.2010.21.2.83","article-title":"The monomer state of beta-amyloid: where the Alzheimer's disease protein meets physiology","volume":"21","author":"Giuffrida","year":"2010","journal-title":"Rev. Neurosci."},{"key":"B23","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1002\/ajmg.c.31439","article-title":"Down syndrome: cognitive and behavioral functioning across the lifespan","volume":"169","author":"Grieco","year":"2015","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"B24","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1111\/j.1750-3639.2012.00624.x","article-title":"Early pharmacotherapy with fluoxetine rescues dendritic pathology in the Ts65Dn mouse model of down syndrome","volume":"23","author":"Guidi","year":"2013","journal-title":"Brain Pathol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1038\/s41582-018-0079-7","article-title":"Blood-based biomarkers for Alzheimer disease: mapping the road to the clinic","volume":"14","author":"Hampel","year":"2018","journal-title":"Nat. Rev. Neurol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"700","DOI":"10.1016\/j.jalz.2014.10.007","article-title":"Down syndrome and Alzheimer's disease: common pathways, common goals","volume":"11","author":"Hartley","year":"2015","journal-title":"Alzheimers Dement."},{"key":"B27","doi-asserted-by":"publisher","first-page":"637","DOI":"10.1111\/j.1651-2227.1978.tb17815.x","article-title":"Follicular development in ovaries of children with Down's syndrome","volume":"67","author":"Hojager","year":"1978","journal-title":"Acta Paediatr. Scand."},{"key":"B28","doi-asserted-by":"publisher","first-page":"434","DOI":"10.2174\/1871527315666160321104916","article-title":"A link between nerve growth factor metabolic deregulation and amyloid-\u03b2-driven inflammation in down syndrome","volume":"15","author":"Iulita","year":"","journal-title":"CNS Neurol. Disord. Drug Targets"},{"key":"B29","doi-asserted-by":"publisher","first-page":"e2212910","DOI":"10.1001\/jamanetworkopen.2022.12910","article-title":"Association of alzheimer disease with Life expectancy in people with down syndrome","volume":"5","author":"Iulita","year":"2022","journal-title":"JAMA Netw. Open"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1132","DOI":"10.1016\/j.jalz.2016.05.001","article-title":"An inflammatory and trophic disconnect biomarker profile revealed in Down syndrome plasma: relation to cognitive decline and longitudinal evaluation","volume":"12","author":"Iulita","year":"","journal-title":"Alzheimers Dement."},{"key":"B31","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1186\/s12974-023-02751-8","article-title":"TGF-\u03b21 signalling in Alzheimer's pathology and cytoskeletal reorganization: a specialized Tau perspective","volume":"20","author":"Kapoor","year":"2023","journal-title":"J. Neuroinflammation"},{"key":"B32","doi-asserted-by":"publisher","first-page":"389","DOI":"10.12688\/f1000research.7506.1","article-title":"The importance of understanding individual differences in Down syndrome","volume":"5","author":"Karmiloff-Smith","year":"2016","journal-title":"F1000Res"},{"key":"B33","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1007\/s40120-017-0071-y","article-title":"A review of biomarkers for Alzheimer's disease in down syndrome","volume":"6","author":"Lee","year":"2017","journal-title":"Neurol. Ther."},{"key":"B34","doi-asserted-by":"publisher","first-page":"870","DOI":"10.1111\/dmcn.15517","article-title":"State-of-the-art therapy for Down syndrome","volume":"65","author":"Lorenzon","year":"2023","journal-title":"Dev. Med. Child. Neurol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1016\/S1474-4422(10)70112-5","article-title":"Cognitive deficits and associated neurological complications in individuals with Down's syndrome","volume":"9","author":"Lott","year":"2010","journal-title":"Lancet Neurol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1038\/s41582-018-0132-6","article-title":"Dementia in Down syndrome: unique insights for Alzheimer disease research","volume":"15","author":"Lott","year":"2019","journal-title":"Nat. Rev. Neurol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"831","DOI":"10.1016\/j.mayocp.2013.04.024","article-title":"The National Task Group on Intellectual Disabilities and Dementia Practices consensus recommendations for the evaluation and management of dementia in adults with intellectual disabilities","volume":"88","author":"Moran","year":"2013","journal-title":"Mayo Clin. Proc."},{"key":"B38","doi-asserted-by":"publisher","first-page":"111691","DOI":"10.1016\/j.mad.2022.111691","article-title":"Blood circulating miR-28-5p and let-7d-5p associate with premature ageing in Down syndrome","volume":"206","author":"Morsiani","year":"2022","journal-title":"Mech. Ageing Dev."},{"key":"B39","doi-asserted-by":"publisher","first-page":"1063","DOI":"10.1007\/s10815-019-01457-2","article-title":"Down syndrome and infertility: what support should we provide?","volume":"36","author":"Parizot","year":"2019","journal-title":"J. Assist. Reprod. Genet."},{"key":"B40","doi-asserted-by":"publisher","first-page":"605","DOI":"10.1002\/alz.12229","article-title":"Nerve growth factor (NGF) pathway biomarkers in Down syndrome prior to and after the onset of clinical Alzheimer's disease: a paired CSF and plasma study","volume":"17","author":"Pentz","year":"2021","journal-title":"Alzheimers Dement."},{"key":"B41","doi-asserted-by":"publisher","first-page":"699","DOI":"10.1002\/dneu.22714","article-title":"Blood-based biomarkers for Down syndrome and Alzheimer's disease: a systematic review","volume":"79","author":"Petersen","year":"2019","journal-title":"Dev. Neurobiol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1016\/j.cca.2014.03.002","article-title":"Alterations of ectonucleotidases and acetylcholinesterase activities in lymphocytes of Down syndrome subjects: relation with inflammatory parameters","volume":"433","author":"Rodrigues","year":"2014","journal-title":"Clin. Chim. Acta"},{"key":"B43","doi-asserted-by":"publisher","first-page":"2","DOI":"10.2174\/1567205012999151021102914","article-title":"The link between Alzheimer's disease and down syndrome. A historical perspective","volume":"13","author":"Salehi","year":"2016","journal-title":"Curr. Alzheimer Res."},{"key":"B44","doi-asserted-by":"publisher","first-page":"1065","DOI":"10.1002\/alz.12112","article-title":"Further understanding the connection between Alzheimer's disease and Down syndrome","volume":"16","author":"Snyder","year":"2020","journal-title":"Alzheimers Dement."},{"key":"B45","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1016\/j.nbd.2014.12.005","article-title":"Long-term effects of neonatal treatment with fluoxetine on cognitive performance in Ts65Dn mice","volume":"74","author":"Stagni","year":"2015","journal-title":"Neurobiol. Dis."},{"key":"B46","doi-asserted-by":"publisher","first-page":"693","DOI":"10.3389\/fphar.2019.00693","article-title":"Fluoxetine and vortioxetine reverse depressive-like phenotype and memory deficits induced by a\u03b21-42 oligomers in mice: a key role of transforming growth factor-\u03b21","volume":"10","author":"Torrisi","year":"2019","journal-title":"Front. Pharmacol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"1432","DOI":"10.1016\/j.ridd.2011.02.010","article-title":"Depression in Down syndrome: a review of the literature","volume":"32","author":"Walker","year":"2011","journal-title":"Res. Dev. Disabil."},{"key":"B48","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1002\/ddrr.1128","article-title":"Atypical aging in Down syndrome","volume":"18","author":"Zigman","year":"2013","journal-title":"Dev. Disabil. Res. Rev."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2024.1379965\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,3,21]],"date-time":"2024-03-21T05:02:18Z","timestamp":1710997338000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2024.1379965\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,21]]},"references-count":48,"alternative-id":["10.3389\/fphar.2024.1379965"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2024.1379965","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,21]]},"article-number":"1379965"}}