Cell and Tissue Research

, Volume 318, Issue 1, pp 81–92 | Cite as

Histological changes of the dopaminergic nigrostriatal system in aging

  • A. K. StarkEmail author
  • B. Pakkenberg


Although the maximum human lifespan has not increased in recent history, average life expectancy has risen dramatically since the beginning of the last century. Lengthening of lifespan has little merit if the quality of life is not preserved. In the elderly, the decline in memory and cognitive abilities is of great concern, as is motor weakening, which increases with age. The dopaminergic system mediates some aspects of manual dexterity, in addition to cognition and emotion, and may be especially vulnerable to aging. Therefore, the aging of this system has both clinical and vocational aspects. This review includes studies quantitating age-related changes of the nigrostriatal system, with emphasis on the use of stereological methods, and provides tables of stereological studies performed in the nigrostriatal system.


Stereology Total cell number Postmortem Substantia nigra Parkinson’s disease Alzheimer’s disease Aging 



We acknowledge Drs. Julie E. Yoon and Paul Gosink for critical reading of the manuscript.


  1. Aguirre JA, Andbjer B, Gonzalez-Baron S, Hansson A, Stromberg I, Agnati LF, Fuxe K (2001) Group I mGluR antagonist AIDA protects nigral DA cells from MPTP-induced injury. Neuroreport 12:2615–2617CrossRefPubMedGoogle Scholar
  2. Anglade P, Vyas S, Hirsch EC, Agid Y (1997) Apoptosis in dopaminergic neurons of the human substantia nigra during normal aging. Histol Histopathol 12:603–610PubMedGoogle Scholar
  3. Antonini A, Leenders KL (1993) Dopamine D2 receptors in normal human brain: effect of age measured by positron emission tomography (PET) and [11C]-raclopride. Ann N Y Acad Sci 695:81–85PubMedGoogle Scholar
  4. Arranz B, Blennow K, Ekman R, Eriksson A, Mansson JE, Marcusson J (1996) Brain monoaminergic and neuropeptidergic variations in human aging. J Neural Transm 103:101–115Google Scholar
  5. Bannon MJ, Poosch MS, Xia Y, Goebel DJ, Cassin B, Kapatos G (1992) Dopamine transporter mRNA content in human substantia nigra decreases precipitously with age. Proc Natl Acad Sci USA 89:7095–7099PubMedGoogle Scholar
  6. Bohlen und Halbach von, Unsicker K (2002) Morphological alterations in the amygdala and hippocampus of mice during ageing. Eur J Neurosci 16:2434–2440Google Scholar
  7. Bøttcher J (1975) Morphology of the basal ganglia in Parkinson’s disease. Acta Neurol Scand Suppl 62:1–87PubMedGoogle Scholar
  8. Braak H, Goebel HH (1979) Pigmentoarchitectonic pathology of the isocortex in juvenile neural ceroid-lipofuscinosis: axonal enlargements in layer II and cell loss in layer V. Acta Neuropathol 46:79–83PubMedGoogle Scholar
  9. Cabello CR, Thune JJ, Pakkenberg H, Pakkenberg B (2002) Ageing of substantia nigra in humans: cell loss may be compensated by hypertrophy. Neuropathol Appl Neurobiol 28:283–291CrossRefPubMedGoogle Scholar
  10. Calhoun ME, Kurth D, Phinney AL, Long JM, Hengemihle J, Mouton PR, Ingram DK, Jucker M (1998) Hippocampal neuron and synaptophysin-positive bouton number in aging C57BL/6 mice. Neurobiol Aging 19:599–606CrossRefPubMedGoogle Scholar
  11. Cantuti-Castelvetri I, Shukitt-Hale B, Joseph JA (2003) Dopamine neurotoxicity: age-dependent behavioral and histological effects. Neurobiol Aging 24:697–706CrossRefPubMedGoogle Scholar
  12. Canudas AM, Friguls B, Planas AM, Gabriel C, Escubedo E, Camarasa J, Camins A, Pallas M (2000) MPP(+) injection into rat substantia nigra causes secondary glial activation but not cell death in the ipsilateral striatum. Neurobiol Dis 7:343–361CrossRefPubMedGoogle Scholar
  13. Carlsson A (1987) Brain neurotransmitters in aging and dementia: similar changes across diagnostic dementia groups. Gerontology 33:159–167PubMedGoogle Scholar
  14. Carlsson A, Winblad B (1976) Influence of age and time interval between death and autopsy on dopamine and 3-methoxytyramine levels in human basal ganglia. J Neural Transm 38:271–276PubMedGoogle Scholar
  15. Chadi G, Moller A, Rosen L, Janson AM, Agnati LA, Goldstein M, Ogren SO, Pettersson RF, Fuxe K (1993) Protective actions of human recombinant basic fibroblast growth factor on MPTP-lesioned nigrostriatal dopamine neurons after intraventricular infusion. Exp Brain Res 97:145–158PubMedGoogle Scholar
  16. Chen EY, Kallwitz E, Leff SE, Cochran EJ, Mufson EJ, Kordower JH, Mandel RJ (2000) Age-related decreases in GTP-cyclohydrolase-I immunoreactive neurons in the monkey and human substantia nigra. J Comp Neurol 426:534–548CrossRefPubMedGoogle Scholar
  17. Chu Y, Kompoliti K, Cochran EJ, Mufson EJ, Kordower JH (2002) Age-related decreases in Nurr1 immunoreactivity in the human substantia nigra. J Comp Neurol 450:203–214CrossRefPubMedGoogle Scholar
  18. Cross AJ, Crow TJ, Ferrier IN, Johnson JA, Markakis D (1984) Striatal dopamine receptors in Alzheimer-type dementia. Neurosci Lett 52:1–6CrossRefPubMedGoogle Scholar
  19. Cruz-Sánchez FF, Cardozo A, Tolosa E (1995) Neuronal changes in the substantia nigra with aging: a Golgi study. J Neuropathol Exp Neurol 54:74–81PubMedGoogle Scholar
  20. De Keyser J, Ebinger G, Vauquelin G (1990) Age-related changes in the human nigrostriatal dopaminergic system. Ann Neurol 27:157–161PubMedGoogle Scholar
  21. De Keyser J, De Backer JP, Vauquelin G, Ebinger G (1991) D1 and D2 dopamine receptors in human substantia nigra: localization and the effect of aging. J Neurochem 56:1130–1133Google Scholar
  22. DeGiorgio LA, Dibinis C, Milner TA, Saji M, Volpe BT (1998) Histological and temporal characteristics of nigral transneuronal degeneration after striatal injury. Brain Res 795:1–9CrossRefPubMedGoogle Scholar
  23. Dyck CH van, Seibyl JP, Malison RT, Laruelle M, Wallace E, Zoghbi SS, Zea-Ponce Y, Baldwin RM, Charney DS, Hoffer PB (1995) Age-related decline in striatal dopamine transporter binding with iodine-123-beta-CITSPECT. J Nucl Med 36:1175–1181PubMedGoogle Scholar
  24. Emborg ME, Ma SY, Mufson EJ, Levey AI, Taylor MD, Brown WD, Holden JE, Kordower JH (1998) Age-related declines in nigral neuronal function correlate with motor impairments in Rhesus monkeys. J Comp Neurol 401:253–265CrossRefPubMedGoogle Scholar
  25. Esiri MM, Hyman BT, Beyreuther K, Masters CL (1997) Ageing and dementia. In: Graham DI, Lantos PL (eds) Greenfield’s neuropathology, vol 2. Arnold, London, pp 153–233Google Scholar
  26. Faraldi F, Reyes MG, Alfieri E, Levi AC (1994) The aging substantia nigra: quantitative histologic study. Panminerva Med 36:103–108PubMedGoogle Scholar
  27. Fearnley JM, Lees AJ (1991) Ageing and Parkinson’s disease: substantia nigra regional selectively. Brain 114:2283–2301PubMedGoogle Scholar
  28. Felberg RA, Grotta JC, Shirzadi AL, Strong R, Narayana P, Hill-Felberg SJ, Aronowski J (2002) Cell death in experimental intracerebral hemorrhage: the “black hole” model of hemorrhagic damage. Ann Neurol 51:517–524CrossRefPubMedGoogle Scholar
  29. Finch CE (1993) Neuroatrophy during aging: programmed or sporadic? Trends Neurosci 16:104–110CrossRefPubMedGoogle Scholar
  30. Gerhardt GA, Cass WA, Yi A, Zhang Z, Gash DM (2002) Changes in somatodendritic but not terminal dopamine regulation in aged rhesus monkeys. J Neurochem 80:168–177Google Scholar
  31. Gibb WR, Lees AJ (1991) Anatomy, pigmentation, ventral and dorsal subpopulations of the substantia nigra, and differential cell death in Parkinson’s disease. J Neurol Neurosurg Psychiatry 54:388–396Google Scholar
  32. Giovannelli L, Decorosi F, Dolara P, Pulvirenti L (2003) Vulnerability to DNA damage in the aging rat substantia nigra: a study with the comet assay. Brain Res 969:244–247CrossRefPubMedGoogle Scholar
  33. Godefroy F, Bassant MH, Weil-Fugazza J, Lamour Y (1989) Age-related changes in dopaminergic and serotonergic indices in the rat forebrain. Neurobiol Aging 10:187–190CrossRefPubMedGoogle Scholar
  34. Gundersen HJG (1985) Stereology of arbitrary particles: a review of unbiased number and size estimators and the presentation of some new ones, in memory of William R. Thomsen. J Microsc 143:3–45Google Scholar
  35. Himi T, Cao M, Mori N (1995) Reduced expression of the molecular markers of dopaminergic neuronal atrophy in the aging rat brain. J Gerontol A Biol Sci Med Sci 50:B193–B200PubMedGoogle Scholar
  36. Itoh K, Weis S, Mehraein P, Muller-Hocker J (1996) Cytochrome c oxidase defects of the human substantia nigra in normal aging. Neurobiol Aging 17:843–848Google Scholar
  37. Jagadha V, Becker LE (1988) Brain morphology in Duchenne muscular dystrophy: a Golgi study. Pediatr Neurol 4:87–92CrossRefPubMedGoogle Scholar
  38. Kaasinen V, Rinne JO (2002) Functional imaging studies of dopamine system and cognition in normal aging and Parkinson’s disease. Neurosci Biobehav Rev 26:785–793CrossRefPubMedGoogle Scholar
  39. Katzung BG (1998) Introduction to autonomic pharmacology. In: Katzung BG (ed) Basic and clinical pharmacology. Appleton and Lange, Stamford, pp 73–89Google Scholar
  40. Kemppainen N, Roytta M, Collan Y, Ma SY, Hinkka S, Rinne JO (2002) Unbiased morphological measurements show no neuronal loss in the substantia nigra in Alzheimer’s disease. Acta Neuropathol 103:43–47CrossRefPubMedGoogle Scholar
  41. Kish SJ, Shannak K, Rajput A, Deck JH, Hornykiewicz O (1992) Aging produces a specific pattern of striatal dopamine loss: implications for the etiology of idiopathic Parkinson’s disease. J Neurochem 58:642–648Google Scholar
  42. Knapowski J, Wieczorowska-Tobis K, Witowski J (2002) Pathophysiology of ageing. J Physiol Pharmacol 53:135–146PubMedGoogle Scholar
  43. Kubis N, Faucheux BA, Ransmayr G, Damier P, Duyckaerts C, Henin D, Forette B, Le Charpentier Y, Hauw J-J, Agid Y, Hirsch EC (2000) Preservation of midbrain catecholaminergic neurons in very old human subjects. Brain 123:366–373CrossRefPubMedGoogle Scholar
  44. Lai H, Bowden DM, Horita A (1987) Age-related decreases in dopamine receptors in the caudate nucleus and putamen of the rhesus monkey (Macaca mulatta). Neurobiol Aging 8:45–49CrossRefPubMedGoogle Scholar
  45. Luo Y, Roth GS (2000) The roles of dopamine oxidative stress and dopamine receptor signaling in aging and age-related neurodegeneration. Antioxid Redox Signal 2:449–460CrossRefPubMedGoogle Scholar
  46. Ma SY, Roytt M, Rinne JO, Collan Y, Rinne UK (1997) Correlation between neuromorphometry in the substantia nigra and clinical features in Parkinson’s disease using disector counts. J Neurol Sci 151:83–87Google Scholar
  47. Ma SY, Ciliax BJ, Stebbins G, Jaffar S, Joyce JN, Cochran EJ, Kordower JH, Mash DC, Levey AI, Mufson EJ (1999a) Dopamine transporter-immunoreactive neurons decrease with age in the human substantia nigra. J Comp Neurol 409:25–37CrossRefPubMedGoogle Scholar
  48. Ma SY, Roytt M, Collan Y, Rinne JO (1999b) Unbiased morphometrical measurements show loss of pigmented nigral neurones with ageing. Neuropathol Appl Neurobiol 25:394–399CrossRefPubMedGoogle Scholar
  49. Mann DM, Yates PO (1974) Lipoprotein pigments—their relationship to ageing in the human nervous system. II. The melanin content of pigmented nerve cells. Brain 97:489–498PubMedGoogle Scholar
  50. Mann DM, Yates PO (1979) The effects of ageing on the pigmented nerve cells of the human locus caeruleous and substantia nigra. Acta Neuropathol 47:93–97PubMedGoogle Scholar
  51. Mann DM, Yates PO, Barton CM (1977) Variations in melanin content with age in the human substantia nigra. Biochem Exp Biol 13:137–139PubMedGoogle Scholar
  52. Mann DM, Yates PO, Marcyniuk B (1984) Monoaminergic neurotransmitter systems in presenile Alzheimer’s disease and in senile dementia of Alzheimer type. Clin Neuropathol 3:199–205PubMedGoogle Scholar
  53. McGeer PL, McGeer EG, Suzuki JS (1977) Aging and extrapyramidal function. Arch Neurol 34:33–35PubMedGoogle Scholar
  54. Mesco ER, Carlson SG, Joseph JA, Roth GS (1993) Decreased striatal D2 dopamine receptor mRNA synthesis during aging. Brain Res Mol Brain Res 17:160–162CrossRefPubMedGoogle Scholar
  55. Miller GW, Staley JK, Heilman CJ, Perez JT, Mash DC, Rye DB, Levey AI (1997) Immuno-chemical analysis of dopamine transporter protein in Parkinson’s disease. Ann Neurol 41:530–539PubMedGoogle Scholar
  56. Morgan DG, Finch CE (1988) Dopaminergic changes in the basal ganglia. A generalized phenomenon of aging in mammals. Ann N Y Acad Sci 515:145–160PubMedGoogle Scholar
  57. Morgan DG, Marcusson JO, Nyberg P, Wester P, Winblad B, Gordon MN, Finch CE (1987) Divergent changes in D-1 and D-2 dopamine binding sites in human brain during aging. Neurobiol Aging 8:195–201CrossRefPubMedGoogle Scholar
  58. Møller A (1992) Mean volume of pigmented neurons in the substantia nigra in Parkinson’s disease. Acta Neurol Scand Suppl 137:37–39PubMedGoogle Scholar
  59. Muthane U, Yasha TC, Shankar SK (1998) Low numbers and no loss of melanized nigral neurons with increasing age in normal human brains from India. Ann Neurol 43:283–287PubMedGoogle Scholar
  60. Nabeshima T, Yamada K, Hayashi T, Hasegawa T, Ishihara S, Kameyama T, Morimasa T, Kaneyuki T, Shohmori T (1994) Changes in muscarinic cholinergic, PCP, GABAA, D1, and 5-HT2A receptor binding, but not in benzodiazepine receptor binding in the brains of aged rats. Life Sci 55:1585–1593CrossRefPubMedGoogle Scholar
  61. Naoi M, Maruyama W (1999) Cell death of dopamine neurons in aging and Parkinson’s disease. Mech Ageing Dev 111:175–188CrossRefPubMedGoogle Scholar
  62. Oorschot DE (1996) Total number of neurons in the neostriatal, pallidal, subthalamic, and substantia nigral nuclei of the rat basal ganglia: a stereological study using the Cavalieri and optical disector methods. J Comp Neurol 366:580–599CrossRefPubMedGoogle Scholar
  63. Pakkenberg B, Gundersen HJG (1997) Neocortical neuron number in humans: effect of sex and age. J Comp Neurol 384:312–320CrossRefPubMedGoogle Scholar
  64. Pakkenberg B, Moller A, Gundersen HJ, Mouritzen Dam A, Pakkenberg H (1991) The absolute number of nerve cells in substantia nigra in normal subjects and in patients with Parkinson’s disease estimated with an unbiased stereological method. J Neurol Neurosurg Psychiatry 54:30–33Google Scholar
  65. Pakkenberg H, Andersen BB, Burns RS, Pakkenberg B (1995) A stereological study of substantia nigra in young and old rhesus monkeys. Brain Res 693:201–206CrossRefPubMedGoogle Scholar
  66. Perl DP, Good PF, Bussiere T, Morrison JH, Erwin JM, Hof PR (2000) Practical approaches to stereology in the setting of aging- and disease-related brain banks. J Chem Neuroanat 20:7–19CrossRefPubMedGoogle Scholar
  67. Peterson DA, Dickinson-Anson HA, Leppert JT, Lee KF, Gage FH (1999) Central neuronal loss and behavioral impairment in mice lacking neurotrophin receptor p75. J Comp Neurol 404:1–20CrossRefPubMedGoogle Scholar
  68. Poyot T, Conde F, Gregoire MC, Frouin V, Coulon C, Fuseau C, Hinnen F, Dolle F, Hantraye P, Bottlaender M (2001) Anatomic and biochemical correlates of the dopamine transporter ligand 11C-PE2I in normal and parkinsonian primates: comparison with 6-[18F]fluoro-l-dopa. J Cereb Blood Flow Metab 21:782–792CrossRefPubMedGoogle Scholar
  69. Rapp PR, Gallagher M (1996) Preserved neuron number in the hippocampus of aged rats with spatial learning deficits. Proc Natl Acad Sci USA 93:9926–9930CrossRefPubMedGoogle Scholar
  70. Rasmussen T, Schliemann T, Sorensen JC, Zimmer J, West MJ (1996) Memory impaired aged rats: no loss of principal hippocampal and subicular neurons. Neurobiol Aging 17:143–147Google Scholar
  71. Reeves S, Bench C, Howard R (2002) Ageing and the nigrostriatal dopaminergic system. Int J Geriatr Psychiatry 17:359–370Google Scholar
  72. Rinne JO (1987) Muscarinic and dopaminergic receptors in the aging human brain. Brain Res 404:162–168CrossRefPubMedGoogle Scholar
  73. Rinne JO, Lonnberg P, Marjamaki P (1990) Age-dependent decline in human brain dopamine D1 and D2 receptors. Brain Res 508:349–352CrossRefPubMedGoogle Scholar
  74. Rinne JO, Hietala J, Ruotsalainen U, Sako E, Laihinen A, Nagren K, Lehikoinen P, Oikonen V, Syvalahti E (1993) Decrease in human striatal dopamine D2 receptor density with age: a PET study with [11C]raclopride. J Cereb Blood Flow Metab 13:310–314PubMedGoogle Scholar
  75. Seeman P, Bzowej NH, Guan HC, Bergeron C, Becker LE, Reynolds GP, Bird ED, Riederer P, Jellinger K, Watanabe S, et al (1987) Human brain dopamine receptors in children and aging adults. Synapse 1:399–404PubMedGoogle Scholar
  76. Severson JA, Marcusson J, Winblad B, Finch CE (1982) Age-correlated loss of dopaminergic binding sites in human basal ganglia. J Neurochem 39:1623–1631Google Scholar
  77. Siddiqi Z, Kemper TL, Killiany R (1999) Age-related neuronal loss from the substantia nigra-pars compacta and ventral tegmental area of the rhesus monkey. J Neuropathol Exp Neurol 58:959–971Google Scholar
  78. Simic G, Kostovic I, Winblad B, Bogdanovic N (1997) Volume and number of neurons of the human hippocampal formation in normal aging and Alzheimer’s disease. J Comp Neurol 379:482–494CrossRefPubMedGoogle Scholar
  79. Stanford JA, Vorontsova E, Surgener SP, Gerhardt GA, Fowler SC (2003) Aged Fischer 344 rats exhibit altered orolingual motor function: relationships with nigrostriatal neurochemical measures. Neurobiol Aging 24:259–266CrossRefPubMedGoogle Scholar
  80. Sugama S, Yang L, Cho BP, DeGiorgio LA, Lorenzl S, Albers DS, Beal MF, Volpe BT, Joh TH (2003) Age-related microglial activation in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurodegeneration in C57BL/6 mice. Brain Res 964:288–294CrossRefPubMedGoogle Scholar
  81. Suhara T, Fukuda H, Inoue O, Itoh T, Suzuki K, Yamasaki T, Tateno Y (1991) Age-related changes in human D1 dopamine receptors measured by positron emission tomography. Psychopharmacology 103:41–45PubMedGoogle Scholar
  82. Theoret H, Boire D, Herbin M, Ptito M (1999) Stereological evaluation of substantia nigra cell number in normal and hemispherectomized monkeys. Brain Res 835:354–359CrossRefPubMedGoogle Scholar
  83. Thiessen B, Rajput AH, Desai H (1990) Age, environments, and the number of substantia nigra neurons. Adv Neurol 53:201–206PubMedGoogle Scholar
  84. Tooyama I, McGeer EG, Kawamata T, Kimura H, McGeer PL (1994) Retention of basic fibroblast growth factor immunoreactivity in dopaminergic neurons of the substantia nigra during normal aging in humans contrasts with loss in Parkinson’s disease. Brain Res 656:165–168CrossRefPubMedGoogle Scholar
  85. Uchida K, Kihara N, Hashimoto K, Nakayama H, Yamaguchi R, Tateyama S (2003) Age-related histological changes in the canine substantia nigra. J Vet Med Sci 65:179–185CrossRefPubMedGoogle Scholar
  86. Van de Berg WD, Schmitz C, Steinbusch HW, Blanco CE (2002) Perinatal asphyxia induced neuronal loss by apoptosis in the neonatal rat striatum: a combined TUNEL and stereological study. Exp Neurol 174:29–36CrossRefPubMedGoogle Scholar
  87. Volkow ND, Ding YS, Fowler JS, Wang GJ, Logan J, Gatley SJ, Hitzemann R, Smith G, Fields SD, Gur R (1996) Dopamine transporters decrease with age. J Nucl Med 37:554–559PubMedGoogle Scholar
  88. Volpe BT, Wildmann J, Altar CA (1998) Brain-derived neurotrophic factor prevents the loss of nigral neurons induced by excitotoxic striatal-pallidal lesions. Neuroscience 83:741–748CrossRefPubMedGoogle Scholar
  89. Wang Y, Chan GL, Holden JE, Dobko T, Mak E, Schulzer M, Huser JM, Snow BJ, Ruth TJ, Calne DB, Stoessl AJ (1998) Age-dependent decline of dopamine D1 receptors in human brain: a PET study. Synapse 30:56–61CrossRefPubMedGoogle Scholar
  90. West MJ, Ostergaard K, Andreassen OA, Finsen B (1996) Estimation of the number of somatostatin neurons in the striatum: an in situ hybridization study using the optical fractionator method. J Comp Neurol 370:11–22CrossRefPubMedGoogle Scholar
  91. West MJ, Kawas CH, Martin LJ, Troncoso JC (2000) The CA1 region of the human hippocampus is a hot spot in Alzheimer’s disease. Ann N Y Acad Sci 908:255–259PubMedGoogle Scholar
  92. Wong DF, Broussolle EP, Wand G, Villemagne V, Dannals RF, Links JM, Zacur HA, Harris J, Naidu S, Braestrup C, et al (1988) In vivo measurement of dopamine receptors in human brain by positron emission tomography. Age and sex differences. Ann N Y Acad Sci 515:203–214PubMedGoogle Scholar
  93. Zaborszky L, Vadasz C (2001) The midbrain dopaminergic system: anatomy and genetic variation in dopamine neuron number of inbred mouse strains. Behav Genet 31:47–59CrossRefPubMedGoogle Scholar
  94. Zhao M, Momma S, Delfani K, Carlen M, Cassidy RM, Johansson CB, Brismar H, Shupliakov O, Frisen J, Janson AM (2003) Evidence for neurogenesis in the adult mammalian substantia nigra. Proc Natl Acad Sci USA 100:7925–7930CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  1. 1.Research Laboratory for Stereology and NeuroscienceBispebjerg University HospitalCopenhagenDenmark

Personalised recommendations