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Keywords:

  • Alzheimer;
  • amyloid;
  • mild cognitive impairment;
  • plaque;
  • tangle

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. AROUND 1900
  5. RESEARCH IN JAPAN
  6. AFTER 1960
  7. FURTHER STUDIES
  8. ACKNOWLEDGMENTS
  9. REFERENCES

In the present review, I look back upon the 100-year history of Alzheimer pathology. The significance of senile plaque formation was shown in the early 1900s, but was argued further in the 1990s after the identification of β-amyloid protein. Neuropathological studies on a large number of brains from both non-demented and demented subjects demonstrated the process of transformation from normal aging to Alzheimer-type dementia, which includes both the presenile and senile form. Recently, lifestyle issues, such as food, exercise and environment, have been shown to influence Alzheimer pathology (plaque and tangles) in the brains of experimental animals. Such studies are expected to contribute to the eventual development of a curative treatment for Alzheimer-type dementia.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. AROUND 1900
  5. RESEARCH IN JAPAN
  6. AFTER 1960
  7. FURTHER STUDIES
  8. ACKNOWLEDGMENTS
  9. REFERENCES

To avoid confusion, in the present review, I use the term ‘Alzheimer’s disease' (AD) to describe the presenile form only and the term ‘Alzheimer-type dementia’ to include both the presenile and senile forms.

AROUND 1900

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. AROUND 1900
  5. RESEARCH IN JAPAN
  6. AFTER 1960
  7. FURTHER STUDIES
  8. ACKNOWLEDGMENTS
  9. REFERENCES

Alzheimer briefly reported the clinical and pathological findings in 51-year-old woman at a meeting held in 1906.1 In 1911, he described the precise pathology, senile plaques (Drusen) and neurofibrillary tangles, in a second case with onset at 54 years of age.2 Because Alzheimer used the Bielshowsky silver method, he clearly showed the process of neurofibrillary tangle formation in the AD brain (Fig. 1b–d). He described extracellular tangles that were penetrated by glial processes (Fig. 1d). Alzheimer proposed the independence of AD as an entity showing a special form of senile dementia. He described the difference between AD and senile dementia as follows: young onset in the 6th decade; focal symptoms, such as aphasia, apraxia and agnosia; severe psychosis and rapid progression; and serious neurodegeneration. In 1910, Kraepelin,3 who directed Alzheimer, described AD in his textbook including that AD may be ‘senium praecox’, a more or less age-independent unique disease process, because AD sometimes starts around the age of 40 years.

image

Figure 1. (a) Senile plaques and (b) early, (c) advanced- and (d) end-stage neurofibrillary tangles, which were described by Alzheimer.1

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In 1989, Redlich4 described the presence of numerous senile plaques, miliare Sklerose, in the brains of two subjects with senile dementia (Fig. 2). This was the first report of senile plaques in senile dementia. In 1906, when Miyake5 visited Obersteiner's laboratory in Vienna, he examined the brains of 26 aged subjects and found numerous senile plaques, Gliarosetten, in two of three brains with senile dementia, although he found no senile plaques in 23 non-demented subjects. Miyake5 also reported a case of vascular dementia as Dementia arteriosklerotica. In 1911, Simchowicz6 examined a large number of aged brains: 40 with senile dementia, 11 non-demented subjects, six with dementia praecox, six with arteriosclerotic dementia, nine other forms of senile psychosis, two dogs (aged 12 and 17 years) and one horse (aged 22 years). Simchowicz6 showed the importance of the size, arrangement and number of plaques rather than the presence or absence of senile plaques for the pathological diagnosis of senile dementia, because senile plaques sometimes appear in non-demented brains or in other forms of senile psychosis. In 1907, 1910 and 1912, Fischer7–9 examined 158 brains and divided dementia into three groups: (i) PresbiophreneDemenz (senile dementia), with numerous senile plaques, in 72 cases (46%); (ii) Einfachen senilen Demenzen (simple dementia), without senile plaques, in 42 cases (27%); and (iii) arteriosklerotic dementia in 44 cases (28%). Fischer found senile plaques in two of 35 (6%) non-demented subjects. Based on these results, he proposed that the presence of massive senile plaques is a characteristic feature of senile dementia. Furthermore, he precisely examined the brains using the Bielschowsky silver method and classified senile plaques into eight forms.8 One of the eight forms, Diffuse Infiltration des nervösen Gewebes durch die fäedigen Massen (Fig. 3), is diffuse plaques, which was later found by β protein immunostaining.10 Diffuse plaques were lost from the history of AD neuropathology after that time, because the major method used to examine brains after World War II was Bodian silver staining on paraffin sections, which does not recognize small amounts of amyloid.11 In the 1970s, diffuse plaques found in aged brains using the Bielschwsky method were considered an artefact (i.e. a non-specific adhesion of silver particles). However, in the late 1980s, these plaques were found with β protein immunostaining and were termed ‘diffuse plaques’ because their morphology is quite similar to that of the Diffuse Infiltration des nervösen Gewebes durch die fäedigen Massen.10 Uyematsu12 examined 100 brains with senile psychosis in 1923, when he visited Boston. He also classified senile plaques and reported a ‘diffuse form without nuclear-like central mass’, which is just a diffuse plaque.

image

Figure 2. Numerous senile plaques in the cerebral cortex with senile dementia, described by Redlich in 1989.4

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image

Figure 3. Diffuse plaques, described by Fischer in 1910 as Diffuse Infiltration des nervösen Gewebes durch die fädigen Massen.5

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RESEARCH IN JAPAN

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. AROUND 1900
  5. RESEARCH IN JAPAN
  6. AFTER 1960
  7. FURTHER STUDIES
  8. ACKNOWLEDGMENTS
  9. REFERENCES

In 1915, Kure et al.13 reported three demented subjects. Two cases, aged 62 and 76 years, demonstrated senile dementia with an abundance of senile plaques and tangles. The other case showed delusion and an abundance of tangles in the hippocampus without plaques. The last case may have been ‘tangle predominant form of senile dementia’, but not Alzheimer-type dementia. In 1932, Watanabe et al.14 examined 50 aged brains and found that tangle formation in the frontal association cortex is useful to distinguish senile dementia from non-dementia. In 1952, Tsuyuki first reported the pathology of AD (presensile form) at a medical meeting, but the precise findings were not described. In 1955, Inose15 reported nine cases of Alzheimer-type dementia, including two cases of AD. He diagnosed a 60-year-old patient with onset at 57 years as having senile dementia, but not AD, and proposed two criteria to diagnose AD: (i) severe clinical symptoms, including apraxia, agnosia and aphasia; and (ii) severe pathological changes compared with those in senile patients.

AFTER 1960

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. AROUND 1900
  5. RESEARCH IN JAPAN
  6. AFTER 1960
  7. FURTHER STUDIES
  8. ACKNOWLEDGMENTS
  9. REFERENCES

The 1960s was a decade of ultrastructural study using the electron microscope. The precise structure of the plaque was shown to have amyloid fibrils (8–10 nm in diameter), swollen neuritis and glial proliferation.16 Neurofibrillary tangles were shown to consist of paired helical filaments (twisted tubules; 10–20 nm) or straight tubules.16

In the 1980s, protein chemical studies demonstrated the major components of plaques and tangles. In 1984, Glenner et al.17 purified β protein 1–24 from vascular amyloid. In 1987, Kang et al.18 found the β protein precursor (APP) gene. In 1986, tau was found to be a major constituent of paired helical filaments in tangles by Ihara and other researchers.19 Then, immunostaining using β protein and tau antibodies became a major tool used in histopathological studies. By sensitive β protein immunostaining, numerous diffuse plaques were found even in non-demented aged subjects. This finding led to the misunderstanding that β protein deposition is not important in the development of dementia. However, powerful studies based on numerous non-demented brains from middle-aged subject to centenarians showed the process of progression of pathological findings; plaques precede tangles by 10–20 years in the association cortex and tangles have a characteristic pattern of development (Braak's tangle stage).20,21 From these studies, we now know why the density of senile plaques does not correlate well with the degree of dementia. Deposition of β-amyloid (plaque) is necessary for the diagnosis of Alzheimer-type dementia as a cause of the disease, but is not sufficient for the development of dementia. Additional lesions, such as tangles and neuronal loss, are necessary for the manifestation of clinical symptoms.

Nearly 10 years ago, I had a chance to observe tissue sections of a long-lived patient with Alzheimer-type dementia in the terminal stage, who had been bedridden for a long period of time. The density of plaques was much less than expected. Then, it suddenly stuck me that senile plaques may disappear during the long course of the disease. I found diffuse plaques associated with β protein-positive granules in the brains of non-demented subjects (Fig. 4). With double immunolabeling, the granules were found inside the astrocytes.22 This may indicate clearance of β-amyloid by astrocytes. This hypothesis was proven by immunization therapy in APP-transgenic mouse brains, where β protein immunization markedly reduced the density of senile plaques. Microglia may play an important role for the clearance of β protein in immunization therapy.23

image

Figure 4. Diffuse plaques, associated with astroglial β protein-positive granules (arrows), showing the stage at which the plaques gradually disappear (β protein immunostaining).5

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FURTHER STUDIES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. AROUND 1900
  5. RESEARCH IN JAPAN
  6. AFTER 1960
  7. FURTHER STUDIES
  8. ACKNOWLEDGMENTS
  9. REFERENCES

Recently, lifestyle factors, such as food,24,25 exercise26 and environment,27 have been shown to influence AD-related neurodegeneration in brains of experimental animals. The intake of curcumin, a tyype of polyphenol, was shown to reduce cerebral β-amyloid deposition in APP-transgenic mice.25 Environmental enrichment reduced the density of plaques in APP-transgenic mice.27 Exercise during middle age was shown to reduce the risk of Alzheimer-type dementia in an epidemiological study.28 Social contact also reduces the risk of dementia.29 I hope that future neuropathological studies can further elucidate the effect of lifestyle factors in reducing Alzheimer pathology and contribute to the prevention of the progression of dementia.

ACKNOWLEDGMENTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. AROUND 1900
  5. RESEARCH IN JAPAN
  6. AFTER 1960
  7. FURTHER STUDIES
  8. ACKNOWLEDGMENTS
  9. REFERENCES

The author thanks Dr Shunsaku Hirai (Professor Emeritus, Gunma University, Maebashi, Japan) for supervision of my research work and Dr Marion Maat-Schieman (Leiden University Medical Center, Leiden, The Nederlands) for collaboration.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. AROUND 1900
  5. RESEARCH IN JAPAN
  6. AFTER 1960
  7. FURTHER STUDIES
  8. ACKNOWLEDGMENTS
  9. REFERENCES
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    Alzheimer. Über eigenartige Krankheits fälle des späteren Alters. Z Gesamte Neurol Psychiatr 1911; 4: 356385.
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    Kraepelin E. Das senile und präsenilar Irrsein. In: Psychiatrie: Ein Lehrbuch für Studierende und Älzte. Leipzig: Verlag von Johann Ambrosius Barth, 1910; 533554 and 593–632.
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