Abstract
Background: Down syndrome (DS) is associated with a high prevalence of cognitive impairment and dementia in middle age and older adults. Given the presence of common neuropathological findings and similar pathogenic mechanisms, dementia in DS is regarded as a form of genetically determined, early-onset AD. The clinical characterization of cognitive decline in persons with DS is a difficult task, due to the presence intellectual disability and pre-existing cognitive impairment. Subtle changes that occur at early stages of the dementing process may not be perceived clinically, given that most cognitive screening tests are not sensitive enough to detect them. Therefore, biological markers will provide support to the diagnosis of DS-related cognitive impairment and dementia, particularly at early stages of this process.
Objective: To perform a systematic review of the literature on AD-related biomarkers in DS.
Method: We searched PubMed, Web of Science and Cochrane Library for scientific papers published between 2008 and 2018 using as primary mesh terms ‘Down’, ‘Alzheimer’, ‘biomarker’.
Results: 79 studies were retrieved, and 39 were considered eligible for inclusion in the systematic review: 14 post-mortem studies, 10 neuroimaging, 4 addressing cerebrospinal fluid biomarkers, and 11 on peripheral markers.
Conclusion: There is consistent growth in the number of publication in this field over the past years. Studies in DS-related dementia tend to incorporate many of the diagnostic technologies that have been more extensively studied and validated in AD. In many instances, the study of CNS and peripheral biomarkers reinforces the presence of AD pathology in DS.
Keywords: Down syndrome (DS), Alzheimer's disease (AD), aging, biomarkers, amyloid-beta (Aβ), amyloid precursor protein (APP).
Graphical Abstract
[1]
Carfì A, Antocicco M, Brandi V, et al. Characteristics of adults with Down syndrome: prevalence of age-related conditions. Front Med 2014; 1: 51.
[2]
Head E, Lott IT, Wilcock DM, et al. Aging in Down syndrome and the development of Alzheimer’s disease neuropathology hhs public access. Curr Alzheimer Res 2016; 13: 18-29.
[3]
World Health Organization. Genes and human disease: Dowm
Syndrome. WHO; [accessed 3 July 2017]. Available at. http://www. who.int/genomics/public/geneticdiseases/en/index1.html
[4]
NDSS / Down syndrome fact sheet. National Down Syndrome
Society; [accessed 19 March 2017]. Availabale at. http://www. ndss.org/PageFiles/1474/NDSS Fact Sheet 2015.pdf
[5]
Bush A, Beail N. Risk Factors for dementia in people with down syndrome: issues in assessment and diagnosis. Am Assoc Ment Retard Am J Ment Retard 2004; 83: 83-97.
[6]
Mann DM, Yates PO, Marcyniuk B. Alzheimer’s presenile dementia, senile dementia of Alzheimer type and Down’s syndrome in middle age form an age related continuum of pathological changes. Neuropathol Appl Neurobiol 1984; 10: 185-207.
[7]
Mann DM, Esiri MM. The pattern of acquisition of plaques and tangles in the brains of patients under 50 years of age with Down’s syndrome. J Neurol Sci 1989; 89: 169-79.
[8]
Mann DM, Jones D, Prinja D, et al. The prevalence of amyloid (A4) protein deposits within the cerebral and cerebellar cortex in Down’s syndrome and Alzheimer’s disease. Acta Neuropathol 1990; 80: 318-27.
[9]
Wisniewski KE, Dalton AJ, McLachlan C, et al. Alzheimer’s disease in Down’s syndrome: clinicopathologic studies. Neurology 1985; 35: 957-61.
[10]
Zigman WB, Lott IT. Alzheimer’s disease in Down syndrome: Neurobiology and risk. Ment Retard Dev Disabil Res Rev 2007; 13: 237-46.
[11]
Covelli V, Raggi A, Meucci P, et al. Ageing of people with Down’s syndrome: a systematic literature review from 2000 to 2014. Int J Rehabil Res 2016; 39: 20-8.
[13]
Kusters MA, Verstegen RH, de Vries E. Down syndrome: is it really characterized by precocious immunosenescence? Aging Dis 2011; 2: 538-45.
[14]
Vaziri H, Schächter F, Uchida I, et al. Loss of telomeric DNA during aging of normal and trisomy 21 human lymphocytes. Am J Hum Genet 1993; 52: 661-7.
[16]
Gulesserian T, Seidl R, Hardmeier R, et al. Superoxide dismutase sod1, encoded on chromosome 21, but not SOD2 is overexpressed in brains of patients with Down syndrome. J Investig Med 2001; 49: 41-6.
[17]
Pagano G, Castello G. Oxidative stress and mitochondrial dysfunction in Down syndrome. Adv Exp Med Biol 2012; 724: 291-9.
[18]
Busciglio J, Yankner BA. Apoptosis and increased generation of reactive oxygen species in Down’s syndrome neurons in vitro. Nature 1995; 378: 776-9.
[19]
Rueda N, Flórez J, Martínez-Cué C. Apoptosis in Down’s syndrome: lessons from studies of human and mouse models. Apoptosis 2013; 18: 121-34.
[20]
Tramutola A, Pupo G, Di Domenico F, et al. Activation of p53 in Down syndrome and in the Ts65Dn mouse brain is associated with a pro-apoptotic phenotype. J Alzheimers Dis 2016; 52: 359-71.
[21]
Jenkins EC, Ye L, Gu H, et al. Increased “absence” of telomeres may indicate Alzheimer’s disease/dementia status in older individuals with Down syndrome. Neurosci Lett 2008; 440: 340-3.
[22]
Jenkins EC, Ye L, Gu H, et al. Shorter telomeres may indicate dementia status in older individuals with Down syndrome. Neurobiol Aging 2010; 31: 765-71.
[23]
Jenkins EC, Ye L, Velinov M, et al. Mild cognitive impairment identified in older individuals with Down syndrome by reduced telomere signal numbers and shorter telomeres measured in microns. Am J Med Genet B Neuropsychiatr Genet 2012; 159B: 598-604.
[24]
Royston MC, McKenzie JE, Gentleman SM, et al. Overexpression of s100beta in Down’s syndrome: correlation with patient age and with beta-amyloid deposition. Neuropathol Appl Neurobiol 1999; 25: 387-93.
[25]
Hartley D, Blumenthal T, Carrillo M, et al. Down syndrome and Alzheimer’s disease: Common pathways, common goals HHS Public Access. Alzheimers Dement 2015; 11: 700-9.
[27]
Annus T, Wilson LR, Hong YT, et al. The pattern of amyloid accumulation in the brains of adults with Down syndrome. Alzheimers Dement 2016; 12: 538-45.
[28]
Lee N-C, Yang S-Y, Chieh J-J, et al. Blood Beta-Amyloid and Tau in Down Syndrome: A Comparison with Alzheimer’s Disease. Front Aging Neurosci 2016; 8: 316.
[29]
Fletcher RJ, Barnhill J, McCarthy J, et al. From DSM to DM-ID. J Ment Health Res Intellect Disabil 2016; 9: 189-204.
[30]
Sheehan R, Sinai A, Bass N, et al. Dementia diagnostic criteria in Down syndrome. Int J Geriatr Psychiatry 2015; 30: 857-63.
[31]
Hithersay R, Hamburg S, Knight B, et al. Cognitive decline and dementia in Down syndrome. Curr Opin Psychiatry 2017; 30: 102-7.
[32]
Motter R, Vigo-Pelfrey C, Kholodenko D, et al. Reduction of? -amyloid peptide42 in the cerebrospinal fluid of patients with Alzheimer’s disease. Ann Neurol 1995; 38: 643-8.
[33]
Blennow K, Hampel H. CSF markers for incipient Alzheimer’s disease. Lancet Neurol 2003; 2: 605-13.
[34]
Buchhave P, Minthon L, Zetterberg H, et al. Cerebrospinal Fluid Levels ofβ-Amyloid 1-42, but Not of Tau, Are Fully Changed Already 5 to 10 Years Before the Onset of Alzheimer Dementia. Arch Gen Psychiatry 2012; 69: 98.
[35]
van Harten AC, Visser PJ, Pijnenburg YAL, et al. Cerebrospinal fluid Aβ42 is the best predictor of clinical progression in patients with subjective complaints. Alzheimers Dement 2013; 9: 481-7.
[36]
Blennow K, Dubois B, Fagan AM, et al. Clinical utility of cerebrospinal fluid biomarkers in the diagnosis of early Alzheimer’s disease. Alzheimers Dement 2015; 11: 58-69.
[37]
Downes EC, Robson J, Grailly E, et al. Loss of synaptophysin and synaptosomal-associated protein 25-kDa (SNAP-25) in elderly Down syndrome individuals. Neuropathol Appl Neurobiol 2008; 34(1): 12-22.
[38]
Martin SB, Dowling ALS, Lianekhammy J, et al. Synaptophysin and Synaptojanin-1 in Down Syndrome are differentially affected by Alzheimer’s disease. J Alzheimers Dis 2014; 42: 767-75.
[39]
Cremona O, Nimmakayalu M, Haffner C, et al. Assignment 1 of SYNJ1 to human chromosome 21q22.2 and Synj12 to the murine homologous region on chromosome 16C3-4 by in situ hybridization. Cytogenet Cell Genet 2000; 88(1-2): 89-90.
[40]
Cremona O, Di Paolo G, Wenk MR, et al. Essential role of phosphoinositide metabolism in synaptic vesicle recycling. Cell 1999; 99: 179-88.
[41]
Cossec J-C, Lavaur J, Berman DE, et al. Trisomy for Synaptojanin1 in Down syndrome is functionally linked to the enlargement of early endosomes. Hum Mol Genet 2012; 21: 3156-72.
[42]
McIntire LBJ, Berman DE, Myaeng J, et al. Reduction of synaptojanin 1 ameliorates synaptic and behavioral impairments in a mouse model of Alzheimer’s Disease. J Neurosci 2012; 32: 15271-6.
[43]
Voronov SV, Frere SG, Giovedi S, et al. Synaptojanin 1-linked phosphoinositide dyshomeostasis and cognitive deficits in mouse models of Down’s syndrome. Proc Natl Acad Sci 2008; 105: 9415-20.
[44]
Chang KT, Min K-T. Upregulation of three Drosophila homologs of human chromosome 21 genes alters synaptic function: Implications for Down syndrome. Proc Natl Acad Sci 2009; 106: 17117-22.
[45]
Miller JA, Oldham MC, Geschwind DH. A systems level analysis of transcriptional changes in Alzheimer’s disease and normal aging. J Neurosci 2008; 28: 1410-20.
[46]
Cheon MS, Shim KS, Kim SH, et al. Protein levels of genes encoded on chromosome 21 in fetal Down syndrome brain: Challenging the gene dosage effect hypothesis (Part IV). Amino Acids 2003; 25: 41-7.
[47]
Arai Y, Ijuin T, Takenawa T, et al. Excessive expression of synaptojanin in brains with Down syndrome. Brain Dev 2002; 24: 67-72.
[48]
Wiedenmann B, Franke WW, Kuhn C, et al. Synaptophysin: A marker protein for neuroendocrine cells and neoplasms (synaptic vesicles/neurosecretory granules/pancreatic islets/carcinolds/ tumor diagnosis). Proc Natl Acad Sci USA 1986; 83: 3500-4.
[49]
Mucke L, Masliah E, Yu GQ, et al. High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci 2000; 20: 4050-8.
[50]
Shankar GM, Walsh DM. Molecular Neurodegeneration Alzheimer’s disease: synaptic dysfunction and Aβ. Mol Neurodegener 2009; 4(48): 1-13.
[51]
Noor A, Zahid S. A review of the role of synaptosomal-associated protein 25 (SNAP-25) in neurological disorders. Int J Neurosci 2017; 127: 805-11.
[52]
Zheng X, Bobich JA. A sequential view of neurotransmitter release. Brain Res Bull 1998; 47: 117-28.
[53]
Clinton J, Blackman SE, Royston MC, et al. Differential synaptic loss in the cortex in Alzheimer’s disease: a study using archival material. Neuroreport 1994; 5: 497-500.
[54]
Cenini G, Dowling ALS, Beckett TL, et al. Association between frontal cortex oxidative damage and beta-amyloid as a function of age in Down syndrome. Biochim Biophys Acta 2012; 1822: 130-8.
[55]
Cenini G, Fiorini A, Sultana R, et al. An investigation of the molecular mechanisms engaged before and after the development of Alzheimer disease neuropathology in Down syndrome: a proteomics approach. Free Radic Biol Med 2014; 76: 89-95.
[56]
Ling M, Merante F, Chen HS, et al. The human mitochondrial elongation factor tu (EF-Tu) gene: cDNA sequence, genomic localization, genomic structure, and identification of a pseudogene. Gene 1997; 197: 325-36.
[57]
Butterfield DA, Lange MLB. Multifunctional roles of enolase in Alzheimer’s disease brain: beyond altered glucose metabolism. J Neurochem 2009; 111: 915-33.
[58]
Hauser PS, Narayanaswami V, Ryan RO, Apolipoprotein E. From lipid transport to neurobiology. Prog Lipid Res 2011; 50: 62-74.
[59]
Reddy PH, Mani G, Park BS, et al. Differential loss of synaptic proteins in Alzheimer’s disease: implications for synaptic dysfunction. J Alzheimers Dis 2005; 7: 103-17.
[60]
Ju J-S, Fuentealba RA, Miller SE, et al. Valosin-containing protein (VCP) is required for autophagy and is disrupted in VCP disease. J Cell Biol 2009; 187: 875-88.
[61]
Butterfield DA, Di Domenico F, Swomley AM, et al. Redox proteomics analysis to decipher the neurobiology of Alzheimer-like neurodegeneration: overlaps in Down’s syndrome and Alzheimer’s disease brain. Biochem J 2014; 463: 177-89.
[62]
Di Domenico F, Pupo G, Tramutola A, et al. Redox proteomics analysis of HNE-modified proteins in Down syndrome brain: clues for understanding the development of Alzheimer disease. Free Radic Biol Med 2014; 71: 270-80.
[63]
Miners JS, Morris S, Love S, et al. Accumulation of Insoluble Amyloid-β in Down’s Syndrome is Associated with Increased BACE-1 and Neprilysin Activities. J Alzheimers Dis 2011; 23: 101-8.
[64]
Kanemitsu H, Tomiyama T, Mori H. Human neprilysin is capable of degrading amyloid beta peptide not only in the monomeric form but also the pathological oligomeric form. Neurosci Lett 2003; 350: 113-6.
[65]
El-Amouri SS, Zhu H, Yu J, et al. Neprilysin protects neurons against Aβ peptide toxicity. Brain Res 2007; 1152: 191-200.
[66]
Landt J, D’Abrera JC, Holland AJ, et al. Using positron emission tomography and carbon 11-labeled pittsburgh compound b to image brain fibrillar β-amyloid in adults with Down Syndrome. Arch Neurol 2011; 68: 890.
[67]
Sabbagh MN, Fleisher A, Chen K, et al. Positron emission tomography and neuropathologic estimates of fibrillar amyloid-β in a patient with Down syndrome and Alzheimer disease. Arch Neurol 2011; 68: 1461-6.
[68]
Nelson LD, Siddarth P, Kepe V, et al. Positron emission tomography of brain β-amyloid and tau levels in adults with down syndrome. Arch Neurol 2011; 68: 768-74.
[69]
Handen BL, Cohen AD, Channamalappa U, et al. Imaging brain amyloid in nondemented young adults with Down syndrome using Pittsburgh compound B. Alzheimers Dement 2012; 8: 496-501.
[70]
Sabbagh MN, Chen K, Rogers J, et al. Florbetapir PET, FDG PET, and MRI in Down syndrome individuals with and without Alzheimer’s dementia. Alzheimers Dement 2015; 11: 994-1004.
[71]
Head E, Lott IT, Patterson D, et al. Possible compensatory events in adult Down syndrome brain prior to the development of Alzheimer disease neuropathology: targets for nonpharmacological intervention. J Alzheimers Dis 2007; 11: 61-76.
[72]
Haier RJ, Head K, Head E, et al. Neuroimaging of individuals with Down’s syndrome at-risk for dementia: Evidence for possible compensatory events. Neuroimage 2008; 39: 1324-32.
[73]
Jennings D, Seibyl J, Sabbagh M, et al. Age dependence of brain -amyloid deposition in Down syndrome: An [18F]florbetaben PET study. Neurology 2015; 84: 500-7.
[74]
Rafii MS, Wishnek H, Brewer JB, et al. 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; 9: 239.
[75]
Portelius E, Soininen H, Andreasson U, et al. Exploring Alzheimer molecular pathology in Down’s Syndrome cerebrospinal fluid. Neurodegener Dis 2014; 14: 98-106.
[76]
Portelius E, Hölttä M, Soininen H, et al. Altered cerebrospinal fluid levels of amyloid β and amyloid precursor-like protein 1 peptides in Down’s Syndrome. Neuromolecular Med 2014; 16: 510-6.
[77]
Wasco W, Brook JD, Tanzi RE. The Amyloid Precursor-like Protein (APLP) Gene Maps to the Long Arm of Human Chromosome 19. Genomics 1993; 15: 237-9.
[78]
Yanagida K, Okochi M, Tagami S, et al. The 28-amino acid form of an APLP1-derived Aβ-like peptide is a surrogate marker for Aβ42 production in the central nervous system. EMBO Mol Med 2009; 1: 223-35.
[79]
García-Ayllón M-S, Lopez-Font I, Boix CP, et al. C-terminal fragments of the amyloid precursor protein in cerebrospinal fluid as potential biomarkers for Alzheimer disease. Sci Rep 2017; 7: 2477.
[80]
Sogorb-Esteve A, García-Ayllón M-S, Fortea J, et al. Cerebrospinal fluid Presenilin-1 increases at asymptomatic stage in genetically determined Alzheimer’s disease. Mol Neurodegener 2016; 11: 66.
[81]
Conti E, Galimberti G, Piazza F, et al. Increased Soluble APPα, Abeta 1-42, and Anti-Abeta 1-42 Antibodies in plasma from Down Syndrome patients. Alzheimer Dis Assoc Disord 2010; 24: 96-100.
[82]
Jones EL, Hanney M, Francis PT, et al. Amyloid β concentrations in older people with Down syndrome and dementia. Neurosci Lett 2009; 451: 162-4.
[83]
Head E, Doran E, Nistor M, et al. Plasma amyloid-β as a function of age, level of intellectual disability, and presence of dementia in Down syndrome. J Alzheimers Dis 2011; 23: 399-409.
[84]
Prasher VP, Sajith SG, Mehta P, et al. Plasma β -amyloid and duration of Alzheimer’s disease in adults with Down syndrome. Int J Geriatr Psychiatry 2010; 25: 202-7.
[85]
Lee N-C, Yang S-Y, Chieh J-J, et al. Blood beta-amyloid and tau in Down Syndrome: A comparison with Alzheimer’s Disease. Front Aging Neurosci 2016; 8: 316.
[86]
Iulita MF, Ower A, Barone C, et al. An inflammatory and trophic disconnect biomarker profile revealed in Down syndrome plasma: Relation to cognitive decline and longitudinal evaluation. Alzheimers Dement 2016; 12: 1132-48.
[87]
Tatebe H, Kasai T, Ohmichi T, et al. Quantification of plasma phosphorylated tau to use as a biomarker for brain Alzheimer pathology: pilot case-control studies including patients with Alzheimer’s disease and Down syndrome. Mol Neurodegener 2017; 12: 63.
[88]
Kasai T, Tatebe H, Kondo M, et al. Increased levels of plasma total tau in adult Down syndrome. PLoS One 2017; 12: e0188802.
[89]
Strydom A, Heslegrave A, Startin CM, et al. Neurofilament light as a blood biomarker for neurodegeneration in Down syndrome. Alzheimers Res Ther 2018; 10: 39.
[90]
Zetterberg H. Neurofilament Light: A Dynamic Cross-Disease Fluid Biomarker for Neurodegeneration. Neuron 2016; 91: 1-3.
[91]
Mattsson N, Andreasson U, Zetterberg H, et al. Association of Plasma Neurofilament Light With Neurodegeneration in Patients With Alzheimer Disease. JAMA Neurol 2017; 74: 557-66.
[92]
Weston PSJ, Poole T, Ryan NS, et al. Serum neurofilament light in familial Alzheimer disease. Neurology 2017; 89: 2167-75.
Article Metrics
19
4
1