Charting the future: current and future directions in translational research for individuals with Down syndrome

Lejeune J, Turpin R, Gautier M. Mongolism; a chromosomal disease (trisomy). Bull Acad Natl Med. 1959;143(11–12):256–65 Epub 1959/04/07 PubMed PMID: 13662687.

CAS  PubMed  Google Scholar 

Stallings EB, Isenburg JL, Rutkowski RE, Kirby RS, Nembhard WN, Sandidge T, Villavicencio S, Nguyen HH, McMahon DM, Nestoridi E, Pabst LJ, National Birth Defects Prevention N. National population-based estimates for major birth defects, 2016–2020. Birth Defects Res. 2024;116(1):e2301. https://doi.org/10.1002/bdr2.2301. PubMed PMID: 38277408; PMCID: PMC10898112.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Down JL. Observations on an ethnic classification of idiots 1866. Ment Retard. 1995;33(1):54–6 Epub 1995/02/01. PubMed PMID: 7707939.

CAS  PubMed  Google Scholar 

Iulita MF, Garzon Chavez D, Klitgaard Christensen M, Valle Tamayo N, Plana-Ripoll O, Rasmussen SA, Roque Figuls M, Alcolea D, Videla L, Barroeta I, Benejam B, Altuna M, Padilla C, Pegueroles J, Fernandez S, Belbin O, Carmona-Iragui M, Blesa R, Lleo A, Bejanin A, Fortea J. Association of Alzheimer Disease With Life Expectancy in People With Down Syndrome. JAMA Netw Open. 2022;5(5):e2212910. Epub 2022/05/24. https://doi.org/10.1001/jamanetworkopen.2022.12910. PubMed PMID: 35604690; PMCID: PMC9127560 from Fujirebio-Europe, Roche Diagnostics, Nutricia, Krka Farmaceutica S.L, Zambon SAU, and Esteve Pharmaceuticals SA outside the submitted work. Dr Belbin reported receiving personal fees from ADx NeuroSciences outside the submitted work. Dr Lleo reported receiving grants from CIBERNED and the Instituto de Salud Carlos III and serving as a consultant or at advisory boards for Fujirebio-Europe, Roche, Biogen, and Nutricia outside the submitted work. Dr Fortea reported receiving personal fees from Novartis Consultancy, Lundbeck Consultancy, Esteve, Novonordisk, Roche, Biogen, and Zambon Consultancy outside the submitted work. Drs Alcolea, Belbin, LLeo, and Fortea reported holding a patent for markers of synaptopathy in neurodegenerative disease (licenced to ADx, EPI8382175.0). No other disclosures were reported.

Xu J, Murphy SL, Kochanek KD, Arias E. Mortality in the United States, 2021. NCHS Data Brief. 2022;456:1–8 PubMed PMID: 36598387.

Google Scholar 

Ijezie OA, Healy J, Davies P, Balaguer-Ballester E, Heaslip V. Quality of life in adults with Down syndrome: A mixed methods systematic review. PLoS One. 2023;18(5):e0280014. https://doi.org/10.1371/journal.pone.0280014. PubMed PMID: 37126503; PMCID: PMC10150991.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Antonarakis SE, Skotko BG, Rafii MS, Strydom A, Pape SE, Bianchi DW, Sherman SL, Reeves RH. Down syndrome Nat Rev Dis Primers. 2020;6(1):9. https://doi.org/10.1038/s41572-019-0143-7. PubMed PMID: 32029743; PMCID: PMC8428796.

Article  PubMed  Google Scholar 

Baksh RA, Pape SE, Chan LF, Aslam AA, Gulliford MC, Strydom A, Consortium G-D. Multiple morbidity across the lifespan in people with Down syndrome or intellectual disabilities: a population-based cohort study using electronic health records. Lancet Public Health. 2023;8(6):e453–62. https://doi.org/10.1016/S2468-2667(23)00057-9. PubMed PMID: 37119823.

Article  Google Scholar 

Fortea J, McGlinchey E, Espinosa JM, Rafii MS. Addressing challenges in health care and research for people with Down syndrome. Lancet. 2024;403(10439):1830–3. Epub 20240320. https://doi.org/10.1016/S0140-6736(24)00478-1. PubMed PMID: 38521088.

Bull MJ, Trotter T, Santoro SL, Christensen C, Grout RW, Council On G, Burke LW, Berry SA, Geleske TA, Holm I, Hopkin RJ, Introne WJ, Lyons MJ, Monteil DC, Scheuerle A, Stoler JM, Vergano SA, Chen E, Hamid R, Downs SM, Grout RW, Cunniff C, Parisi MA, Ralston SJ, Scott JA, Shapira SK, Spire P. Health Supervision for Children and Adolescents With Down Syndrome. Pediatrics. 2022;149(5). https://doi.org/10.1542/peds.2022-057010. PubMed PMID: 35490285.

Tsou AY, Bulova P, Capone G, Chicoine B, Gelaro B, Harville TO, Martin BA, McGuire DE, McKelvey KD, Peterson M, Tyler C, Wells M, Whitten MS, Global Down Syndrome Foundation Medical Care Guidelines for Adults with Down Syndrome W. Medical Care of Adults With Down Syndrome: A Clinical Guideline. JAMA. 2020;324(15):1543–56. https://doi.org/10.1001/jama.2020.17024. PubMed PMID: 33079159.

de Graaf G, Buckley F, Skotko BG. Estimates of the live births, natural losses, and elective terminations with Down syndrome in the United States. Am J Med Genet A. 2015;167A(4):756–67. Epub 2015/03/31. https://doi.org/10.1002/ajmg.a.37001. PubMed PMID: 25822844.

Chicoine B, Rivelli A, Fitzpatrick V, Chicoine L, Jia G, Rzhetsky A. Prevalence of Common Disease Conditions in a Large Cohort of Individuals With Down Syndrome in the United States. J Patient Cent Res Rev. 2021;8(2):86–97. Epub 20210419. https://doi.org/10.17294/2330-0698.1824. PubMed PMID: 33898640; PMCID: PMC8060042.

Clift AK, Coupland CAC, Keogh RH, Hemingway H, Hippisley-Cox J. COVID-19 Mortality Risk in Down Syndrome: Results From a Cohort Study of 8 Million Adults. Ann Intern Med. 2021;174(4):572–6. Epub 20201021. https://doi.org/10.7326/M20-4986. PubMed PMID: 33085509; PMCID: PMC7592804.

Capone G, Stephens M, Santoro S, Chicoine B, Bulova P, Peterson M, Jasien J, Smith AJ, Workgroup DSMIGAH. Co‐occurring medical conditions in adults with Down syndrome: A systematic review toward the development of health care guidelines. Part II. American Journal of Medical Genetics Part A. 2020;182(7):1832–45.

Rahman MM, Fatema K. Seizures in Down Syndrome: An Update. Mymensingh Med J. 2019;28(3):712–5 PubMed PMID: 31391451.

CAS  PubMed  Google Scholar 

Bradbury KR, Anderberg EI, Huang-Storms L, Vasile I, Greene RK, Duvall SW. Co-occurring Down syndrome and autism spectrum disorder: cognitive, adaptive, and behavioral characteristics. J Autism Dev Disord. 2022;52(3):1235–46.

Article  PubMed  Google Scholar 

Gorelick PB, Sorond FA. What is brain health? Cereb Circ Cogn Behav. 2024;6:100190. Epub 20231025. https://doi.org/10.1016/j.cccb.2023.100190. PubMed PMID: 38292017; PMCID: PMC10826122.

Gami AS, Caples SM, Somers VK. Obesity and obstructive sleep apnea. Endocrinol Metab Clin. 2003;32(4):869–94.

Article  Google Scholar 

Van Hulsteijn L, Pasquali R, Casanueva F, Haluzik M, Ledoux S, Monteiro M, Salvador J, Santini F, Toplak H, Dekkers O. Prevalence of endocrine disorders in obese patients: systematic review and meta-analysis. Eur J Endocrinol. 2020;182(1):11–21.

Article  PubMed  Google Scholar 

Valenzuela PL, Carrera-Bastos P, Castillo-García A, Lieberman DE, Santos-Lozano A, Lucia A. Obesity and the risk of cardiometabolic diseases. Nat Rev Cardiol. 2023;20(7):475–94.

Article  PubMed  Google Scholar 

Andrade AG, Bubu OM, Varga AW, Osorio RS. The relationship between obstructive sleep apnea and Alzheimer’s disease. J Alzheimers Dis. 2018;64(s1):S255–70.

Article  PubMed  PubMed Central  Google Scholar 

Pugazhenthi S, Qin L, Reddy PH. Common neurodegenerative pathways in obesity, diabetes, and Alzheimer's disease. Biochimica et biophysica acta (BBA)-molecular basis of disease. 2017;1863(5):1037–45.

Patel V, Edison P. Cardiometabolic risk factors and neurodegeneration: a review of the mechanisms underlying diabetes, obesity and hypertension in Alzheimer’s disease. J Neurol Neurosurg Psychiatry. 2024;95(6):581–9.

Article  PubMed  Google Scholar 

Livingston G, Huntley J, Liu KY, Costafreda SG, Selbæk G, Alladi S, Ames D, Banerjee S, Burns A, Brayne C, Fox NC, Ferri CP, Gitlin LN, Howard R, Kales HC, Kivimäki M, Larson EB, Nakasujja N, Rockwood K, Samus Q, Shirai K, Singh-Manoux A, Schneider LS, Walsh S, Yao Y, Sommerlad A, Mukadam N. Dementia prevention, intervention, and care: 2024 report of the <em>Lancet</em> standing Commission. The Lancet. 2024;404(10452):572–628. https://doi.org/10.1016/S0140-6736(24)01296-0.

Article  Google Scholar 

Snyder HM, Bain LJ, Brickman AM, Carrillo MC, Esbensen AJ, Espinosa JM, Fernandez F, Fortea J, Hartley SL, Head E. Further understanding the connection between Alzheimer’s disease and Down syndrome. Alzheimers Dement. 2020;16(7):1065–77.

Article  PubMed  Google Scholar 

Bardhan S, Li H, Tarver E, Schramm C, Brown M, Garcia L, Schwartz B, Mazzucco A, Natarajan N, Walsh E, Ryan L, Pearson G, Parisi MA. The National Institutes of Health INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE (INCLUDE) Project: Accelerating research discoveries for people with Down syndrome across the lifespan. Am J Med Genet C Semin Med Genet. 2024;196(1):e32081. https://doi.org/10.1002/ajmg.c.32081. PMID: 38197535; PMCID: PMC10939900.

National Institutes of Health. NIH INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE (INCLUDE) Down Syndrome Research Plan 2022 [cited 2024 October 2024]. Available from: https://www.nih.gov/include-project/include-project-down-syndrome-ds-research-plan#goals-objectives.

Frank Stephens Hearing before the United States House of Representatives(October 25, 2017).

Friedersdorf C. ‘I Am a Man With Down Syndrome and My Life Is Worth Living’: Congressional testimony that illuminates what a developmental disability means—and doesn’t mean. The Atlantic. October 30, 2017.

Baumer NT, Becker ML, Capone GT, Egan K, Fortea J, Handen BL, Head E, Hendrix JE, Litovsky RY, Strydom A. Conducting clinical trials in persons with Down syndrome: summary from the NIH INCLUDE Down syndrome clinical trials readiness working group. J Neurodev Disord. 2022;14(1):22.

Article  PubMed  PubMed Central  Google Scholar 

Moyer AJ, Gardiner K, Reeves RH. All Creatures Great and Small: New Approaches for Understanding Down Syndrome Genetics. Trends Genet. 2021;37(5):444–59. Epub 20201020. https://doi.org/10.1016/j.tig.2020.09.017. PubMed PMID: 33097276; PMCID: PMC8208824.

Aldinger KA, Thomson Z, Phelps IG, Haldipur P, Deng M, Timms AE, Hirano M, Santpere G, Roco C, Rosenberg AB, Lorente-Galdos B, Gulden FO, O'Day D, Overman LM, Lisgo SN, Alexandre P, Sestan N, Doherty D, Dobyns WB, Seelig G, Glass IA, Millen KJ. Spatial and cell type transcriptional landscape of human cerebellar development. Nat Neurosci. 2021;24(8):1163–75. Epub 20210617. https://doi.org/10.1038/s41593-021-00872-y. PubMed PMID: 34140698; PMCID: PMC8338761.

Guedj F, Bianchi DW, Delabar JM. Prenatal treatment of Down syndrome: a reality? Curr Opin Obstet Gynecol. 2014;26(2):92–103. https://doi.org/10.1097/GCO.0000000000000056. PubMed PMID: 24573065.

Article  PubMed  Google Scholar 

Serrano ME, Kim E, Siow B, Ma D, Rojo L, Simmons C, Hayward D, Gibbins D, Singh N, Strydom A, Fisher EMC, Tybulewicz VLJ, Cash D. Investigating brain alterations in the Dp1Tyb mouse model of Down syndrome. Neurobiol Dis. 2023;188:106336. https://doi.org/10.1016/j.nbd.2023.06336. PubMed PMID:38317803; PMCID:PMC7615598.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Wu D, Zhang Y, Cheng B, Mori S, Reeves RH, Gao FJ. Time-dependent diffusion MRI probes cerebellar microstructural alterations in a mouse model of Down syndrome. Brain Commun. 2021;3(2):fcab062. Epub 20210405. https://doi.org/10.1093/braincomms/fcab062. PubMed PMID: 33937769; PMCID: PMC8063586.

Chen Y, Dyakin VV, Branch CA, Ardekani B, Yang D, Guilfoyle DN, Peterson J, Peterhoff C, Ginsberg SD, Cataldo AM, Nixon RA. In vivo MRI identifies cholinergic circuitry deficits in a Down syndrome model. Neurobiol Aging. 2009;30(9):1453–65. Epub 20080103. https://doi.org/10.1016/j.neurobiolaging.2007.11.026. PubMed PMID: 18180075; PMCID: PMC2771203.

Santin MD, Valabregue R, Rivals I, Penager R, Paquin R, Dauphinot L, Albac C, Delatour B, Potier MC. In vivo 1H MRS study in microlitre voxels in the hippocampus of a mouse model of Down syndrome at 11.7 T. NMR Biomed. 2014;27(10):1143–50. Epub 20140801. https://doi.org/10.1002/nbm.3155. PubMed PMID: 25088227.

Reeves RH, Irving NG, Moran TH, Wohn A, Kitt C, Sisodia SS, Schmidt C, Bronson RT, Davisson MT. A mouse model for Down syndrome exhibits learning and behaviour deficits. Nat Genet. 1995;11(2):177–84. https://doi.org/10.1038/ng1095-177. PubMed PMID: 7550346.

Article  CAS  PubMed  Google Scholar 

Olmos-Serrano JL, Tyler WA, Cabral HJ, Haydar TF. Longitudinal measures of cognition in the Ts65Dn mouse: Refining windows and defining modalities for therapeutic intervention in Down syndrome. Exp Neurol. 2016;279:40–56. Epub 20160224. https://doi.org/10.1016/j.expneurol.2016.02.005. PubMed PMID: 26854932; PMCID: PMC5716476.

Braudeau J, Delatour B, Duchon A, Pereira PL, Dauphinot L, de Chaumont F, Olivo-Marin JC, Dodd RH, Herault Y, Potier MC. Specific targeting of the GABA-A receptor alpha5 subtype by a selective inverse agonist restores cognitive deficits in Down syndrome mice. J Psychopharmacol. 2011;25(8):1030–42. Epub 20110621. https://doi.org/10.1177/0269881111405366. PubMed PMID: 21693554; PMCID: PMC3160204.

Powers BE, Velazquez R, Kelley CM, Ash JA, Strawderman MS, Alldred MJ, Ginsberg SD, Mufson EJ, Strupp BJ. Attentional function and basal forebrain cholinergic neuron morphology during aging in the Ts65Dn mouse model of Down syndrome. Brain Struct Funct. 2016;221(9):4337–52. Epub 20151230. https://doi.org/10.1007/s00429-015-1164-y. PubMed PMID: 26719290; PMCID: PMC4929047.

Hamlett ED, Ledreux A, Potter H, Chial HJ, Patterson D, Espinosa JM, Bettcher BM, Granholm AC. Exosomal biomarkers in Down syndrome and Alzheimer's disease. Free Radic Biol Med. 2018;114:110–21. Epub 20170905. https://doi.org/10.1016/j.freeradbiomed.2017.08.028. PubMed PMID: 28882786; PMCID: PMC6135098.

Lockrow J, Prakasam A, Huang P, Bimonte-Nelson H, Sambamurti K, Granholm AC. Cholinergic degeneration and memory loss delayed by vitamin E in a Down syndrome mouse model. Exp Neurol. 2009;216(2):278–89. Epub 20081210. https://doi.org/10.1016/j.expneurol.2008.11.021. PubMed PMID: 19135442; PMCID: PMC2704550.

Lanzillotta C, Tramutola A, Di Giacomo G, Marini F, Butterfield DA, Di Domenico F, Perluigi M, Barone E. Insulin resistance, oxidative stress and mitochondrial defects in Ts65dn mice brain: A harmful synergistic path in Down syndrome. Free Radic Biol Med. 2021;165:152–70. Epub 20210129. https://doi.org/10.1016/j.freeradbiomed.2021.01.042. PubMed PMID: 33516914.

Corrales A, Parisotto EB, Vidal V, Garcia-Cerro S, Lantigua S, Diego M, Wilhem Filho D, Sanchez-Barcelo EJ, Martinez-Cue C, Rueda N. Pre- and post-natal melatonin administration partially regulates brain oxidative stress but does not improve cognitive or histological alterations in the Ts65Dn mouse model of Down syndrome. Behav Brain Res. 2017;334:142–54. Epub 20170723. https://doi.org/10.1016/j.bbr.2017.07.022. PubMed PMID: 28743603.

Valenti D, Stagni F, Emili M, Guidi S, Bartesaghi R, Vacca RA. Impaired Brain Mitochondrial Bioenergetics in the Ts65Dn Mouse Model of Down Syndrome Is Restored by Neonatal Treatment with the Polyphenol 7,8-Dihydroxyflavone. Antioxidants (Basel). 2021;11(1). Epub 20211228. https://doi.org/10.3390/antiox11010062. PubMed PMID: 35052567; PMCID: PMC8773005.

Shukkur EA, Shimohata A, Akagi T, Yu W, Yamaguchi M, Murayama M, Chui D, Takeuchi T, Amano K, Subramhanya KH, Hashikawa T, Sago H, Epstein CJ, Takashima A, Yamakawa K. Mitochondrial dysfunction and tau hyperphosphorylation in Ts1Cje, a mouse model for Down syndrome. Hum Mol Genet. 2006;15(18):2752–62. Epub 20060804. https://doi.org/10.1093/hmg/ddl211. PubMed PMID: 16891409.

Ortega M, De Toma I, Fernandez-Blanco A, Calderon A, Barahona L, Trullas R, Sabido E, Dierssen M. Proteomic profiling reveals mitochondrial dysfunction in the cerebellum of transgenic mice overexpressing DYRK1A, a Down syndrome candidate gene. Front Mol Neurosci. 2022;15:1015220. Epub 20221215. https://doi.org/10.3389/fnmol.2022.1015220. PubMed PMID: 36590914; PMCID: PMC9800213.

Schuchmann S, Muller W, Heinemann U. Altered Ca2+ signaling and mitochondrial deficiencies in hippocampal neurons of trisomy 16 mice: a model of Down’s syndrome. J Neurosci. 1998;18(18):7216–31. https://doi.org/10.1523/JNEUROSCI.18-18-07216.1998. PubMed PMID:9736644; PMCID:PMC6793219.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Holtzman DM, Santucci D, Kilbridge J, Chua-Couzens J, Fontana DJ, Daniels SE,

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