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June 25, 2002

Phases of Aβ-deposition in the human brain and its relevance for the development of AD

June 25, 2002 issue
58 (12) 1791-1800

Abstract

Background: The deposition of the amyloid β protein (Aβ) is a histopathologic hallmark of AD. The regions of the medial temporal lobe (MTL) are hierarchically involved in Aβ-deposition.
Objective: To clarify whether there is a hierarchical involvement of the regions of the entire brain as well and whether there are differences in the expansion of Aβ-pathology between clinically proven AD cases and nondemented cases with AD-related pathology, the authors investigated 47 brains from demented and nondemented patients with AD-related pathology covering all phases of β-amyloidosis in the MTL (AβMTL phases) and four control brains without any AD-related pathology.
Methods: Aβ deposits were detected by the use of the Campbell-Switzer silver technique and by immunohistochemistry in sections covering all brain regions and brainstem nuclei. It was analyzed how often distinct regions exhibited Aβ deposits.
Results: In the first of five phases in the evolution of β-amyloidosis Aβ deposits are found exclusively in the neocortex. The second phase is characterized by the additional involvement of allocortical brain regions. In phase 3, diencephalic nuclei, the striatum, and the cholinergic nuclei of the basal forebrain exhibit Aβ deposits as well. Several brainstem nuclei become additionally involved in phase 4. Phase 5, finally, is characterized by cerebellar Aβ-deposition. The 17 clinically proven AD cases exhibit Aβ-phases 3, 4, or 5. The nine nondemented cases with AD-related Aβ pathology show Aβ-phases 1, 2, or 3.
Conclusions: Aβ-deposition in the entire brain follows a distinct sequence in which the regions are hierarchically involved. Aβ-deposition, thereby, expands anterogradely into regions that receive neuronal projections from regions already exhibiting Aβ. There are also indications that clinically proven AD cases with full-blown β-amyloidosis may be preceded in early stages by nondemented cases exhibiting AD-related Aβ pathology.

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References

1.
Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol (Berl) . 1991; 82: 239–259.
2.
Dickson DW. The pathogenesis of senile plaques. J Neuropathol Exp Neurol . 1997; 56: 321–339.
3.
Esiri MM, Hyman BT, Beyreuther K, Masters CL. Ageing and dementia. In: Graham DI, Lantos PL, eds. Greenfields neuropathology, Vol 2. London: Arnold, 1996: 153–233.
4.
Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyreuther K. Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci USA . 1985; 82: 4245–4249.
5.
Bancher C, Braak H, Fischer P, Jellinger KA. Neuropathological staging of Alzheimer lesions and intellectual status in Alzheimer’s and Parkinson’s disease patients. Neurosci Lett . 1993; 162: 179–182.
6.
The National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer’s Disease. Consensus recommendations for the postmortem diagnosis of Alzheimer’s disease. The National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer’s Disease. Neurobiol Aging . 1997; 18 (4 suppl): S1–S2.
7.
Cummings BJ, Cotman CW. Image analysis of beta-amyloid load in Alzheimer’s disease and relation to dementia severity. Lancet . 1995; 346: 1524–1528.
8.
Naslund J, Haroutunian V, Mohs R, et al. Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. JAMA . 2000; 283: 1571–1577.
9.
Thal DR, Arendt T, Waldmann G, et al. Progression of neurofibrillary changes and PHF-tau in end-stage Alzheimer’s disease is different from plaque and cortical microglial pathology. Neurobiol Aging . 1998; 19: 517–525.
10.
Thal DR, Holzer M, Rüb U, et al. Alzheimer-related tau-pathology in the perforant path target zone and in the hippocampal stratum oriens and radiatum correlates with onset and degree of dementia. Exp Neurol . 2000; 163: 98–110.
11.
Thal DR, Rüb U, Schultz C, et al. Sequence of Abeta-protein deposition in the human medial temporal lobe. J Neuropathol Exp Neurol . 2000; 59: 733–748.
12.
Duyckaerts C, Hauw JJ, Bastenaire F, et al. Laminar distribution of neocortical senile plaques in senile dementia of the Alzheimer type. Acta Neuropathol (Berl) . 1986; 70: 249–256.
13.
Gearing M, Schneider JA, Robbins RS, et al. Regional variation in the distribution of apolipoprotein E and A beta in Alzheimer’s disease. J Neuropathol Exp Neurol . 1995; 54: 833–841.
14.
Braak H, Braak E, Bohl J, Lang W. Alzheimer’s disease: amyloid plaques in the cerebellum. J Neurol Sci . 1989; 93: 277–287.
15.
Braak H, Braak E, Kalus P. Alzheimer’s disease: areal and laminar pathology in the occipital isocortex. Acta Neuropathol (Berl) . 1989; 77: 494–506.
16.
Braak H, Braak E. Alzheimer’s disease: striatal amyloid deposits and neurofibrillary changes. J Neuropathol Exp Neurol . 1990; 49: 215–224.
17.
van de Nes JA, Kamphorst W, Ravid R, Swaab DF. Comparison of beta-protein/A4 deposits and Alz-50-stained cytoskeletal changes in the hypothalamus and adjoining areas of Alzheimer’s disease patients: amorphic plaques and cytoskeletal changes occur independently. Acta Neuropathol (Berl) . 1998; 96: 129–138.
18.
Braak H, Braak E. Alzheimer’s disease affects limbic nuclei of the thalamus. Acta Neuropathol (Berl) . 1991; 81: 261–268.
19.
Arendt T, Taubert G, Bigl V, Arendt A. Amyloid deposition in the nucleus basalis of Meynert complex: a topographic marker for degenerating cell clusters in Alzheimer’s disease. Acta Neuropathol (Berl) . 1988; 75: 226–232.
20.
Mann DM, Jones D, Prinja D, Purkiss MS. The prevalence of amyloid (A4) protein deposits within the cerebral and cerebellar cortex in Down’s syndrome and Alzheimer’s disease. Acta Neuropathol (Berl) . 1990; 80: 318–327.
21.
Iseki E, Matsushita M, Kosaka K, Kondo H, Ishii T, Amano N. Distribution and morphology of brain stem plaques in Alzheimer’s disease. Acta Neuropathol (Berl) . 1989; 78: 131–136.
22.
Arriagada PV, Marzloff K, Hyman BT. Distribution of Alzheimer-type pathologic changes in nondemented elderly individuals matches the pattern in Alzheimer’s disease. Neurology . 1992; 42: 1681–1688.
23.
Price JL, Davis PB, Morris JC, White DL. The distribution of tangles, plaques and related immunohistochemical markers in healthy aging and Alzheimer’s disease. Neurobiol Aging . 1991; 12: 295–312.
24.
Yamada M, Mehraein P. Distribution of senile changes in brain stem nuclei [in Japanese]. Folia Psychiatr Neurol Jpn . 1977; 31: 219–224.
25.
Ogomori K, Kitamoto T, Tateishi J, Sato Y, Suetsugu M, Abe M. Beta-protein amyloid is widely distributed in the central nervous system of patients with Alzheimer’s disease. Am J Pathol . 1989; 134: 243–251.
26.
Parvizi J, Van Hoesen GW, Damasio A. The selective vulnerability of brainstem nuclei to Alzheimer’s disease. Ann Neurol . 2001; 49: 53–66.
27.
Scinto LF, Wu CK, Firla KM, Daffner KR, Saroff D, Geula C. Focal pathology in the Edinger-Westphal nucleus explains pupillary hypersensitivity in Alzheimer’s disease. Acta Neuropathol (Berl) . 1999; 97: 557–564.
28.
Hughes CP, Berg L, Danziger WL, Coben LA, Martin RL. A new clinical scale for the staging of dementia. Br J Psychiatry . 1982; 140: 566–572.
29.
Braak H, Braak E. Demonstration of amyloid deposits and neurofibrillary changes in whole brain sections. Brain Pathol . 1991; 1: 213–216.
30.
Iqbal K, Braak H, Braak E, Grundke-Iqbal I. Silver labeling of Alzheimer neurofibrillary changes and brain β-amyloid. J Histotechnol . 1993; 16: 335–342.
31.
Thal DR, Sassin I, Schultz C, Haass C, Braak E, Braak H. Fleecy amyloid deposits in the internal layers of the human entorhinal cortex are comprised of N-terminal truncated fragments of Abeta. J Neuropathol Exp Neurol . 1999; 58: 210–216.
32.
Mirra SS, Heyman A, McKeel D, et al. The consortium to establish a registry for Alzheimer’s disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology . 1991; 41: 479–486.
33.
Hsu SM, Raine L, Fanger H. Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabeled antibody (PAP) procedures. J Histochem Cytochem . 1981; 29: 577–580.
34.
Cochran WG. Some methods for strengthening the common χ2-test. Biometrics . 1954; 10: 417–451.
35.
Lemere CA, Blusztajn JK, Yamaguchi H, Wisniewski T, Saido TC, Selkoe DJ. Sequence of deposition of heterogeneous amyloid beta-peptides and APO E in Down syndrome: implications for initial events in amyloid plaque formation. Neurobiol Dis . 1996; 3: 16–32.
36.
Leverenz JB, Raskind MA. Early amyloid deposition in the medial temporal lobe of young Down syndrome patients: a regional quantitative analysis. Exp Neurol . 1998; 150: 296–304.
37.
McGowan E, Sanders S, Iwatsubo T, et al. Amyloid phenotype characterization of transgenic mice overexpressing both mutant amyloid precursor protein and mutant presenilin 1 transgenes. Neurobiol Dis . 1999; 6: 231–244.
38.
Irizarry MC, Soriano F, McNamara M, et al. Abeta deposition is associated with neuropil changes, but not with overt neuronal loss in the human amyloid precursor protein V717F (PDAPP) transgenic mouse. J Neurosci . 1997; 17: 7053–7059.
39.
Braak H, Braak E, Yilmazer D, de Vos RA, Jansen EN, Bohl J. Pattern of brain destruction in Parkinson’s and Alzheimer’s diseases. J Neural Transm . 1996; 103: 455–490.
40.
Witter MP. Organization of the entorhinal-hippocampal system: a review of current anatomical data. Hippocampus . 1993; 3 (Spec No): 33–44.
41.
Jones RS. Entorhinal-hippocampal connections: a speculative view of their function. Trends Neurosci . 1993; 16: 58–64.
42.
Paxinos G. The human nervous system. San Diego: Academic Press, 1990.
43.
Beitz AJ. Central gray. In: Paxinos G, ed. The human nervous system. San Diego: Academic Press, 1990; 307–320.
44.
Webster WR, Garey LJ. Auditory system. In: Paxinos G, ed. The human nervous system. San Diego: Academic Press, 1990; 889–944.
45.
Cotman CW, Monaghan DT, Ottersen OP, Storm-Mathisen J. Anatomical organization of excitatory amino acid receptors and their pathways. Trends Neurosci . 1987; 10: 273–280.
46.
Hayakawa T, Zyo K. Afferent connections of Gudden’s tegmental nuclei in the rabbit. J Comp Neurol . 1985; 235: 169–181.
47.
Leichnetz GR, Carlton SM, Katayama Y, et al. Afferent and efferent connections of the cholinoceptive medial pontine reticular formation (region of the ventral tegmental nucleus) in the cat. Brain Res Bull . 1989; 22: 665–688.
48.
Gonzalo-Ruiz A, Leichnetz GR, Smith DJ. Origin of cerebellar projections to the region of the oculomotor complex, medial pontine reticular formation, and superior colliculus in New World monkeys: a retrograde horseradish peroxidase study. J Comp Neurol . 1988; 268: 508–526.
49.
Gold G, Kovari E, Corte G, Herrmann FR, Canuto A, Bussiere T, Hof PR, Bouras C, Giannakopoulos P. Clinical validity of A beta-protein deposition staging in brain aging and Alzheimer disease. J Neuropathol Exp Neurol . 2001; 60: 946–952.
50.
Skovronsky DM, Zhang B, Kung M-P, Kung HF, Trojanowski JQ, Lee V M-Y. In vivo detection of amyloid plaques in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA 2000;97:7609–7614.
51.
Wengenack TM, Curran GL, Poduslo JF. Targeting Alzheimer amyloid plaques in vivo. Nat Biotech . 2000; 1: 868–872.

Information & Authors

Information

Published In

Neurology®
Volume 58Number 12June 25, 2002
Pages: 1791-1800
PubMed: 12084879

Publication History

Received: September 24, 2001
Accepted: March 12, 2002
Published online: June 25, 2002
Published in print: June 25, 2002

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Authors

Affiliations & Disclosures

Dietmar R. Thal, MD
From the Department of Anatomy (Drs. Thal, Rüb, and Braak), J. W. Goethe University, Frankfurt am Main; Department of Neuropathology (Dr. Thal), University of Bonn Medical Center, Bonn; and Department of Pathology (Dr. Orantes), Municipal Hospital of Offenbach, Offenbach am Main, Germany.
Udo Rüb, MD
From the Department of Anatomy (Drs. Thal, Rüb, and Braak), J. W. Goethe University, Frankfurt am Main; Department of Neuropathology (Dr. Thal), University of Bonn Medical Center, Bonn; and Department of Pathology (Dr. Orantes), Municipal Hospital of Offenbach, Offenbach am Main, Germany.
Mario Orantes, MD
From the Department of Anatomy (Drs. Thal, Rüb, and Braak), J. W. Goethe University, Frankfurt am Main; Department of Neuropathology (Dr. Thal), University of Bonn Medical Center, Bonn; and Department of Pathology (Dr. Orantes), Municipal Hospital of Offenbach, Offenbach am Main, Germany.
Heiko Braak, MD
From the Department of Anatomy (Drs. Thal, Rüb, and Braak), J. W. Goethe University, Frankfurt am Main; Department of Neuropathology (Dr. Thal), University of Bonn Medical Center, Bonn; and Department of Pathology (Dr. Orantes), Municipal Hospital of Offenbach, Offenbach am Main, Germany.

Notes

Address correspondence and reprint requests to Dr. D.R. Thal, Institut für Neuropathologie, Universität Bonn, Sigmund Freud Str. 25, D-53105 Bonn, Germany; e-mail: [email protected]

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