Presymptomatic and Symptomatic Stages of Intracerebral Inclusion Body Pathology in Idiopathic Parkinson’s Disease

  • Heiko Braak
  • Kelly Del Tredici
Chapter

Abstract

The pathological process that underlies idiopathic Parkinson’s disease (IPD) progresses relentlessly and requires years to reach its full extent, provided it is not terminated prematurely by death. The severity of the pathology increases gradually during the course of the disorder (1, 2, 3, 4, 5, 6, 7, 8). As such, the lesions develop already, to a mild or moderate degree, even in the nervous system of persons whose clinical protocols fail to note the onset or presence of classical IPD-associated motor symptoms (9, 10, 11, 12, 13, 14, 15, 16, 17). Thus, the course of the disease process can be subdivided into presymptomatic and symptomatic phases (Fig. 1A). (3, 5) Like the tip of an iceberg, it is only the symptomatic, later phase of the larger degenerative process that presently can be detected clinically.

Fig. 1. (A)

Presymptomatic and symptomatic phases of idiopathic Parkinson’s disease (IPD). The presymptomatic phase of the disorder is characterized by the appearance of IPD-associated lesions in the brain of asymptomatic persons. Individuals first become symptomatic when the neuropathological threshold is exceeded (approximated by the white vertical line). Increasing density of the shading in areas underneath the diagonal indicates the growing severity of the pathology in vulnerable key regions indicated at the right-hand margin. Arabic numerals mark the stages of the neuropathological process. (B-D) Schematic diagrams showing the gradual ascent of the pathological process underlying IPD (white arrows). (E) Selective vulnerability and resistance of specific neuronal types to IPD. Projection cells that generate long and thin axons are among the nerve cell types most vulnerable to the pathology, whereas projection cells and local circuit neurons with short axon resist the lesions. Heavy axonal myelination offers the following advantages: high speed of conduction, low energy expenditure, greater stability of the parent neuron. Resistant against IPD-related pathology are long-axoned and sturdily myelinated projection neurons. In contrast, vulnerable neuronal types give off unmyelinated or poorly myelinated and thin axons. Reproduced from ref. 6 with permission from Steinkopff Verlag.

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References

  1. 1.
    Fearnley J, Lees A. Pathology of Parkinson’s disease. In: Calne DB, ed. Neurodegenerative Diseases. Philadelphia: Saunders, 1994:545–554.Google Scholar
  2. 2.
    Forno LS. Neuropathology of Parkinson’s disease. J Neuropathol Exp Neurol 1996; 55:259–272.PubMedCrossRefGoogle Scholar
  3. 3.
    Braak H, Braak E. Pathoanatomy of Parkinson’s disease. J Neurol (Suppl 2) 2000; 247:3–10.CrossRefGoogle Scholar
  4. 4.
    Braak H, de Vos RAI, Jansen ENH, Bratzke HJ, Braak E. Neuropathological hallmarks of Alzheimer’s and Parkinson’s diseases. Progr Brain Res 1998; 117:267–285.CrossRefGoogle Scholar
  5. 5.
    Braak H, del Tredici K, Bratzke H, Hamm-Clement J, Sandmann-Keil D, Rüb U. Staging of the intracerebral inclusion body pathology associated with idiopathic Parkinson’s disease (preclinical and clinical stages). J Neurol (Suppl 3) 2002; 249:1–5.CrossRefGoogle Scholar
  6. 6.
    Braak H, del Tredici K, Rüb U, de Vos RAI, Jansen Steur ENH, Braak E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 2003; 24:197–210.PubMedCrossRefGoogle Scholar
  7. 7.
    del Tredici K, Rüb U, de Vos RAI, Bohl JRE, Braak H. Where does Parkinson disease pathology begin in the brain? J Neuropathol Exp Neurol 2002; 61:413–426.PubMedGoogle Scholar
  8. 8.
    Takahashi H, Wakabayashi K. The cellular pathology of Parkinson’s disease. Neuropathology 2001; 21:315–322.PubMedCrossRefGoogle Scholar
  9. 9.
    Hoehn MM, Yahr MD. Parkinsonism: onset, progression, and mortality. Neurology 1967; 17:427–442.PubMedGoogle Scholar
  10. 10.
    Calne DB, Snow BJ, Lee C. Criteria for diagnosing Parkinson’s disease. Ann Neurol 1992; 32:125–127.CrossRefGoogle Scholar
  11. 11.
    Koller WC. When does Parkinson’s disease begin? Neurology 1992; 42(Suppl 4):27–31.PubMedGoogle Scholar
  12. 12.
    Sawle GV. The detection of preclinical Parkinson’s disease: what is the role of positron emission tomography? Mov Disord 1993; 8:271–277.PubMedCrossRefGoogle Scholar
  13. 13.
    Rajput AH. Clinical features and natural history of Parkinson’s disease (special consideration of aging). In: Calne DP, ed. Neurodegenerative Diseases. Philadelphia: Saunders, 1994:555–571.Google Scholar
  14. 14.
    de Vos RAI, Jansen ENH, Yilmazer D, Braak H, Braak E. Pathological and clinical features of Parkinson’s disease with and without dementia. In: Perry RH, McKeith IG, Perry EK, eds. Dementia with Lewy Bodies. New York: Cambridge University Press, 1996:255–267.Google Scholar
  15. 15.
    Poewe WH, Wenning GK. The natural history of Parkinson’s disease. Ann Neurol 1998; 44(Suppl 1):1–9.Google Scholar
  16. 16.
    Gelb DJ, Oliver E, Gilman S. Diagnostic criteria for Parkinson’s disease. Arch Neurol 1999; 56:33–39.PubMedCrossRefGoogle Scholar
  17. 17.
    Wolters EC, Francot C, Bergmans P, et al. Preclinical (premotor) Parkinson’s disease. J Neurol 2000; 247(Suppl 2):103–109.Google Scholar
  18. 18.
    Lewy FH. Paralysis agitans. I. Pathologische Anatomie. In: Lewandowski M, ed. Handbuch der Neurologie. Vol. 3. Berlin: Springer, 1912:920–933.Google Scholar
  19. 19.
    Gibb WRG, Scott T, Lees AJ. Neuronal inclusions of Parkinson’s disease. Mov Disord 1991; 6:2–11.PubMedCrossRefGoogle Scholar
  20. 20.
    Pollanen MS, Dickson DW, Bergeron C. Pathology and biology of the Lewy body. J Neuropathol Exp Neurol 1993; 52:183–191.PubMedCrossRefGoogle Scholar
  21. 21.
    Lowe J. Lewy bodies. In: Calne DP, ed. Neurodegenerative Diseases. Philadelphia: Saunders, 1994:51–69.Google Scholar
  22. 22.
    McNaught KSP, Shashidharan P, Perl DP, Jenner P, Olanow CW. Aggresome-related biogenesis of Lewy bodies. Eur J Neurosci 2002; 16:2136–2148.PubMedCrossRefGoogle Scholar
  23. 23.
    Wakabayashi K, Takahashi H, Obata K, Ikuta F. Immunocytochemical localization of synaptic vesicle-specific protein in Lewy body-containing neurons in Parkinson’s disease. Neurosci Lett 1992; 138:237–240.PubMedCrossRefGoogle Scholar
  24. 24.
    Spillantini MG, Schmidt ML, Lee VMY, Trojanowski JQ, Jakes R, Goedert M. α-synuclein in Lewy bodies. Nature 1997; 388:839–840.PubMedCrossRefGoogle Scholar
  25. 25.
    Giasson BI, Galvin JE, Lee VM-Y, Trojanowski JQ. The cellular and molecular pathology of Parkinson’s disease. In: Clark CM, Trojanowski JQ, eds. Neurodegenerative dementias: Clinical Features and Pathological Mechanisms. New York: McGraw-Hill, 2000:219–228.Google Scholar
  26. 26.
    Jensen PH, Gai WP. Alpha-synuclein. Axonal transport, ligand interaction, and neurodegeneration. In: Tolnay M, Probst A, eds. Neuropathology and Genetics of dementia. New York: Kluwer Academic/Plenum 2001:129–134.Google Scholar
  27. 27.
    Braak H, del Tredici K, Gai WP, Braak E. Alpha-synuclein is not a requisite component of synaptic boutons in the adult human central nervous system. J Chem Neuroanat 2001; 20:245–252.CrossRefGoogle Scholar
  28. 28.
    Perrin RJ, Woods WS, Clayton DF, George JM. Interaction of human alpha-synuclein and Parkinson’s disease variants with phospholipids. J Biol Chem 2000; 44:34,393-34,398.Google Scholar
  29. 29.
    Kopito RR. Aggresomes, inclusion bodies and protein aggregation. Trends Cell Biol 2000; 10:524–530.PubMedCrossRefGoogle Scholar
  30. 30.
    Trojanowski JQ, Lee VMY. “Fatal attractions” of proteins. A comprehensive hypothetical mechanism unrlying Alzheimer’s disease and other neurodegenerative disorders. Ann NY Acad Sci 2000; 924:62–67.PubMedGoogle Scholar
  31. 31.
    Uversky VN, Li J, Fink AL. Evidence for a partially folded intermediate in α-synuclein fibril formation. J Biol Chem 2001; 276:10,737–10,744.PubMedCrossRefGoogle Scholar
  32. 32.
    Walker LC, LeVine H. The cerebral proteopathies. Neurodegenerative disorders of protein conformation and assembly. Mol Neurobiol 2001; 21:83–95.CrossRefGoogle Scholar
  33. 33.
    Chung KKK, Dawson VL, Dawson TM. The role of the ubiquitin-proteasomal pathway in Parkinson’s disease and other neurodegenerative disorders. Trends Neurosci 2001; 24: 7–14.CrossRefGoogle Scholar
  34. 34.
    McNaught KSP, Jenner P. Proteasomal function is impaired in substantia nigra in Parkinson’s disease. Neurosci Lett 2001; 297:191–194.PubMedCrossRefGoogle Scholar
  35. 35.
    McNaught KSP, Belizaire R, Isacson O, Jenner P, Olanow CW. Altered proteasomal function in sporadic Parkinson’s disease. Exp Neurol 2003; 179:38–46.PubMedCrossRefGoogle Scholar
  36. 36.
    Olanow CW. An introduction to the free radical hypothesis in Parkinson’s disease. Ann Neurol 1992; 32:2–9.CrossRefGoogle Scholar
  37. 37.
    Beal MF. Aging, energy, and oxidative stress in neurodegenerative diseases. Ann Neurol 1995; 38:357–366.PubMedCrossRefGoogle Scholar
  38. 38.
    Trojanowski JQ, Lee VMY. Aggregation of neurofilament and α-synuclein proteins in Lewy bodies—implications for the pathogenesis of Parkinson-disease and Lewy body dementia. Arch Neurol 1998; 55:151–152.PubMedCrossRefGoogle Scholar
  39. 39.
    Dickson DW. Tau and synuclein and their role in neuropathology. Brain Pathol 1999; 9:657–661.PubMedCrossRefGoogle Scholar
  40. 40.
    Golbe LI. Alpha-synuclein and Parkinson’s disease. Mov Disord 1999; 14:6–9.PubMedCrossRefGoogle Scholar
  41. 41.
    Goedert M. Filamentous nerve cell inclusions in neurodegenerative diseases: tauopathies and α-synucleinopathies. Phil Trans R Soc Lond B. 1999; 354:1101–1108.CrossRefGoogle Scholar
  42. 42.
    Duda JE, Lee VMY, Trojanowski JQ. Neuropathology of synuclein aggregates: new insights into mechanism of neurodegenerative diseases. J Neurosci Res 2000; 61: 121–127.PubMedCrossRefGoogle Scholar
  43. 43.
    Goedert M, Spillantini MG. Tauopathies and α-synucleinopathies. In: Lee VMY, Trojanowski JQ, Bué L, Christen Y, eds. Fatal Attractions: Protein Aggregates in Neurodegenerative Disorders. Berlin: Springer, 2000:66–86.Google Scholar
  44. 44.
    Galvin JE, Lee VMY, Trojanowski JQ. Synucleinopathies. Clinical and pathological implications. Arch Neurol 2001; 58:186–190.PubMedCrossRefGoogle Scholar
  45. 45.
    Goedert M. The significance of tau and α-synuclein inclusions in neurodegenerative diseases. Curr Opin Genet dev 2001; 11:343–351.PubMedCrossRefGoogle Scholar
  46. 46.
    Arawaka S, Saito Y, Murayama S, Mori H. Lewy body in neuro degeneration with brain iron accumulation type 1 is immunoreactive for α-synuclein. Neurology 1998; 51:887–889.PubMedGoogle Scholar
  47. 47.
    Gai WP, Power JHT, Blumbergs PC, Blessing WW. Multiple-system atrophy: a new α-synuclein disease? Lancet 1998; 352:547–548.PubMedCrossRefGoogle Scholar
  48. 48.
    Gai WP, Power JH, Blumbergs PC, Culvenor JG, Jensen PH. Alpha-synuclein immunoisolation of glial inclusions from multiple system atrophy brain tissue reveals multiprotein components. J Neurochem 1999; 73:2093–2100.PubMedGoogle Scholar
  49. 49.
    Braak H, Braak E, Yilmazer D, Schultz C, Bohl J. Age-related changes of the human cerebral cortex. In: Cruz-Sanchez FF, Ravid R, Cuzner ML, Neuropathological Diagnostic Criteria for Brain Banking. Biomedical Health Research, Vol. 10. Amsterdam: IOS Press, 1995:14–19.Google Scholar
  50. 50.
    Dickson DW. Aging in the central nervous system. In: Markesbery WR, ed. Neuropathology of dementing Disorders. London, New York: Arnold, 1998:56–88.Google Scholar
  51. 51.
    Hassler R. Zur Pathologie der Paralysis agitans und des postencephalitischen Parkinsonismus. J Psychol Neurol 1938; 48:387–476.Google Scholar
  52. 52.
    Jellinger K. Pathology of Parkinson’s disease. Changes other than the nigrostriatal pathway. Mol Chem Neuropathol 1991; 14:153–197.PubMedCrossRefGoogle Scholar
  53. 53.
    Braak H, Rüb U, Gai WP, del Tredici K. Idiopathic Parkinson’s disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J Neural Transm 2003; 110:517–536.PubMedCrossRefGoogle Scholar
  54. 54.
    Nieuwenhuys R. Structure and organisation of fibre systems. In: Nieuwenhuys R, Ten Donkelaar HJ, Nicholson C, eds. The Central Nervous System of Vertebrates. Vol. 1. Berlin: Springer, 1999:113–157.Google Scholar
  55. 55.
    Kapfhammer JP, Schwab ME. Inverse patterns of myelination and GAP-43 expression in the adult CNS: neurite growth inhibitors as regulators of neuronal plasticity. J Comp Neurol 1994; 340:194–206.PubMedCrossRefGoogle Scholar
  56. 56.
    Sanides F. Comparative architectonics of the neocortex of mammals and their evolutionary interpretation. Ann NY Acad Sci 1969; 167:404–423.CrossRefGoogle Scholar
  57. 57.
    Braak H. Architectonics of the Human Telencephalic Cortex. Berlin: Springer, 1980:1–147.Google Scholar
  58. 58.
    Zilles K. Architecture of the human cortex. In: Paxinos G, Mai JK, eds. The Human Nervous System. 2nd ed. San Diego, CA: Academic Press, 2004: 997–1060.Google Scholar
  59. 59.
    Insausti R, Amaral DG. Hippocampal formation. In: Paxinos G, Mai JK, eds. The Human Nervous System. 2nd ed. San Diego, CA: Academic Press, 2004: 872–915.Google Scholar
  60. 60.
    Witter MP. Organization of the entorhinal-hippocampal system: A review of current anatomical data. Hippocampus 1993;3:33–44.PubMedGoogle Scholar
  61. 61.
    Braak H, Braak E. The human entorhinal cortex: normal morphology and lamina-specific pathology in various diseases. Neurosci Res 1992; 15:6–31.PubMedCrossRefGoogle Scholar
  62. 62.
    Pandya DN, Yeterian EH. Architecture and connections of cerebral cortex: implications for brain evolution and function. In: Scheibel AB, Wechsler AF, eds. Neurobiology of Higher Function. New York: Guilford Press, 1990:53–84.Google Scholar
  63. 63.
    Rockland KS, Pandya DN. Laminar origins and terminations of cortical connections of the occipital lobe in the rhesus monkey. Brain Res 1979; 179:3–20.PubMedCrossRefGoogle Scholar
  64. 64.
    Alexander GE, Crutcher MD, DeLong MR. Basal ganglia-thalamocortical circuits: Parallel substrates for motor, oculomotor, “prefrontal” and “limbic” functions. Progr Brain Res 1990; 85:119–146.CrossRefGoogle Scholar
  65. 65.
    Haber SN, Gdowski MJ. The basal ganglia. In:Paxinos G, Mai JK, eds. The Human Nervous System. 2nd ed. San Diego, CA: Academic Press, 2004:677–738.Google Scholar
  66. 66.
    Albin RL, Young AB, Peney JB. The functional anatomy of disorders of the basal ganglia. Trends Neurosci 1995; 18:63–64.PubMedCrossRefGoogle Scholar
  67. 67.
    Nauta HJW. Circuitous connections linking cerebral cortex, limbic system, and corpus striatum. In: Doane BK, Livingstone KE, eds. The Limbic System. New York: Raven Press, 1986:43–54.Google Scholar
  68. 68.
    Heimer L, Switzer RD, van Hoesen GW. Ventral striatum and ventral pallidum. Components of the motor system? Trends Neurosci 1982; 5:83–87.CrossRefGoogle Scholar
  69. 69.
    Heimer L, de Olmos J, Alheid GF, Zaborszky L. “Perestroikarr in the basal forebrain: Opening the border between neurology and psychiatry. Progr Brain Res 1991; 87:109–165.CrossRefGoogle Scholar
  70. 70.
    Huang XF, Törk I, Paxinos G. Dorsal motor nucleus of the vagus nerve: a cyto-and chemoarchitectonic study in the human. J Comp Neurol 1993; 330:158–182.PubMedCrossRefGoogle Scholar
  71. 71.
    Hopkins DA, Bieger D, de Vente J, Steinbusch HWM. Vagal efferent projections: viscerotopy, neurochemistry and effects of vagotomy. Progr Brain Res 1996; 107:79–96.CrossRefGoogle Scholar
  72. 72.
    Wakabayashi K, Takahashi H, Ohama E, Ikuta F. Parkinson’s disease: an immunohistochemical study of Lewy body-containing neurons in the enteric nervous system. Acta Neuropathol 1990; 79:581–583.PubMedCrossRefGoogle Scholar
  73. 73.
    Wakabayashi K, Takahashi H, Ohama E, Takeda S, Ikuta F. Lewy bodies in the visceral autonomic nervous system in Parkinson’s disease. Adv Neurol 1993; 60:609–612.PubMedGoogle Scholar
  74. 74.
    Holstege G. The emotional motor system. Europ J Morphol 1992; 30:67–79.Google Scholar
  75. 75.
    Holstege G. The somatic motor system. Progr Brain Res 1996;107:9–26.CrossRefGoogle Scholar
  76. 76.
    Martin GF, Holstege G, Mehler WM. Reticular formation of the pons and medulla. In: Paxinos G, ed. The Human Nervous System, New York: Academic Press 1990:203–220.Google Scholar
  77. 77.
    Nieuwenhuys R. The greater limbic system, the emotional motor system and the brain. Progr Brain Res 1996; 107:551–580.CrossRefGoogle Scholar
  78. 78.
    Braak H, Rüb U, Sandmann-Keil D, et al. Parkinson’s disease: affection of brain stem nuclei controlling premotor and motor neurons of the somatomotor system. Acta Neuropathol 2000; 99:489–495.PubMedCrossRefGoogle Scholar
  79. 79.
    Del Tredici K, Braak H. Idiopathic Parkinson’s disease: Staging an α-synucleinopathy with a predictable pathoanatomy. In: Kahle P, Haass C, eds. Molecular Mechanisms in Parkinson’s Disease. Georgetown, TX: Landes Bioscience Press, 2004:1–32.Google Scholar
  80. 80.
    Yakovlev PI, Lecours AR. The myelogenetic cycles of regional maturation of the brain. In: Minkowksi A, ed. Regional Development of the Brain in Early Life. Oxford: Blackwell, 1967:3–70.Google Scholar
  81. 81.
    Kinney HC, Brody BA, Kloman AS, Gilles FH. Sequence of central nervous system myelination in human infancy. II. Patterns of myelination in autopsied infants. J Neuropathol Exp Neurol 1988; 47:217–234.PubMedCrossRefGoogle Scholar
  82. 82.
    Hasegawa M, Houdou S, Mito T, Takashima S, Asanuma K, Ohno T. Development of myelination in the human fetal and infant cerebrum: a myelin basic protein immunohisto-chemical study. Brain Dev 1992; 14:1–6.PubMedGoogle Scholar
  83. 83.
    Hassler R. Zur Normalanatomie der Substantia nigra. Versuch einer architektonischen Gliederung. J Psychol Neurol 1937; 48:1–55.Google Scholar
  84. 84.
    Braak H, Braak E. Nuclear configuration and neuronal types of the nucleus niger in the brain of the human adult. Human Neurobiol 1986;5:71–82.Google Scholar
  85. 85.
    Gibb WRG, Lees AJ. Anatomy, pigmentation, ventral and dorsal subpopulations of the substantia nigra, and differential cell death in Parkinson’s disease. J Neurol Neurosurg Psychiatry 1991;54:388–396.PubMedCrossRefGoogle Scholar
  86. 86.
    van Domburg PHMF, ten Donkelaar HJ. The human substantia nigra and ventral tegmental area. In: Beck F, Hild W, Kriz W, Pauly JE, Sano Y, Schiebler TH, eds. Advances in Anatomy, Embryology and Cell Biology, Vol.21, Berlin: Springer, 1991.Google Scholar
  87. 87.
    Hirsch E C, Graybiel AM, Duyckaerts C, Javoy-Agid F. Neuronal loss in the pedunculopontine tegmental nucleus in Parkinson disease and in progressive supranuclear palsy. Proc Natl Acad Sci USA 1987; 84:5976–5980.PubMedCrossRefGoogle Scholar
  88. 88.
    Jellinger K. The pedunculopontine nucleus in Parkinson’s disease, progressive supranuclear palsy and Alzheimer’s disease. J Neurol Neurosurg Psychiatry 1988;51:540–543.PubMedCrossRefGoogle Scholar
  89. 89.
    Zweig RM, Jankel WR, Hedreen JC, Mayeux R, Price DL. The pedunculopontine nucleus in Parkinson’s disease. Ann Neurol 1989; 26:41–46.PubMedCrossRefGoogle Scholar
  90. 90.
    Mesulam MM, Geula C, Bothwell MA, Hersh LB. Human reticular formation: Cholinergic neurons of the pedunculopontine and laterodorsal tegmental nuclei and some cytochemical comparisons to forebrain cholinergic neurons. J Comp Neurol 1989; 281:611–633.CrossRefGoogle Scholar
  91. 91.
    Garcia-Rill E. The pedunculopontine nucleus. Prog Neurobiol 1991; 36:363–389.PubMedCrossRefGoogle Scholar
  92. 92.
    Inglis WL, Winn P. The pedunculopontine tegmental nucleus: where the striatum meets the reticular formation. Prog Neurobiol 1995; 47:1–29.PubMedCrossRefGoogle Scholar
  93. 93.
    Pahapill PA, Lozano AM. The pedunculopontine nucleus and Parkinson’s disease. Brain 2000; 123:1767–1783.PubMedCrossRefGoogle Scholar
  94. 94.
    Steckler T, Inglis W, Winn P, Sahgal A. The pedunculopontine tegmental nucleus: A role in cognitive processes? Brain Res Rev 1994; 19:298–318.PubMedCrossRefGoogle Scholar
  95. 95.
    Lee MS, Rinne JO, Marsden CD. The pedunculopontine nucleus: its role in the genesis of movement disorders. Yonsei Med J 2000; 41:167–184.PubMedGoogle Scholar
  96. 96.
    Vincent SR. The ascending reticular activating system — from aminergic neurons to nitric oxide. J Chem Neuroanat 2000; 18:23–30.PubMedCrossRefGoogle Scholar
  97. 97.
    Rye DB. Contributions of the pedunculopontine region to normal and altered REM sleep. Sleep 1997;29:757–788.Google Scholar
  98. 98.
    Saper CB. Function of the locus coeruleus. Trends Neurosci 1987; 10:343–344.CrossRefGoogle Scholar
  99. 99.
    Saper CB Diffuse cortical projection systems: Anatomical organization and role in cortical function. In: Plum F, ed. Handbook of Physiology, Vol. 5, The Nervous System. Bethesda: American Physiological Society, 1987:169–210.Google Scholar
  100. 100.
    Fallon JH, Loughlin SE. Monoamine Innervation of Cerebral Cortex and a Theory of the role of monoamines in cerebral cortex and basal ganglia. In: Jones EG, Peters A, eds. Cerebral Cortex. Further Aspects of Cortical Function, Including Hippocampus. Vol. 6. New York London: Plenum Press, 1987:41–127.Google Scholar
  101. 101.
    Pearson J, Halliday G, Sakamoto N, Michel JP. Catecholaminergic neurons. In: Paxinos G, ed. The Human Nervous System. San Diego: Academic Press, 1990:1023–1049.Google Scholar
  102. 102.
    Whitehouse PJ, Hedreen JC, White CL, Price DL. Basal forebrain neurons in the dementia of Parkinson’s disease. Ann Neurol 1983; 13:243 248.PubMedCrossRefGoogle Scholar
  103. 103.
    Saper CB, Sorrentino DM, German DC, de Lacalle S. Medullary catecholaminergic neurons in the normal human brain and in Parkinson’s disease. Ann Neurol 1991; 29:577–584.PubMedCrossRefGoogle Scholar
  104. 104.
    Braak H, Braak E, Yilmazer D, et al. Amygdala pathology in Parkinson’s disease. Acta Neuropathol 1994; 88:493–500.PubMedCrossRefGoogle Scholar
  105. 105.
    Iseki E, Odawara T, Suzuki K, Kosaka K, Akiyama H, Ikeda K. A pathological study of Lewy bodies and senile changes in the amygdala in diffuse Lewy body disease. Neuropathol 1995; 15:112–116.CrossRefGoogle Scholar
  106. 106.
    Amaral DG, Price JL, Pitkänen A, Carmichael ST. Anatomical organization of the primate amygdaloid complex. In: Aggleton JP, ed. The Amygdala: Neurobiological Aspects of Emotion, Memory, and Mental Dysfunction. New York: Wiley-Liss, 1987:1–66.Google Scholar
  107. 107.
    Price JL, Russchen FT, Amaral DG. The amygdaloid complex. In: Björklund A, Hökfelt T, Swansen LW, eds. Handbook of Chemical Neuroanatomy, Vol. 5(1), Integrated systems, Amsterdam: Elsevier 1987:279–388.Google Scholar
  108. 108.
    De Olmos JS. Amygdala. In: Paxinos G, Mai JK eds. The Human Nervous System. 2nd ed. Academic Press, San Diego, CA, 2004:739–860.Google Scholar
  109. 109.
    Sims KS, Williams RS. The human amygdaloid complex: a cytologic and histochemical atlas using Nissl, myelin, acetylcholinesterase and nicotinamide adenine dinucleotide phosphate diaphorase staining. Neuroscience 1990; 36:449–472.PubMedCrossRefGoogle Scholar
  110. 110.
    Bohus B, Koolhaas JM, Luiten PGM, Korte SM, Roozendaal B, Wiersma A. The neurobiology of the central nuleus of the amygdala in relation to neuroendocrine and autonomic outflow. Progr Brain Res 1996; 107:447–460.CrossRefGoogle Scholar
  111. 111.
    Rüb U, Del Tredici K, Schultz C, et al. Parkinson’s disease: the thalamic components of the limbic loop are severely impaired by α-synuclein immunopositive inclusion body pathology. Neurobiol Aging 2002; 23:245–254.PubMedCrossRefGoogle Scholar
  112. 112.
    Dickson DW, Schmidt ML, Lee VMY, Zhao ML, Yen SH, Trojanowski JQ. Immunoreactivity profile of hippocampal CA2/3 neurites in diffuse Lewy body disease. Acta Neuropathol 1994; 87:269–276.PubMedCrossRefGoogle Scholar
  113. 113.
    Sherk H. The claustrum and the cerebral cortex. In: Jones EG, Peters A, eds. Cerebral Cortex. Sensory-Motor Areas and Aspects of Cortical Connectivity. Vol 5. New York, London: Plenum Press, 1986:467–499.Google Scholar
  114. 114.
    Mesulam MM, Mufson EJ. The insula of Reil in man and monkey. In: Jones EG, Peters A, eds. Cerebral Cortex. Association and Auditory Cortices. Vol 4. New York, London: Plenum Press, 1993:179–225.Google Scholar
  115. 115.
    Augustine JR. Circuitry and functional aspects of the insular lobe in primates including humans. Brain Res Rev 1996;22:229–244.PubMedCrossRefGoogle Scholar
  116. 116.
    Cechetto DF, Saper CB. Role of the cerebral cortex in autonomic function. In:Loewy AD, Spyer KM, eds. Central Regulation of Autonomic Function. New York: Oxford University Press, 1990:208–223.Google Scholar
  117. 117.
    Price JL, Carmichael ST, Drevets WC. Networks related to the orbital and medial prefrontal cortex: a substrate for emotional behavior? Progr Brain Res 1996; 107:528–536.Google Scholar
  118. 118.
    Wakabayashi K, Hansen LA, Masliah E. Cortical Lewy body-containing neurons are pyramidal cells. Laser confocal imaging of double immunolabeled sections with anti-ubiquitin and SMI32. Acta Neuropathol 1995; 89:404–408.PubMedCrossRefGoogle Scholar
  119. 119.
    Rapoport SI. Brain evolution and Alzheimer’s disease. Rev Neurol (Paris) 1988; 144:79–90.Google Scholar
  120. 120.
    Rapoport SI. Integrated phylogeny of the primate brain, with special reference to humans and their diseases. Brain Res Rev 1990; 15:267–294.PubMedCrossRefGoogle Scholar
  121. 121.
    Bachevalier J, Mishkin M. Ontogenetic development and decline of memory functions in nonhuman primates. In: Kostovic I, Knezevic S, Wisniewski HM, Spillich GJ, eds. Neurodevelopment, Aging and Cognition. Boston: Birkhäuser, 1992:37–59.Google Scholar
  122. 122.
    Reisberg B, Pattschull-Furlan A, Franssen E, et al. Dementia of the Alzheimer type recapitulates ontogeny inversely on specific ordinal and temporal parameters. In: Kostovic I, Knezevic S, Wisniewski HM, Spillich GJ, eds. Neurodevelopment, Aging and Cognition. Boston: Birkhäuser, 1992:345–369.Google Scholar
  123. 123.
    van der Knaap MS, Valk J, Bakker CJ, Schooneveld M, Faber JAJ, Willemse J, Gooskens PHJM. Myelination as an expression of the functional maturity of the brain. Dev Med Child Neurol 1991; 33:849–857.PubMedCrossRefGoogle Scholar
  124. 124.
    Braak H, Braak E. Development of Alzheimer-related neurofibrillary changes in the neocortex inversely recapitulates cortical myelogenesis. Acta Neuropathol 1996; 92:197–201.PubMedCrossRefGoogle Scholar
  125. 125.
    Pearce RK, Hawkes CH, Daniel SE. The anterior olfactory nucleus in Parkinson’s disease. Mov Disord 1995; 10:283–287.PubMedCrossRefGoogle Scholar
  126. 126.
    Doty RL, Deems DA, Stellar S. Olfactory dysfunction in parkinsonism: a general deficit unrelated to neurologic signs, disease stage, or disease duration. Neurology 1988; 38:1237–1244.PubMedGoogle Scholar
  127. 127.
    Sakuma K, Nakashima K, Takahashi K. Olfactory evoked potentials in Parkinson’s disease, Alzheimer’s disease and anosmic patients. Psychiatr Clin Neurosci 1996; 50:35–40.CrossRefGoogle Scholar
  128. 128.
    Mesholam RL, Moberg PJ, Mahr RN, Doty RL. Olfaction in neurodegenerative disease. A meta-analysis of olfactory functioning in Alzheimer’s and Parkinson’s diseases. Arch Neurol 1998; 55:84–90.PubMedCrossRefGoogle Scholar
  129. 129.
    Hawkes CH, Shephard BC, Daniel SE. Is Parkinson’s disease a primary olfactory disorder? Q J Med 1999; 92:473–480.Google Scholar
  130. 130.
    Parkinson JD. The Shaking Palsy. London: Sherwood, Neely and Jones, 1817.Google Scholar
  131. 131.
    Goetz CG, Luthe W, Tanner CM. Autonomic dysfunction in Parkinson’s disease. Neurology 1986; 36:73–75.PubMedGoogle Scholar
  132. 132.
    Ludin SM, Steiger UH, Ludin HP. Autonomic disturbances and cardiovascular reflexes in idiopathic Parkinson’s disease. J Neurol 1987; 235:10–15.PubMedCrossRefGoogle Scholar
  133. 133.
    Korczyn AD. Autonomic nervous system disturbances in Parkinson’s disease. Adv Neurol 1990; 53:463–468.PubMedGoogle Scholar
  134. 134.
    Meco G, Pratesi L, Bonifati V. Cardiovascular reflexes and autonomic dysfunction in Parkinson’s disease. J Neurol 1991; 238:195–199.PubMedCrossRefGoogle Scholar
  135. 135.
    van Dijk JG, Haan J, Zwinderman K, Kremer B, van Hilten BJ. Autonomic nervous system dysfunction in Parkinson’s disease: relationships with age, medication, duration, and severity. J Neurol Neurosurg Psychiatry 1993; 56:1090–1095.PubMedCrossRefGoogle Scholar
  136. 136.
    Gorell JM, Johnson CC, Rybicki BA. Parkinson’s disease and its comorbid disorders: an analysis of Michigan mortality data, 1970 to 1990. Neurology 1994; 44:1865–1868.PubMedGoogle Scholar
  137. 137.
    Damasio AR, Tranel D, Damasio H. Individuals with sociopathic behavior caused by frontal damage fail to respond automatically to social stimuli. Behav Brain Res 1990; 41:81–94.PubMedCrossRefGoogle Scholar
  138. 138.
    Lane RD, Reiman EM, Ahern GL, Schwartz GE, Davidson RJ. Neuroanatomical correlates of happiness, sadness, and disgust. Am J Psychiatr 1997; 154:926–933.PubMedGoogle Scholar
  139. 139.
    Damasio AR. Emotion in the perspective of an integrated nervous system. Brain Res Rev 1998; 26:83–86.PubMedCrossRefGoogle Scholar
  140. 140.
    Berthier M, Starkstein S, Leiguarda R. Asymbolia for pain: a sensory-limbic disconnection syndrome. Ann Neurol 1988; 24:41–49.PubMedCrossRefGoogle Scholar
  141. 141.
    Damasio AR, Damasio H. Disorders of higher brain function. In: Rosenberg RN, ed. Comprehensive Neurology. New York: Raven Press, 1991:639–657.Google Scholar
  142. 142.
    Squire LR, Zola-Morgan S. The medial temporal lobe memory system. Science 1991; 253:1380–1386.PubMedCrossRefGoogle Scholar
  143. 143.
    Zola-Morgan S, Squire LR. Neuroanatomy of memory. Ann Rev Neurosci 1993; 16:547–563.PubMedCrossRefGoogle Scholar
  144. 144.
    Mesulam MM. From sensation to cognition. Brain 1998; 121:1013–1052.PubMedCrossRefGoogle Scholar
  145. 145.
    Jellinger K, Bancher C. Structural basis of mental impairment in Parkinson’s disease. Neuropsychiatrie 1995; 9:9–14.Google Scholar
  146. 146.
    Dubois B, Pillon B. Cognitive deficits in Parkinson’s disease. J Neurol 1997;244:2–8.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 2005

Authors and Affiliations

  • Heiko Braak
    • 1
  • Kelly Del Tredici
    • 1
  1. 1.Institute for Clinical NeuroanatomyJ. W. Goethe UniversityFrankfurt/MainGermany

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