Current means for identifying the latent stage of a neurodegenerative process

Cover Page

Cite item

Full Text


A characteristic feature of neurodegenerative diseases is the presence of a long-term latent stage, while manifestation of symptoms occurs after 40–60% cells loss in vulnerable neuron populations. Therefore, potential for neuroprotection is maximal just at the latent stage of the process. In this paper, current technologies of presymptomatic diagnosis of the two most common neurodegenerative disorders, Alzheimer’s and Parkinson’s
disease, are presented. On the basis of our own experience and data from the literature it is shown that neuroimaging methods (identification of beta-amyloid in the brain, or phenomenon of hyperechogenecity of the s.nigra, etc) in combination with a number of neurophysiological and molecular/pathobiochemical tests are principal in revealing persons with high risk of these disorders. Validation of biomarkers under discussion and their integration
into uniform diagnostic screening algorithms is at present one of the most actual fields of neurology.

About the authors

Sergey N. Illarioshkin

Research Center of Neurology

Author for correspondence.
Russian Federation, Moscow

A. G. Vlassenko

Department of Radiology, Washington University School of Medicine

United States, St. Louis

Ekaterina Yu. Fedotova

Research Center of Neurology

ORCID iD: 0000-0001-8070-7644

D. Sci. (Med.), Head of the 5th Neurology department

Russian Federation, Moscow


  1. Алексеева Н.С., Иллариошкин С.Н., Пономарева Т.А. и др. Нарушения обоняния при болезни Паркинсона. Неврол. журн. 2012; 1: 10–14.
  2. Базиян Б.Х., Чигалейчик Л.А., Тесленко Е.Л. и др. Анализ траектории движений для раннего обнаружения нейродегенеративного процесса при болезни Паркинсона. В кн.: Болезнь Паркинсона и расстройства движений. Руководство для врачей (по материалам II Национального конгресса). М., 2011: 145–149.
  3. Власенко А.Г., Моррис Д.К., Минтон М.А. Регионарная характеристика накопления бета-амилоида на доклинической и клинической стадиях болезни Альцгеймера. Анн. клин. и эксперимент. неврол. 2010; 4: 10–14.
  4. Власенко А.Г., Моррис Д.К., Минтон М.А., Иллариошкин С.Н. Доклиническая стадия болезни Альцгеймера. Неврол. журн. 2012;2: 39–44.
  5. Иллариошкин С.Н. Конформационные болезни мозга. М.: Янус-К, 2003.
  6. Иллариошкин С.Н. Течение болезни Паркинсона и подходы к ранней диагностике. В кн.: Болезнь Паркинсона и расстройства движений. Руководство для врачей по материалам II Национального конгресса (под ред. С.Н. Иллариошкина, О.С. Левина). М., 2011; 41–47.
  7. Федин П.А., Федотова Е.Ю., Полещук В.В. и др. Новые возможности диагностики нарушений цветовосприятия у пациентов с болезнью Паркинсона. В кн.: Болезнь Паркинсона и расстройства движений. Руководство для врачей (по материалам II Национального конгресса). М., 2011: 328.
  8. Федотова Е.Ю., Чечеткин А.О., Шадрина М.И. и др. Транскраниальная сонография при болезни Паркинсона. Журн. неврол. и психиатрии им. С.С. Корсакова 2011; 1: 49–55.
  9. Abbott R.D., Petrovitch H., White L.R. et al. Frequency of bowel movements and the future risk of Parkinson’s disease. Neurology 2001;57: 456–462.
  10. Abdulkadir A., Ronneberger O., Wolf R.C. et al. Functional and structural MRI biomarkers to detect pre-clinical neurodegeneration. Curr Alzheimer Res. 2013; 10: 125–134.
  11. Aizenstein H.J., Nebes R.D., Saxton J.A. et al. Frequent amyloid deposition without significant cognitive impairment among the elderly. Arch. Neurol. 2008; 65: 1509–1517.
  12. Arabia G., Grossardt B.R., Geda Y.E. et al. Increased risk of depressive and anxiety disorders in relatives of patients with Parkinson disease. Arch. Gen. Psychiatry 2007; 64: 1385–1392.
  13. Beach T.G., Adler C.H., Dugger B.N. et al. Submandibular gland biopsy for the diagnosis of Parkinson disease. J. Neuropathol. Exp. Neurol. 2013; 72: 130–136.
  14. Berendse H.W., Roos D.S., Raijmakers P., Doty R.L. Motor and non-motor correlates of olfactory dysfunction in Parkinson’s disease. J. Neurol. Sci. 2011; 310: 21–24.
  15. Berg D., Becker G., Zeiler B. et al. Vulnerability of the nigrostriatal system as detected by transcranial ultrasound. Neurology 1999; 53: 1026–1031.
  16. Berg D., Behnke S., Seppi K. et al. Enlarged hyperechogenic substantia nigra as a risk marker for Parkinson’s disease. Mov. Disord. 2013; 28: 216–219.
  17. Berg D., Godau J., Seppi K. et al. The PRIPS study: screening battery for subjects at risk for Parkinson’s disease. Eur. J. Neurol. 2013; 20: 102–108.
  18. Bourgeat P., Chetelat G., Villemagne V. L. et al. Beta-amyloid burden in the temporal neocortex is related to hippocampal atrophy in elderly subjects without dementia. Neurology 2010; 74: 121–127.
  19. 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.
  20. Braak H., de Vos R.A., Bohl J., Del Tredici K. Gastric alpha-synuclein immunoreactive inclusions in Meissner’s and Aurbach’s plexuses in cases staged for Parkinson’s disease-related brain pathology. Neurosci. Lett. 2006; 396: 67–72.
  21. Brookmeyer R., Johnson E., Ziegler-Graham K., Arrighi M.H. Forecasting the global burden of Alzheimer’s disease. Alzheimer’s and Dementia 2007; 3: 186–191.
  22. Buerger K., Zinlowski R., Teipel S.J. et al. Differential diagnosis of Alzheimer disease with cerebrospinal fluid levels of tau protein phosphorylated at threonine 231. Arch. Neurol. 2002; 59: 1267–1272.
  23. Claassen D.O., Josephs K.A., Ahlskog J.E. et al. REM sleep behavior disorder preceding other aspects of synucleinopathies by up to half a century. Neurology 2010; 75: 494–499.
  24. Diederich N.J., Pieri V., Hipp G. et al. Discriminative power of different nonmotor signs in early Parkinson’s disease. A case-control study. Mov. Disord. 2010; 25: 882–887.
  25. Doty R.L. Neurology of olfaction. NY, 2009.
  26. Eisensehr I., Linke R., Tatsch K. et al. Increased muscle activity during rapid eye movement sleep correlates with decrease of striatal presynaptic dopamine transporters. IPT and IBZM SPECT imaging in subclinical and clinically manifest idiopathic REM sleep behavior disorder, Parkinson’s disease, and controls. Sleep 2003; 26: 507–512.
  27. Fagan A.M., Mintun M.A., Shah A.R. et al. Cerebrospinal fluid tau and ptau181 increase with cortical amyloid deposition in cognitively normal individuals: implications for future clinical trials of Alzheimer’s disease. EMBO Mol. Med. 2009; 1: 371–380.
  28. Fearnley J.M., Lees A.J. Ageing and Parkinson’s disease: substantia nigra regional selectivity. Brain 1991; 114: 2283–2301.
  29. Fekete R., Jankovic J. Revisiting the relationship between essentialtremor and Parkinson’s disease. Mov. Disord. 2011; 26: 391–398.
  30. Galvin J.E., Powlishta K.K., Wilkins K. et al. Predictors of preclinical Alzheimer disease and dementia: a clinicopathologic study. Arch. Neurol. 2005; 62: 758–765.
  31. Gonera E.G., van’t Hof M., Berger H.J. et al. Symptoms and duration of the prodromal phase in Parkinson’s disease. Mov. Disord. 1997; 12: 871–876.
  32. Greenbaum L., Lorberboym M., Melamed E. et al. Perspective: identification of genetic variants associated with dopaminergic compensatory mechanisms in early Parkinson’s disease. Frontiers Neurosci. 2013; 7: Article 52 (doi: 10.3389/fnins.2013.00052).
  33. Grinberg L.T., Rueb U., di Lorenzo Alho A.T., Heinsen H. Brainstem pathology and non-motor symptoms in PD. J. Neurol. Sci. 2010; 289: 81–88.
  34. Guttman M., Burkholder J., Kish S.J. et al. [11C]RTI-32 PET studies of the dopamine transporter in early dopa-naive Parkinson’s disease: implications for the symptomatic threshold. Neurology 1997; 48: 1578–1583.
  35. Hampel H., Buerger K., Zinkowski R. et al. Measurement of phosphorylated tau epitopes in the differential diagnosis of Alzheimer disease: a comparative cerebrospinal fluid study. Arch. Gen. Psychiatry 2004; 61: 95–102.
  36. Hawkes C.H., Tredici K.D., Braak H. A timeline for Parkinson’s disease. Parkinsonism Relat. Disord. 2010; 16: 79–84.
  37. Hedden T., Van Dijk K. R. A., Becker J. A. et al. Disruption of functional connectivity in clinically normal older adults harboring amyloid burden. J. Neurosci. 2009; 29: 12686–12694.
  38. Iranzo A., Molinuevo J.L., Santamarнa J. et al. Rapid-eye-movement sleep behaviour disorder as an early marker for a neurodegenerative disorder: a descriptive study. Lancet Neurol. 2006; 5: 572–577.
  39. Ishihara L., Brayne C. A systematic review of depression and mental illness preceding Parkinson’s disease. Acta Neurol. Scand. 2006; 113:211–220.
  40. Jellinger K.A. Synuclein deposition and non-motor symptoms in Parkinson disease. J. Neurol. Sci. 2011; 310: 107–111.
  41. Jellinger K.A. Neuropathology of sporadic Parkinson’s disease: evaluation and changes of concepts. Mov. Disord. 2012; 27: 8–30.
  42. Karlsson M.K., Sharma P., Aasly J. et al. Found in transcription: Accurate Parkinson’s disease classification in peripheral blood. J. Park. Dis. 2013; 3: 19–29.49
  43. Kasten M., Chade A., Tanner C.M. Epidemiology of Parkinson’s disease. In: Parkinson’s disease and related disorders. Advances in neurology, Vol.83, Part I (ed. W.C.Koller, E.Melamed). Edinburgh: Elsevier, 2007: 129−151.
  44. Kojovic M., Bologna M., Kassavetis P. et al. Functional reorganization of sensorimotor cortex in early Parkinson disease. Neurology 2012;78: 1441–1448.
  45. Kuo Y.M., Emmerling M.R., Vigo-Pelfrey C. et al. Water-soluble Abeta (N-40, N-42) oligomers in normal and Alzheimer disease brains. J. Biol. Chem. 1996; 271: 4077−4081.
  46. Marek K., Innis R., van Dyck C. et al. [123I]beta-CIT SPECT imaging assessment of the rate of Parkinson’s disease progression. Neurology 2001; 57: 2089–2094.
  47. Marion M.H., Qurashi M., Marshall G., Foster O. Is REM sleep behaviour disorder (RBD) a risk factor of dementia in idiopathic Parkinson’s disease? J. Neurol. 2008; 255: 192–196.
  48. Minguez-Castellanos A., Chamorro C.E., Escamilla-Sevilla F. et al. Do alpha-synuclein aggregates in autonomic plexuses predate Lewy body disorders?: a cohort study. Neurology 2007; 68: 2012–2018.
  49. Morris J.C., Price J.L. Pathologic correlates of nondemented aging, mild cognitive impairment, and early-stage Alzheimer’s disease. J. Mol. Neurosci. 2001; 17: 101–118.
  50. Morris J.C., Roe C.M., Grant E.A. et al. Pittsburgh compound B imaging and prediction of progression from cognitive normality to symptomatic Alzheimer disease. Arch. Neurol. 2009; 66: 1469–1475.
  51. Morris J C., Roe C.M., Xiong C. et al. APOE predicts amyloid-beta but not tau Alzheimer pathology in cognitively normal aging. Ann. Neurol. 2010; 67: 122–131.
  52. Moschos M.M., Tagaris G., Markopoulos I. et al. Morphologic changes and functional retinal impairment in patients with Parkinson disease without visual loss. J. Ophthalmol. 2011; 21: 24–29.
  53. Mosharov E.V., Larsen K.E., Kanter E. et al. Interplay between cytosolic dopamine, calcium, and alpha-synuclein causes selective death of substantia nigra neurons. Neuron 2009; 62; 218–229.
  54. Oh H., Mormino E.C., Madison C., Hayenga A. et al. beta-Amyloid affects frontal and posterior brain networks in normal aging. Neuroimage 2011; 54: 1887–1895.
  55. Petrovitch A., Abbott R.D., Ross G.W. et al. Bowel movement frequency in late-life and substantia nigra neuron density at death. Mov. Disord. 2008; 24: 371–376.
  56. Pieri V., Diederich N.J., Raman R., Goetz C.G. Decreased color discrimination and contrast sensitivity in Parkinson’s disease. J. Neurol. Sci. 2000; 172: 7–11.
  57. Poewe W. Non-motor symptoms in Parkinson’s disease. Eur. J. Neurol. 2008; 15 (Suppl.1): 14–20.
  58. Ponsen M.M., Stoffers D., Booij J. et al. Idiopathic hyposmia as a preclinical sign of Parkinson’s disease. Ann. Neurol. 2004; 56: 173–181.
  59. Postuma R.B., Montplaisir J. Predicting Parkinson’s disease — why, when, and how? Parkinsonism Relat Disord. 2009; 15 (Suppl. 3): S105–109.
  60. Potter W.Z. Mining the secrets of the CSF: developing biomarkers of neurodegeneration. J. Clin. Invest. 2012; 122: 3051–3053.
  61. Price J.L., Ko A.I., Wade M.J. et al. Neuron number in the entorhinal cortex and CA1 in preclinical Alzheimer disease. Arch. Neurol. 2001; 58: 1395–1402.
  62. Rodriguez-Levya I., Renteria-Palomo A.A., Valdes Rodriguez R. et al. Utility of alpha-synuclein as an early diagnostic marker in skin of patients with Parkinson’s disease and parkinsonism plus syndromes. In:
  63. th International Congress of Parkinson’s disease and Movement Disorders: Late breaking abstracts. Toronto, 2011: 6 (LB11).
  64. Ross G.W., Petrovitch H., Abbott R.D. et al. Association of olfactory dysfunction with risk for future Parkinson’s disease. Ann. Neurol. 2008; 63:167–173.
  65. Rowe C.C., Ellis K.A., Rimajova M. et al. Amyloid imaging results from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging. Neurobiol. Aging 2010; 31: 1275–1283.
  66. Ruprecht-Dörfler P., Berg D., Tucha O. et al. Echogenicity of the substantia nigra in relatives of patients with sporadic Parkinson’s disease. Neuroimage 2003; 18: 416–422.
  67. Schuff N. Potential role of high-field MRI for studies in Parkinson’s disease. Mov. Disord. 2009; 24 (Suppl.2): S684–S690.
  68. Selkoe D.J. Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior. Behav. Brain Res. 2008; 192: 106–113.
  69. Shaw L.M., Vanderstichele H., Knapik-Czajka M. et al.
  70. Cerebrospinal fluid biomarker signature in Alzheimer’s disease neuroimaging initiative subjects. Ann. Neurol. 2009; 65: 403–413.
  71. Sheline Y.I., Raichle M.E., Snyder A.Z. et al. Amyloid plaques disrupt resting state default mode network connectivity in cognitively normal elderly. Biol. Psychiatry 2010; 67: 584–587.
  72. Shim Y.S., Morris J.C. Biomarkers predicting Alzheimer’s disease in cognitively normal aging. J. Clin. Neurol. 2011; 7: 60–68.
  73. Small S.A., Duff K. Linking Abeta and tau in late-onset Alzheimer’s disease: a dual pathway hypothesis. Neuron 2008; 60: 534–542.
  74. Sperling R.A., Aisen P.S., Beckett L.A. 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. Alzheimer’s & Dementia 2011; 2: 280–292.
  75. Spiegel J., Möllers M.O., Jost W.H. et al. FP-CIT and MIBG scintigraphy in early Parkinson’s disease. Mov. Disord. 2005; 20: 552–561.
  76. Stern M.B., Siderowf A. Parkinson’s at risk syndrome: can Parkinson’s disease be predicted? Mov. Disord. 2010; 25 (Suppl. 1): S89–S93.
  77. Stern Y. Cognitive reserve and Alzheimer disease. Alzheimer Dis. Assoc. Disord. 2006; 20: 112–117.
  78. Stoessl A.J., Martin W.W., McKeown M.J., Sossi V. Advances in imaging in Parkinson’s disease. Lancet Neurol. 2011; 10: 987–1001.
  79. Tessa C., Gianelly M., Della Nave R. A whole-brain analysis in de novo Parkinson disease. AJNR 2008; 29: 674–680
  80. Uc E.Y., Tippin J., Chou K.L. et al. Non-motor symptoms in Parkinson’s disease. Eur. Neurol. Review 2012; 7: 35–40.
  81. Vaishnavi S.N., Vlassenko A.G., Rundle M.M. et al. Regional aerobic glycolysis in the human brain. Proc. Natl. Acad. Sci. USA 2010; 107: 17757–17762.
  82. Villemagne V.L., Pike K.E., Chetelat G. et al. Longitudinal assessment of Abeta and cognition in aging and Alzheimer disease. Ann. Neurol. 2011; 69:181–192.
  83. Vlaar A.M.M., Bouwmans A., Mess W.H. et al. Transcranial duplex in the differential diagnosis of parkinsonian syndromes. A systematic review. J. Neurol. 2009; 256: 530–538.
  84. Vlassenko A.G., Mintun M.A., Xiong C. et al. Amyloid-beta plaque growth in cognitively normal adults: longitudinal PIB data. Ann. Neurol. 2011; 70: 857–861.
  85. Vlassenko A.G., Vaishnavi S.N., Couture L. et al. Spatial correlation between brain aerobic glycolysis and amyloid-beta (Abeta) deposition. Proc. Natl. Acad. Sci. USA 2010; 107: 17763–17767.
  86. Walter U., Behnke S., Eyding J. et al. Transcranial brain parenchyma sonography in movement disorders: state of the art. Ultrasound Med. Biol. 2007; 33.

Supplementary files

Supplementary Files

Copyright (c) 2013 Illarioshkin S.N., Vlassenko A.G., Fedotova E.Y.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия ПИ № ФС 77-83204 от 12.05.2022.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies