Abstract
Alzheimer´s disease (AD) and related forms of dementia are increasingly affecting the aging population throughout the world, at an alarming rate. The World Alzheimer´s Report indicates a prevalence of 46.8 million people affected by AD worldwide. As population ages, this number is projected to triple by 2050 unless effective interventions are developed and implemented. Urgent efforts are required for an early detection of this disease. The ultimate goal is the identification of viable targets for the development of molecular markers and validation of their use for early diagnosis of AD that may improve treatment and the disease outcome in patients. The diagnosis of AD has been difficult to resolve since approaches for early and accurate detection and follow-up of AD patients at the clinical level have been reported only recently. Some proposed AD biomarkers include the detection of pathophysiological processes in the brain in vivo with new imaging techniques and novel PET ligands, and the determination of pathogenic proteins in cerebrospinal fluid showing anomalous levels of hyperphosphorylated tau and low Aβ peptide. These biomarkers have been increasingly accepted by AD diagnostic criteria and are important tools for the design of clinical trials, but difficulties in accessibility to costly and invasive procedures have not been completely addressed in clinical settings. New biomarkers are currently being developed to allow determinations of multiple pathological processes including neuroinflammation, synaptic dysfunction, metabolic impairment, protein aggregation and neurodegeneration. Highly specific and sensitive blood biomarkers, using less-invasive procedures to detect AD, are derived from the discoveries of peripheric tau oligomers and amyloid variants in human plasma and platelets. We have also developed a blood tau biomarker that correlates with a cognitive decline and also with neuroimaging determinations of brain atrophy.
Keywords: Alzheimer's disease, molecular biomarkers, blood markers, CSF markers, neuroimaging, amyloid β and tau protein targets.
[1]
Alzheimar A. Über eine eigenartige Erkrankung der Hirnrinde. Psychiatr Psych gericht Med 64: 146-8. 1907
[2]
Farias G, Cornejo A, Jimenez J, Guzman L, Maccioni RB. Mechanisms of tau self-aggregation and neurotoxicity. Curr Alzheimer Res 8(6): 608-14. (2011)
[3]
Farias G, Perez P, Slachevsky A, Maccioni RB. Platelet tau pattern correlates with cognitive status in Alzheimer’s disease. J Alzheimers Dis 31(1): 65-9. (2012)
[4]
Gasic-Milenkovic J, Dukic-Stefanovic S, Deuther-Conrad W, Gartner U, Munch G. Beta-amyloid peptide potentiates inflammatory responses induced by lipopolysaccharide, interferon -gamma and ‘advanced glycation endproducts’ in a murine microglia cell line. Eur J Neurosci 17(4): 813-21. (2003)
[5]
Maccioni RB, Perry G. Current Hypotheses and Research Milestones in Alzheimer's Disease New York: Springer Science+Bussiness Media, LLC; 3-241. (2009)
[6]
Maccioni RB, Cambiazo V. Role of microtubule-associated proteins in the control of microtubule assembly. Physiol Rev 75(4): 835-64. (1995)
[7]
Association As 2018 Alzheimer’s disease facts and figures. Alzheimer's & Dementia 14(3): 367-429. (2018)
[8]
Maccioni RB, Munoz JP, Barbeito L. The molecular bases of Alzheimer’s disease and other neurodegenerative disorders. Arch Med Res 32(5): 367-81. (2001)
[9]
Maccioni RB, Lavados M, Maccioni CB, Mendoza-Naranjo A. Biological markers of Alzheimer’s disease and mild cognitive impairment. Curr Alzheimer Res 1(4): 307-14. (2004)
[10]
Maccioni RB, Lavados M, Guillon M, Mujica C, Bosch R, Farias G, et al. Anomalously phosphorylated tau and Abeta fragments in the CSF correlates with cognitive impairment in MCI subjects. Neurobiol Aging 27(2): 237-44. (2006)
[11]
Lavados M, Farias G, Rothhammer F, Guillon M, Mujica MC, Maccioni C, et al. ApoE alleles and tau markers in patients with different levels of cognitive impairment. Arch Med Res 36(5): 474-9. (2005)
[12]
Maccioni RB, Farias G, Morales I, Navarrete L. The revitalized tau hypothesis on Alzheimer’s disease. Arch Med Res 41(3): 226-31. (2010)
[13]
McGeer EG, McGeer PL. Pharmacologic approaches to the treatment of amyotrophic lateral sclerosis. BioDrugs: clinical immunotherapeutics, biopharmaceuticals and gene therapy 19(1): 31-7. (2005)
[14]
Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297(5580): 353-6. (2002)
[15]
Walker LC, Diamond MI, Duff KE, Hyman BT. Mechanisms of protein seeding in neurodegenerative diseases. JAMA Neurol 70(3): 304-10. (2013)
[16]
Maccioni RB. Introductory remarks. Molecular, biological and clinical aspects of Alzheimer’s disease. Arch Med Res 43(8): 593-4. (2012)
[17]
Farias GA, Guzman-Martinez L, Delgado C, Maccioni RB. Nutraceuticals: a novel concept in prevention and treatment of Alzheimer’s disease and related disorders. J Alzheimers Dis 42(2): 357-67. (2014)
[18]
Alvarez A, Toro R, Caceres A, Maccioni RB. Inhibition of tau phosphorylating protein kinase cdk5 prevents beta-amyloid-induced neuronal death. FEBS Lett 459(3): 421-6. (1999)
[19]
Fernandez JA, Rojo L, Kuljis RO, Maccioni RB. The damage signals hypothesis of Alzheimer’s disease pathogenesis. J Alzheimers Dis 14(3): 329-33. (2008)
[20]
Orellana DI, Quintanilla RA, Gonzalez-Billault C, Maccioni RB. Role of the JAKs/STATs pathway in the intracellular calcium changes induced by interleukin-6 in hippocampal neurons. Neurotox Res 8(3-4): 295-304. (2005)
[21]
Saez JC, Retamal MA, Basilio D, Bukauskas FF, Bennett MV. Connexin-based gap junction hemichannels: gating mechanisms. Biochimica et Biophys Acta 1711(2): 215-24. (2005)
[22]
Morales I, Jimenez JM, Mancilla M, Maccioni RB. Tau oligomers and fibrils induce activation of microglial cells. J Alzheimer Res 37(4): 849-5. (2013)
[23]
Thaweepoksomboon J, Senanarong V, Poungvarin N, Chakorn T, Siwasariyanon N, Washirutmangkur L, et al. Assessment of cerebrospinal fluid (CSF) beta-amyloid (1-42), phosphorylated tau (ptau-181) and total Tau protein in patients with Alzheimer’s disease (AD) and other dementia at Siriraj Hospital, Thailand. J Med Assoc 94(1): S77-83. (2011)
[24]
Kandimalla RJ, Prabhakar S, Binukumar BK, Wani WY, Gupta N, Sharma DR, et al. Apo-Eepsilon4 allele in conjunction with Abeta42 and tau in CSF: biomarker for Alzheimer’s disease. Curr Alzheimer Res 8(2): 187-96. (2011)
[25]
Sohma H, Kokai Y. Plasma Biomarkers in Alzheimer’s Disease. In: Moretti DV, editor.Update on Dementia: InTech. (2016); pp. 67-83.
[26]
Kandimalla RJ. S P, Bk B, Wani WY, Sharma DR, Grover VK, et al. Cerebrospinal fluid profile of amyloid beta42 (Abeta42), hTau and ubiquitin in North Indian Alzheimer’s disease patients. Neurosci Lett 487(2): 134-8. (2011)
[27]
Kandimalla RJ, Prabhakar S, Wani WY, Kaushal A, Gupta N, Sharma DR, et al. CSF p-Tau levels in the prediction of Alzheimer’s disease. Biol Open 2(11): 1119-24. (2013)
[28]
Patterson BW, Elbert DL, Mawuenyega KG, Kasten T, Ovod V, Ma S, et al. Age and amyloid effects on human central nervous system amyloid-beta kinetics. Ann Neurol 78(3): 439-53. (2015)
[29]
Toledo JB, Zetterberg H, van Harten AC, Glodzik L, Martinez-Lage P, Bocchio-Chiavetto L, et al. Alzheimer’s disease cerebrospinal fluid biomarker in cognitively normal subjects. Brain 138(Pt 9): 2701-15. (2015)
[30]
Wiltfang J, Esselmann H, Bibl M, Hull M, Hampel H, Kessler H, et al. Amyloid beta peptide ratio 42/40 but not A beta 42 correlates with phospho-Tau in patients with low- and high-CSF A beta 40 load. J Neurochem 101(4): 1053-9. (2007)
[31]
Salvadores N, Shahnawaz M, Scarpini E, Tagliavini F, Soto C. Detection of misfolded Abeta oligomers for sensitive biochemical diagnosis of Alzheimer’s disease. Cell Rep 7(1): 261-8. (2014)
[32]
Dunys J, Valverde A, Checler F. Are N- and C-terminally truncated Abeta species key pathological triggers in Alzheimer’s disease? J Biol Chem 293(40): 15419-28. (2018)
[33]
Ranaldi S, Caillava C, Prome S, Rubrecht L, Cobo S, Salvetat N, et al. N-truncated Abeta peptides in complex fluids unraveled by new specific immunoassays. Neurobiol Aging 34(2): 523-39. (2013)
[34]
Bibl M, Gallus M, Welge V, Esselmann H, Wolf S, Ruther E, et al. Cerebrospinal fluid amyloid-beta 2-42 is decreased in Alzheimer’s, but not in frontotemporal dementia. J Neural Transm (Vienna) 119(7): 805-13. (2012)
[35]
Cummings J, Zhong K. Biomarker-driven therapeutic management of Alzheimer’s disease: establishing the foundations. Clin Pharmacol Ther 95(1): 67-77. (2014)
[36]
van Rossum IA, Vos SJ, Burns L, Knol DL, Scheltens P, Soininen H, et al. Injury markers predict time to dementia in subjects with MCI and amyloid pathology. Neurology 79(17): 1809-16. (2012)
[37]
McGhee DJ, Ritchie CW, Thompson PA, Wright DE, Zajicek JP, Counsell CE. A systematic review of biomarkers for disease progression in Alzheimer’s disease. PLoS One 9(2)e88854 (2014)
[38]
Olsson B, Lautner R, Andreasson U, Ohrfelt A, Portelius E, Bjerke M, et al. CSF and blood biomarkers for the diagnosis of Alzheimer’s disease: a systematic review and meta-analysis. Lancet Neurol 15(7): 673-84. (2016)
[39]
Kandimalla RJ, Anand R, Veeramanikandan R, Wani WY, Prabhakar S, Grover VK, et al. CSF ubiquitin as a specific biomarker in Alzheimer’s disease. Curr Alzheimer Res 11(4): 340-8. (2014)
[40]
Sjodin S, Hansson O, Ohrfelt A, Brinkmalm G, Zetterberg H, Brinkmalm A, et al. Mass spectrometric analysis of cerebrospinal fluid ubiquitin in Alzheimer's disease and Parkinsonian disorders. Proteom Clin App 11(11-12) (2017)
[41]
Rizzi L, Roriz-Cruz M. Cerebrospinal fluid inflammatory markers in amnestic mild cognitive impairment. Geriatr Gerontol Int 17(2): 239-45. (2017)
[42]
Du Y, Wu HT, Qin XY, Cao C, Liu Y, Cao ZZ, et al. Postmortem brain, cerebrospinal fluid, and blood neurotrophic factor levels in Alzheimer’s disease: a systematic review and meta-analysis. J Mol Neurosci 65(3): 289-300. (2018)
[43]
Benussi L, Binetti G, Ghidoni R. Loss of neuroprotective factors in neurodegenerative dementias: the end or the starting point? Front Neurosci 11: 672. (2017)
[44]
Clark LF, Kodadek T. The immune system and neuroinflammation as potential sources of blood-based biomarkers for Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. ACS Chem Neurosci 7(5): 520-7. (2016)
[45]
Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, et al. Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7(3): 280-92. (2011)
[46]
Epelbaum S, Genthon R, Cavedo E, Habert MO, Lamari F, Gagliardi G, et al. Preclinical Alzheimer’s disease: A systematic review of the cohorts underlying the concept. Alzheimers Dement 13(4): 454-67. (2017)
[47]
Ritchie C, Smailagic N, Noel-Storr AH, Ukoumunne O, Ladds EC, Martin S. CSF tau and the CSF tau/ABeta ratio for the diagnosis of Alzheimer’s disease dementia and other dementias in people with mild cognitive impairment (MCI). The Cochrane Database Syst Rev 3CD010803 (2017)
[48]
Rojo L, Sjoberg MK, Hernandez P, Zambrano C, Maccioni RB. Roles of cholesterol and lipids in the etiopathogenesis of Alzheimer’s disease. J Biomed Biotechnol 2006(3): 73976. (2006)
[49]
Rojo LE, Fernandez JA, Maccioni AA, Jimenez JM, Maccioni RB. Neuroinflammation: implications for the pathogenesis and molecular diagnosis of Alzheimer’s disease. Arch Med Res 39(1): 1-16. (2008)
[50]
Luchsinger JA, Tang MX, Miller J, Green R, Mehta PD, Mayeux R. Relation of plasma homocysteine to plasma amyloid beta levels. Neurochem Res 32(4-5): 775-81. (2007)
[51]
Fukumoto H, Tennis M, Locascio JJ, Hyman BT, Growdon JH, Irizarry MC. Age but not diagnosis is the main predictor of plasma amyloid beta-protein levels. Arch Neurol 60(7): 958-64. (2003)
[52]
Irizarry MC. Biomarkers of Alzheimer disease in plasma. NeuroRx: the journal of the American Society for Experimental NeuroTherapeutics 1(2): 226-34. (2004)
[53]
Rosenberg RN, Baskin F, Fosmire JA, Risser R, Adams P, Svetlik D, et al. Altered amyloid protein processing in platelets of patients with Alzheimer disease. Arch Neurol 54(2): 139-44. (1997)
[54]
Padovani A, Borroni B, Colciaghi F, Pettenati C, Cottini E, Agosti C, et al. Abnormalities in the pattern of platelet amyloid precursor protein forms in patients with mild cognitive impairment and Alzheimer disease. Arch Neurol 59(1): 71-5. (2002)
[55]
Baskin F, Rosenberg RN, Iyer L, Hynan L, Cullum CM. Platelet APP isoform ratios correlate with declining cognition in AD. Neurology 54(10): 1907-9. (2000)
[56]
Borroni B, Colciaghi F, Pastorino L, Pettenati C, Cottini E, Rozzini L, et al. Amyloid precursor protein in platelets of patients with Alzheimer disease: effect of acetylcholinesterase inhibitor treatment. Arch Neurol 58(3): 442-6. (2001)
[57]
Borroni B, Colciaghi F, Caltagirone C, Rozzini L, Broglio L, Cattabeni F, et al. Platelet amyloid precursor protein abnormalities in mild cognitive impairment predict conversion to dementia of Alzheimer type: a 2-year follow-up study. Arch Neurol 60(12): 1740-4. (2003)
[58]
Baskin F, Rosenberg RN, Fang X, Hynan LS, Moore CB, Weiner M, et al. Correlation of statin-increased platelet APP ratios and reduced blood lipids in AD patients. Neurology 60(12): 2006-7. (2003) E
[59]
Andreasson U, Blennow K, Zetterberg H. Update on ultrasensitive technologies to facilitate research on blood biomarkers for central nervous system disorders. Alzheimers Dement (Amst) 3: 98-102. (2016)
[60]
Lue LF, Guerra A, Walker DG. Amyloid beta and tau as alzheimer’s disease blood biomarkers: promise from new technologies. Neurol Ther 6(1): 25-36. (2017)
[61]
Janelidze S, Stomrud E, Palmqvist S, Zetterberg H, van Westen D, Jeromin A, et al. Plasma beta-amyloid in Alzheimer’s disease and vascular disease. Sci Rep 6: 26801. (2016)
[62]
Tatebe H, Kasai T, Ohmichi T, Kishi Y, Kakeya T, Waragai M, 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 12(1): 63. (2017)
[63]
Yang CC, Chiu MJ, Chen TF, Chang HL, Liu BH, Yang SY. Assay of plasma phosphorylated tau protein (threonine 181) and total tau protein in early-stage Alzheimer’s disease. J Alzheimers Dis 61(4): 1323-32. (2018)
[64]
Winston CN, Goetzl EJ, Akers JC, Carter BS, Rockenstein EM, Galasko D, et al. Prediction of conversion from mild cognitive impairment to dementia with neuronally derived blood exosome protein profile. Alzheimers Dement (Amst) 3: 63-72. (2016)
[65]
Lee M, Guo JP, Kennedy K, McGeer EG, McGeer PL. A Method for Diagnosing Alzheimer’s Disease Based on Salivary Amyloid-beta Protein 42 Levels. J Alzheimers Dis 55(3): 1175-82. (2017)
[66]
Martinez B, Peplow PV. MicroRNAs as diagnostic and therapeutic tools for Alzheimer’s disease: advances and limitations. Neural Regen Res 14(2): 242-55. (2019)
[67]
Geekiyanage H, Chan C. MicroRNA-137/181c regulates serine palmitoyltransferase and in turn amyloid beta, novel targets in sporadic Alzheimer’s disease. J Neurosci 31(41): 14820-30. (2011)
[68]
Hebert SS, Horre K, Nicolai L, Papadopoulou AS, Mandemakers W, Silahtaroglu AN, et al. Loss of microRNA cluster miR-29a/b-1 in sporadic Alzheimer’s disease correlates with increased BACE1/beta-secretase expression. Proc Natl Acad Sci USA 105(17): 6415-20. (2008)
[69]
Leidinger P, Backes C, Deutscher S, Schmitt K, Mueller SC, Frese K, et al. A blood based 12-miRNA signature of Alzheimer disease patients. Genome Biol 14(7): R78. (2013)
[70]
Nagaraj S, Laskowska-Kaszub K, Debski KJ, Wojsiat J, Dabrowski M, Gabryelewicz T, et al. Profile of 6 microRNA in blood plasma distinguish early stage Alzheimer’s disease patients from non-demented subjects. Oncotarget 8(10): 16122-43. (2017)
[71]
Cosin-Tomas M, Alvarez-Lopez MJ, Companys-Alemany J, Kaliman P, Gonzalez-Castillo C, Ortuno-Sahagun D, et al. temporal integrative analysis of mrna and micrornas expression profiles and epigenetic alterations in female samp8, a model of age-related cognitive decline. Front Genet 9: 596. (2018)
[72]
Chang WS, Wang YH, Zhu XT, Wu CJ. Genome-wide profiling of miRNA and mRNA expression in Alzheimer’s disease. Med Sci 23: 2721-31. (2017)
[73]
Maldonado-Lasuncion I, Atienza M, Sanchez-Espinosa MP, Cantero JL. Aging-related changes in cognition and cortical integrity are associated with serum expression of candidate MicroRNAs for Alzheimer disease. Cereb Cortex (2018) Epub 2018/12/28..
[http://dx.doi.org/10.1093/cercor/bhy323]
[http://dx.doi.org/10.1093/cercor/bhy323]
[74]
Zarrouk A, Debbabi M, Bezine M, Karym EM, Badreddine A, Rouaud O, et al. Lipid Biomarkers in Alzheimer’s Disease. Curr Alzheimer Res 15(4): 303-12. (2018)
[75]
Zverova M, Kitzlerova E, Fisar Z, Jirak R, Hroudova J, Benakova H, et al. Interplay between the APOE genotype and possible plasma biomarkers in alzheimer’s disease. Curr Alzheimer Res 15(10): 938-50. (2018)
[76]
Neumann K, Farias G, Slachevsky A, Perez P, Maccioni RB. Human platelets tau: a potential peripheral marker for Alzheimer’s disease. J Alzheimers Dis 25(1): 103-9. (2011)
[77]
Guzman-Martinez L, Farias GA, Maccioni RB. Emerging noninvasive biomarkers for early detection of Alzheimer’s disease. Arch Med Res 43(8): 663-6. (2012)
[78]
Slachevsky A, Guzman-Martinez L, Delgado C, Reyes P, Farias GA, Munoz-Neira C, et al. Tau platelets correlate with regional brain atrophy in patients with Alzheimer’s disease. J Alzheimers Dis 55(4): 1595-603. (2017)
[79]
Morales I, Farias G, Maccioni RB. Neuroimmunomodulation in the pathogenesis of Alzheimer’s disease. Neuroimmunomodulation 17(3): 202-4. (2010)
[80]
Morales I, Guzman-Martinez L, Cerda-Troncoso C, Farias GA, Maccioni RB. Neuroinflammation in the pathogenesis of Alzheimer’s disease. A rational framework for the search of novel therapeutic approaches. Front Cell Neurosci 8: 112. (2014)
[81]
Hirsch EC, Vyas S, Hunot S. Neuroinflammation in Parkinson’s disease. Parkinsonism Relat Disord 18(Suppl. 1): S210-2. (2012)
[82]
Meraz-Rios MA, Toral-Rios D, Franco-Bocanegra D, Villeda-Hernandez J, Campos-Pena V. Inflammatory process in Alzheimer’s Disease. Front Integr Nuerosci 7: 59. (2013)
[83]
Adunsky A, Baram D, Hershkowitz M, Mekori YA. Increased cytosolic free calcium in lymphocytes of Alzheimer patients. J Neuroimmunol 33(2): 167-72. (1991)
[84]
Peskind ER, Griffin WS, Akama KT, Raskind MA, Van Eldik LJ. Cerebrospinal fluid S100B is elevated in the earlier stages of Alzheimer’s disease. Neurochem Int 39(5-6): 409-13. (2001)
[85]
Mrak RE, Griffin WS. Potential inflammatory biomarkers in Alzheimer’s disease. J Alzheimers Dis 8(4): 369-75. (2005)
[86]
Hampel H, Schoen D, Schwarz MJ, Kotter HU, Schneider C, Sunderland T, et al. Interleukin-6 is not altered in cerebrospinal fluid of first-degree relatives and patients with Alzheimer’s disease. Neurosci Lett 1997; 228(3): 143-6. Epub 1997/06/13.
[87]
Marz P, Heese K, Hock C, Golombowski S, Muller-Spahn F, Rose-John S, et al. Interleukin-6 (IL-6) and soluble forms of IL-6 receptors are not altered in cerebrospinal fluid of Alzheimer’s disease patients. Neurosci Lett 239(1): 29-32. (1997)
[88]
Wada-Isoe K, Wakutani Y, Urakami K, Nakashima K. Elevated interleukin-6 levels in cerebrospinal fluid of vascular dementia patients. Acta Neurol Scand 110(2): 124-7. (2004)
[89]
Maes M, DeVos N, Wauters A, Demedts P, Maurits VW, Neels H, et al. Inflammatory markers in younger vs elderly normal volunteers and in patients with Alzheimer’s disease. J Psychiatr Res 33(5): 397-405. (1999)
[90]
Lombardi VR, Garcia M, Rey L, Cacabelos R. Characterization of cytokine production, screening of lymphocyte subset patterns and in vitro apoptosis in healthy and Alzheimer’s Disease (AD) individuals. J Neuroimmunol 97(1-2): 163-71. (1999)
[91]
Rosenberg PB. Clinical aspects of inflammation in Alzheimer’s disease. Int Rev Psychiatry 17(6): 503-14. (2005)
[92]
Tarkowski E, Blennow K, Wallin A, Tarkowski A. Intracerebral production of tumor necrosis factor-alpha, a local neuroprotective agent, in Alzheimer disease and vascular dementia. J Clin Immunol 19(4): 223-30. (1999)
[93]
Engelborghs S, De Brabander M, De Cree J, D’Hooge R, Geerts H, Verhaegen H, et al. Unchanged levels of interleukins, neopterin, interferon-gamma and tumor necrosis factor-alpha in cerebrospinal fluid of patients with dementia of the Alzheimer type. Neurochem Int 34(6): 523-30. (1999)
[94]
Holmes C, Cunningham C, Zotova E, Culliford D, Perry VH. Proinflammatory cytokines, sickness behavior, and Alzheimer disease. Neurology 77(3): 212-8. (2011)
[95]
Gezen-Ak D, Dursun E, Hanagasi H, Bilgic B, Lohman E, Araz OS, et al. BDNF, TNFalpha, HSP90, CFH, and IL-10 serum levels in patients with early or late onset Alzheimer's disease or mild cognitive impairment. J Alzheimer's Dis 37(1): 185-95. (2013)
[96]
Ray S, Britschgi M, Herbert C, Takeda-Uchimura Y, Boxer A, Blennow K, et al. Classification and prediction of clinical Alzheimer’s diagnosis based on plasma signaling proteins. Nature medicine 13(11): 1359-62. (2007)
[97]
Doecke JD, Laws SM, Faux NG, Wilson W, Burnham SC, Lam CP, et al. Blood-based protein biomarkers for diagnosis of Alzheimer disease. Arch Neurol 69(10): 1318-25. (2012)
[98]
Nuzzo D, Picone P, Caruana L, Vasto S, Barera A, Caruso C, et al. Inflammatory mediators as biomarkers in brain disorders. Inflammation (3): 639-48. (2014)
[99]
Wei H, Zhu X, Li Y. Application value of serum biomarkers for choosing memantine therapy for moderate AD. J Neurol 265(8): 1844-9. (2018)
[100]
Femminella GD, Ninan S, Atkinson R, Fan Z, Brooks DJ, Edison P. Does microglial activation influence hippocampal volume and neuronal function in Alzheimer’s disease and Parkinson’s disease dementia? J Alzheimers Dis 51(4): 1275-89. (2016)
[101]
Tarasoff-Conway JM, Carare RO, Osorio RS, Glodzik L, Butler T, Fieremans E, et al. Clearance systems in the brain-implications for Alzheimer disease. Nat Rev Neurol 11(8): 457-70. (2015)
[102]
Jansen WJ, Ossenkoppele R, Knol DL, Tijms BM, Scheltens P, Verhey FR, et al. Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. JAMA 313(19): 1924-38. (2015)
[103]
Parent MJ, Zimmer ER, Shin M, Kang MS, Fonov VS, Mathieu A, et al. Multimodal imaging in rat model recapitulates alzheimer’s disease biomarkers abnormalities. J Neurosci 37(50): 12263-71. (2017)
[104]
Ruan Q, D’Onofrio G, Sancarlo D, Bao Z, Greco A, Yu Z. Potential neuroimaging biomarkers of pathologic brain changes in Mild Cognitive Impairment and Alzheimer’s disease: a systematic review. BMC Geriatr 16: 104. (2016)
[106]
Nettiksimmons J, Harvey D, Brewer J, Carmichael O, DeCarli C, Jack CR Jr, et al. Subtypes based on cerebrospinal fluid and magnetic resonance imaging markers in normal elderly predict cognitive decline. Neurobiol Aging 31(8): 1419-28. (2010)
[107]
Mosconi L. Glucose metabolism in normal aging and Alzheimer's disease: methodological and physiological considerations for PET studies. Clin Trans Imag 1(4) (2013)
[108]
Perani D, Schillaci O, Padovani A, Nobili FM, Iaccarino L, Della Rosa PA, et al. A survey of FDG- and amyloid-PET imaging in dementia and GRADE analysis. BioMed Res Int 2014785039 (2014)
[109]
Siemers ER, Sundell KL, Carlson C, Case M, Sethuraman G, Liu-Seifert H, et al. Phase 3 solanezumab trials: Secondary outcomes in mild Alzheimer’s disease patients. Alzheimers Dement 12(2): 110-20. (2016)
[110]
Rowe CC, Villemagne VL. Amyloid imaging with PET in early Alzheimer disease diagnosis. The Medical Clinics of North Am 97(3): 377-98. (2013)
[111]
Johnson KA, Minoshima S, Bohnen NI, Donohoe KJ, Foster NL, Herscovitch P, et al. Update on appropriate use criteria for amyloid PET imaging: dementia experts, mild cognitive impairment, and education. Amyloid Imaging Task Force of the Alzheimer’s Association and Society for Nuclear Medicine and Molecular Imaging. Alzheimers Dement 9(4): e106-9. (2013)
[112]
Frederiksen KS, Hasselbalch SG, Hejl AM, Law I, Hojgaard L, Waldemar G. Added diagnostic value of (11)C-PiB-PET in memory clinic patients with uncertain diagnosis. Dement Geriatr Cogn Disord 2(1): 610-21. (2012)
[113]
Salmon E, Bernard Ir C, Hustinx R. Pitfalls and limitations of PET/CT in brain imaging. Semin Nucl Med 45(6): 541-51. (2015)
[114]
Dubois B, Feldman HH, Jacova C, Hampel H, Molinuevo JL, Blennow K, et al. Advancing research diagnostic criteria for Alzheimer’s disease: the IWG-2 criteria. Lancet Neurol 13(6): 614-29. (2014)
[115]
Rojo LE, Alzate-Morales J, Saavedra IN, Davies P, Maccioni RB. Selective interaction of lansoprazole and astemizole with tau polymers: potential new clinical use in diagnosis of Alzheimer’s disease. J Alzheimers Dis 19(2): 573-89. (2010)
[116]
Rojo LE, Gaspar PA, Maccioni RB. Molecular targets in the rational design of AD specific PET tracers: tau or amyloid aggregates? Curr Alzheimer Res 8(6): 652-8. (2011)
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