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Taking the Next Steps in the Diagnosis of Alzheimer's Disease: The Use of Biomarkers

  • Steven T. DeKosky

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Alzheimer's disease (AD) is a progressive disorder in which neurodegeneration begins decades before clinical symptoms appear. Detecting AD during this preclinical phase presents both the enormous challenge of identifying at-risk patients prior to symptom onset and the potential reward of treating patients early enough to prevent or slow disease progression. Given that a 5-year delay in the onset of the clinical manifestations of AD could result in almost a 50% reduction in disease prevalence, early detection of AD is a major focus of clinical research. Several objective, measurable indicators of preclinical and clinical characteristics of AD are currently available or in development. These biomarkers are promising because they promote identification of individuals at risk for AD onset and disease progression; diagnostic accuracy and treatment during the early stages of AD; and the development of disease-modifying therapies that may potentially slow or prevent disease progression during the preclinical phase of AD.

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1.Blennow, K, de Leon, MJ, Zetterberg, H. Alzheimer's disease. Lancet. 2006;368(9533):387403.
2.DeKosky, ST. Pathology and pathways of Alzheimer's disease with an update on new developments in treatment. J Am Geriatr Soc. 2003;51(suppl):S314S320.
3.DeKosky, ST, Marek, K. Looking backward to move forward: early detection of neurodegenerative disorders. Science. 2003;302(5646):830834.
4.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. 1998;88(9):13371342.
5.Petersen, RC, Smith, GE, Waring, SC, Ivnik, RJ, Tangalos, EG, Kokmen, E. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol. 1999;56(3):303308.
6.Hardy, J, Selkoe, DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science. 2002;297(5580):353356.
7.Thal, DR, Rüb, U, Orantes, M, Braak, H. Phases of Aβ-deposition in the human brain and its relevance for the development of AD. Neurology. 2002;58(12):17911800.
8.Braak, H, Braak, E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82(4):239259.
9.Chan, D, Fox, NC, Jenkins, R, Scahill, RI, Crum, WR, Rossor, MN. Rates of global and regional cerebral atrophy in AD and frontotemporal dementia. Neurology. 2001;57(10):17561763.
10.Fox, NC, Schott, JM. Imaging cerebral atrophy: normal ageing to Alzheimer's disease. Lancet. 2004;363(9406):392394.
11.Jack, CR Jr, Shiung, MM, Weigand, SD, et al.Brain atrophy rates predict subseguent clinical conversion in normal elderly and amnestic MCI. Neurology. 2005;65(8):12271231.
12.Resnick, SM, Pham, DL, Kraut, MA, Zonderman, AB, Davatzikos, C. Longitudinal magnetic resonance imaging studies of older adults: a shrinking brain. J Neurosci. 2003;23(8):32953301.
13.Chan, D, Janssen, JC, Whitwell, JL, et al.Change in rates of cerebral atrophy over time in early-onset Alzheimer's disease: longitudinal MRI study. Lancet. 2003;362(9390):11211122.
14.Silbert, LC, Quinn, JF, Moore, MM, et al.Changes in premorbid brain volume predict Alzheimer's disease pathology. Neurology. 2003;61(4):487492.
15.Ridha, BH, Barnes, J, Bartlett, JW, et al.Tracking atrophy progression in familial Alzheimer's disease: a serial MRI study. Lancet Neurol. 2006;5(10):828834.
16.de Leon, MJ, George, AE, Stylopoulos, LA, Smith, G, Miller, DC. Early marker for Alzheimer's disease: the atrophic hippocampus. Lancet. 1989;2(8664):672673.
17.Rusinek, H, De Santi, S, Frid, D, et al.Regional brain atrophy rate predicts future cognitive decline: 6-year longitudinal MR imaging study of normal aging. Radiology. 2003;229(3):691696.
18.Fox, NC, Warrington, EK, Freeborough, PA, et al.Presymptomatic hippocampal atrophy in Alzheimer's disease. A longitudinal MRI study. Brain. 1996;119(pt. 6):20012007.
19.Jack, CR Jr, Petersen, RC, Xu, YC, et al.Prediction of AD with MRI-based hippocampal volume in mild cognitive impairment. Neurology. 1999;52(7):13971403.
20.Silverman, DH, Small, GW, Chang, CY, et al.Positron emission tomography in evaluation of dementia: regional brain metabolism and long-term outcome. JAMA. 2001;286(17):21202127.
21.De Santi, S, de Leon, MJ, Rusinek, H, et al.Hippocampal formation glucose metabolism and volume losses in MCI and AD. Neurobiol Aging. 2001;22(4):529539.
22.de Leon, MJ, Convit, A, Wolf, OT, et al.Prediction of cognitive decline in normal elderly subjects with 2-[(18)F]fluoro-2-deoxy-D-glucose/poitron-emission tomography (FDG/PET). Proc Natl Acad Sci U S A. 2001;98(19):1096610971.
23.Arnáiz, E, Jelic, V, Almkvist, O, et al.Impaired cerebral glucose metabolism and cognitive functioning predict deterioration in mild cognitive impairment. Neuroreport. 2001;12(4):851855.
24.Ray, S, Britschgi, M, Herbert, C, et al.Classification and prediction of clinical Alzheimer's diagnosis based on plasma signaling proteins. Nat Med. 2007;13(11):13591362.
25.Sharma, P, Lindahl, T, Jensen, M, et al. Detection of Alzheimer's disease based on gene expression patterns in peripheral blood cells. Paper presented at: 12th International Congress of the International Psychogeriatric Association; September 22, 2005: Stockholm, Sweden.
26.Mehta, PD, Pirttila, T, Patrick, BA, Barshatzsky, M, Mehta, SP. Amyloid beta protein 1-40 and 1-42 levels in matched cerebrospinal fluid and plasma from patients with Alzheimer disease. Neurosci Lett. 2001;304(1–2):102106.
27.Mayeux, R, Honig, LS, Tang, MX, et al.Plasma Aβ40, and Aβ42 and Alzheimer's disease: relation to age, mortality, and risk. Neurology. 2003;61(9):11851190.
28.van Oijen, M, Hofman, A, Soares, HD, Koudstaal, PJ, Preteler, MM. Plasma Aβ (1-40) and Aβ (1-42) and the risk of dementia: a prospective case-cohort study. Lancet Neurol. 2006;5(8):655660.
29.Burczynski, ME, Dorner, AJ. Transcriptional profiling of peripheral blood cells in clinical pharmacogenomic studies. Pharmacogenomics. 2006;7(2):187202.
30.Moore, DF, Li, H, Jeffries, N, et al.Using peripheral blood mononuclear cells to determine a gene expression profile of acute ischemic stroke: a pilot investigation. Circulation. 2005;111(2):212221.
31.Tang, Y, Lu, A, Ran, R, et al.Human blood genomics: distinct profiles for gender, age and neurofibromatosis type 1. Brain Res Mol Brain Res. 2004;132(2):155167.
32.Achiron, A, Gurevich, M, Friedman, N, Kaminski, N, Mandel, M. Blood transcriptional signatures of multiple sclerosis: unigue gene expression of disease activity. Ann Neurol. 2004;55(3):410417.
33.Maes, OC, Xu, S, Yu, B, Chertkow, HM, Wang, E, Schipper, HM. Transcriptional profiling of Alzheimer blood mononuclear cells by microarray. Neurobiol Aging. 2007;28(12):17951809.
34.Lönneborg, A, Booij, B, Jensen, M, et al. Accurate and early detection of Alzheimer's disease using a gene expression signature in blood. Paper presented at: 2nd Alzheimer's Association International Conference on Prevention of Dementia; June 10, 2007; Washington, DC.
35.Blennow, K, Hampel, H. CSF markers for incipient Alzheimer's disease. Lancet Neurol. 2003;2(10):605613.
36.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. 2003;289(16):20942103.
37.Fagan, AM, Roe, CM, Xiong, C, Mintun, MA, Morris, JC, Holtzman, DM. Cerebrospinal fluid tau/beta-amyloid(42) ratio as a prediction of cognitive decline in nondemented older adults. Arch Neurol. 2007;64(3):343349.
38.Hansson, O, Zetterberg, H, Buchhave, P, Londos, E, Blennow, K, Minthon, L. Association between CSF biomarkers and incipient Alzheimer's disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol. 2006;5(3):228234.
39.Buerger, K, Teipel, SJ, Zinkowski, R, et al.CSF tau protein phosphorylated at threonine 231 correlates with cognitive decline in MCI subjects. Neurology. 2002;59(4):627629.
40.Small, GW, Kepe, V, Ercoli, LM, et al.PET of brain amyloid and tau in mild cognitive impairment. N Engl J Med. 2006;355(25):26522663.
41.Klunk, WE, Engler, H, Nordberg, A, et al.Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B. Ann Neurol. 2004;55(3):306319.
42.Bacskai, BJ, Frosch, MP, Freeman, SH, et al.Molecular imaging with Pittsburgh Compound B confirmed at autopsy: a case report. Arch Neurol. 2007;64(3):431434.
43.Ikonomovic, MD, Klunk, WE, Abrahamson, EE, et al.Post-mortem correlates of in vivo PIB-PET amyloid imaging in a typical case of Alzheimer's disease. Brain. 2007. In press.
44.Rowe, CC, Ng, S, Ackermann, U, et al.Imaging beta-amyloid burden in aging and dementia. Neurology. 2007;68(20):17181725.
45.Edison, P, Archer, HA, Hinz, R, et al.Amyloid, hypometabolism, and cognition in Alzheimer disease: an [11C]PIB and [18F]FDG PET study. Neurology. 2007;68(7):501508.
46.Rabinovici, GD, Furst, AJ, O'Neil, JP, et al.11C-PIB PET imaging in Alzheimer disease and frontotemporal lobar degeneration. Neurology. 2007;68(15):12051212.
47.Fagan, AM, Mintun, MA, Mach, RH, et al.Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Aβ42 in humans. Ann Neurol. 2006;59(3):512519.

Taking the Next Steps in the Diagnosis of Alzheimer's Disease: The Use of Biomarkers

  • Steven T. DeKosky

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