Biomarkers for Alzheimer's disease

Expert Review of Neurotherapeutics

Volumn 7, Issue 8, 2007, Pages 1021-1028

  Sonnen, Joshua A ^b   Keene, C Dirk ^a   Montine, Kathleen S ^b   Li, Ge ^c   Peskind, Elaine R ^d   Zhang, Jing ^b   Montine, Thomas J ^a  

^a UNIVERSITY OF WASHINGTON   (United States)

^b UNIVERSITY OF WASHINGTON   (United States)

^c UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE   (United States)

^d VA PUGET SOUND HEALTH CARE SYSTEM   (United States)

Author keywords

Alzheimer's disease; Biomarkers; Dementia; Latency; Neuroimaging; Prodrome

Indexed keywords

ALPHA TOCOPHEROL; AMYLOID BETA PROTEIN[1-42]; ASCORBIC ACID; BIOLOGICAL MARKER; TAU PROTEIN;

ALZHEIMER DISEASE; CEREBROSPINAL FLUID; DEMENTIA; DISEASE COURSE; GENETIC RISK; HUMAN; LATENT PERIOD; MEDICAL DECISION MAKING; MONOTHERAPY; NEUROIMAGING; PATHOGENESIS; PLASMA; REVIEW; RISK BENEFIT ANALYSIS; SERUM; STANDARDIZATION; URINE; VALIDATION STUDY; VITAMIN SUPPLEMENTATION;

ALZHEIMER DISEASE; ANIMALS; BIOLOGICAL MARKERS; HUMANS;

EID: 34548050672     PISSN: 14737175     EISSN: 17448360     Source Type: Journal    
DOI: 10.1586/14737175.7.8.1021     Document Type: Review

References (107)

1. Tsuang DW, Bird TD. Genetics of dementia. Med. Clin. North Am. 86(3), 591-614 (2002).
2. OTA USC. US Congress OTA. Losing a million minds: confronting the tragedy of Alzheimer's disease and other dementias. Government Printing Office, Washington, DC, USA (1987).
3. Evans DA. Estimated prevalence of Alzheimer's disease in the United States. Milbank Q. 68, 267-289 (1990).
4. Saunders AM, Strittmatter WJ, Schmechel D et al. Association of apolipoprotein E allele ε4 with late-onset familial and sporadic Alzheimer's disease. Neurology 43(8), 1467-1472 (1993).
5. Ernst RL, Hay JW. The US economic and social costs of Alzheimer's disease revisited. Am. J. Public Health 84(8), 1261-1264 (1994).
6. McCormick WC, Hardy J, Kukull WA et al. Healthcare utilization and costs in managed care patients with Alzheimer's disease during the last few years of life. J. Am. Geriatr. Soc. 49(9), 1156-1160 (2001).
7. Welch HG, Walsh JS, Larson EB. The cost of institutional care in Alzheimer's disease: nursing home and hospital use in a prospective cohort. J. Am. Geriatr. Soc. 40(3), 221-224 (1992).
8. Brookmeyer R, Gray S, Kawas C. Projections of Alzheimer's disease in the United States and the public health impact of delaying disease onset. Am. J. Public Health 88(9), 1337-1342 (1998).
9. Katzman R. The prevalence and malignancy of Alzheimer disease. A major killer. Arch. Neurol. 33(4), 217-218 (1976). • Classic paper.
10. Petersen R, Doody R, Kurz A et al. Current concepts in mild cognitive impairment. Arch. Neurol. 58, 1985-1992 (2001).
11. Arriagada PV, Marzloff K, Hyma BT. Distribution of Alzheimer-type pathologic changes in nondemented elderly individuals matches the pattern in Alzheimer's disease. Neurology 42(9), 1681-1688 (1992).
12. Berg L, McKeel DW, Miller JP, Baty J, Morris JC. Neuropathological indexes of Alzheimer's disease in demented and nondemented persons aged 80 years and older. Arch. Neurol. 50(4), 349-358 (1993).
13. Crystal HA, Dickson DW, Sliwinski MJ et al. Pathological markers associated with normal aging and dementia in the elderly. Ann. Neurol. 34(4), 566-573 (1993).
14. Davis DG, Schmitt FA, Wekstein DR, Markesbery W. Alzheimer neuropathological alterations in aged cognitively normal subjects. J. Neuropathol. Exp. Neurol. 58(4), 376-388 (1999).
15. Green MS, Kaye JA, Ball MJ. The Oregon brain aging study: neuropathology accompanying health aging in the oldest old. Neurology 54(1), 105-113 (2000).
16. Haroutunian V, Purohit DP, Perl DP et al. Neurofibrillary tangles in nondemented elderly subjects and mild Alzheimer disease. Arch. Neurol. 56(6), 713-718 (1999).
17. Hulette CM, Welsh-Bohmer KA, Murray MG, Saunders AM, Mash DC, McIntyre LM. Neuropathological and neuropsychological changes in "normal" aging: evidence for preclinical Alzheimer disease in cognitively normal individuals. J. Neuropathol. Exp. Neurol. 57(12), 1168-1174 (1998).
18. Morris JC, Price AL. Pathologic correlates of nondemented aging, mild cognitive impairment, and early-stage Alzheimer's disease. J. Mol. Neurosci. 17(2), 101-118 (2001).
19. Price JL, Morris JC. Tangles and plaques in nondemented aging and "preclinical" Alzheimer's disease. Ann. Neurol. 45(3), 358-368 (1999).
20. Price JL, Davis PB, Morris JC, White DL. The distribution of tangles, plaques and related immunohistochemical markers in healthy aging and Alzheimer's disease. Neurobiol. Aging 12(4), 295-312 (1991).
21. Riley KP, Snowdon DA, Markesbery WR. Alzheimer's neurofibrillary pathology and the spectrum of cognitive function: findings from the nun study. Ann. Neurol. 51(5), 567-577 (2002).
22. Schmitt FA, Davis DG, Wekstein DR, Smith CD, Ashford JW, Markesbery WR. "Preclinical" AD revisited. Neuropathology of cognitively normal older adults. Neurology 55, 370-376 (2000).
23. Xuereb JH, Brayne C, Dufouil C et al. Neuropathological findings in the very old. Results from the first 101 brains of a population-based longitudinal study of dementing disorders. Ann. NY Acad. Sci. 903, 490-496 (2000).
24. Blennow K, de Leon MJ, Zetterberg H. Alzheimer's disease. Lancet 368(9533), 387-403 (2006). • Excellent review.
25. Fagan AM, Csernansky CA, Morris JC, Holtzman DM. The search for antecedent biomarkers of Alzheimer's disease. J. Alzheimers Dis. 8(4), 347-358 (2005).
26. Mintun MA, Larossa GN, Sheline Y et al. 11CPIB in a nondemented population: potential antecedent marker of Alzheimer disease. Neurology 67(3), 446-452 (2006).
27. Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297, 353-356 (2002).
28. Martin BK, Meinert CL, Breitner JC. Double placebo design in a prevention trial for Alzheimer's disease. Control. Clin. Trials 23(1), 93-99 (2002).
29. Petersen RC. Mild cognitive impairment clinical trials. Nat. Rev. Drug Discov. 2(8), 646-653 (2003). • Excellent review.
30. Henderson VW. Estrogen-containing hormone therapy and Alzheimer's disease risk: understanding discrepant inferences from observational and experimental research. Neuroscience 138(3), 1031-1039 (2006).
31. Pasinetti GM. From epidemiology to therapeutic trials with anti-inflammatory drugs in Alzheimer's disease: the role of NSAIDs and cyclooxygenase in β-amyloidosis and clinical dementia. J. Alzheimers Dis. 4(5), 435-445 (2002).
32. Hansen L, Salmon D, Galasko D et al. The Lewy body variant of Alzheimer's disease: a clinical and pathologic entity. Neurology 40(1), 1-8 (1990).
33. White L, Petrovitch H, Hardman J et al. Cerebrovascular pathology and dementia in autopsied Honolulu-Asia Aging Study participants. Ann. NY Acad. Sci. 977, 9-23 (2002).
34. Petrovitch H, White LR, Izmirilian G et al. Midlife blood pressure and neuritic plaques, neurofibrillary tangles, and brain weight at death: the HAAS. Honolulu-Asia Aging Study. Neurobiol. Aging 21, 57-62 (2002).
35. de Leon MJ, Mosconi L, Blennow K et al. Imaging and CSF studies in the preclinical diagnosis of Alzheimer's disease. Ann. NY Acad. Sci. 1097, 114-145 (2007).
36. Thal LJ, Kantarci K, Reiman EM et al. The role of biomarkers in clinical trials for Alzheimer disease. Alzheimer Dis. Assoc. Disord. 20(1), 6-15 (2006).
37. Andreasen N, Minthon L, Clarberg A et al. Sensitivity, specificity, and stability of CSF-tau in AD in a community-based patient sample. Neurology 53(7), 1488-1494 (1999).
38. Andreasen N, Vanmechelen E, Van de Voorde A et al. Cerebrospinal fluid tau protein as a biochemical marker for Alzheimer's disease: a community based follow up study. J. Neurol. Neurosurg. Psychiatry 64(3), 298-305 (1998).
39. Herukka SK, Helisalmi S, Hallikainen M, Tervo S, Soininen H, Pirttila T. CSF Aβ42, tau and phosphorylated tau, APOE ε4 allele and MCI type in progressive MCI. Neurobiol. Aging 28(4), 507-514 (2007).
40. Bibl M, Mollenhauer B, Esselmann H et al. CSF amyloid-β- peptides in Alzheimer's disease, dementia with Lewy bodies and Parkinson's disease dementia. Brain 129(Pt 5), 1177-1187 (2006).
41. Buerger K, Ewers M, Pirttila T et al. CSF phosphorylated tau protein correlates with neocortical neurofibrillary pathology in Alzheimer's disease. Brain 129(Pt 11), 3035-3041 (2006).
42. Hansson O, Zetterberg H, Buchhave P et al. Prediction of Alzheimer's disease using the CSF Aβ42/Aβ40 ratio in patients with mild cognitive impairment. Dement. Geriatr. Cogn. Disord. 23(5), 316-320 (2007).
43. de Jong D, Jansen R, Kremer BPH, Verbeek MM. Cerebrospinal fluid amyloid β(42)/phosphorylated tau ratio discriminates between Alzheimer's disease and vascular dementia. J. Gerontol. A Biol. Sci. Med. Sci. 61(7), 755-758 (2006).
44. Gurol ME, Irizarry MC, Smith EE et al. Plasma β-amyloid and white matter lesions in AD, MCI, and cerebral amyloid angiopathy. Neurology 66(1), 23-29 (2006).
45. Engelborghs S, De Vreese K, Van de Casteele T et al. Diagnostic performance of a CSF-biomarker panel in autopsy-confirmed dementia. Neurobiol. Aging (2007) (Epub ahead of print).
46. Fagan AM, Mintun MA, Mach RH et al. Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Aβ42 in humans. Ann. Neurol. 59(3), 512-519 (2006). • Compares PET imaging and cerebrospinal fluid (CSF) biomarkers.
47. Armon C, Evans RW. Addendum to assessment: prevention of post-lumbar puncture headaches: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 65(4), 510-512 (2005).
48. Peskind ER, Riekse R, Quinn JF et al. Safety and acceptability of the research lumbar puncture. Alzheimer Dis. Assoc. Disord. 19(4), 220-225 (2005).
49. Blennow K, Wallin A, Hager O. Low frequency of post-lumbar puncture headache in demented patients. Acta Neurol. Scand. 88(3), 221-223 (1993).
50. Quinn JF, Montine KS, Moore M, Morrow JD, Kaye JA, Montine TJ. Suppression of longitudinal increase in CSF F2-isoprostanes in Alzheimer's disease. J. Alzheimers Dis. 6(1), 93-97 (2004). • Longitudinal changes in CSF F2-isoprostanes in response to antioxidants.
51. Sunderland T, Linker G, Mirza N et al. Decreased β-amyloid1-42 and increased tau levels in cerebrospinal fluid of patients with Alzheimer disease. JAMA 289, 2094-2103 (2003).
52. Blennow K. Cerebrospinal fluid protein biomarkers for Alzheimer's disease. NeuroRx 1(2), 213-225 (2004).
53. Otto M, Wiltfang J, Cepek L et al. Tau protein and 14-3-3 protein in the differential diagnosis of Creutzfeldt-Jakob disease. Neurology 58(2), 192-197 (2002).
54. Galasko D, Chang L, Motter R et al. High cerebrospinal fluid tau and low amyloid β42 levels in the clinical diagnosis of Alzheimer's disease and relation to apolipoprotein E genotype. Arch. Neurol. 55, 937-945 (1998).
55. Hulstaert F, Blennow K, Ivanoiu A et al. Improved discrimination of AD patients using β-amyloid(1-42) and tau levels in CSF. Neurology 52(8), 1555-1562 (1999).
56. Blennow K, Vanmechelen E. CSF markers for pathogenic processes in Alzheimer's disease: diagnostic implications and use in clinical neurochemistry. Brain Res. Bull. 61, 235-242 (2003).
57. Hampel H, Teipel SJ, Fuchsberger T et al. Value of CSF β-amyloid1-42 and tau as predictors of Alzheimer's disease in patients with mild cognitive impairment. Mol. Psychiatry 9(7), 705-710 (2004).
58. Moonis M, Swearer JM, Dayaw MP et al. Familial Alzheimer disease: decreases in CSF Aβ42 levels precede cognitive decline. Neurology 65(2), 323-325 (2005).
59. Fagan AM, Roe CM, Xiong C, Mintun MA, Morris JC, Holtzman DM. Cerebrospinal fluid tau/β-amyloid42 ratio as a prediction of cognitive decline in nondemented older adults. Arch. Neurol. 64(3), 343-349 (2007).
60. Li G, Sokal I, Quinn JF et al. CSF tau/Ab42 ratio for increased risk of mild cognitive impairment: a follow up study. (2007) (In press).
61. Bateman RJ, Munsell LY, Morris JC, Swarm R, Yarasheski KE, Holtzman DM. Human amyloid-β synthesis and clearance rates as measured in cerebrospinal fluid in vivo. Nat. Med. 12(7), 856-861 (2006). • Ingenious new approach.
62. de Leon MJ, DeSanti S, Zinkowski R et al. Longitudinal CSF and MRI biomarkers improve the diagnosis of mild cognitive impairment. Neurobiol. Aging 27(3), 394-401 (2006).
63. de Leon MJ, Segal S, Tarshish CY et al. Longitudinal cerebrospinal fluid tau load increases in mild cognitive impairment. Neurosci. Lett. 333(3), 183-186 (2002).
64. Blomberg M, Jensen M, Basun H, Lannfelt L, Wahlund LO. Increasing cerebrospinal fluid tau levels in a subgroup of Alzheimer patients with apolipoprotein E allele ε4 during 14 months follow-up. Neurosci. Lett. 214(2-3), 163-166 (1996).
65. Tapiola T, Pirttila T, Mikkonen M et al. Three-year follow-up of cerebrospinal fluid tau, β-amyloid 42 and 40 concentrations in Alzheimer's disease. Neurosci. Lett. 280(2), 119-122 (2000).
66. Kanai M, Shizuka M, Urakami K et al. Apolipoprotein E4 accelerates dementia and increases cerebrospinal fluid tau levels in Alzheimer's disease. Neurosci. Lett. 267(1), 65-68 (1999).
67. Huey ED, Mirza N, Putnam KT et al. Stability of CSF β-amyloid(1-42) and tau levels by APOE genotype in Alzheimer patients. Dement. Geriatr. Cogn. Disord. 22(1), 48-53 (2006).
68. Andreasen N, Hesse C, Davidsson P et al. Cerebrospinal fluid β-amyloid(1-42) in Alzheimer disease: differences between early- and late-onset Alzheimer disease and stability during the course of disease. Arch. Neurol. 56(6), 673-680 (1999).
69. Hampel H, Buerger K, Kohnken R et al. Tracking of Alzheimer's disease progression with cerebrospinal fluid tau protein phosphorylated at threonine 231. Ann. Neurol. 49(4), 545-546 (2001).
70. Hardy J. Amyloid, the presenilins and Alzheimer's disease. Trends Neurosci. 20(4), 15415-15419 (1997).
71. Hutton M, Hardy J. The presenilins and Alzheimer's disease. Hum. Mol. Genet. 6(10), 1639-1646 (1997).
72. Mehta PD, Capone G, Jewell A, Freedland RL. Increased amyloid-β protein levels in children and adolescents with Down syndrome. J. Neurol. Sci. 254(1-2), 22-27 (2007).
73. Ertekin-Taner N, Graff-Radford N, Younkin LH et al. Heritability of plasma amyloid-β in typical late-onset Alzheimer's disease pedigrees. Genet. Epidemiol. 21(1), 19-30 (2001).
74. Mayeux R, Honig LS, Tang MX et al. Plasma Aβ40 and Aβ42 and Alzheimer's disease: relation to age, mortality, and risk. Neurology 61(9), 1185-1190 (2003).
75. Pomara N, Willoughby LM, Sidtis JJ, Mehta PD. Selective reductions in plasma Aβ 1-42 in healthy elderly subjects during longitudinal follow-up: a preliminary report. Am. J. Geriatr. Psychiatry 13(10), 914-917 (2005).
76. van Oijen M, Hofman A, Soares HD, Koudstaal PJ, Breteler MM. Plasma Aβ(1-40) and Aβ(1-42) and the risk of dementia: a prospective case-cohort study. Lancet Neurol. 5(8), 655-660 (2006). • Description of a potential plasma biomarker.
77. Graff-Radford NR, Crook JE, Lucas J et al. Association of low plasma Aβ42/Aβ40 ratios with increased imminent risk for mild cognitive impairment and Alzheimer disease. Arch. Neurol. 64(3), 354-362 (2007).
78. Markesbery WR. Oxidative stress hypothesis in Alzheimer's disease. Free Radic. Biol. Med. 23, 134-147 (1997).
79. Montine TJ, Neely MD, Quinn JF et al. Lipid peroxidation in aging brain and Alzheimer's disease. Free Radic. Biol. Med. 33(5), 620-626 (2002).
80. Porter NA, Caldwell SE, Mills KA. Mechanisms of free radical oxidation of unsaturated lipids. Lipids 30, 277-290 (1995).
81. Morrow JD, Hill KE, Burk RF, Nammour TM, Badr KF, Roberts LJ. A series of prostaglandin-like compounds produced in vivo in humans by a non-cyclooxygenase, free radical catalyzed mechanism. Proc. Natl Acad. Sci. USA 87, 9383-9387 (1990).
82. Feillet-Coudray C, Tourtauchaux R, Niculescu M et al. Plasma levels of 8-εPGF2α, an in vivo marker of oxidative stress, are not affected by aging or Alzheimer's disease. Free Rad. Biol. Med. 2, 463-469 (1999).
83. Pratico D, Barry OP, Lawson JA et al. IPF2α-I - an index of lipid peroxidation in humans. Proc. Natl Acad. Sci. USA 95, 3449-3454 (1998).
84. Bohnstedt KC, Karlberg B, Wahlund L, Jonhagen ME, Basun H, Schmidt S. Determination of isoprostanes in urine samples from Alzheimer patients using porous graphitic carbon liquid chromatography-tandem mass spectrometry. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 796(1), 11-19 (2003).
85. Montine TJ, Beal MF, Cudkowicz ME et al. Increased cerebrospinal fluid F2-isoprostane concentration in probable Alzheimer's disease. Neurology 52, 562-565 (1999).
86. Montine TJ, Beal MF, Robertson D et al. Cerebrospinal fluid F2-isoprostanes are elevated in Huntington's disease. Neurology 52, 1104-1105 (1999).
87. Montine TJ, Sidell KS, Crews BC et al. Elevated cerebrospinal fluid prostaglandin E2 levels in patients with probable Alzheimer's disease. Neurology 53, 1495-1498 (1999).
88. Montine TJ, Kaye JA, Montine KS, McFarland L, Morrow JD, Quinn JF. Cerebrospinal fluid Aβ42, tau, and f2-isoprostane concentrations in patients with Alzheimer disease, other dementias, and in age-matched controls. Arch. Pathol. Lab. Med. 125(4), 510-512 (2001).
89. Pratico D, Clack CM, Lee VMY, Trojanowski JQ, Rokach J, FitzGerald G. Increased 8,12-iso-iPF2a-IV in Alzheimer's disease: correlation of a noninvasive index of lipid peroxidation with disease severity. Ann. Neurol. 48, 809-812 (2000).
90. Pratico D, Clark CM, Liun F, Rokach J, Lee VY, Trojanowski JQ. Increase of brain oxidative stress in mild cognitive impairment: a possible predictor of Alzheimer disease. Arch. Neurol. 59(6), 972-976 (2002).
91. Zandi PP, Anthony JC, Khachaturian AS et al. Reduced risk of Alzheimer disease in users of antioxidant vitamin supplements: the Cache County Study. Arch. Neurol. 61, 82-88 (2004).
92. Riekse RG, Li G, Petrie EC et al. Effect of statins on Alzheimer's disease biomarkers in cerebrospinal fluid. J. Alzheimers Dis. 10(4), 399-406 (2006).
93. Fishel MA, Watson GS, Montine TJ et al. Hyperinsulinemia provokes synchronous increases in central inflammation and β-amyloid in normal adults. Arch. Neurol. 62(10), 1539-1544 (2005).
94. Waddington E, Croft K, Clarnette R, Mori T, Martins R. Plasma F2-isoprostane levels are increased in Alzheimer's disease: evidence of increased oxidative stress in vivo. Alzheimers Rep. 2, 277-282 (1999).
95. Tuppo EE, Forman LJ, Spur BW, Chan-Ting RE, Chopra A, Cavalieri TA. Sign of lipid peroxidation as measured in the urine of patients with probable Alzheimer's disease. Brain Res. Bull. 54, 565-568 (2001).
96. Montine TJ, Quinn JF, Milatovic D et al. Peripheral F2-isoprostanes and F4-neuroprostanes are not increased in Alzheimer's disease. Ann. Neurol. 52(2), 175-179 (2002).
97. Montine TJ, Shinobu L, Montine KS et al. No difference in plasma or urine F2-isoprostanes among patients with Huntington's disease or Alzheimer's disease, and controls. Ann. Neurol. 48, 950 (2000).
98. Puchades M, Hansson SF, Nilsson CL, Andreasen N, Blennow K, Davidsson P. Proteomic studies of potential cerebrospinal fluid protein markers for Alzheimer's disease. Brain Res. Mol. Brain Res. 118(1-2), 140-146 (2003).
99. Zhang J, Goodlett DR, Quinn JF et al. Quantitative proteomics of cerebrospinal fluid from patients with Alzheimer disease. J. Alzheimers Dis. 7(2), 125-133 (2005).
100. Hu Y, Malone JP, Fagan AM, Townsend RR, Holtzman DM. Comparative proteomic analysis of intra- and interindividual variation in human cerebrospinal fluid. Mol. Cell. Proteomics 4(12), 2000-2009 (2005).
101. Castano EM, Roher AE, Esh CL, Kokjohn TA, Beach T. Comparative proteomics of cerebrospinal fluid in neuropathologically-confirmed Alzheimer's disease and non-demented elderly subjects. Neurol. Res. 28(2), 155-163 (2006).
102. Abdi F, Quinn JF, Jankovic J et al. Detection of biomarkers with a multiplex quantitative proteomic platform in cerebrospinal fluid of patients with neurodegenerative disorders. J. Alzheimers Dis. 9(3), 293-348 (2006).
103. Han X, Gross RW. Global analyses of cellular lipidomes directly from crude extracts of biological samples by ESI mass spectrometry: a bridge to lipidomics. J. Lipid Res. 44(6), 1071-1079 (2003).
104. Iqbal K, Flory M, Khatoon S et al. Subgroups of Alzheimer's disease based on cerebrospinal fluid molecular markers. Ann. Neurol. 58(5), 748-757 (2005).
105. Okamura N, Arai H, Maruyama M et al. Combined analysis of CSF Tau levels and [123I]Iodoamphetamine SPECT in mild cognitive impairment: implications for a novel predictor of Alzheimer's disease. Am. J. Psychiatry 159(3), 474-476 (2002).
106. Pijnenburg YA, Schoonenboom SN, Barkhof F et al. CSF biomarkers in frontotemporal lobar degeneration: relations with clinical characteristics, apolipoprotein E genotype, and neuroimaging. J. Neurol. Neurosurg. Psychiatry 77(2), 246-248 (2006).
107. Borroni B, Perani D, Broli M et al. Pre-clinical diagnosis of Alzheimer disease combining platelet amyloid precursor protein ratio and rCBF spect analysis. J. Neurol. 252(11), 1359-1362 (2005).