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Improving Memory and Cognition in Individuals with Down Syndrome

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Abstract

Down syndrome (DS), often due to trisomy 21, is the most common genetic cause of intellectual disability (ID). In addition, virtually all individuals with DS develop the neuropathology of Alzheimer’s disease (AD) by the age of 40 years and almost 60 % will manifest symptoms of AD dementia by the age of 65 years. Currently, there are no pharmacological treatments available for ID in individuals with DS and only limited symptomatic treatments for AD dementia. Advances in our understanding in both the molecular basis of ID and the pathogenesis of AD have created opportunities to study potential therapeutic targets. Recent studies in animal models of DS continue to provide a rational basis for translating specific compounds into human clinical trials. However, target and compound selection are only initial steps in the drug development pathway. Other necessary considerations include appropriate study designs to assess efficacy in the DS population, as well as operational aspects specifically tailored to assess cognition in this population. We discuss recent progress in the development of compounds for both ID and AD in individuals with DS, as well as concepts for the design and conduct of clinical trials with such compounds.

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References

  1. 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.

    Article  PubMed  Google Scholar 

  2. Presson AP, Partyka G, Jensen KM, Devine OJ, Rasmussen SA, McCabe LL, McCabe ER. Current estimate of Down Syndrome population prevalence in the United States. J Pediatr. 2013;163(4):1163–8.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Lott IT, Dierssen M. Cognitive deficits and associated neurological complications in individuals with Down’s syndrome. Lancet Neurol. 2010;9:623–33.

    Article  PubMed  Google Scholar 

  4. Grieco J, Pulsifer M, Seligsohn K, Skotko B, Schwartz A. Down syndrome: cognitive and behavioral functioning across the lifespan. Am J Med Genet Part C. 2015;169C:135–49.

    Article  Google Scholar 

  5. Carr J. Six weeks to 45 years: a longitudinal study of a population with Down syndrome. J Appl Res Intellect Disabil. 2012;25(5):414–22.

    Article  PubMed  Google Scholar 

  6. 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;11:177–84.

    Article  CAS  PubMed  Google Scholar 

  7. Belichenko NP, Belichenko PV, Kleschevnikov AM, Salehi A, Reeves RH, Mobley WC. The “Down syndrome critical region” is sufficient in the mouse model to confer behavioral, neurophysiological, and synaptic phenotypes characteristic of Down syndrome. J Neurosci. 2009;29:5938–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hanson JE, Blank M, Valenzuela RA, Garner CC, Madison DV. The functional nature of synaptic circuitry is altered in area CA3 of the hippocampus in a mouse model of Down’s syndrome. J Physiol. 2007;579:53–67.

    Article  CAS  PubMed  Google Scholar 

  9. Siarey RJ, Carlson EJ, Epstein CJ, Balbo A, Rapoport SI, Galdzicki Z. Increased synaptic depression in the Ts65Dn mouse, a model for mental retardation in Down syndrome. Neuropharmacology. 1999;38(12):1917–20.

    Article  CAS  PubMed  Google Scholar 

  10. Kleschevnikov AM, Belichenko PV, Villar AJ, Epstein CJ, Malenka RC, Mobley WC. Hippocampal long-term potentiation suppressed by increased inhibition in the Ts65Dn mouse, a genetic model of Down syndrome. J Neurosci. 2004;24(37):8153–60.

    Article  CAS  PubMed  Google Scholar 

  11. Costa AC, Grybko MJ. Deficits in hippocampal CA1 LTP induced by TBS but not HFS in the Ts65Dn mouse: a model of Down syndrome. Neurosci Lett. 2005;382(3):317–22.

    Article  CAS  PubMed  Google Scholar 

  12. Siarey RJ, Kline-Burgess A, Cho M, Balbo A, Best TK, Harashima C, Klann E, Galdzicki Z. Altered signaling pathways underlying abnormal hippocampal synaptic plasticity in the Ts65Dn mouse model of Down syndrome. J Neurochem. 2006;98(4):1266–77 (Erratum in: J Neurochem. 2006;99(4):1320).

  13. Fernandez F, Morishita W, Zuniga E, Nguyen J, Blank M, Malenka RC, Garner CC. Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome. Nat Neurosci. 2007;10(4):411–3.

    CAS  PubMed  Google Scholar 

  14. Kleschevnikov AM, Belichenko PV, Gall J, George L, Nosheny R, Maloney MT, Salehi A, Mobley WC. Increased efficiency of the GABAA and GABAB receptor-mediated neurotransmission in the Ts65Dn mouse model of Down syndrome. Neurobiol Dis. 2012;45(2):683–91.

    Article  CAS  PubMed  Google Scholar 

  15. Mann DM, Yates PO, Marcyniuk B, Ravindra CR. Pathological evidence for neurotransmitter deficits in Down’s syndrome of middle age. J Ment Defic Res. 1985;29(Pt 2):125–35.

    PubMed  Google Scholar 

  16. German DC, Manaye KF, White CL 3rd, Woodward DJ, McIntire DD, Smith WK, Kalaria RN, Mann DM. Disease-specific patterns of locus coeruleus cell loss. Ann Neurol. 1992;32(5):667–76.

    Article  CAS  PubMed  Google Scholar 

  17. Dierssen M, Vallina IF, Baamonde C, García-Calatayud S, Lumbreras MA, Flórez J. Alterations of central noradrenergic transmission in Ts65Dn mouse, a model for Down syndrome. Brain Res. 1997;749(2):238–44.

    Article  CAS  PubMed  Google Scholar 

  18. Salehi A, Faizi M, Colas D, Valletta J, Laguna J, Takimoto-Kimura R, Kleschevnikov A, Wagner SL, Aisen P, Shamloo M, Mobley WC. Restoration of norepinephrine-modulated contextual memory in a mouse model of Down syndrome. Sci Transl Med. 2009;1(7):7ra17.

  19. Faizi M, Bader PL, Tun C, Encarnacion A, Kleschevnikov A, Belichenko P, Saw N, Priestley M, Tsien RW, Mobley WC, Shamloo M. Comprehensive behavioral phenotyping of Ts65Dn mouse model of Down syndrome: activation of β1-adrenergic receptor by xamoterol as a potential cognitive enhancer. Neurobiol Dis. 2011;43(2):397–413.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Hajszan T, MacLusky NJ, Leranth C. Short-term treatment with the antidepressant fluoxetine triggers pyramidal dendritic spine synapse formation in rat hippocampus. Eur J Neurosci. 2005;21(5):1299–303.

    Article  PubMed  Google Scholar 

  21. Li WL, Cai HH, Wang B, Chen L, Zhou QG, Luo CX, Liu N, Ding XS, Zhu DY. Chronic fluoxetine treatment improves ischemia-induced spatial cognitive deficits through increasing hippocampal neurogenesis after stroke. J Neurosci Res. 2009;87(1):112–22.

    Article  CAS  PubMed  Google Scholar 

  22. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci. 2000;20(24):9104–10.

    CAS  PubMed  Google Scholar 

  23. Maya Vetencourt JF, Sale A, Viegi A, Baroncelli L, De Pasquale R, O’Leary OF, Castrén E, Maffei L. The antidepressant fluoxetine restores plasticity in the adult visual cortex. Science. 2008;320(5874):385–8.

  24. Begenisic T, Baroncelli L, Sansevero G, Milanese M, Bonifacino T, Bonanno G, Cioni G, Maffei L, Sale A. Fluoxetine in adulthood normalizes GABA release and rescues hippocampal synaptic plasticity and spatial memory in a mouse model of Down syndrome. Neurobiol Dis. 2014;63:12–9.

    Article  CAS  PubMed  Google Scholar 

  25. Guidi S, Stagni F, Bianchi P, Ciani E, Giacomini A, De Franceschi M, Moldrich R, Kurniawan N, Mardon K, Giuliani A, Calzà L, Bartesaghi R. Prenatal pharmacotherapy rescues brain development in a Down’s syndrome mouse model. Brain. 2014;137(Pt 2):380–401.

    Article  PubMed  Google Scholar 

  26. Becker W, Soppa U, Tejedor FJ. DYRK1A: a potential drug target for multiple Down syndrome neuropathologies. CNS Neurol Disord Drug Targets. 2014;13(1):26–33.

    Article  CAS  PubMed  Google Scholar 

  27. Martinez de Lagran M, Benavides-Piccione R, Ballesteros-Yañez I, Calvo M, Morales M, Fillat C, Defelipe J, Ramakers GJ, Dierssen M. Dyrk1A influences neuronal morphogenesis through regulation of cytoskeletal dynamics in mammalian cortical neurons. Cereb Cortex. 2012;22(12):2867–77.

  28. Guedj F, Sébrié C, Rivals I, Ledru A, Paly E, Bizot JC, Smith D, Rubin E, Gillet B, Arbones M, Delabar JM. Green tea polyphenols rescue of brain defects induced by overexpression of DYRK1A. PLoS One. 2009;4(2):e4606.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Souchet B, Guedj F, Penke-Verdier Z, Daubigney F, Duchon A, Herault Y, Bizot JC, Janel N, Créau N, Delatour B, Delabar JM. Pharmacological correction of excitation/inhibition imbalance in Down syndrome mouse models. Front Behav Neurosci. 2015;20(9):267.

    Google Scholar 

  30. De la Torre R, De Sola S, Pons M, Duchon A, de Lagran MM, Farré M, Fitó M, Benejam B, Langohr K, Rodriguez J, Pujadas M, Bizot JC, Cuenca A, Janel N, Catuara S, Covas MI, Blehaut H, Herault Y, Delabar JM, Dierssen M. Epigallocatechin-3-gallate, a DYRK1A inhibitor, rescues cognitive deficits in Down syndrome mouse models and in humans. Mol Nutr Food Res. 2014;58(2):278–88.

    Article  CAS  PubMed  Google Scholar 

  31. Schupf N, Sergievsky GH. Genetic and host factors for dementia in Down’s syndrome. Br J Psychiatry. 2002;180:405–10.

    Article  PubMed  Google Scholar 

  32. Wisniewski KE, Wisniewski HM, Wen GY. Occurrence of neuropathological changes and dementia of Alzheimer’s disease in Down’s syndrome. Ann Neurol. 1985;17(3):278–82.

    Article  CAS  PubMed  Google Scholar 

  33. Glenner GG, Wong CW. Alzheimer’s disease and Down’s syndrome: sharing of a unique cerebrovascular amyloid fibril protein. Biochem Biophys Res Commun. 1984;122(3):1131–5.

    Article  CAS  PubMed  Google Scholar 

  34. Yates CM, Simpson J, Maloney AF, Gordon A, Reid AH. Alzheimer-like cholinergic deficiency in Down syndrome. Lancet. 1980;2(8201):979.

  35. Lemere CA, Blusztajn JK, Yamaguchi H, Wisniewski T, Saido TC, Selkoe DJ. Sequence of deposition of heterogeneous amyloid beta-peptides and APO E in Down syndrome: implications for initial events in amyloid plaque formation. Neurobiol Dis. 1996;3(1):16–32.

    Article  CAS  PubMed  Google Scholar 

  36. Janicki MP, Dalton AJ. Prevalence of dementia and impact on intellectual disability services. Ment Retard. 2000;38(3):276–88.

    Article  CAS  PubMed  Google Scholar 

  37. Rafii MS, Wishnek H, Brewer JB, Donohue MC, Ness S, Mobley WC, Aisen PS, Rissman RA. The down syndrome biomarker initiative (DSBI) pilot: proof of concept for deep phenotyping of Alzheimer’s disease biomarkers in down syndrome. Front Behav Neurosci. 2015;14(9):239.

    Google Scholar 

  38. Handen BL, Cohen AD, Channamalappa U, Bulova P, Cannon SA, Cohen WI, Mathis CA, Price JC, Klunk WE. Imaging brain amyloid in nondemented young adults with Down syndrome using Pittsburgh compound B. Alzheimers Dement. 2012;8(6):496–501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Hyman BT, West HL, Rebeck GW, Lai F, Mann DM. Neuropathological changes in Down’s syndrome hippocampal formation. Effect of age and apolipoprotein E genotype. Arch Neurol. 1995;52(4):373–8.

    Article  CAS  PubMed  Google Scholar 

  40. Schupf N, Kapell D, Lee JH, Zigman W, Canto B, Tycko B, Mayeux R. Onset of dementia is associated with apolipoprotein E epsilon4 in Down’s syndrome. Ann Neurol. 1996;40(5):799–801.

    Article  CAS  PubMed  Google Scholar 

  41. Prasher VP, Farrer MJ, Kessling AM, Fisher EM, West RJ, Barber PC, Butler AC. Molecular mapping of Alzheimer-type dementia in Down’s syndrome. Ann Neurol. 1998;43(3):380–3.

    Article  CAS  PubMed  Google Scholar 

  42. Beacher F, Simmons A, Daly E, Prasher V, Adams C, Margallo-Lana ML, Morris R, Lovestone S, Murphy K, Murphy DG. Hippocampal myo-inositol and cognitive ability in adults with Down syndrome: an in vivo proton magnetic resonance spectroscopy study. Arch Gen Psychiatry. 2005;62(12):1360–5.

    Article  PubMed  Google Scholar 

  43. Shonk T, Ross BD. Role of increased cerebral myo-inositol in the dementia of Down syndrome. Magn Reson Med. 1995;33(6):858–61.

    Article  CAS  PubMed  Google Scholar 

  44. Fenili D, Brown M, Rappaport R, McLaurin J. Properties of scyllo-inositol as a therapeutic treatment of AD-like pathology. J Mol Med. 2007;85:603–11.

    Article  CAS  PubMed  Google Scholar 

  45. McLaurin J, Kierstead ME, Brown ME, et al. Cyclohexanehexol inhibitors of Aβ aggregation prevent and reverse Alzheimer phenotype in a mouse model. Nat Med. 2006;12:801–8.

    Article  CAS  PubMed  Google Scholar 

  46. Salloway S, Sperling R, Keren R, Porsteinsson AP, van Dyck CH, Tariot PN, Gilman S, Arnold D, Abushakra S, Hernandez C, Crans G, Liang E, Quinn G, Bairu M, Pastrak A, Cedarbaum JM, ELND005-AD201 Investigators. A phase 2 randomized trial of ELND005, scyllo-inositol, in mild to moderate Alzheimer disease. Neurology. 2011;77(13):1253–62.

  47. Rafii MS, Skotko B, Lott I, Kesslak P, Abushakra S. Phase 2a study of ELND005 in adults with Down syndrome. Clinical Trials on Alzheimer’s Disease 2014; Philadelphia, PA; 22–22 November 2014.

  48. Muhs A, Hickman DT, Pihlgren M, Chuard N, Giriens V, Meerschman C, van der Auwera I, Van Leuven F, Sugawara M, Weingertner MC, Bechinger B, Greferath R, Kolonko N, Nagel-Steger L, Riesner D, Brady RO, Pfeifer A, Nicolau C. Liposomal vaccines with conformation-specific amyloid peptide antigens define immune response and efficacy in APP transgenic mice. Proc Natl Acad Sci. 2007;104(23):9810–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hickman DT, López-Deber MP, Ndao DM, Silva AB, Nand D, Pihlgren M, Giriens V, Madani R, St-Pierre A, Karastaneva H, Nagel-Steger L, Willbold D, Riesner D, Nicolau C, Baldus M, Pfeifer A, Muhs A. Sequence-independent control of peptide conformation in liposomal vaccines for targeting protein misfolding diseases. J Biol Chem. 2011;286(16):13966–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Gilman S, Koller M, Black RS, Jenkins L, Griffith SG, Fox NC, Eisner L, Kirby L, Rovira MB, Forette F, Orgogozo JM, AN1792(QS-21)-201 Study Team. Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology. 2005;64(9):1553–62.

    Article  CAS  PubMed  Google Scholar 

  51. Ryan JM, Grundman M. Anti-amyloid-beta immunotherapy in Alzheimer’s disease: ACC-001 clinical trials are ongoing. J Alzheimers Dis. 2009;17(2):243.

    PubMed  Google Scholar 

  52. Winblad B, Andreasen N, Minthon L, Floesser A, Imbert G, Dumortier T, Maguire RP, Blennow K, Lundmark J, Staufenbiel M, Orgogozo JM, Graf A. Safety, tolerability, and antibody response of active Aβ immunotherapy with CAD106 in patients with Alzheimer’s disease: randomised, double-blind, placebo-controlled, first-in-human study. Lancet Neurol. 2012;11(7):597–604.

    Article  CAS  PubMed  Google Scholar 

  53. Pasquier F, Sadowsky C, Holstein A, Leterme Gle P, Peng Y, Jackson N, Fox NC, Ketter N, Liu E, Ryan JM, ACC-001 (QS-21) Study Team. Two phase 2 multiple ascending-dose studies of vanutide cridificar (ACC-001) and QS-21 adjuvant in mild-to-moderate Alzheimer’s disease. J Alzheimers Dis. 2016;51(4):1131–43.

  54. Farlow MR, Andreasen N, Riviere ME, Vostiar I, Vitaliti A, Sovago J, Caputo A, Winblad B, Graf A. Long-term treatment with active Aβ immunotherapy with CAD106 in mild Alzheimer’s disease. Alzheimers Res Ther. 2015;7(1):23.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Boada R, Hutaff-Lee C, Schrader A, Weitzenkamp D, Benke T, Goldson E, Costa A. Antagonism of NMDA receptors as a potential treatment for Down syndrome: a pilot randomized controlled trial. Transl Psychiatry. 2012;17(2):e141.

    Article  Google Scholar 

  56. Liogier d’Ardhuy X, Edgin JO, Bouis C, de Sola S, Goeldner C, Kishnani P, Nöldeke J, Rice S, Sacco S, Squassante L, Spiridigliozzi G, Visootsak J, Heller J, Khwaja O. Assessment of cognitive scales to examine memory, executive function and language in individuals with Down syndrome: implications of a 6-month observational study. Front Behav Neurosci. 2015;9:300.

  57. Edgin JO, Mason GM, Allman MJ, Capone GT, DeLeon I, Maslen C, Reeves RH, Sherman SL, Nadel L. Development and validation of the Arizona Cognitive Test Battery for Down syndrome. J Neurodev Disord. 2010;2(3):149–64.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Sparrow S, Cicchetti DV, Balla DA. Vineland II: vineland adaptive behavior scales. Circle Pines: American Guidance Service; 2005.

  59. Jones B, Kenward MG. Design and analysis of cross-over trials. 2nd ed. Boca Raton: Chapman & Hall/CRC; 2003.

    Google Scholar 

  60. D’Agostino RB Sr. The delayed-start study design. N Engl J Med. 2009;361(13):1304–6.

    Article  PubMed  Google Scholar 

  61. Olanow CW, Rascol O, Hauser R, et al. A double-blind, delayed-start trial of rasagiline in Parkinson’s disease. N Engl J Med. 2009;361:1268–78.

    Article  CAS  PubMed  Google Scholar 

  62. Liu-Seifert H, Siemers E, Holdridge KC, Anderson SW, Lipkovich I, Carlson C, Sethuraman G, Hoog S, Hayduk R, Doody R, Aisen PS. Delayed-start analysis: mild Alzheimer’s disease patients in solanezumab trials, 3.5 years. Alzheimers Dement Transl Res Clin Inter. 2015;1(2):111–121.

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Authors and Affiliations

  1. Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive #0949, La Jolla, CA, 92093-0949, USA

    Michael S. Rafii

  2. Department of Neurology, Alzheimer’s Therapeutic Research Institute, University of Southern California, San Diego, CA, USA

    Michael S. Rafii

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Correspondence to Michael S. Rafii.

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There was no specific funding used to assist with the preparation of this review.

Conflict of interest

MSR is funded by an NIH R01 as principal investigator for a multicenter clinical trial of ACI-24 in Down syndrome (AG047922-01). He has also received research grants from Elan Corporation (Dublin, Ireland), Hoffmann-La Roche (Basel, Switzerland) and Janssen Pharmaceuticals (Titusville, New Jersey). He was a site investigator for the ELND005 study as well as the RG1662 phase I and phase II studies.

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Rafii, M.S. Improving Memory and Cognition in Individuals with Down Syndrome. CNS Drugs 30, 567–573 (2016). https://doi.org/10.1007/s40263-016-0353-4

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