Neuropathological stageing of Alzheimer-related changes

Summary

Eighty-three brains obtained at autopsy from nondemented and demented individuals were examined for extracellular amyloid deposits and intraneuronal neurofibrillary changes. The distribution pattern and packing density of amyloid deposits turned out to be of limited significance for differentiation of neuropathological stages. Neurofibrillary changes occurred in the form of neuritic plaques, neurofibrillary tangles and neuropil threads. The distribution of neuritic plaques varied widely not only within architectonic units but also from one individual to another. Neurofibrillary tangles and neuropil threads, in contrast, exhibited a characteristic distribution pattern permitting the differentiation of six stages. The first two stages were characterized by an either mild or severe alteration of the transentorhinal layer Pre-α (transentorhinal stages I–II). The two forms of limbic stages (stages III–IV) were marked by a conspicuous affection of layer Pre-α in both transentorhinal region and proper entorhinal cortex. In addition, there was mild involvement of the first Ammon's horn sector. The hallmark of the two isocortical stages (stages V–VI) was the destruction of virtually all isocortical association areas. The investigation showed that recognition of the six stages required qualitative evaluation of only a few key preparations.

This is a preview of subscription content, log in to check access.

References

  1. 1.

    Bondareff W, Mountjoy CQ, Roth M, Hauser DL (1989) Neurofibrillary degeneration and neuronal loss in Alzheimer's disease. Neurobiol Aging 10:709–715

    Google Scholar 

  2. 2.

    Braak H (1980) Architectonics of the human telecephalic cortex. In: Braitenberg V, Barlow HB, Bizzi E, Florey E, Grüsser OJ, van der Loos H (eds) Studies of brain function, vol 4. Springer, Berlin Heidelberg New York, pp 1–147

    Google Scholar 

  3. 3.

    Braak H, Braak E (1985) On areas of transition between entorhinal allocortex and temporal isocortex in the human brain. Normal morphology and lamina-specific pathology in Alzheimer's disease. Acta Neuropathol (Berl) 68:325–332

    Google Scholar 

  4. 4.

    Braak H, Braak E (1988) Morphology of the human isocortex in young and aged individuals: qualitative and quantitative findings. Interdiscip Top Gerontol 25:1–15

    Google Scholar 

  5. 5.

    Braak H, Braak E (1988) Neuropil threads occur in dendrites of tangle-bearing nerve cells. Neuropathol Appl Neurobiol 14:39–44

    Google Scholar 

  6. 6.

    Braak H, Braak E (1989) Cortical and subcortical argyrophilic grains characterize a disease associated with adult onset dementia. Neuropathol Appl Neurobiol 15:13–26

    Google Scholar 

  7. 7.

    Braak H, Braak E (1990) Alzheimer's disease: striatal amyloid deposits and neurofibrillary changes. J Neuropathol Exp Neurol 49:215–224

    Google Scholar 

  8. 8.

    Braak H, Braak E (1990) Morphology of the cerebral cortex in relation to Alzheimer's dementia. In: Maurer K, Riederer P, Beckmann H (eds) Alzheimer's disease. Epidemiology, Neuropathology, Neurochemistry, and Clinics. Key Topics in Brain Research. Springer, Wien, pp 85–91

    Google Scholar 

  9. 9.

    Braak H, Braak E (1990) Neurofibrillary changes confined to the entorhinal region and an abundance of cortical amyloid in cases of presenile and senile dementia. Acta Neuropathol 80:479–486

    Google Scholar 

  10. 10.

    Braak H, Braak E (1991) Alzheimer's disease affects limbic nuclci of the thalamus. Acta Neuropathol 81:261–268

    Google Scholar 

  11. 11.

    Braak H, Braak E (1991) Demonstration of amyloid deposits and neurofibrillary changes in whole brain sections. Brain Pathol 1:213–216

    Google Scholar 

  12. 12.

    Braak H, Braak E, Grundke-Iqbal I, Iqbal K (1986) Occurrence of neuropil threads in the senile human brain and in Alzheimer's disease: a third location of paired helical filaments outside of neurofibrillary tangles and neuritic plaques. Neurosci Lett 65:351–355

    Google Scholar 

  13. 13.

    Braak H, Braak E, Ohm T, Bohl J (1988) Silver impregnation of Alzheimer's neurofibrillary changes counterstained for basophilic material and lipofuscin pigment. Stain Technol 63:197–200

    Google Scholar 

  14. 14.

    Braak H, Braak E, Kalus P (1989) Alzheimer's disease: areal and laminar pathology in the occipital isocortex. Acta Neuropathol 77:494–506

    Google Scholar 

  15. 15.

    Braak H, Braak E, Ohm T, Bohl J (1989) Alzheimer's disease: mismatch between amyloid plaques and neuritic plaques. Neurosci Lett 103:24–28

    Google Scholar 

  16. 16.

    Braak H, Braak E, Bohl J, Lang W (1989) Alzheimer's disease: amyloid plaques in the cerebellum. J Neurol Sci 93:277–287

    Google Scholar 

  17. 17.

    Campbell SK, Switzer RC, Martin TL (1987) Alzheimer's plaques and tangles: a controlled and enhanced silver-staining method. Soc Neurosci Abstr 13:678

    Google Scholar 

  18. 18.

    Castano EM, Frangione B (1988) Biology of disease. Human amyloidosis, Alzheimer's disease and related disorders. Lab Invest 58:122–132

    Google Scholar 

  19. 19.

    Davies L, Wolska B, Hilbich C, Multhaup G, Martins R, Simms G, Beyreuther K, Masters CL (1988) A4 amyloid protein deposition and the diagnosis of Alzheimer's disease: prevalence in aged brains determined by immunocytochemistry compared with conventional neuropathologic techniques. Neurology 38:1688–1693

    Google Scholar 

  20. 20.

    Dayan AD (1970) Quantitative histological studies on the aged human brain. I. Senile plaques and neurofibrillary tangles in normal patients. Acta Neuropathol (Berl) 16:85–94

    Google Scholar 

  21. 21.

    Delaère P, Duyckaerts C, Masters C, Beyreuther K, Piette F, Hauw JJ (1990) Large amounts of neocortical βA4 deposits without neuritic plaques nor tangles in a psychometrically assessed, non-demented person. Neurosci Lett 116:87–93

    Google Scholar 

  22. 22.

    Duyckaerts C, Delaère P, Poulain V, Brion JP, Hauw JJ (1988) Does amyloid precede paired helical filaments in the senile plaques? A study of 15 cases with graded intellectual status in aging and Alzheimer's disease. Neurosci Lett 91:354–359

    Google Scholar 

  23. 23.

    Duyckaerts C, Delaère P, Hauw JJ, Abbamondi-Pinto AL, Sorbi S, Allen I, Brion JP, Flament-Durand J, Duchen L, Kauss J, Schlote W, Lowe J, Probst A, Ravid R, Swaab DF, Renkawek K, Tomlinson B (1990) Rating of lesions in senile dementia of the Alzheimer type: concordance between laboratories. A European multicenter study under the auspices of EURAGE. J Neurol Sci 97:295–323

    Google Scholar 

  24. 24.

    Esiri MM, Pearson RCA, Powell TPS (1986) The cortex of the primary auditory area in Alzheimer's disease. Brain Res 366:385–388

    Google Scholar 

  25. 25.

    Gallyas F (1971) Silver staining of Alzheimer's neurofibrillary changes by means of physical development. Acta Morphol Acad Sci Hung 19:1–8

    Google Scholar 

  26. 26.

    Gallyas F, Wolff JR (1986) Metal-catalyzed oxidation renders silver intensification selective. Applications for the histochemistry of diaminobenzidine and neurofibrillary changes. J Histochem Cytochem 34:1667–1672

    Google Scholar 

  27. 27.

    Giaccone G, Tagliavini F, Linoli G, Bouras C, Frigero B, Bugiani O (1989) Down patients: extracellular preamyloid deposits precede neuritic degeneration and senile plaques. Neurosci Lett 97:232–238

    Google Scholar 

  28. 28.

    Grünthal E (1930) Die pathologische Anatomie der senilen Demenz und der Alzheimerschen Krankheit. In: Bumke O (ed) Handbuch der Geisteskrankheiten. Die Anatomie der Psychosen, vol 11. Springer, Berlin, pp 638–672

    Google Scholar 

  29. 29.

    Gutzmann H (1988) Senile Demenz vom Alzheimer Typ. Enke, Stuttgart, pp 1–130

    Google Scholar 

  30. 30.

    Hubbard BM, Fenton GW, Anderson JM (1990) A quantitative histological study of early clinical and preclinical Alzheimer's disease. Neuropathol Appl Neurobiol 16:111–121

    Google Scholar 

  31. 31.

    Hyman BT, van Hoesen GW, Damasio AR, Barnes CL (1984) Alzheimer's disease: cell-specific pathology isolates the hippocampal formation. Science 25:1168–1170

    Google Scholar 

  32. 32.

    Jellinger K, Lassmann H, Fischer P, Danielczyk W (1991) Validation of diagnostic criteria for Alzheimer's disease. In: Iqbal K, McLachlan DRC, Winblad B, Wisniewski HM (eds) Alzheimer's disease: basic mechanisms, diagnosis and therapeutic strategies. Wiley, Chichester, pp 75–89

    Google Scholar 

  33. 33.

    Kalus P, Braak H, Braak E, Bohl J (1989) The presubicular region in Alzheimer's disease: topography of amyloid deposits and neurofibrillary changes. Brain Res 494:198–203

    Google Scholar 

  34. 34.

    Kemper TL (1978) Senile dementia: a focal disease in the temporal lobe. In: Nandy E (ed) Senile dementia: a biomedical approach. Elsevier, Amsterdam, pp 105–113

    Google Scholar 

  35. 35.

    Khachaturian ZS (1985) Diagnosis of Alzheimer's disease. Arch Neurol 42:1097–1105

    Google Scholar 

  36. 36.

    Kurz AF, Lauter H, Zimmer R (1988) What are the early and late clinical manifestations of the disease? In: Henderson AS, Henderson JH (eds) Etiology of dementia of Alzheimer's type. Wiley and Sons, Chichester New York Brisbane Toronto Singapore, pp 83–103

    Google Scholar 

  37. 37.

    Lauter H, Kurz A, Haupt M, Romero B, Zimmer R (1990) Clinical diagnosis of Alzheimer's disease: DSM-III-R, ICD-10 — what else? In: Maurer K, Riederer P, Beckmann H (eds) Alzheimer's disease. Epidemiology, Neuropathology, Neurochemistry, and Clinics. Key Topics in Brain Research, Springer, Wien, pp 365–371

    Google Scholar 

  38. 38.

    Lewis DA, Campbell MJ, Terry RD, Morrison JH (1987) Laminar and regional distributions of neurofibrillary tangles and neuritic plaques in Alzheimer's disease: a quantitative study of visual and auditory cortices. J Neurosci 7:1799–1808

    Google Scholar 

  39. 39.

    Mann DMA (1985) The neuropathology of Alzheimer's disease: a review with pathogenetic, aetiological and therapeutic considerations. Mech Ageing Dev 31:213–255

    Google Scholar 

  40. 40.

    Mann DMA, Jones D, Prinja D, Purkiss MS (1990) The prevalence of amyloid (A4) protein deposits within the cerebral and cerebellar cortex in Down's syndrome and Alzheimer's disease. Acta Neuropathol 80:318–327

    Google Scholar 

  41. 41.

    Masliah E, Terry RD, Mallory M, Alford M, Hansen LA (1990) Diffuse plaques do not accentuate synapse loss in Alzheimer's disease. Am J Pathol 137:1293–1297

    Google Scholar 

  42. 42.

    McKhann G, Drachman D, Folstein MF, Katzman R, Price D, Stadlan EM (1984) 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 34:939–944

    Google Scholar 

  43. 43.

    Ogomori K, Kitamoto T, Tateishi J, Sato Y, Suetsugu M, Abe M (1989) β-Protein amyloid is widely distributed in the central nervous system of patients with Alzheimer's disease. Am J Pathol 134:243–251

    Google Scholar 

  44. 44.

    Pearson RCA, Esiri MM; Hiorns W, Wilcock GK, Powell TPS (1985) Anatomical correlates of the distribution of the pathological changes in the neocortex in Alzheimer's disease. Proc Natl Acad Sci USA 82:4531–4534

    Google Scholar 

  45. 45.

    Reisberg B, Ferris SH, Anand R, DeLeon MJ, Schneck MK, Buttinger C, Borenstein J (1984) Functional staging of dementia of the Alzheimer type. Ann NY Acad Sci 435:481–483

    Google Scholar 

  46. 46.

    Reisberg B, Ferris SH, DeLeon MJ (1985) Senile dementia of the Alzheimer type: diagnostic and differential diagnostic features with special reference to functional assessment staging (FAST). In: Traber J, Gispen WH (eds) Senile dementia of the Alzheimer Type. Springer, Berlin Heidelberg New York Tokio, pp 18–37

    Google Scholar 

  47. 47.

    Reisberg B, Ferris SH, DeLeon MJ, Kluger A, Franssen E, Borenstein J, Alba RC (1989) The stage specific temporal course of Alzheimer's disease: functional and behavioral concomitants based upon cross-sectional and longitudinal observation. In: Iqbal K, Wisniewski HM, Winblad B (eds) Alzheimer's disease and related disorders. Liss, New York, pp 23–41

    Google Scholar 

  48. 48.

    Rogers J, Morrison JH (1985) Quantitative morphology and regional and laminar distributions of senile plaques in Alzheimer's disease. J Neurosci 5:2801–2808

    Google Scholar 

  49. 49.

    Simchowicz T (1911) Histologische Studien über die senile Demenz. In: Nissl F, Alzheimer A (eds) Histologische und histopathologische Arbeiten über die Großhirnrinde mit besonderer Berücksichtigung der pathologischen Anatomie der Geisteskrankheiten, vol 4. Fischer, Jena, pp 267–444

    Google Scholar 

  50. 50.

    Sjögren T, Sjögren H, Lindgren AGH (1952) Morbus Alzheimer and Morbus Pick. Acta Psychiatr Neurol Scand [Suppl] 82:1–152

    Google Scholar 

  51. 51.

    Smithson KG, MacVicar BA, Hatton GI (1983) Polyethylene glycol embedding: a technique compatible with immunocytochemistry, enzyme histochemistry, histofluorescence and intracellular staining. J Neurosci Methods 7:27–41

    Google Scholar 

  52. 52.

    Tabaton M, Mandybur TI, Perry G, Onorato M, Autilio-Gambetti L, Gambetti P (1989) The widespread alteration of neurites in Alzheimer's disease may be unrelated to amyloid deposition. Ann Neurol 26:771–778

    Google Scholar 

  53. 53.

    Terry RD (1985) Alzheimer's disease. In: Davis RL, Robertson DM (eds) Textbook of neuropathology. Williams and Wilkins, Baltimore, pp 824–841

    Google Scholar 

  54. 54.

    Tierney MC, Fisher RH, Lewis AJ, Zorzitto ML, Snow WG, Reid DW, Nieuwstaten P (1988) The NINCDS-ADRDA work group criteria for the clinical diagnosis of probable Alzheimer's disease: a clinicopathologic study of 57 cases. Neurology 38:359–364

    Google Scholar 

  55. 55.

    Tomlinson BE (1989) The neuropathology of Alzheimer's disease — Issues in need of resolution. Neuropathol Appl Neurobiol 15:491–512

    Google Scholar 

  56. 56.

    Tomlinson BE, Corsellis JAN (1984) Ageing and the dementias. In: Adams JH, Corsellis JAN, Duchen LW (eds) Greenfield's neuropathology. Arnold, London, pp 951–1025

    Google Scholar 

  57. 57.

    Tourtellotte WG, van Hoesen GW, Hyman BT, Tikoo RK, Damasio AR (1989) Alz-50 immunoreactivity in the thalamic reticular nucleus in Alzheimer's disease. Brain Res 515:227–234

    Google Scholar 

  58. 58.

    Van Hoesen GW, Hyman BT (1990) Hippocampal formation: anatomy and the patterns of pathology in Alzheimer's disease. Prog Brain Res 83:445–457

    Google Scholar 

  59. 59.

    Von Braunmühl A (1957) Alterserkrankungen des Zentralnervensystems. Senile Involution. Senile Demenz. Alzheimersche Krankheit. In: Lubarsch O, Henke F, Rössle R (eds) Handbuch der speziellen pathologischen Anatomie und Histologie, vol 13/1A. Springer, Berlin, pp 337–539

    Google Scholar 

  60. 60.

    Wilcock G, Esiri MM (1982) Plaques, tangles and dementia. A quantitative study. J Neurol Sci 56:343–356

    Google Scholar 

  61. 61.

    Wisniewski HM, Rabe A, Zigman W, Silverman W (1989) Neuropathological diagnosis of Alzheimer's disease. J Neuropathol Exp Neurol 48:606–609

    Google Scholar 

  62. 62.

    Yamaguchi H, Hirai S, Morimatsu M, Ihara Y (1988) A variety of cerebral amyloid deposits in the brains of the Alzheimer-type dementia demonstrated by β protein immunostaining. Acta Neuropathol 76:541–549

    Google Scholar 

  63. 63.

    Yamaguchi H, Nakazato Y, Shoji M, Ihara Y, Hirai S (1990) Ultrastructure of neuropil threads in the Alzheimer brain: their dendritic origin and accumulation in the senile plaques. Acta Neuropathol 80:368–374

    Google Scholar 

Download references

Author information

Affiliations

Authors

Additional information

Supported by the Deutsche Forschungsgemeinschaft

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Braak, H., Braak, E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82, 239–259 (1991). https://doi.org/10.1007/BF00308809

Download citation

Key words

  • Amyloid
  • Neurofibrillary changes
  • Dementia
  • Alzheimer's disease
  • Stageing