Biomarkers for prediction and targeted prevention of Alzheimer's and Parkinson's diseases: Evaluation of drug clinical efficacy

EPMA Journal

Volumn 1, Issue 2, 2010, Pages 273-292

  Mandel, Silvia A ^a   Morelli, Micaela ^b   Halperin, Ilan ^c   Korczyn, Amos D ^d  

^a TECHNION ISRAEL INSTITUTE OF TECHNOLOGY   (Israel)

^b UNIVERSITY OF CAGLIARI   (Italy)

^c The Israeli Psycological Association   (Israel)

^d TEL AVIV UNIVERSITY   (Israel)

Author keywords

Alzheimer's disease; Apolipoprotein E; Biomarker; Disease modifying therapy; Neuroimaging; Parkinson's disease

Indexed keywords

ALPHA SYNUCLEIN; AMYLOID BETA PROTEIN; APOLIPOPROTEIN E4; IRON; LEUCINE RICH REPEAT KINASE 2; PARKIN; PROSTAGLANDIN D SYNTHASE; TAU PROTEIN; URATE;

ALZHEIMER DISEASE; CHROMOSOMAL LOCALIZATION; CLINICAL EFFECTIVENESS; DEPRESSION; DIAGNOSTIC TEST; DISEASE MARKER; DOMINANT INHERITANCE; DOPPLER ECHOGRAPHY; DRUG EFFICACY; DRUG SCREENING; DRUG TARGETING; EARLY DIAGNOSIS; FUNCTIONAL MAGNETIC RESONANCE IMAGING; GENE EXPRESSION PROFILING; GENE FUNCTION; GENE LOCUS; GENE MUTATION; GENETIC LINKAGE; GENETIC MARKER; HUMAN; MOLECULAR PATHOLOGY; NEUROANATOMY; NEUROIMAGING; NEUROPATHOLOGY; PARKINSON DISEASE; PATHOLOGICAL ANATOMY; POSITRON EMISSION TOMOGRAPHY; PREVENTION STUDY; PRIORITY JOURNAL; PROGNOSIS; PROTEIN BLOOD LEVEL; PROTEIN CEREBROSPINAL FLUID LEVEL; PROTON NUCLEAR MAGNETIC RESONANCE; RECESSIVE INHERITANCE; REM SLEEP; REVIEW; SINGLE PHOTON EMISSION COMPUTER TOMOGRAPHY; SLEEP DISORDER; SMELLING DISORDER;

EID: 79953048063     PISSN: 18785077     EISSN: 18785085     Source Type: Journal    
DOI: 10.1007/s13167-010-0036-z     Document Type: Review

References (184)

1. Weiner WJ. A differential diagnosis of Parkinsonism. Rev Neurol Dis. 2005; 2: 124-31.
2. Poewe W, Wenning G. The differential diagnosis of Parkinson's disease. Eur J Neurol. 2002; 9 Suppl 3: 23-30.
3. Galasko D, Hansen LA, Katzman R, et al. Clinical-neuropathological correlations in Alzheimer's disease and related dementias. Arch Neurol. 1994; 51: 888-95.
4. Hulette C, Nochlin D, McKeel D, et al. Clinical-neuropathologic findings in multi-infarct dementia: a report of six autopsied cases. Neurology. 1997; 48: 668-72.
5. Hulka BS, Wilcosky T. Biological markers in epidemiologic research. Arch Environ Health. 1988; 43: 83-9.
6. Naylor S. Biomarkers: current perspectives and future prospects. Expert Rev Mol Diagn. 2003; 3: 525-9.
7. Masterman DL, Mendez MF, Fairbanks LA, et al. Sensitivity, specificity, and positive predictive value of technetium 99-HMPAO SPECT in discriminating Alzheimer's disease from other dementias. J Geriatr Psychiatry Neurol. 1997; 10: 15-21.
8. Fratiglioni L, Launer LJ, Andersen K, et al. Incidence of dementia and major subtypes in Europe: a collaborative study of population-based cohorts. Neurologic Diseases in the Elderly Research Group. Neurology. 2000; 54: S10-5.
9. Lobo A, Launer LJ, Fratiglioni L, et al. Prevalence of dementia and major subtypes in Europe: a collaborative study of population-based cohorts. Neurologic Diseases in the Elderly Research Group. Neurology. 2000; 54: S4-9.
10. Graham JE, Rockwood K, Beattie BL, et al. Prevalence and severity of cognitive impairment with and without dementia in an elderly population. Lancet. 1997; 349: 1793-6.
11. Kawas C, Gray S, Brookmeyer R, et al. Age-specific incidence rates of Alzheimer's disease: the Baltimore Longitudinal Study of Aging. Neurology. 2000; 54: 2072-7.
12. McKhann G, Drachman D, Folstein M, et al. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. 1984; 34: 939-44.
13. Lyketsos CG, Szekely CA, Mielke MM, et al. Developing new treatments for Alzheimer's disease: the who, what, when, and how of biomarker-guided therapies. Int Psychogeriatr. 2008; 20: 871-89.
14. Sunderland T, Hampel H, Takeda M, et al. Biomarkers in the diagnosis of Alzheimer's disease: are we ready? J Geriatr Psychiatry Neurol. 2006; 19: 172-9.
15. Clark CM, Davatzikos C, Borthakur A, et al. Biomarkers for early detection of Alzheimer pathology. Neurosignals. 2008; 16: 11-8.
16. Halperin I, Korczyn AD. Mild cognitive impairment (MCI): characteristics, risk factors and prevention. Harefuah. 2006; 145: 229-34.
17. Korczyn AD. Mixed dementia-the most common cause of dementia. Ann N Y Acad Sci. 2002; 977: 129-34.
18. Andreasen N, Minthon L, Davidsson P, et al. Evaluation of CSF-tau and CSF-Abeta42 as diagnostic markers for Alzheimer disease in clinical practice. Arch Neurol. 2001; 58: 373-9.
19. Hanninen T, Hallikainen M, Tuomainen S, et al. Prevalence of mild cognitive impairment: a population-based study in elderly subjects. Acta Neurol Scand. 2002; 106: 148-54.
20. Jack Jr CR, Petersen RC, Xu Y, et al. Rates of hippocampal atrophy correlate with change in clinical status in aging and AD. Neurology. 2000; 55: 484-9.
21. Gasser T. Overview of the genetics of parkinsonism. Adv Neurol. 2003; 91: 143-52.
22. Bertram L, Tanzi RE. Thirty years of Alzheimer's disease genetics: the implications of systematic meta-analyses. Nat Rev Neurosci. 2008; 9: 768-78.
23. Mulder C, Scheltens P, Visser JJ, et al. Genetic and biochemical markers for Alzheimer's disease: recent developments. Ann Clin Biochem. 2000; 37(Pt 5): 593-607.
24. Strittmatter WJ, Weisgraber KH, Huang DY, et al. Binding of human apolipoprotein E to synthetic amyloid beta peptide: isoform-specific effects and implications for late-onset Alzheimer disease. Proc Natl Acad Sci U S A. 1993; 90: 8098-102.
25. Tanzi RE, Bertram L. Twenty years of the Alzheimer's disease amyloid hypothesis: a genetic perspective. Cell. 2005; 120: 545-55.
26. Roses AD, Lutz MW, Amrine-Madsen H, et al. A TOMM40 variable-length polymorphism predicts the age of late-onset Alzheimer's disease. Pharmacogenomics J. 2009. doi: 10. 1038/tpj. 2009. 69.
27. Grossman I, Lutz MW, Crenshaw D, et al. A. D. Alzheimer's disease: diagnostics, prognostics and the road to prevention. EPMA-J. 2010; doi: 10. 1007/s13167-010-0024-3.
28. Reiman EM, Caselli RJ, Chen K, et al. Declining brain activity in cognitively normal apolipoprotein E epsilon 4 heterozygotes: a foundation for using positron emission tomography to efficiently test treatments to prevent Alzheimer's disease. Proc Natl Acad Sci U S A. 2001; 98: 3334-9.
29. Reiman EM, Chen K, Alexander GE, et al. Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's dementia. Proc Natl Acad Sci U S A. 2004; 101: 284-9.
30. Bookheimer SY, Strojwas MH, Cohen MS, et al. Patterns of brain activation in people at risk for Alzheimer's disease. N Engl J Med. 2000; 343: 450-6.
31. Lindsten K, Menendez-Benito V, Masucci MG, et al. A transgenic mouse model of the ubiquitin/proteasome system. Nat Biotechnol. 2003; 21: 897-902.
32. Morgan D, Diamond DM, Gottschall PE, et al. A beta peptide vaccination prevents memory loss in an animal model of Alzheimer's disease. Nature. 2000; 408: 982-5.
33. Schenk D, Barbour R, Dunn W, et al. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature. 1999; 400: 173-7.
34. Rockenstein E, Crews L, Masliah E. Transgenic animal models of neurodegenerative diseases and their application to treatment development. Adv Drug Deliv Rev. 2007; 59: 1093-102.
35. Korczyn AD. The amyloid cascade hypothesis. Alzheimers Dement. 2008; 4: 176-8.
36. Corder EH, Saunders AM, Strittmatter WJ, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993; 261: 921-3.
37. Csernansky JG, Wang L, Joshi S, et al. Early DAT is distinguished from aging by high-dimensional mapping of the hippocampus. Dementia of the Alzheimer type. Neurology. 2000; 55: 1636-43.
38. Dickerson BC, Goncharova I, Sullivan MP, et al. MRI-derived entorhinal and hippocampal atrophy in incipient and very mild Alzheimer's disease. Neurobiol Aging. 2001; 22: 747-54.
39. Rosen AC, Prull MW, Gabrieli JD, et al. Differential associations between entorhinal and hippocampal volumes and memory performance in older adults. Behav Neurosci. 2003; 117: 1150-60.
40. Leung KK, Barnes J, Ridgway GR, et al. Automated cross-sectional and longitudinal hippocampal volume measurement in mild cognitive impairment and Alzheimer's disease. Neuroimage. 2010; 51(4): 1345-59.
41. Reiber H, Peter JB. Cerebrospinal fluid analysis: disease-related data patterns and evaluation programs. J Neurol Sci. 2001; 184: 101-22.
42. DeKosky ST, Ikonomovic MD, Styren SD, et al. Upregulation of choline acetyltransferase activity in hippocampus and frontal cortex of elderly subjects with mild cognitive impairment. Ann Neurol. 2002; 51: 145-55.
43. Davis KL, Mohs RC, Marin D, et al. Cholinergic markers in elderly patients with early signs of Alzheimer disease. JAMA. 1999; 281: 1401-6.
44. Resnick SM, Goldszal AF, Davatzikos C, et al. One-year age changes in MRI brain volumes in older adults. Cereb Cortex. 2000; 10: 464-72.
45. Sullivan EV, Pfefferbaum A, Adalsteinsson E, et al. Differential rates of regional brain change in callosal and ventricular size: a 4-year longitudinal MRI study of elderly men. Cereb Cortex. 2002; 12: 438-45.
46. Chetelat G, Baron JC. Early diagnosis of Alzheimer's disease: contribution of structural neuroimaging. Neuroimage. 2003; 18: 525-41.
47. Connor DM, Benveniste H, Dilmanian FA, et al. Computed tomography of amyloid plaques in a mouse model of Alzheimer's disease using diffraction enhanced imaging. Neuroimage. 2009; 46: 908-14.
48. Borthakur A, Wheaton AJ, Gougoutas AJ, et al. In vivo measurement of T1rho dispersion in the human brain at 1. 5 tesla. J Magn Reson Imaging. 2004; 19: 403-9.
49. Klunk WE, Panchalingam K, Moossy J, et al. N-acetyl-L-aspartate and other amino acid metabolites in Alzheimer's disease brain: a preliminary proton nuclear magnetic resonance study. Neurology. 1992; 42: 1578-85.
50. Kwo-On-Yuen PF, Newmark RD, Budinger TF, et al. Brain N-acetyl-L-aspartic acid in Alzheimer's disease: a proton magnetic resonance spectroscopy study. Brain Res. 1994; 667: 167-74.
51. Jessen F, Block W, Traber F, et al. Proton MR spectroscopy detects a relative decrease of N-acetylaspartate in the medial temporal lobe of patients with AD. Neurology. 2000; 55: 684-8.
52. Schuff N, Capizzano AA, Du AT, et al. Selective reduction of N-acetylaspartate in medial temporal and parietal lobes in AD. Neurology. 2002; 58: 928-35.
53. Kantarci K, Jack Jr CR, Xu YC, et al. Regional metabolic patterns in mild cognitive impairment and Alzheimer's disease: a 1H MRS study. Neurology. 2000; 55: 210-7.
54. Valenzuela MJ, Sachdev PS, Wen W, et al. Dual voxel proton magnetic resonance spectroscopy in the healthy elderly: subcortical-frontal axonal N-acetylaspartate levels are correlated with fluid cognitive abilities independent of structural brain changes. Neuroimage. 2000; 12: 747-56.
55. MacKay S, Ezekiel F, Di Sclafani V, et al. Alzheimer disease and subcortical ischemic vascular dementia: evaluation by combining MR imaging segmentation and H-1 MR spectroscopic imaging. Radiology. 1996; 198: 537-45.
56. Leinonen V, Alafuzoff I, Aalto S, et al. Assessment of {beta}-Amyloid in a frontal cortical brain biopsy specimen and by positron emission tomography with carbon 11-labeled Pittsburgh compound B. Arch Neurol. 2008; 65(10): 1304-9.
57. Foster NL, Heidebrink JL, Clark CM, et al. FDG-PET improves accuracy in distinguishing frontotemporal dementia and Alzheimer's disease. Brain. 2007; 130: 2616-35.
58. 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: 2120-7.
59. Jagust W. Molecular neuroimaging in Alzheimer's disease. NeuroRx. 2004; 1: 206-12.
60. Johnson KA, Holman BL, Rosen TJ, et al. Iofetamine I 123 single photon emission computed tomography is accurate in the diagnosis of Alzheimer's disease. Arch Intern Med. 1990; 150: 752-6.
61. Eberling JL, Jagust WJ, Reed BR, et al. Reduced temporal lobe blood flow in Alzheimer's disease. Neurobiol Aging. 1992; 13: 483-91.
62. Johnson KA, Jones K, Holman BL, et al. Preclinical prediction of Alzheimer's disease using SPECT. Neurology. 1998; 50: 1563-71.
63. Herholz K, Salmon E, Perani D, et al. Discrimination between Alzheimer dementia and controls by automated analysis of multicenter FDG PET. Neuroimage. 2002; 17: 302-16.
64. Archer HA, Edison P, Brooks DJ, et al. Amyloid load and cerebral atrophy in Alzheimer's disease: an 11C-PIB positron emission tomography study. Ann Neurol. 2006; 60: 145-7.
65. Engler H, Forsberg A, Almkvist O, et al. Two-year follow-up of amyloid deposition in patients with Alzheimer's disease. Brain. 2006; 129: 2856-66.
66. Mosconi L. Brain glucose metabolism in the early and specific diagnosis of Alzheimer's disease. FDG-PET studies in MCI and AD. Eur J Nucl Med Mol Imaging. 2005; 32: 486-510.
67. Kemppainen NM, Aalto S, Wilson IA, et al. Voxel-based analysis of PET amyloid ligand [11C]PIB uptake in Alzheimer disease. Neurology. 2006; 67: 1575-80.
68. Machulda MM, Ward HA, Borowski B, et al. Comparison of memory fMRI response among normal, MCI, and Alzheimer's patients. Neurology. 2003; 61: 500-6.
69. Jagust W, Thisted R, Devous Sr MD, et al. SPECT perfusion imaging in the diagnosis of Alzheimer's disease: a clinical-pathologic study. Neurology. 2001; 56: 950-6.
70. Kung MP, Hou C, Zhuang ZP, et al. Binding of two potential imaging agents targeting amyloid plaques in postmortem brain tissues of patients with Alzheimer's disease. Brain Res. 2004; 1025: 98-105.
71. Petersen RC, Aisen PS, Beckett LA, et al. Alzheimer's Disease Neuroimaging Initiative (ADNI): clinical characterization. Neurology. 2010; 74: 201-9.
72. Shoji M, Golde TE, Ghiso J, et al. Production of the Alzheimer amyloid beta protein by normal proteolytic processing. Science. 1992; 258: 126-9.
73. Blennow K. Cerebrospinal fluid protein biomarkers for Alzheimer's disease. NeuroRx. 2004; 1: 213-25.
74. Blennow K, Vanmechelen E, Hampel H. CSF total tau, Abeta42 and phosphorylated tau protein as biomarkers for Alzheimer's disease. Mol Neurobiol. 2001; 24: 87-97.
75. Clark CM, Xie S, Chittams J, et al. Cerebrospinal fluid tau and beta-amyloid: how well do these biomarkers reflect autopsy-confirmed dementia diagnoses? Arch Neurol. 2003; 60: 1696-702.
76. Arai H, Nakagawa T, Kosaka Y, et al. Elevated cerebrospinal fluid tau protein level as a predictor of dementia in memory-impaired patients. Alzheim Res. 1997; 3: 211-3.
77. Visser PJ, Verhey F, Knol DL, et al. Prevalence and prognostic value of CSF markers of Alzheimer's disease pathology in patients with subjective cognitive impairment or mild cognitive impairment in the DESCRIPA study: a prospective cohort study. Lancet Neurol. 2009; 8: 619-27.
78. Boban M, Grbic K, Mladinov M, et al. Cerebrospinal fluid markers in differential diagnosis of Alzheimer's disease and vascular dementia. Coll Antropol. 2008; 32 Suppl 1: 31-6.
79. 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. 2001; 49: 545-6.
80. 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: 627-9.
81. Hulstaert F, Blennow K, Ivanoiu A, et al. Improved discrimination of AD patients using beta-amyloid(1-42) and tau levels in CSF. Neurology. 1999; 52: 1555-62.
82. Samuels SC, Silverman JM, Marin DB, et al. CSF beta-amyloid, cognition, and APOE genotype in Alzheimer's disease. Neurology. 1999; 52: 547-51.
83. Tapiola T, Pirttila T, Mikkonen M, et al. Three-year follow-up of cerebrospinal fluid tau, beta-amyloid 42 and 40 concentrations in Alzheimer's disease. Neurosci Lett. 2000; 280: 119-22.
84. Jensen M, Schroder J, Blomberg M, et al. Cerebrospinal fluid A beta42 is increased early in sporadic Alzheimer's disease and declines with disease progression. Ann Neurol. 1999; 45: 504-11.
85. van Everbroeck B, Green AJ, Pals P, et al. Decreased levels of Amyloid-beta 1-42 in cerebrospinal fluid of Creutzfeldt-Jakob disease patients. J Alzheimers Dis. 1999; 1: 419-24.
86. Otto M, Esselmann H, Schulz-Shaeffer W, et al. Decreased beta-amyloid1-42 in cerebrospinal fluid of patients with Creutzfeldt-Jakob disease. Neurology. 2000; 54: 1099-102.
87. Kanemaru K, Kameda N, Yamanouchi H. Decreased CSF amyloid beta42 and normal tau levels in dementia with Lewy bodies. Neurology. 2000; 54: 1875-6.
88. Ringman JM, Younkin SG, Pratico D, et al. Biochemical markers in persons with preclinical familial Alzheimer disease. Neurology. 2008; 71: 85-92.
89. Crystal HA, Davies P. Toward a plasma marker for Alzheimer disease: some progress, but still a long way to go. Neurology. 2008; 70: 586-7.
90. 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: 1359-62.
91. Hye A, Lynham S, Thambisetty M, et al. Proteome-based plasma biomarkers for Alzheimer's disease. Brain. 2006; 129: 3042-50.
92. Montine TJ, Beal MF, Cudkowicz ME, et al. Increased CSF F2-isoprostane concentration in probable AD. Neurology. 1999; 52: 562-5.
93. Irizarry MC, Hyman BT. Brain isoprostanes: a marker of lipid peroxidation and oxidative stress in AD. Neurology. 2003; 61: 436-7.
94. Rosner S, Giladi N, Orr-Urtreger A. Advances in the genetics of Parkinson's disease. Acta Pharmacol Sin. 2008; 29: 21-34.
95. Farrer MJ. Genetics of Parkinson disease: paradigm shifts and future prospects. Nat Rev Genet. 2006; 7: 306-18.
96. Greenamyre JT, Betarbet R, Sherer TB. The rotenone model of Parkinson's disease: genes, environment and mitochondria. Parkinsonism Relat Disord. 2003; 9 Suppl 2: S59-64.
97. Obeso JA, Rodriguez-Oroz MC, Rodriguez M, et al. Pathophysiology of the basal ganglia in Parkinson's disease. Trends Neurosci. 2000; 23: S8-19.
98. Fearnley JM, Lees AJ. Ageing and Parkinson's disease: substantia nigra regional selectivity. Brain. 1991; 114: 2283-301.
99. Schapira AH, Bezard E, Brotchie J, et al. Novel pharmacological targets for the treatment of Parkinson's disease. Nat Rev Drug Discov. 2006; 5: 845-54.
100. Langston JW. The Parkinson's complex: parkinsonism is just the tip of the iceberg. Ann Neurol. 2006; 59: 591-6.
101. Braak H, Del Tredici K, Rub U, et al. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging. 2003; 24: 197-211.
102. Braak H, Muller CM, Rub U, et al. Pathology associated with sporadic Parkinson's disease-where does it end? J Neural Transm Suppl. 2006; 70; 89-97.
103. Bloch A, Probst A, Bissig H, et al. Alpha-synuclein pathology of the spinal and peripheral autonomic nervous system in neurologically unimpaired elderly subjects. Neuropathol Appl Neurobiol. 2006; 32: 284-95.
104. Fahn S, Elton R, Committee UD. Unified Parkinson's disease rating scale. In: Fahn S, Marsden C, Calne DB, Goldstein M, editors. Recent developments in Parkinson's disease. Florham Park: Macmillan Health Care Information; 1987. p. 153-63.
105. Hoehn MM, Yahr MD. Parkinsonism: onset, progression and mortality. Neurology. 1967; 17: 427-42.
106. Tolosa E, Wenning G, Poewe W. The diagnosis of Parkinson's disease. Lancet Neurol. 2006; 5: 75-86.
107. Vendette M, Gagnon JF, Decary A, et al. REM sleep behavior disorder predicts cognitive impairment in Parkinson disease without dementia. Neurology. 2007; 69: 1843-9.
108. Postuma RB, Gagnon JF, Vendette M, et al. REM sleep behaviour disorder in Parkinson's disease is associated with specific motor features. J Neurol Neurosurg Psychiatry. 2008; 79: 1117-21.
109. Burn DJ. Beyond the iron mask: towards better recognition and treatment of depression associated with Parkinson's disease. Mov Disord. 2002; 17: 445-54.
110. Remy P, Doder M, Lees A, et al. Depression in Parkinson's disease: loss of dopamine and noradrenaline innervation in the limbic system. Brain. 2005; 128: 1314-22.
111. McKinnon JH, Demaerschalk BM, Caviness JN, et al. Sniffing out Parkinson disease: can olfactory testing differentiate parkinsonian disorders? Neurologist. 2007; 13: 382-5.
112. Hudry J, Thobois S, Broussolle E, et al. Evidence for deficiencies in perceptual and semantic olfactory processes in Parkinson's disease. Chem Senses. 2003; 28: 537-43.
113. Montgomery Jr EB, Koller WC, LaMantia TJ, et al. Early detection of probable idiopathic Parkinson's disease: I. Development of a diagnostic test battery. Mov Disord. 2000; 15: 467-73.
114. Montgomery Jr EB, Lyons K, Koller WC. Early detection of probable idiopathic Parkinson's disease: II. A prospective application of a diagnostic test battery. Mov Disord. 2000; 15: 474-8.
115. Troster AI. Neuropsychological characteristics of dementia with Lewy bodies and Parkinson's disease with dementia: differentiation, early detection, and implications for "mild cognitive impairment" and biomarkers. Neuropsychol Rev. 2008; 18: 103-19.
116. Korczyn AD. Autonomic nervous system disturbances in Parkinson's disease. Adv Neurol. 1990; 53: 463-8.
117. Wolters E, Braak H. Parkinson's disease: premotor clinico-pathological correlations. J Neural Transm Suppl. 2006; 70; 309-19.
118. Sommer C, Lauria G. Skin biopsy in the management of peripheral neuropathy. Lancet Neurol. 2007; 6: 632-42.
119. Rossi A, Giovenali P, Benvenuti M, et al. Skin biopsy: a new diagnostic tool for autonomic dysfunctions in Parkinson's disease? Lancet Neurol. 2007; 6: 848-9.
120. Leroux P-D (1880) Contribution à l'Étude des Causes de la Paralysie Agitante (in French). Thèse de Paris, Imprimeur de la Faculté de Médecine.
121. Gowers WR. A manual of diseases of the nervous system. London: Churchill; 1886-1888.
122. Wider C, Foroud T, Wszolek ZK. Clinical implications of gene discovery in Parkinson's disease and parkinsonism. Mov Disord. 2010; 25 Suppl 1: S15-20.
123. Polymeropoulos MH, Lavedan C, Leroy E, et al. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science. 1997; 276: 2045-7.
124. Kruger R, Kuhn W, Muller T, et al. Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease. Nat Genet. 1998; 18: 106-8.
125. Zarranz JJ, Alegre J, Gomez-Esteban JC, et al. The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol. 2004; 55: 164-73.
126. Singleton AB, Farrer M, Johnson J, et al. alpha-Synuclein locus triplication causes Parkinson's disease. Science. 2003; 302: 841.
127. Ibanez P, Bonnet AM, Debarges B, et al. Causal relation between alpha-synuclein gene duplication and familial Parkinson's disease. Lancet. 2004; 364: 1169-71.
128. Chartier-Harlin MC, Kachergus J, Roumier C, et al. Alpha-synuclein locus duplication as a cause of familial Parkinson's disease. Lancet. 2004; 364: 1167-9.
129. Leroy E, Boyer R, Auburger G, et al. The ubiquitin pathway in Parkinson's disease. Nature. 1998; 395: 451-2.
130. Lowe J, McDermott H, Landon M, et al. Ubiquitin carboxyl-terminal hydrolase (PGP 9. 5) is selectively present in ubiquitinated inclusion bodies characteristic of human neurodegenerative diseases. J Pathol. 1990; 161: 153-60.
131. Aharon-Peretz J, Rosenbaum H, Gershoni-Baruch R. Mutations in the glucocerebrosidase gene and Parkinson's disease in Ashkenazi Jews. N Engl J Med. 2004; 351: 1972-7.
132. Ozelius LJ, Senthil G, Saunders-Pullman R, et al. LRRK2 G2019S as a cause of Parkinson's disease in Ashkenazi Jews. N Engl J Med. 2006; 354: 424-5.
133. Kitada T, Asakawa S, Hattori N, et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature. 1998; 392: 605-8.
134. Valente EM, Abou-Sleiman PM, Caputo V, et al. Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science. 2004; 304: 1158-60.
135. Bonifati V, Rizzu P, van Baren MJ, et al. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science. 2003; 299: 256-9.
136. Ramirez A, Heimbach A, Grundemann J, et al. Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat Genet. 2006; 38: 1184-91.
137. Shimura H, Hattori N, Kubo S, et al. Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat Genet. 2000; 25: 302-5.
138. Plun-Favreau H, Klupsch K, Moisoi N, et al. The mitochondrial protease HtrA2 is regulated by Parkinson's disease-associated kinase PINK1. Nat Cell Biol. 2007; 9: 1243-52.
139. Park J, Lee SB, Lee S, et al. Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature. 2006; 441: 1157-61.
140. Brooks DJ. Technology insight: imaging neurodegeneration in Parkinson's disease. Nat Clin Pract Neurol. 2008; 4: 267-77.
141. Eckert T, Tang C, Eidelberg D. Assessment of the progression of Parkinson's disease: a metabolic network approach. Lancet Neurol. 2007; 6: 926-32.
142. Berg D. Biomarkers for the early detection of Parkinson's and Alzheimer's disease. Neurodegener Dis. 2008; 5: 133-6.
143. Zecca L, Youdim MB, Riederer P, et al. Iron, brain ageing and neurodegenerative disorders. Nat Rev Neurosci. 2004; 5: 863-73.
144. Gerlach M, Double KL, Youdim MB, et al. Potential sources of increased iron in the substantia nigra of parkinsonian patients. J Neural Transm Suppl. 2006; 70; 133-42.
145. Koeppen AH. The history of iron in the brain. J Neurol Sci. 1995; 134(Suppl): 1-9.
146. Hallgren B, Sourander P. The effect of age on the nonhemin iron in the human brain. J Neurochem. 1958; 3(1): 41-51.
147. Jellinger K, Paulus W, Grundke-Iqbal I, et al. Brain iron and ferritin in Parkinson's and Alzheimer's diseases. J Neural Transm Park Dis Dement Sect. 1990; 2: 327-40.
148. Sofic E, Paulus W, Jellinger K, et al. Selective increase of iron in substantia nigra zona compacta of parkinsonian brains. J Neurochem. 1991; 56: 978-82.
149. Zecca L, Shima T, Stroppolo A, et al. Interaction of neuromelanin and iron in substantia nigra and other areas of human brain. Neuroscience. 1996; 73: 407-15.
150. Berg D, Siefker C, Becker G. Echogenicity of the substantia nigra in Parkinson's disease and its relation to clinical findings. J Neurol. 2001; 248: 684-9.
151. Berg D, Roggendorf W, Schroder U, et al. Echogenicity of the substantia nigra: association with increased iron content and marker for susceptibility to nigrostriatal injury. Arch Neurol. 2002; 59: 999-1005.
152. Harrington MG, Merril CR. Two-dimensional electrophoresis and "ultrasensitive" silver staining of cerebrospinal fluid proteins in neurological diseases. Clin Chem. 1984; 30: 1933-7.
153. Nagai Y, Ueno S, Saeki Y, et al. Decrease of the D3 dopamine receptor mRNA expression in lymphocytes from patients with Parkinson's disease. Neurology. 1996; 46: 791-5.
154. Caronti B, Antonini G, Calderaro C, et al. Dopamine transporter immunoreactivity in peripheral blood lymphocytes in Parkinson's disease. J Neural Transm. 2001; 108: 803-7.
155. Parker Jr WD, Boyson SJ, Parks JK. Abnormalities of the electron transport chain in idiopathic Parkinson's disease. Ann Neurol. 1989; 26: 719-23.
156. Benecke R, Strumper P, Weiss H. Electron transfer complexes I and IV of platelets are abnormal in Parkinson's disease but normal in Parkinson-plus syndromes. Brain. 1993; 116(Pt 6): 1451-63.
157. Haas RH, Nasirian F, Nakano K, et al. Low platelet mitochondrial complex I and complex II/III activity in early untreated Parkinson's disease. Ann Neurol. 1995; 37: 714-22.
158. Migliore L, Petrozzi L, Lucetti C, et al. Oxidative damage and cytogenetic analysis in leukocytes of Parkinson's disease patients. Neurology. 2002; 58: 1809-15.
159. Harrington MG, Fonteh AN, Biringer RG, et al. Prostaglandin D synthase isoforms from cerebrospinal fluid vary with brain pathology. Dis Markers. 2006; 22: 73-81.
160. Davis JW, Grandinetti A, Waslien CI, et al. Observations on serum uric acid levels and the risk of idiopathic Parkinson's disease. Am J Epidemiol. 1996; 144: 480-4.
161. Weisskopf MG, O'Reilly E, Chen H, et al. Plasma urate and risk of Parkinson's disease. Am J Epidemiol. 2007; 166: 561-7.
162. Schwarzschild MA, Schwid SR, Marek K, et al. Serum urate as a predictor of clinical and radiographic progression in Parkinson disease. Arch Neurol. 2008; 65: 716-23.
163. Bogdanov M, Matson WR, Wang L, et al. Metabolomic profiling to develop blood biomarkers for Parkinson's disease. Brain. 2008; 131: 389-96.
164. Ascherio A, LeWitt PA, Xu K, et al. Urate as a predictor of the rate of clinical decline in Parkinson disease. Arch Neurol. 2009; 66: 1460-8.
165. Varani K, Vincenzi F, Tosi A, et al. A2A adenosine receptor overexpression and functionality, as well as TNF-alpha levels, correlate with motor symptoms in Parkinson's disease. Faseb J. 2010; 24: 587-98.
166. Morelli M, Di Paolo T, Wardas J, et al. Role of adenosine A2A receptors in parkinsonian motor impairment and l-DOPA-induced motor complications. Prog Neurobiol. 2007; 83: 293-309.
167. Goldknopf IL. Blood-based proteomics for personalized medicine: examples from neurodegenerative disease. Expert Rev Proteomics. 2008; 5: 1-8.
168. Sheta EA, Appel SH, Goldknopf IL. 2D gel blood serum biomarkers reveal differential clinical proteomics of the neurodegenerative diseases. Expert Rev Proteomics. 2006; 3: 45-62.
169. Goldknopf IL, Sheta EA, Bryson J, et al. Complement C3c and related protein biomarkers in amyotrophic lateral sclerosis and Parkinson's disease. Biochem Biophys Res Commun. 2006; 342: 1034-9.
170. Zhang J, Sokal I, Peskind ER, et al. CSF multianalyte profile distinguishes Alzheimer and Parkinson diseases. Am J Clin Pathol. 2008; 129: 526-9.
171. Mollenhauer B, Cullen V, Kahn I, et al. Direct quantification of CSF alpha-synuclein by ELISA and first cross-sectional study in patients with neurodegeneration. Exp Neurol. 2008; 213: 315-25.
172. El-Agnaf OM, Salem SA, Paleologou KE, et al. Detection of oligomeric forms of alpha-synuclein protein in human plasma as a potential biomarker for Parkinson's disease. FASEB J. 2006; 20: 419-25.
173. Duran R, Barrero FJ, Morales B, et al. Plasma alpha-synuclein in patients with Parkinson's disease with and without treatment. Mov Disord. 2010; 25: 489-93.
174. Barbour R, Kling K, Anderson JP, et al. Red blood cells are the major source of alpha-synuclein in blood. Neurodegener Dis. 2008; 5: 55-9.
175. Michell AW, Luheshi LM, Barker RA. Skin and platelet alpha-synuclein as peripheral biomarkers of Parkinson's disease. Neurosci Lett. 2005; 381: 294-8.
176. Maita C, Tsuji S, Yabe I, et al. Secretion of DJ-1 into the serum of patients with Parkinson's disease. Neurosci Lett. 2008; 431: 86-9.
177. Waragai M, Wei J, Fujita M, et al. Increased level of DJ-1 in the cerebrospinal fluids of sporadic Parkinson's disease. Biochem Biophys Res Commun. 2006; 345: 967-72.
178. Waragai M, Nakai M, Wei J, et al. Plasma levels of DJ-1 as a possible marker for progression of sporadic Parkinson's disease. Neurosci Lett. 2007; 425: 18-22.
179. Zetterberg H, Ruetschi U, Portelius E, et al. Clinical proteomics in neurodegenerative disorders. Acta Neurol Scand. 2008; 118: 1-11.
180. Mandel S, Amit T, Kalfon L, et al. Applying transcriptomic and proteomic knowledge to Parkinson's disease drug discovery. Expert Opin Drug Discov. 2007; 2: 1225-40.
181. Sullivan PF, Fan C, Perou CM. Evaluating the comparability of gene expression in blood and brain. Am J Med Genet B Neuropsychiatr Genet. 2006; 141B: 261-8.
182. Burczynski ME, Dorner AJ. Transcriptional profiling of peripheral blood cells in clinical pharmacogenomic studies. Pharmacogenomics. 2006; 7: 187-202.
183. Scherzer CR, Eklund AC, Morse LJ, et al. Molecular markers of early Parkinson's disease based on gene expression in blood. Proc Natl Acad Sci U S A. 2007; 104: 955-60.
184. Scherzer CR, Grass JA, Liao Z, et al. GATA transcription factors directly regulate the Parkinson's disease-linked gene alpha-synuclein. Proc Natl Acad Sci U S A. 2008; 105: 10907-12.