eISSN: 1509-572x
ISSN: 1641-4640
Folia Neuropathologica
Current issue Archive Manuscripts accepted About the journal Editorial board Journal's reviewers Abstracting and indexing Subscription Contact Instructions for authors Ethical standards and procedures
SCImago Journal & Country Rank
vol. 49

Original article
Density and spatial pattern of β-amyloid (Aβ) deposits in corticobasal degeneration

Richard A. Armstrong

Folia Neuropathol 2011; 49 (1): 14-20
Online publish date: 2011/03/31
Article file
Get citation
JabRef, Mendeley
Papers, Reference Manager, RefWorks, Zotero


Corticobasal degeneration (CBD) is a rare, progre­s­sive movement disorder [29], the most characteris­tic clinical features of which in­clude limb dysfunction [42,43,51], parkinsonism [49], apraxia [43], and de­men­­tia [49]. An individual patient, however, may exhi­bit a wide variety of clinical symptoms [46] including myoclonus [23], memory loss, be­ha­viour­al change, speech, and gait problems [43].

Neuropathologically, CBD is characterized by a pro­gressive cortical atrophy affecting the anterior ce­rebral cortex [46], the fronto-parietal region [33], and the superior temporal cortex [33]. As a consequence, the disease is regarded as a subtype of frontotemporal lobar degeneration (FTLD) [22]. There is atrophy of the basal ganglia, including the caudate nucleus [39,47] and substantia nigra (Kawasaki et al. 1996). In addition, widespread neuronal and glial pathology is present including ballooned neurons (BN) [41], neuropil threads [35], tau-immunoreactive neuronal cytoplasmic inclusions (NCI) [33], oligodendroglial inclusions (GI) [40], and astrocytic plaques (AP) [26]. CBD is therefore also classified as a tauopathy, a group of disorders that includes Alzheimer’s disease (AD), Pick’s disease (PiD), progressive supranuclear palsy (PSP), the NFT-predominant form of senile dementia (NFT-SD), argyrophilic grain disease (AGD), and the parkinsonism-dementia complex of Guam (Guam PDC) [28].

During a quantitative study of the pathology of 12 cases of CBD [17], -amyloid (A) deposits were observed in the cerebral cortex and/or hippocampus in three cases. A deposits have been reported previously in CBD [43] and could represent the overlap or co-occurrence of CBD with AD [10,18]. Hence, to clarify the role of A deposition in CBD, the density, distribution, and spatial pattern of the A deposits were studied in these three cases and compared with previously reported data from normal elderly brains [2,3] and from AD [2,11,15].

Material and methods


The CBD cases (Table I) were obtained from the Brain Bank, Department of Neuropathology, Institute of Psychiatry, King’s College London, UK. There is no specific clinical phenotype of CBD as diverse presentations of the disease are present [27]. However, the pathology of the cases was consistent with the criteria recommended by the National Institute of Health (NIH) Office of Rare Diseases for the pathological diagnosis of CBD [27]. First, NCI, GI and AP were present. Second, inclusions were present in the white and grey matter of various cortical and striatal regions. Third, neuronal loss was present in focal cortical areas and in the substantia nigra. CBD can be confused with PSP with cortical involvement and these two disorders were separated by the absence of ‘tuft-shaped astrocytes’ [50] and the lower density of inclusions in the subthalamic nucleus in CBD [48]. The apolipoprotein E (APOE) genotype of two of the cases (A, B) was 2/3 or 3/3 while the genotype of the third case (C) was 3/4.

Tissue preparation

After death, the consent of the next of kin was obtained for brain removal, following local Ethical Committee procedure and the 1995 Declaration of Helsinki (as modified Edinburgh, 2000). Tissue blocks were taken from the frontal cortex at the level of the genu of the corpus callosum to study the superior frontal gyrus (SFG) and motor cortex (MC), parietal cortex (PC) to study the superior parietal gyrus (SPG) at the level of the splenium of the corpus callosum, occipital cortex to study areas B17 and B18, and temporal cortex at the level of the lateral geniculate body. Within the temporal lobe, the superior temporal gyrus (STG) (B22), parahippocampal gyrus (PHG) (B28), hippocampus (HC), and dentate gyrus (DG) were investigated. Sequential tissue sections were stained by the following procedures: (1) haematoxylin and eosin (H/E), (2) ubiquitin, (3) phosphorylation-independent rabbit polyclonal antibody TP007 against tau [21], and (4) rabbit polyclonal antibody raised against the 12-28 amino acid sequence of the A protein [45]. The three most common morphological subtypes of A depo­sit were identified in the A-immunolabelled sections using previously defined criteria [6,24]: (1) dif­fuse deposits were 10-200 µm in diameter, irregular in shape with diffuse boundaries, and lightly stained, (2) primitive deposits were 20-60 µm, well demarcated, more symmetrical in shape, and strongly stained, (3) classic deposits were 20-100 µm, had a distinct central ‘core’ surrounded by a ‘corona’ of dystrophic neu­rites, and (4) compact deposits comprised a conden­sed core of A without the presence of a corona.

Morphometric methods

In each cortical region, A deposits were counted along a strip of tissue using 1000 × 200 µm contiguous sample fields, the short edge of the sample field being aligned with the pia mater [8,12]. Contiguous samples were located in the upper cortical laminae and included lamina I, II, and most of III, the short edge of the sample field being aligned with the surface of the pia mater. In the hippocampus, the lesions were counted from CA1 to CA4. From CA1 to CA3, the short dimension of the contiguous sample field was aligned with the alveus. Sampling was continued into sector CA4 using a guideline marked on the slide. In the DG, the sample field was aligned with the upper edge of the granule cell layer since A deposits were present within the molecular layer.

Data analysis

The spatial pattern of the A deposits in each brain region was studied using spatial pattern analysis described previously [1,5,9,12]. This method uses the variance-mean ratio (V/M) of the data to determine whether the A deposits were distributed randomly (V/M = 1), regularly (V/M < 1), or were clustered (V/M > 1) along a strip of tissue. Counts of deposits in adjacent sample fields were added together successively to provide data for increasing field sizes, e.g., 200 × 1000 µm, 400 × 1000 µm, 800 × 1000 µm etc., up to a size limited by the length of the strip sampled and the V/M ratio calculated for each size. V/M was then plotted against field size to determine whether the clusters of a feature were regularly or randomly distributed and to estimate the mean cluster size parallel to the tissue boundary. A V/M peak indicates the presence of regularly spaced clusters while an in­crease in V/M to an asymptotic level suggests the presence of randomly distributed clusters. The statistical significance of a peak was tested using a 't' test [5].


The three most common morphological types of A deposit commonly found in AD, viz., diffuse, pri­mitive, and classic deposits, were also observed in the CBD cases (Fig. 1). In addition, a smaller number of more ‘compact’ A deposits were identified. Two of the cases (A, C) had all four types of A deposit while case B had diffuse and classic-type deposits only.

The density of A deposits in each brain region of each case is shown in Table II. In two cases (A, B), the density of the primitive, classic and compact A deposits was generally low (<1 deposit per mm2) and their distribution was restricted to either the frontal and motor cortex (case A) or to the occipital cortex (case B). Of these cases, case A had greater numbers of diffuse deposits in the frontal and motor cortex. In one case (case C), there was a greater density of A deposits throughout the cerebral cortex and deposits were also present in the CA sectors of the hippocampus and molecular layer of the DG. In case C, the density of the diffuse deposits was greatest in the occipital and temporal cortex (16-18 deposits per mm2), primitive deposits in the temporal cortex (14 deposits per mm2), classic deposits in the frontal cortex (5.3 deposits per mm2), and compact deposits in the parietal cortex (2.65 deposits per mm2).

The spatial pattern of the A deposits in each brain region is shown in Table III. Clustering of the A deposits, with clusters ranging in size from 200 to >6400 µm in diameter, was evident in 25/27 (93%) of the brain areas analysed. In addition, clusters of A deposits were regularly distributed parallel to the tissue boundary in 52% of the brain areas exhibiting clustering. In two cortical areas of case C, there was evidence of clustering at two scales, suggesting that the smaller clusters were aggregated into larger clusters. In the remaining analyses, large clusters of A deposits were observed, of at least 6400 µm in diame­ter, but without evidence of regular spacing.


Of the original 12 cases of CBD studied using quantitative methods [17], A deposition was observed in three of the cases. In two cases, the density of the A deposits was low and their distribution was restricted to a small number of cortical regions. The density of the A deposit subtypes in these two cases was within the range reported for elderly non-demented brains [2,3]. A pathology in the remaining CBD case, however, was more extensive and showed similarities to that previously reported in AD [2,13,15]. The densities of A deposits in the frontal, occipital and temporal cortex were similar to AD [2-4] but the density in the parietal cortex was significantly lower than in AD. In addition, the spatial pattern of the A deposits, i.e., clustering of deposits with a regular distribution of clusters parallel to the tissue boundary, was similar to that reported in AD [1,7,11].

A number of hypotheses could account for A de­position in CBD. First, the presence of A deposits could be age-related. The density and distribution of A de­posits in two of the CBD cases is similar to normal control brains [2,3], consistent with aging. A number of studies of A pathology have demonstrated overlaps between AD and aging. Mann and Jones [38], for example, observed A deposits in non-demented individuals older than 60 years, deposits being rare before this age. After 60 years of age, A deposits were present in a variety of different disorders due to aging, especially in the temporal cortex [37]. In 14 non-demented elderly cases [3], A deposits were present in the temporal lobe in eight cases, but only in cortical gyri, the CA sectors of the HC and DG being spared. In addition, there were variations in the density of A deposits in control cases with a significant overlap with AD. The pattern of clustering of the A deposits was also similar in control and AD cases, i.e., the deposits were aggregated into clusters that were regularly distributed parallel to the pia mater, suggesting that the formation of A deposits was similar in AD and in aging [3]. In a further study of non-demented centenarians [25], A deposits were recorded in the PHG, whether demented or not demented, but the hippocampus was spared, suggesting little relationship between lesion density and severity of mental deficits.

Secondly, in case C the density and distribution of the deposits were similar to those reported in AD [2,3] and therefore A deposition in this case may be the result of the co-existence of AD and CBD [10,11,18]. The clinical syndrome of CBD is complex and variable and at least 50% of patients exhibit the signs and symptoms of an additional disorder, e.g., AD, PSP, or Parkinson’s disease (PD) [43]. Typical AD cases, however, also have abundant neurofibrillary tangles (NFT). The paired helical filaments (PHF) of the inclusions present in CBD are wider than those of AD and have a longer periodicity [36]. In addition, PHF-tau in CBD is composed predominantly of 4-repeat (4R) tau [44] while abnormally aggregated tau from AD contains both 3R and 4R tau [30]. Hence, although the A pathology in the present case resembles that of AD, there are differences in tau-immunoreactive pathology compared with AD.

Third, A deposits in CBD could be associated with the development of capillary amyloid angiopathy (CAA), which often results in increased A deposition [14]. The deposition of A in capillary and arteriolar walls is a common pathological observation in AD and in unselected post-mortems with age [19]. There was no evidence in the present cases, however, of any significant A deposition in relation to the vessel walls.

Fourth, A deposition is also related to APOE genotype, enhanced deposition being observed in cases expressing the e4 allele [20]. An increased frequency of allele e4 has been recorded in cases of CBD, and in 5/7 patients expressing the e4 allele, A deposition was recorded in the hippocampus and cerebral cortex [43]. In the present study, case C had the highest densities and most widespread distribution of A deposits and expressed genotype 3/4 whereas the other two cases with low densities of deposits expressed either genotype 2/3 or 3/3. Hence, it is hypothesized that enhanced A deposition in case C represents the influence of APOE allele e4.

In conclusion, in a quantitative study of 12 cases of CBD, three were shown to possess AD-type patho­logy in the form of A deposits. The density of A deposits in two of the cases was similar to that of elderly non-demented brains but in one case, the den­sity and spatial patterns of the deposits resembled those of AD. A pathology has now been shown to be associated with dementia with Lewy bodies (DLB) [16], amyotrophic lateral sclerosis (ALS) [31], Creutzfeldt-Jakob disease (CJD) [31], as well as CBD [43]. Hence, A pathology can be observed in several distinct clinical contexts and it is possible that pre­sence of the APOE e4 allele is the common feature in these disorders enhancing A deposition.


The assistance of the Brain Bank, Institute of Psychiatry, London in providing tissue sections for this study is gratefully acknowledged. We thank Mr. David Mackay and Mrs. Heidi Barnes for their excellent technical assistance.


 1. Armstrong RA. The usefulness of spatial pattern analysis in understanding the pathogenesis of neurodegenerative disorders with particular reference to plaque formation in Alz­hei­mer’s disease. Neurodegeneration 1993; 2: 73-80.  

2. Armstrong RA. -amyloid deposition in elderly non-demented patients and patients with Alzheimer’s disease. Neurosci Lett 1994; 178: 59-62.  

3. Armstrong RA. Beta-amyloid deposition in the medial temporal lobe in elderly non-demented brains and in Alzheimer’s disease. Dement Geriatr Cogn Disord 1995; 6: 121-125.  

4. Armstrong RA. A comparison of -amyloid (A) deposition in the medial temporal lobe in late-onset sporadic Alzheimer’s disease, and Down’s syndrome. Int J Exp Clin Invest 1995; 2: 107-113.  

5. Armstrong RA. Analysis of spatial patterns in histological sections of brain tissue. J Neuro Sci Methods 1997; 73: 141-147.  

6. Armstrong RA. -amyloid plaques: stages in life history or independent origin? Dement Geriatr Cogn Disord 1998; 9: 227-238.  

7. Armstrong RA. The spatial patterns of -amyloid deposits and neurofibrillary tangles in the cerebral cortex in patients with Alzheimer’s disease. Alz Rep 2000; 3: 133-141.  

8. Armstrong RA. Quantifying the pathology of neurodegenerative disorders: quantitative measurements, sampling strategies and data analysis. Histopathology 2003; 42: 521-529.

9. Armstrong RA. Methods of studying the planar distribution of objects in histological sections of brain tissue. J Microsc (Oxford) 2006; 221: 153-158.

10. Armstrong RA. The interface between Alzheimer’s disease, normal aging and related disorders. Curr Aging Sci 2008; 1: 122-132.

11. Armstrong RA. A spatial pattern analysis of -amyloid (A) deposition in the temporal lobe in Alzheimer’s disease. Folia Neuropathol 2010; 48: 67-74.

12. Armstrong RA. Quantitative methods in neuropathology. Folia Neuropathol 2010; 48: 217-230.

13. Armstrong RA, Myers D, Smith CUM. The spatial patterns of /A4 deposit subtypes in Alzheimer’s disease. Acta Neuropathol 1993; 86: 36-41.

14. Armstrong RA, Myers D, Smith CUM. The ratio of diffuse to mature /A4 deposits in Alzheimer’s disease varies in cases with and without pronounced congophilic angiopathy. Dement Geriatr Cogn Disord 1993; 4: 251-255.

15. Armstrong RA, Cairns NJ, Myers D, Smith CUM, Lantos OL, Rossor MN. A comparison of -amyloid deposition in the medial temporal lobe in sporadic Alzheimer’s disease, Down’s syndrome, and normal elderly brains. Neurodegeneration 1996; 5: 35-41.

16. Armstrong RA, Cairns NJ, Lantos PL. -amyloid (A) deposition in the medial temporal lobe of patients with dementia with Lewy bodies. Neurosci Lett 1997; 227: 193-196.

17. Armstrong RA, Cairns NJ, Lantos PL. A quantitative study of the pathological lesions in the neocortex and hippocampus of 12 patients with corticobasal degeneration. Exp Neurol 2000; 163: 348-356.

18. Armstrong RA, Lantos PL, Cairns NJ. Overlap between neurodegenerative disorders. Neuropathology 2005; 25: 111-124.

19. Bergeron C, Ranalli PJ, Miceli PN. Amyloid angiopathy in Alz­hei­mer’s disease. Can J Neurol Sci 1987; 14: 564-569.

20. Berr C, Hauw JJ, Delaere P, Duyckaerts C, Amouyel P. Apolipo­protein E allele e4 is linked to increased deposition of the amyloid -peptide (A) in cases with or without Alzheimer’s disease. Neurosci Lett 1994; 178: 221-224.

21. Cairns NJ, Atkinson PF, Hanger D, Anderton BH, Daniel SE, Lantos PL. Tau protein in the glial cytoplasmic inclusions in multiple system atrophy can be distinguished from abnormal tau in Alzheimer’s disease. Neurosci Lett 1997; 230: 49-52.

22. Cairns NJ, Bigio EH, Mackenzie IRA, Neumann M, Lee VMY, Hatanpaa KJ, White CL, Schneider JA, Halliday G, Duyckaertes C, Lowe JS, Holm IE, Tolnay M, Okamoto K, Yokoo H, Murayama S, Woulfe J, Munoz DG, Dickson DW, Ince PG, Trojanowski JQ, Mann DMA. Neuropathologic diagnostic and nosological crite­ria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration. Acta Neuro­pathol 2007; 114: 5-22.

23. Carelli F, Ciano C, Panzica F, Scaioli V. Myoclonus in corticobasal degeneration. Move Disord 1997; 12: 598-603.

24. Delaere P, Duyckaerts C, He Y, Piette F, Hauw JJ. Subtypes and differential laminar distributions of b/A4 deposits in Alz­hei­mer’s disease: relationship with the intellectual status of 26 cases. Acta Neuropathol 1991; 81: 328-335.

25. Delaere P, He Y, Fayet G, Duyckaerts C, Hauw J. A4 deposits are constant in the brains of the oldest old: An immunocytochemical study of 20 French Centenarians. Neurobiol Aging 1993; 14: 191-194.

26. Dickson DW, Feany MB, Yen SH, Mattiace LA, Davies P. Cyto­skeletal pathology in non-Alzheimer degenerative dementia: new lesions in diffuse Lewy body disease, Pick's disease and corticobasal degeneration. J Neural Transm (Suppl) 1996; 47: 31-46.

27. Dickson DW, Bergeron C, Chin SS, Duyckaerts C, Horoupian D, Ikeda K, Jellinger K, Lantos PL, Lippa CF, Mirra SS, Tabaton M, Vonsattel JP, Wakabayashi K, Litvan I. Office of rare diseases neuropathologic criteria for corticobasal degeneration. J Neuro­path Exp Neurol 2002; 61: 935-946.

28. Dickson DW. Neurodegeneration: The Molecular Pathology of Dementia and Movement Disorders. International Society for Neuropathology (ISN) Press, Basel 2003.

29. Feany MB, Dickson DW. Widespread cytoskeletal pathology characterises corticobasal degeneration. Am J Pathol 1995; 146: 1388-1396.

30. Goedert M, Spillantini MG, Cairns NJ, Crowther RA. Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms. Neuron 1992; 8: 159-168.

31. Hainfellner JA, Aanschutz J, Jellinger K, Liberski PP, Gullota F, Budka H. Coexistence of Alzheimer type neuropathology in Creutzfeldt-Jakob disease. Acta Neuropathology 1998; 96: 116-122.

32. Hamilton RL, Bouser R. Alzheimer disease pathology in amyotrophic lateral sclerosis. Acta Neuropathol 2004; 107: 515-522.

33. Ikeda K. Basic pathology of corticobasal degeneration. Neuro­pathology 1997; 17: 127-133.

34. Kawasaki K, Iwanaga K, Wakabayashi K, Yamada M, Nagai H, Idezuka J, Homna Y, Ikuta F. Corticobasal degeneration with neither argyrophilic inclusions nor tau abnormalities: a new subgroup. Acta Neuropathol 1996; 91: 140-144.

35. Komori T, Arai N, Oda M, Nakayama H, Murayama S, Amano N, Shibata N, Kobayashi M, Sasaki S, Yagishita S. Morphologic differences in neuropil threads in Alzheimer’s disease, corticobasal degeneration and progressive supranuclear palsy: a morphometric study. Neurosci Lett 1997; 233: 89-92.

36. Ksiezak-Reding H, Tracz E, Yang LS, Dickson DW, Simon M, Walt JS. Ultrastructural instability of paired helical filaments from corticobasal degeneration as examined by scanning transmission electron microscopy. Am J Pathol 1996; 149: 639-651.

37. Mann DMA, Tucker CM, Yates PO. Topographic distribution of senile plaques, neurofibrillary tangles in the brains of non demented persons of different age. Neuropath App Neurobiol 1987; 13: 123-139.

38. Mann DMA, Jones D. Deposition of amyloid A4 protein within the brains of persons with dementing disorders other than Alzheimer’s disease and Down’s syndrome. Neurosci Lett 1990; 109: 68-75.

39. Markus HS, Lees AJ, Lennox G, Marsden CD, Costa DC. Patterns of regional cerebral blood flow in corticobasal degeneration studied using HMPAO SPECT: Comparison with Parkinson's disease and normal controls. Move Disord 1995; 10: 179-187.

40. Matsumoto S, Udaka F, Kameyama M, Kusaka H, Ito H, Imai T. Subcortical neurofibrillary tangles, neuropil threads and argentophilic glial inclusions in corticobasal degeneration. Clin Neuropath 1996; 15: 209-214.

41. Mori H, Oda M. Ballooned neurons in corticobasal degeneration and progressive supranuclear palsy. Neuropathology 1997; 17: 248-252.

42. Rinne JO, Lee MS, Thompson PD, Marsden CD. Corticobasal degeneration: a clinical study of 36 cases. Brain 1994; 117: 1183-1196.

43. Schneider JA, Watts RL, Gearing M, Brewer RP, Mirra SS. Corticobasal degeneration: Neuropathological and clinical heterogeneity. Neurology 1997; 48: 959-969.

44. Sergeant N, Wattez A, Delacourte A. Neurofibrillary degeneration in progressive supranuclear palsy and corticobasal degeneration: tau pathologies with exclusive “exon 10” isoforms. J Neurochem 1999; 72: 1243-1249.

45. Spargo E, Luthert PJ, Anderton BH, Bruce M, Smith D, Lantos PL. Antibodies raised against different proteins of A4 protein identify a subset of plaques in Down’s syndrome. Neurosci Lett 1990; 105: 345-350.

46. Tsuchiya K, Ikeda K, Uchihara T, Oda T, Shimada H. Distribution of cerebral cortical lesions in corticobasal degeneration: a clinicopathological study of five autopsy cases in Japan. Acta Neuropathol 1997; 94: 416-424.

47. Tsuchiya K, Miyazaki H, Ikeda K, Watabiki S, Kijima Y, Sano M, Shimada H. Serial brain CT in corticobasal degeneration: radiological and pathological correlation of two autopsy cases. J Neurol Sci 1997; 152: 23-29.

48. Tsuchiya Y, Uchichara T, Oda T, Arima K, Ikeda K, Shimada H. Basal ganglia lesions in corticobasal degeneration differ from those in Pick;s disease and progressive supranuclear palsy: a topographic neuropathological study of 6 autopsy cases. Neuropathology 1997; 17: 208-216.

49. Ueno E. Clinical features of corticobasal degeneration. Neuropathology 1996; 16: 253-256.

50. Wakabayashi K, Takahashi H. Similarities and differences among progressive supranuclear palsy, corticobasal degeneration and Pick’s disease. Neuropathology 1996; 16: 262-268.

51. Wenning GK, Litvan I, Jankovic J, Granata R, Mangone CA, McKee A, Poewe W, Jellinger K, Chandhuri KR, Dolhaberriague L, Pearce RKB. Natural history and survival of 14 patients with corticobasal degeneration confirmed at postmortem examination. J Neurol Neurosurg Psychiatry 1998; 64: 184-189.
Copyright: © 2011 Mossakowski Medical Research Centre Polish Academy of Sciences and the Polish Association of Neuropathologists. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License (http://creativecommons.org/licenses/by-nc-sa/4.0/), allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.

Quick links
© 2021 Termedia Sp. z o.o. All rights reserved.
Developed by Bentus.
PayU - płatności internetowe